Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.[C:7]1([CH2:13][CH2:14]O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C([O-])(=O)C([O-])=O.[Sn+4].C([O-])(=O)C([O-])=O>[CH:1]1([C:4]([O:6][CH2:14][CH2:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: OCCc1ccccc1
Agent: O=C([O-])C(=O)[O-]
Agent: [Sn+4]
Product: O=C(OCCc1ccccc1)C1CC1
Temperature: 175 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
A 1-L, 4-neck, round-bottom flask, fitted with a thermometer, mechanical stirrer, nitrogen inlet tube and Liebig condenser/receiving flask, was charged with 258.3 g (3.00 mol, 1.00 equiv) of cyclopropanecarboxylic acid, 366.5 g (3.00 mol, 1.00 equiv) of 2-phenylethanol, and 1.14 g (0.2 wt. %) of tin oxalate (Fascat® 2001). The air was removed with three cycles of evacuation/nitrogen-fill using a mechanical vacuum pump (50-100 torr). The rate of stirring was set at ca. 200 rpm, the nitrogen sparge was set at 0.05 scfh, and the reaction mixture was heated to 175° C. After a 2-h hold, 78.0 g of distillate had been collected. The temperature was increased to 180° C. and held for 1 h; an additional 9.6 g of distillate was collected. Finally, the temperature was increased to 190° C. and held for 2 h, and an additional 8.6 g of distillate was collected. The acid number was 5.30 mg KOH/g (98.3% conversion). The excess 2-phenylethanol (12.4% by GLC) and cyclopropanecarboxylic acid (0.82% by GLC) were removed by vacuum distillation through a 15-cm Vigreux column at 95-135° C. (10 torr) in a 101-g forecut. The crude product was distilled at 136-139° C. (10 torr) through a 15-cm Vigreux column to afford 410 g (72%) of 2-phenylethyl cyclopropanecarboxylate (99.1% pure by GLC): residual alcohol, 0.6% (GLC); APHA color, 4.0; acid number, 0.14 mg KOH/g; saponification number, 291 mg KOH/g (theor. 295 mg KOH/g). The cyclopropanecarboxylic acid distilled out of the reaction mixture with the water of reaction can be recycled to improve the yield.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])=[CH:6][C:5]([C:18]2[C:19](=[O:38])[N:20]([CH:35]([CH3:37])[CH3:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][N:24]=[C:23]([NH:28][C:29](=O)[O:30]C(C)=C)[CH:22]=3)=[C:4]([CH3:39])[CH:3]=1.Cl.[NH:41]1[CH2:44][CH2:43][CH2:42]1.CN1CCCC1>O1CCOCC1>[F:1][C:2]1[C:7]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:6][C:5]([C:18]2[C:19](=[O:38])[N:20]([CH:35]([CH3:36])[CH3:37])[C:21]3[C:26]([CH:27]=2)=[CH:25][N:24]=[C:23]([NH:28][C:29]([N:41]2[CH2:44][CH2:43][CH2:42]2)=[O:30])[CH:22]=3)=[C:4]([CH3:39])[CH:3]=1
Reactant: C=C(C)OC(=O)Nc1cc2c(cn1)cc(-c1cc(NC(=O)Nc3ccccc3)c(F)cc1C)c(=O)n2C(C)C
Reactant: C1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(F)c(NC(=O)Nc2ccccc2)cc1-c1cc2cnc(NC(=O)N3CCC3)cc2n(C(C)C)c1=O
Temperature: 70 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
A suspension of prop-1-en-2-yl (3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamate (0.1 g, 0.189 mmol) in dioxane (3 mL) was treated with azetidine hydrochloride (0.071 g, 0.755 mmol) and 1-methylpyrrolidine (0.129 g, 1.511 mmol) and heated at 70° C. for 16 h, then cooled to RT and stirred for 24 h. The mixture was concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The fractions were neutralized with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford N-(3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)azetidine-1-carboxamide (43 mg, 43% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.34 (s, 1H), 9.01 (s, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 8.38 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.25 (t, J=7.8 Hz, 2H), 7.14 (d, J=12.2 Hz, 1H), 6.95 (t, J=7.4 Hz, 1H), 5.35 (m, 1H), 4.02 (t, J=7.5 Hz, 4H), 2.17 (t, J=7.7 Hz, 2H), 2.07 (s, 3H), 1.55 (d, J=7.0 Hz, 6H); MS (ESI) m/z: 529.2 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[C:5]([OH:14])=[N:6][C:7]([O:12][CH3:13])=[N:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2].C1(N[S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[CH:1]([C:4]1[C:5]([O:14][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])=[N:6][C:7]([O:12][CH3:13])=[N:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: COc1nc(O)c(C(C)C)c(OC)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: COc1nc(OC)c(C(C)C)c(OS(=O)(=O)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.6 %

