Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]=[C:13]([C:15]([O:17]CC)=O)[O:12][N:11]=2)[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>C(O)C>[Br:9][C:6]1[CH:5]=[C:4]([C:10]2[N:14]=[C:13]([C:15]([NH:28][CH2:27][C:26]3[CH:29]=[CH:30][C:23]([O:22][C:21]([F:20])([F:31])[F:32])=[CH:24][CH:25]=3)=[O:17])[O:12][N:11]=2)[CH:3]=[C:2]([Br:1])[C:7]=1[OH:8]
Reactant: CCOC(=O)c1nc(-c2cc(Br)c(O)c(Br)c2)no1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Solvent: CCO
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1nc(-c2cc(Br)c(O)c(Br)c2)no1
Yield: 53.1 %

Procedure:
A solution of the ethyl 3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylate (78 mg, 0.2 mmol) plus 4-trifluoromethoxybenzyl amine (57 mg, 0.3 mmol) in ethanol (3 mL) was refluxed for 6 hours. The resulting solution was evaporated in vacuo and the residue was dissolved in ethyl acetate (2.5 mL) and washed with 1 N hydrochloric acid (2 mL), then water (2 mL). The organic layer was evaporated to dryness in vacuo and purified by preparative HPLC to give the title compound (57 mg, 53%) as a colourless powder. 1H NMR δ (ppm) (DMSO-d6): 4.55 (2H, d), 7.38 (2H, d), 7.51 (2H, d), 10.07 (1H, t), 10.95 (1H, s, br). LCMS (10 cm_apci_formic) tR 4.14 min; m/z 534/536/538 [M−H]−.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=2)[O:6][CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)COc1cccc(C#N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COc1cccc(-c2nc(=O)c3ccccc3s2)c1
Yield: 19.8 %

Procedure:
A mixture of tert-butyl (3-cyanophenoxy)acetate (4.64 g, 20 mmol), methyl thiosalicylate (3.70 g, 24 mmol), triethylamine (2.54 g, 25 mmol) and toluene (15 ml) was heated and refluxed for 20 hours under a nitrogen flow. After the solvent was distilled off under reduced pressure, the residue was applied to column chromatography using silica gel. From the fractions eluted with hexane-ethyl acetate (3:1, v/v), the title compound (1.46 g, 20%) was obtained as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7](=[O:27])[CH:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.CCS>C(Br)Br>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7](=[O:27])[CH:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(C2=NC(Cc3ccccc3C)C(=O)Nc3ccc(Cl)cc32)cc1
Solvent: CCS
Solvent: BrCBr
Product: Cc1ccccc1CC1N=C(c2ccc(O)cc2)c2cc(Cl)ccc2NC1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of (Z)-7-chloro-5-(4-methoxyphenyl)-3-(2-methylbenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one precursor (0.6 g, 1.4 mmol) in CH2Br2 (20 mL) was added EtSH (7 mL) and then A1Br3 (1.7 g, 6.3 mmol, 4.5 eq). The resulting mixture was stirred overnight and then treated with ice (20 g) and after one hour filtered. The resulting solid was triturated with 50% DCM/heptane and then vacuum dried to give 445 mg (yield of 80%) of (Z)-7-chloro-5-(4-hydroxyphenyl)-3-(2-methylbenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 2.31 (s, 3H), 3.25-3.45 (m, 2H), 3.73 (dd, 1H), 6.80 (d, 2H), 7.02-7.18 (m, 3H), 7.2-7.3 (m, 5H), 7.64 (dd, 1H), 10.0 (br s, 1H), 10.7 (br s, 1H). MS, m/z 391.7 [M+1]
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][C:13](=O)[CH3:14]>>[Br:1][C:2]1[C:3]2[O:10][CH:12]=[C:13]([CH3:14])[C:4]=2[C:5]([F:9])=[C:6]([F:8])[CH:7]=1
Reactant: CC(=O)CBr
Reactant: Oc1cc(F)c(F)cc1Br
Product: Cc1coc2c(Br)cc(F)c(F)c12
Yield: 12 %

