Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CC1C2C(=CC=CC=2)C=CC=1.[C-:25]#[N:26].[Na+]>CN(C)C1C=CN=CC=1.[Cu]I.O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:25]#[N:26])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Reactant: [C-]#N
Agent: [Cu]I
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: O
Solvent: Cc1cccc2ccccc12
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C

Procedure:
A 100-mL, three-necked flask equipped with a mechanical stirrer, thermometer and condenser was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (5.0 g, 0.020 mol, 99.1% purity) and 1-methylnaphthalene (20 g) while maintaining a flow of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature, and powdered sodium cyanide (powdered just prior to use) (1.25 g, 0.024 mol, assuming 95% purity), copper(I) iodide (0.57 g, 0.0030 mol) and 4-(dimethylamino)pyridine (2.10 g, 0.017 mol) were added. The mixture was heated at 160 to 165° C. for 4.25 h and then allowed to cool to 25° C. Water (20 mL) was added dropwise to the reaction mixture over 5 minutes while stirring. After stirring for an additional 30 minutes, the reaction mixture was filtered, and the solid collected was washed with water (3×10 mL) and xylenes (10 mL), and then dried to a constant weight in a vacuum-oven at 50° C. to give the title compound as a light brown solid (3.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([NH2:13])=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:14]1[N:18]2[CH:19]=[CH:20][CH:21]=[N:22][C:17]2=[C:16]([C:23](O)=[O:24])[CH:15]=1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([NH:13][C:23]([C:16]3[CH:15]=[N:14][N:18]4[CH:19]=[CH:20][CH:21]=[N:22][C:17]=34)=[O:24])=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2cccnc12
Reactant: Nc1c[nH]nc1-c1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1c[nH]nc1-c1cccc(Cl)c1)c1cnn2cccnc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 20.3 %

Procedure:
A mixture of 3-(3-chlorophenyl)-1H-pyrazol-4-amine (95.3 mg, 0.492 mmol, 1 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (90.6 mg, 0.555 mmol, 1.13 eq), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uranium hexafluorophosphate (247.3 mg, 0.6504 mmol, 1.32 eq), N,N-diisopropylethylamine (0.20 mL, 1.1 mmol, 2.3 eq), and 4-dimethylaminopyridine (24.1 mg, 0.197 mmol, 0.40 eq) in 5.0 mL N,N-dimethylformamide was stirred at 50° C. for 3 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 33.8 mg (20%) of N-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=339.0; 1H NMR (400 MHz, DMSO-d6) δ: 13.05 (s, 1H), 9.99 (s, 1H), 9.38 (d, 1H), 8.84 (d, 1H), 8.70 (s, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 7.78 (d, 1H), 7.58 (t, 1H), 7.50 (d, 1H), 7.34 (d of d, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:16]=[C:17]([C:21]([O:23][CH3:24])=[S:22])[S:18][C:19]=3[CH3:20])[N:14]=2)=[CH:5][CH:4]=1.[Br:26]CC(C1C=C(C(OC)=S)SC=1C)=O>>[BrH:26].[CH3:25][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:16]=[C:17]([C:21]([O:23][CH3:24])=[S:22])[S:18][C:19]=3[CH3:20])[N:14]=2)=[CH:5][CH:4]=1
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Agent: COC(=S)c1cc(-c2csc(Nc3ccc(N(C)C)cc3)n2)c(C)s1
Product: Br