Procedure:
To a mixture of 5-isopropyl-2,6-dimethoxy-pyrimidin-4-ol (64 mg, 0.322 mmol) and N-phenyltrifluoromethane sulfonamide (127 mg, 1.1 eq.) in 3 mL of DCM, Cs2CO3 (116 mg, 1.1 eq.) was added. The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was concentrated down and purified (silica gel, 0-80% EtOAC/hexane) to give white solid (74 mg, 69%). LC-MS shows 330.9 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([O:32][CH2:33][CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[N:17][C:16]=2[CH3:30])=[CH:9][C:8]=1[CH3:31])C.[Li+].[OH-]>>[CH2:33]([O:32][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)=[N:17][C:16]=2[CH3:30])=[CH:9][C:8]=1[CH3:31])[C:4]([OH:35])=[O:3])[CH3:34]
Reactant: CCOC(=O)C(Cc1ccc(OCc2sc(-c3cccc(C(F)(F)F)c3)nc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2sc(-c3cccc(C(F)(F)F)c3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-ethoxy-3-{2-methyl-4-[4-methyl-2-(3-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-(2-methyl-4-[4-methyl-2-(3-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid as colorless oil.
Reaction SMILES: [C:1]1([N:7]2[N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]3=[CH:9][C:8]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)Cl.[Al]>[Br:17][C:9]1[C:8](=[O:16])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=12
Reactant: O=c1cc2n(n1-c1ccccc1)CCCC2
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: ClCCl
Product: O=c1c(Br)c2n(n1-c1ccccc1)CCCC2
Reaction time: 24 h
Yield: 52.2 %

Procedure:
To a solution of 1-phenyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-2-one (0.21 g) in methylene chloride (4 mL) was added N-bromosuccinimide (0.18 g). The reaction vessel was wrapped in aluminium foil and stirred for 24 hours. The solvent was evaporated in vacuo and the residue was dissolved in EtOAc and water. The phases were separated and the aqueous phase was extracted with more EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo to give a crude residue. Flash column chromatography over silica gel using ISCO combiflash chromatography and eluting with EtOAc/heptane afforded the desired 3-bromo-1-phenyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-2-one (0.15 g) as a light brown solid. MS (ESI+): 295.2 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[CH3:11][N:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH:14]([CH2:22][NH2:23])[CH2:13]1.C([O-])(O)=O.[Na+]>CCO>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:23][CH2:22][CH:14]2[CH2:13][N:12]([CH3:11])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15]2)[CH:7]=1
Reactant: COc1nc(Cl)cc(Cl)n1
Reactant: CN1CC(CN)Oc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1nc(Cl)cc(NCC2CN(C)c3ccccc3O2)n1
Yield: 98.8 %