Procedure:
An operation similar to that in Step 1 of Example 12 was performed using 2-bromo-4,5-difluorophenol (1.05 g, 5.00 mmol) in place of 2-bromo-4-fluorophenol, and bromoacetone (0.504 mL, 6.00 mmol) in place of bromoacetaldehyde dimethyl acetal to thus obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([C:16]([O:18]CCCC)=O)[O:13][C:12]3=[O:23])=[CH:10][C:5]=2[S:4][C:3]1=[O:24].[CH3:25][NH2:26]>CO>[CH3:25][NH:26][C:16]([C@@H:14]1[O:13][C:12](=[O:23])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:24])[S:4][C:5]=3[CH:10]=2)[CH2:15]1)=[O:18]
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C)C(=O)O1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The butyl (5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 29, Step 2, 300 mg, 0.856 mmol) is treated with 2N methylamine in MeOH (8.6 mL) with vigorous stirring, and the mixture is diluted with additional MeOH (10 mL) and stirred at ambient temperature for 1 h. The resulting slurry is filtered to give the title compound, mp 264-267° C.; MS (ESI+) for C13H13N3O4S m/z 308 (M+H)+; [α]25D−44 (c 0.92, DMSO).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14]([OH:16])=O)=[O:4].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C:25]2=[O:30])=[CH:20][CH:19]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14](=[O:16])[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C:25]2=[O:30])=[CH:22][CH:23]=1)=[O:4]
Reactant: COC(=O)c1ccc2[nH]nc(C(=O)O)c2c1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]nc(C(=O)Nc3ccc(N4CCOCC4=O)cc3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 60 mg 1H-Indazole-3,5-dicarboxylic acid 5-methyl ester and 52 mg 4-(4-Amino-phenyl)-morpholin-3-one in 2 mL DCM, 68 mg BOP-Cl and 0.15 mL NEt3 were added and the mixture was stirred for 16 h at RT. Then after the reaction mixture was diluted with 20 mL DCM, the solution was washed with 15 mL of water. The organic phase was dried over MgSO4 and after filtration concentrated under reduced pressure. The crude product was subjected to the next reaction step without further purification. Yield: 71 mg.
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]([N:7]2[C:13](=[O:14])[CH2:12][CH2:11][N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][O:3]1.[CH3:25][NH:26][CH3:27]>>[OH:3][CH2:4][CH2:5][C@H:6]([N:7]1[C:13](=[O:14])[CH2:12][CH2:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=2)[CH2:9][CH2:8]1)[C:2]([N:26]([CH3:27])[CH3:25])=[O:1]
Reactant: CNC
Reactant: O=C1OCC[C@@H]1N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Product: CN(C)C(=O)[C@H](CCO)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O

Procedure:
In analogy to the procedure described in example 17A, 4-((S)-2-oxo-tetrahydro-furan-3-yl)-1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one (example 7) and dimethylamine (5.6 M in EtOH) gave the title compound in quantitative yield as an yellow oil. MS: 388.1 (MH+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][NH2:14])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21].[CH2:24](C(CC)(CC)C([O-])([O-])[O-])[CH3:25]>C1(C)C(C)=CC=CC=1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[C:24]([CH3:25])=[N:14][N:13]=[C:8]1[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21]
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: NNc1cc(-c2ccccc2Cl)c2cc(C(F)(F)F)ccc2n1
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3ccccc3Cl)c3cc(C(F)(F)F)ccc3n12

Procedure:
In the manner given in Example 2, 6-(trifluoromethyl)-4-(o-chlorophenyl)-2-hydrazinoquinoline and triethylorthoaceate are refluxed in xylene to give 7-(trifluoromethyl)-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a] quinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@@H:13]([CH3:14])[C@@H:12]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#N)=[CH:19][CH:18]=3)[O:11][C:10]2=[O:25])=[CH:5][CH:4]=1.C(O)=[O:27]>[Ni]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@@H:13]([CH3:14])[C@@H:12]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:27])=[CH:19][CH:18]=3)[O:11][C:10]2=[O:25])=[CH:5][CH:4]=1
Reactant: O=CO
Reactant: COc1ccc(N2C(=O)O[C@H](COc3ccc(C#N)cc3)[C@@H]2C)cc1
Agent: [Ni]
Product: COc1ccc(N2C(=O)O[C@H](COc3ccc(C=O)cc3)[C@@H]2C)cc1
Yield: 80 %

Procedure:
To a solution of 0.88 g of Compound [82], which had been obtained in Referential Example 12, dissolved in 25 ml of 80% aqueous formic acid, 1.8 g of Raney nickel were added, followed by heating under reflux for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue so obtained was extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by subjecting same to chromatography on a silica gel column using gradient elution with hexane-ethyl acetate, whereby 0.71 g of the title compound was obtained (yield: 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:13])[O:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C(#N)C.S(=O)(=O)(O)O.[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:13])[O:11][C:12]=2[CH2:24][CH2:23][C:22]([O:26][CH3:27])=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: O=c1[nH]c(-c2cccc(Cl)c2)co1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: COC(=O)CCc1oc(=O)[nH]c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
To a solution of 4-(3-chlorophenyl)oxazol-2(3H)-one (3.31 g) and acetonitrile (15 mL) was gradually added conc. sulfuric acid (5.01 g) at 0° C. To the reaction mixture was added methyl acrylate (3.05 mL) at 0° C. and the mixture was stirred at room temperature for 5 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate-tetrahydrofuran (1:1). The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[4-(3-chlorophenyl)-2-oxo-2,3-dihydro-5-oxazolyl]propionate (3.0 g, 63%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[C:38](O)(=[O:41])[CH2:39][CH3:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:38](=[O:41])[CH2:39][CH3:40])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: NS(=O)(=O)c1cnn2c(Nc3cc(F)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Reactant: CCC(=O)O
Product: CCC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(F)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 87.1 %