Procedure:
Methyl 4-(2-{[4-(dimethylamino)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hIydrobromide: Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (50 mg, 0.16 mmol) was allowed to react with 4-N,N-dimethylaminophenyl thiourea (31.5 mg) as described in Example 154, step (a), to give 53.2 mg (75% yield) of methyl 4-(2-{[4-(dimethylamino)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide. 1H NMR (DMSO-d6, 300 MHz) δ 2.69 (s, 3H), 3.15 (s, 6H), 3.83 (s, 3H), 7.36 (s, 1H), 7.55 (bs, 2H), 7.88 (d, 2H, J=8.3 Hz), 8.16 (s, 1H), 10.56 (bs, 1H); Mass Spectrum (ESI) m/z calcd. for C18H19N3O2S3, 405.56 (M+H), found 406.1.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:18][CH3:19].[Br:20]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C.Br>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([Br:20])[CH2:18][CH3:19]
Reactant: CCC1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: BrBr
Agent: Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC1(Br)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To a stirred suspension of (1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)acetic acid (30.3 g., 0.10 moles) in acetic acid (300 ml.) is added a solution of bromine (16.0 g., 0.10 moles) in acetic acid (50 ml.) over a period of 30 minutes. The reaction is catalyzed by the addition of 48% aqueous hydrobromic acid (2 drops). The clear yellow solution is stirred at room temperature for 30 minutes then poured into ice water (1 l.) containing sodium bisulfite (2 g.). The crude (1-oxo-2-bromo-2-ethyl-6,7-dichloro-5-indanyloxy)acetic acid (36 g., 97%) thus obtained is filtered, washed with water and dried. It melts at 189°-191° C. after recrystallization from a mixture of ethyl acetate and hexane.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:35])[N:27]3[C:30]([O:32][CH2:33]Cl)=[O:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.[C:36]([OH:41])(=[O:40])[CH2:37][CH2:38][CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:35])[N:27]3[C:30]([O:32][CH2:33][O:41][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])=[O:31])=[CH:22][CH:21]=2)[CH2:13][CH2:14]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)OCCl
Reactant: CCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(=O)OCOC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloromethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (1.20 g, 2.22 mmol) in dimethyl formamide (20 mL) was added butyric acid (0.30 mL, 3.33 mmol) followed by cesium carbonate (542 mg, 1.67 mmol). The reaction was then stirred at ambient temperature overnight. The reaction was diluted with ethyl acetate (50 mL) and quenched with water/brine (1:1, 50 mL). The reaction was extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (50 mL) then brine (50 mL) and dried (MgSO4) and concentrated. The crude product was purified by column chromatography on silica eluting with 010% tetrahydrofuran/dichloromethane with 1% Et3N to give the product which required further purification. The product was purified by column chromatography on silica eluting with 0.51.5% Et3N/ethyl acetate to give butyryloxymethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate, Compound-88 (348 mg, 26% over 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:16]=[N:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][C:23]=2[CH:24]=1>>[Br:14][C:15]1[CH:16]=[N:17][C:18]2[CH2:19][CH2:20][N:21]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH2:22][C:23]=2[CH:24]=1
Reactant: Brc1cnc2c(c1)CNCC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2ncc(Br)cc2C1
Yield: 66 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-Bromo-5,6,7,8-tetrahydro-[1,6]naphthyridine to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=1[CH2:45][CH2:46][NH2:47].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:47][CH2:46][CH2:45][C:36]3[CH:37]=[CH:38][C:39]([C:41]([F:43])([F:44])[F:42])=[CH:40][C:35]=3[O:34][CH3:33])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: COc1cc(C(F)(F)F)ccc1CCN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C(F)(F)F)cc4OC)cc3)c(Cl)cc21
Reaction time: 0.17 h
Yield: 58.1 %

Procedure:
A portion of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1; 0.7 g, 1.86 mmol) was diluted with dichloromethane (1 mL) followed by the addition of oxalyl chloride in dichloromethane (1.02 ml, 2.04 mmol) and DMF (1 drop). After stirring for 10 minutes, 2-(2-methoxy-4-(trifluoromethyl)phenyl)ethanamine (Preparation 9; 0.448 g, 2.04 mmol) and DIEA (1.13 ml, 6.50 mmol) were added, and the reaction was stirred for 2 hours. The reaction was loaded directly onto a biotage 25 cartridge and eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes to yield ethyl 6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate (624 mg, 1.08 mmol, 58.1% yield).
Reaction SMILES: N.[OH:2][C@H:3]([C:38]1[C:46]2[S:45][C:44](=[O:47])[NH:43][C:42]=2[C:41]([OH:48])=[CH:40][CH:39]=1)[CH2:4][N:5]([CH2:13][CH2:14][C:15]1[CH:19]=[C:18]([CH2:20][N:21]2[CH2:37][CH2:36][C:24]3([O:29][CH2:28][CH2:27][N:26](C(=O)C(F)(F)F)[CH2:25]3)[CH2:23][CH2:22]2)[S:17][CH:16]=1)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]>>[O:29]1[C:24]2([CH2:23][CH2:22][N:21]([CH2:20][C:18]3[S:17][CH:16]=[C:15]([CH2:14][CH2:13][N:5]([CH2:4][C@H:3]([OH:2])[C:38]4[C:46]5[S:45][C:44](=[O:47])[NH:43][C:42]=5[C:41]([OH:48])=[CH:40][CH:39]=4)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH:19]=3)[CH2:37][CH2:36]2)[CH2:25][NH:26][CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N(CCc1csc(CN2CCC3(CC2)CN(C(=O)C(F)(F)F)CCO3)c1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Agent: N
Product: CC(C)(C)OC(=O)N(CCc1csc(CN2CCC3(CC2)CNCCO3)c1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12