Procedure:
A mixture of 4,6-dichloro-2-methoxy-pyrimidine (0.27 g, 1.48 mmol), C-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-methylamine (0.22 g, 1.23 mmol), and NaHCO3 (0.62 g, 7.4 mmol) in EtOH (7 mL) is heated to reflux for 5 h. The mixture is concentrated in vacuo. The residue is partitioned between EtOAc and water, and extracted with EtOAc. The extracts are dried (Na2SO4), and concentrated to afford (6-chloro-2-methoxy-pyrimidin-4-yl)-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-amine (0.39 g). LCMS: RT=3.27 minutes; MS: 321 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([N:37]=[C:38]=[O:39])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:16][CH:17]=2)[C:38]([NH:37][C:29]2[CH:30]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:32]=[C:27]([C:26]([F:25])([F:40])[F:41])[CH:28]=2)=[O:39])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101 %

Procedure:
4-((4-Cyclohexylphenylamino)methyl)benzoic acid methyl ester (2.38 g, 7.36 mmol) was dissolved in DCM (150 mL) and 3,5-bis(trifluoromethyl)phenyl isocyanate (1.36 mL, 8.10 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with water (3×15 mL), dried (magnesium sulphate) and concentrated in vacuo to afford 4.3 g of 4-[3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:37])([CH3:36])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])[CH3:4].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[F:37][C:2]([F:1])([CH3:36])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])[CH3:4]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(F)F
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2,2-difluoro-1-methyl-propyl)-amide (105 mg, 197 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (0.6 ml, 7.9 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (1 ml) and ethylenediamine (0.8 ml, 11.8 mmol) was added. The reaction was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 48 mg (61%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2,2-difluoro-1-methyl-propyl)-amide as an off-white powder. MS: (M+H)+=403; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.85 (br. s., 1H), 9.12 (s, 1H), 8.51 (s, 1H), 8.45 (dd, J=8.9, 5.5 Hz, 1H), 8.32 (d, J=9.8 Hz, 1H), 7.69 (dd, J=9.8, 2.3 Hz, 1H), 7.10 (td, J=9.1, 1.9 Hz, 1H), 4.56-4.80 (m, 1H), 4.15 (s, 3H), 1.72 (t, J=19.3 Hz, 3H), 1.37 (d, J=6.8 Hz, 3H).
Reaction SMILES: O[C@@:2]12[CH2:22][CH2:21][CH:20]3[C:12]([C@@H:13]([C:28]4[CH:33]=[CH:32][C:31]([N:34](C)[C:35](=O)OC(C)(C)C)=[CH:30][CH:29]=4)[CH2:14][C@@:15]4([CH3:27])[CH:19]3[CH2:18][CH2:17][C@@:16]4([OH:26])[C:23]#[C:24][CH3:25])=[C:11]1[CH2:10][CH2:9][C:4]1(OCC[O:5]1)[CH2:3]2.CC1C=CC(S(O)(=O)=O)=CC=1.O.C(Cl)Cl.C1COCC1.C([O-])(O)=O.[Na+]>>[OH:26][C@:16]1([C:23]#[C:24][CH3:25])[CH2:17][CH2:18][C@H:19]2[C@H:20]3[C:12]([C@@H:13]([C:28]4[CH:29]=[CH:30][C:31]([NH:34][CH3:35])=[CH:32][CH:33]=4)[CH2:14][C@:15]12[CH3:27])=[C:11]1[C:2](=[CH:3][C:4](=[O:5])[CH2:9][CH2:10]1)[CH2:22][CH2:21]3
Reactant: CC#C[C@]1(O)CCC2C3CC[C@@]4(O)CC5(CCC4=C3[C@@H](c3ccc(N(C)C(=O)OC(C)(C)C)cc3)C[C@@]21C)OCCO5
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(NC)cc3)C[C@@]21C
Yield: 77.2 %

Procedure:
The compound of Example 1G (36 mg) was dissolved in 0.3 mL of a solution of TsOH.H2O/CH2Cl2/THF (1.9 g/3 mL/3.8 mL); the resultant mixture was stirred at room temperature for 3 hour. The reaction mixture was added dropwise to NaHCO3 solution (2 mL, saturated) and then extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by preparative TLC to provide the titled compound (20 mg, 74% yield).
Reaction SMILES: P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[C:22]1([C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[C:22]1([C:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1c[nH]cn1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: c1ccncc1
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Yield: 82.6 %