Procedure:
Using 7-(2,5-difluorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.094 mmol) obtained in Example 35 step 5 and propionic acid (0.035 mL, 0.471 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.048 g, 86%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]([CH3:17])[C:14]([OH:16])=O.O=S(Cl)Cl>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[CH:5]=[C:4]2[C:3]=1[CH2:12][CH:13]([CH3:17])[C:14]2=[O:16]
Reactant: CC(Cc1ccc(C(C)(C)C)cc1Br)C(=O)O
Solvent: O=S(Cl)Cl
Product: CC1Cc2c(Br)cc(C(C)(C)C)cc2C1=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
A mixture of 3-(2-bromo-4-tert-butylphenyl)-2-methylpropanoic acid (46 g, 150 mmol) and SOCl2 (18 ml, 220 mmol) was stirred for 1 h at 40° C. The excess of SOCl2 was removed in vacuo. The residue was dissolved in CH2Cl2 (50 ml) and added at 0° C. to a suspension of 20 g AlCl3 in CH2Cl2 (200 ml). The reaction mixture was stirred overnight, poured into ice/water (500 g) containing 50 ml of conc. HCl. The organic phase was collected, washed with water, dried over MgSO4 and evaporated. The residue was distilled at 125-130° C. /0.5 torr giving 32 g (76%) of product.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[CH:14]=[C:13]([CH3:15])[C:12](Br)=[CH:11][C:10]=1[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[C:10]([F:17])=[CH:11][C:12]([N:28]2[CH2:27][CH2:26][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29]2)=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(F)cc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(F)cc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A suspension of the product of Example 51A (3.2 g, 8.4 mmol), tert-butyl piperazine-1-carboxylate (1.9 g, 10.1 mmol), palladium(II) acetate (189 mg, 0.84 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.05 g, 1.7 mmol) and cesium carbonate (5.5 g, 16.8 mmol) in toluene (200 mL) was heated at reflux under nitrogen for 16 hours. After concentration, the residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 10/1 petroleum ether/ethyl acetate to give the title compound. MS: 490 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
A mixture of 5 g of p-(p-fluorophenoxy)phenol, 5.1 g of ethyl 2-bromopropionate and 4 g of potassium carbonate is stirred at reflux temperature in 25 ml of acetone for 24 hours. After evaporation of the solvent the residue is taken up in 100 ml of diethyl ether and 100 ml of water. The ether phase is washed with semi-saturated and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. The residue is purified by chromatography on silica gel with n-hexane/ethyl acetate (19:1) to yield pure ethyl 2-[p-(p-fluorophenoxy)phenoxy]-propionate; nD20 =1.5304.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[S:25][CH:26]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:23]=3)[CH2:28][CH2:29]2)=[O:15])[O:4][N:3]=1
Reactant: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)on1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)on1
Yield: 44.8 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl (3-methylisoxazol-5-yl)carbamate (245 mg, 0.897 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.815 mmol) and diisopropylethylamine (0.156 ml, 0.897 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 135 mg (44.9%) of the desired product as a solid.
Reaction SMILES: CO.[F:3][C:4]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([C:13]2[C:14]([CH:23]=[O:24])=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[C:6]([O:25][CH3:26])[CH:5]=1.S(=O)(=O)([OH:29])N.[O-]Cl=O.[Na+]>C1COCC1.O>[F:3][C:4]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([C:13]2[C:14]([C:23]([OH:29])=[O:24])=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[C:6]([O:25][CH3:26])[CH:5]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C=O
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C(=O)O
Reaction time: 1.5 h

Procedure:
An 8.2 g quantity of a mixture of 4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl)methanol 16b and 4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde 56 [obtained, as a mixture, from a Suzuki coupling by methods described in WO2007/005572] was dissolved along with sulfamic acid (3.3 g) in a mixture of THF (50 mL) and water (50 mL). The solution was cooled in an ice bath. A solution of 80% NaClO2 (2.6 g) in water (50 mL) was added dropwise from an addition funnel. When addition was complete, the mixture was stirred at <8° C. for 1.5 hr. The mixture was quenched by addition of water and extracted with EtOAc. The organic phase was concentrated under reduced pressure to a volume of 50 mL and extracted with 2N KOH (20 mL×2). The organic phase was reserved. The aqueous solution was acidified to pH 2, and the solid filtered, to yield 300-400 mg of product 57 as a first crop. The reserved organic solution was concentrated under reduced pressure and the resulting crude product purified by chromatography on silica gel to give a total of 1.4-1.5 g of 57.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4C=CC=[CH:24][N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:4][N:3]=1.OC[C:30]1N=C[N:32](C)[N:31]=1>>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[N:23]=[CH:24][N:31]([CH3:30])[N:32]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:4][N:3]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)on1
Reactant: Cn1cnc(CO)n1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ncn(C)n4)nn23)on1