Procedure:
A mixture of pyridine (15 ml), diphenyl phosphite (2.34 g, 10 mmole), imidazole (0.68 g, 10 mmole) and triphenylmethanol (2.08 g, 8 mmole) was refluxed for 3 hours. Pyridine was removed under reduced pressure, and the residue was extracted with dichloromethane. The extract was washed with a 5% aqueous hydroxide solution and water in order, dried and evaporated. Recrystallization of the residue (2.23 g) from acetonitrile gave 2.05 g of 1-triphenylmethylimidazole as colorless needles. Yield, 82.7%. M.P., 221°-223° C.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]2[N:12]=[C:13]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[O:14][C:15]=2[S:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19]N=2)=[CH:7][N:6]=1)=O.[CH3:31][Mg]Br>C1COCC1.[NH4+].[Cl-]>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([S:16][C:15]2[O:14][C:13]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[N:12][C:11]=2[C:8]2[CH:7]=[N:6][C:5]([CH3:3])=[CH:10][N:9]=2)=[CH:31][CH:19]=1
Reactant: COC(=O)c1cnc(-c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cn1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cnc(-c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cc2)cn1
Yield: 31.7 %

Procedure:
A solution of methyl-5-[5-[(4-chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrazine-2-carboxylate (Example 1) (24 mg, 0.05 mmol) in THF (5 mL) was treated with methylmagnesium bromide (0.2 mL, 0.5 mmol, 3.0 M in THF) at rt. Upon completion of the reaction as judged by TLC analysis, the solution was diluted with saturated aq NH4Cl solution and extracted with EtOAc. The organic layer was removed, dried over MgSO4, filtered and concentrated giving rise to an oil. The oil was purified on silica gel to afford the title compound (6.3 mg). LC/MS: m/e 397.0 (M+H)+. 1H NMR (500 MHz, Acetone-d6): δ 2.55 (s, 3H), 7.46 (m, 5H), 8.06 (m, 2H), 8.50 (s, 1H), 8.55 (s, 1H), 9.10 (d, J=1.1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.3 %

Procedure:
2-Bromophenol (6.7 ml, 57.8 mmole) was dissolved in 200 ml acetonitrile in a 500 ml one neck round bottom flask under nitrogen. The solution was treated successively potassium carbonate (32 g, 231 mmole) and benzyl bromide (6.9 ml, 57.8 mmole). The reaction mixture was stirred for 6 hours at room temperature. The insoluble salts were removed by filtration and the filtrate was concentrated in vacuo to a pale oil. The oil was taken up in 100 ml diethyl ether and the mixture was washed successively with 2×25 ml 1N sodium hydroxide and 1×25 ml saturated sodium chloride. The organics were dried over magnesium sulfate and were concentrated in vacuo to give 14.8 g (97%) of 2-benzyloxy-bromobenzene as a pale oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH:23]([NH:26][CH3:27])([CH3:25])[CH3:24].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:26]([CH:23]([CH3:25])[CH3:24])[CH3:27])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CNC(C)C
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A1) (4.00 g, 11.7 mmol), N-isopropyl-methyl-amine (3.67 ml, 35.2 mmol) and triethylamine (5.73 ml, 41.1 mmol) in DMSO (30 mL) at 50° C. according to the general procedure C. Obtained as a yellow solid (3.27 g, 74%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1B(O)O>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Reactant: COc1ccc(B(O)O)c(F)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(OC)cc1F
Yield: 69.3 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and 2-fluoro-4-methoxyphenylboronic acid (0.085 g; 0.500 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.072 g (68%) of the title compound.
Reaction SMILES: [O:1]=[C:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:19])[O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16].CCCCCCCCCC.C(OO)(C)(C)C.NC1C=CC=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C.O>[C:2]([CH:3]1[CH2:4][C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:11]1[C:12]([O:13][CH2:14][C:15]([Cl:16])([Cl:17])[Cl:18])=[O:19])(=[O:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Nc1ccccc1CCC(=O)c1ccccc1)OCC(Cl)(Cl)Cl
Agent: CC(C)(C)OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCCCCC
Solvent: Nc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)C1Cc2ccccc2N1C(=O)OCC(Cl)(Cl)Cl
Reaction time: 5 h
Yield: 48 %