Procedure:
The title-compound was prepared from the product of Example 120 part a and 3-hydroxymethyl-1-methyl-1,2,4-triazole (prepared using the conditions of Itoh and Okongi, EP-A-421210) following the conditions described for Example 71, mp 270-271.5° C.; 1H NMR (360 MHz, CDCl3) δ 2.50 (3H, s, CH3), 3.97 (3H, s, CH3), 5.73 (2H, s, CH2), 7.31 (1H, s, Ar—H), 7.82 (1H, m, Ar—H), 7.97 (1H, m, Ar—H), 8.09 (1H, s, Ar—H), 8.31 (1H, d, J=8.6 Hz, Ar—H), 8.70 (1H, d, J=8.6 Hz, Ar—H); MS (ES+) m/e 363 [MH]+; Anal. Found. C, 55.92; H, 3.63; N, 30.16. C17H4N8O2. 0.06CH2Cl2 requires C, 55.77; H, 3.87, N, 30.49%.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C@H:10]2[O:22][C@@H:21]([CH2:23][O:24]C(=O)C)[C@H:16]([O:17]C(=O)C)[C@@H:11]2[O:12]C(=O)C)[C:8]2[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:7]=2[N:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].N[C@]1(O)[C@@H](O)[C@H](C(Cl)O)O[C@@H]1N1C2C=C(Cl)C=CC=2N=C1>CO.C(O)C.O>[C:1]([NH:4][C:5]1[N:9]([C@H:10]2[O:22][C@@H:21]([CH2:23][OH:24])[C@H:16]([OH:17])[C@@H:11]2[OH:12])[C:8]2[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:7]=2[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N[C@@]1(O)[C@@H](n2cnc3ccc(Cl)cc32)O[C@@H](C(O)Cl)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-acetamido-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.35 g, 0.75 mmol) in methanol (8 mL) and ethanol (8 mL) was combined with a solution of sodium carbonate (0.12 g, 1.1 mmol) in water (2 mL). The solution was stirred at rt for 24 h, then the methanol and ethanol were removed on the rotoevaporator. The solution was then extracted between ethyl acetate (2×150 mL) and saturated NaCl (20 mL). The organics were concentrated and purified by multiple cyclings on a chromatotron, fitted with a 2 mm rotor, using 1:10 methanol:dichloromethane to give a white solid (0.067 g, 0. 18 mmol, 23%); This material was identified by 1H NMR, MS and HPLC, it contained about 7% of 2-amino-5,6-dichloro-beta-L-ribofuranosyl-1H-benzimidazole by 1H NMR. HPLC showed two small (~5%) impurities.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:14](Cl)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.N>N1C=CC=CC=1.O>[CH3:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNc1c(N)cnc2ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: N
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(-c2ccccc2)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.1 g (0.012 mole) of crude product of 3-amino-4-methylaminoquinoline was dissolved in 20 ml of pyridine, and 1.5 ml (0.013 mole) of benzoyl chloride was added followed by stirring at room temperature for one hour. The reaction solution was concentrated under reduced pressure, and 20 ml of phosphorus oxychloride was added to the concentrate, followed by refluxing with heating for 3 hours. The residues obtained by concentration under reduced pressure were dissolved in water and the solution was made alkaline with ammonia water. The precipitate was collected by filtration, washed with water and purified by silica gel column chromatography (eluting solvent: chloform/methanol=30/1), to afford 2.1 g of Compound a.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH2:16]([O:18][C:19]([C:21]1[C:25]([CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[C:24]([CH:32]=O)[NH:23][C:22]=1[CH3:34])=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[C:25]([CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[C:24]([CH:32]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([S:3](=[O:5])(=[O:4])[NH:2][CH3:1])[CH:7]=3)[NH:11][C:10]2=[O:15])[NH:23][C:22]=1[CH3:34])=[O:20])[CH3:17]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN(C)C
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)NC)cc32)c1CCCN(C)C
Yield: 40.5 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (113 mg, 0.5 mmol) was condensed with 4-(3-dimethylamino-propyl)-5-formyl-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (133 mg) to give 96 mg (40%) of the title compound.