Procedure:
A reactor was charged with 401 mg (0.10 mmol) of 2,2,2-trichloroethyl 2-(3-oxo-3-phenylpropyl)phenylcarbamate (an4) obtained in Synthesis Example 8, 36.9 mg (0.10 mmol) of tetrabutylammonium iodide (Bu4N+I−), and 50 mL of ethyl acetate as a solvent to prepare a solution. Subsequently, 364 μL of 5.5 M decane solution (manufactured by Aldrich) containing 2.0 mmol of tert-butyl hydroperoxide (TBHP) as an oxidizing agent was added to the solution in an amount corresponding to 2 equivalents based on the aniline derivative (an4). After adjusting the temperature of the reaction system to room temperature (about 20° C.), the mixture was stirred for 5 hours, and then stirred (reacted) at 50° C. for 14 hours. After cooling the reaction mixture including the reaction product to room temperature, the reaction mixture was added to 20 mL of water, and extracted twice with ethyl acetate. The resulting organic layer was sequentially washed with a saturated sodium sulfite (Na2SO3) aqueous solution, an NaCl aqueous solution, and water, followed by the addition of anhydrous sodium sulfate (Na2SO4). The solvent was then evaporated under reduced pressure to obtain a concentrate including a crude product. The concentrate was subjected to silica gel flash column chromatography (eluant: hexane/ethyl acetate=6/1) to obtain 2,2,2-trichloroethyl 2-benzoylindoline-1-carboxylate (white solid) represented by the following formula (as4). The yield was 48% (see Table 1-2). The analysis data for the resulting compound (as4) is shown below.
Reaction SMILES: Br[C:2]1C=CC(O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[NH2:37][C:38]1[S:39]C(C(=O)C)=C(C)[N:42]=1.[OH-].[K+]>C(O)C>[NH2:42][C:38]1[S:39][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)=[C:7]([CH3:2])[N:37]=1
Reactant: CC(=O)c1sc(N)nc1C
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(N)sc1-c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 9 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(2-amino-4-methyl-thiazol-5-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (8 mg, 9% yield). MS: 484.19 (M+H+); HPLC Procedure A, retention time=8.57 min.
Reaction SMILES: Br[CH2:2][CH:3]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:4]1[C:12]([O:14]CC)=O.C(=O)([O-])O.[Na+].[CH2:22]([NH2:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O>CN(C)C=O>[CH2:22]([N:28]1[CH2:2][CH:3]2[CH:4]([CH:5]2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:12]1=[O:14])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)C1C(CBr)C1c1ccccc1
Reactant: CCCCCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCN1CC2C(C1=O)C2c1ccccc1
Temperature: 150 °C
Yield: 79.5 %

Procedure:
To a solution of ethyl 2-(bromomethyl)-3-phenylcyclopropanecarboxylate (Preparation 26, 65 mg, 0.22 mmol) in N,N-dimethylformamide (2 ml) was added sodium hydrogen carbonate (30 mg, 0.36 mmol) and hexylamine (33 μl, 26 mg, 0.26 mmol), and the mixture was heated to 150° C. for 3 h. The mixture was cooled, water (30 ml) was added, and the mixture was extracted with diethyl ether (2×30 ml). The extracts were combined, dried (Na2SO4), filtered and concentrated in vacuo. The mixture was purified by silica column (5 g) chromatography eluting with 4:1 dichloromethane:ethyl acetate. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil (45 mg, 76%).