Procedure:
35% Aqueous ammonia (5 mL) was added to (R)-tert-butyl 2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl(2-(5-((4-(2,2,2-trifluoroacetyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)thiophen-3-yl)ethyl)carbamate (Example 264, step c) (0.2 g). After 40 min at 20° C. the solution was concentrated to ˜1 mL and the slurry added to a C18 (10 g) cartridge washing with water (20 mL), then eluting the product with methanol. The fractions containing product were combined and evaporated in vacuo. The resulting solid was dissolved in acetonitrile and evaporated in vacuo. Yield 0.11 g.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([Li])C=CC=CC=1.[Li].BrC1C=CC=CC=1.[F:28][C:29]([F:45])([F:44])[C:30]1[CH:43]=[CH:42][C:33]([C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:35])=[CH:32][CH:31]=1>O.O1CCCC1.C(OCC)C>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:33]1[CH:32]=[CH:31][C:30]([C:29]([F:45])([F:44])[F:28])=[CH:43][CH:42]=1)[OH:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc(C(F)(F)F)cc1
Reactant: c1ccc(Cn2ccnc2)cc1
Agent: [Li]
Agent: [Li]c1ccccc1
Solvent: Brc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccc(C(F)(F)F)cc1)c1nccn1Cc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 14.2 g (0.09 mol) of 1-benzylimidazole (A. M. Roe, J. Chem. Soc., 1963, 2195) in 60 ml. of tetrahydrofuran was added dropwise at -20° to -30° C. under a nitrogen atmosphere to 0.1 mol phenyl lithium (prepared from 1.52 g (0.22 gr. at.) of lithium and 15.7 g (0.19 mol) of bromobenzene) in 70 ml. of diethyl ether. The reaction mixture was stirred for one hour and then 22.5 g (0.09 mol) of 4-(trifluoromethyl)benzophenone in 35 ml. of tetrahydrofuran were added dropwise. The reaction mixture was stirred under the nitrogen atmosphere for two hours at -20° to -30° C. and for 15 hours at room temperature. The mixture was then poured into a mixture of ice and water. The aqueous phase was twice extracted with diethyl ether and the combined extracts were concentrated. The residue was taken up in diethyl ether and the undissolved solid matter (ketone starting material) was filtered off. The ether was distilled off and the residue was again taken up in a small amount of diethyl ether. The undissolved material, which now appeared to be the desired product, was filtered off. This procedure (evaporating the ether and taking up the residue in ether again) was repeated a few times and the solid materials filtered off were combined. The substance was crystallised from isopropyl alcohol with a small amount of water. 1-Benzyl-α-phenyl-α-(p-trifluoromethylphenyl)-imidazole-2-methanol was obtained.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][CH:18]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:19][CH:18]=1
Reactant: NCc1ccncc1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: CO
Product: O=c1[nH]c2ncccc2c2cc(NCc3ccncc3)ccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
9-Chloro-5H-benzo[c][1,8]naphthyridin-6-one (50 mg, 0.22 mmol), 1-pyridin-4-ylmethanamine (47 mg, 0.43 mmol), palladium(II) acetate (2 mg, 0.01 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (10 mg, 0.02 mmol), and sodium tert-butoxide (83 mg, 0.87 mmol) were suspended in dioxane (2 mL), and stirred overnight at 100° C. The reaction mixture was diluted with MeOH, filtered through a membrane, and purified via prep-LC-MS to provide 124 (10 mg, 15% yield) as a tan solid. LC-MS (M+H=303, obsd.=303). 1H NMR (400 MHz, d6-DMSO): δ 11.50 (s, 1H), 8.52 (m, 3H), 8.41 (d, 1H), 8.01 (dd, 1H), 7.42 (d, 2H), 7.35 (m, 2H), 7.24 (m, 1H), 6.95 (d, 1H), 4.58 (d, 2H).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:11][OH:12])[CH3:10].[OH-].[K+]>CO.O>[CH3:10][C:9]1[C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[O:12][N:11]=1
Reactant: CC(=NO)c1ccc(O)cc1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1noc2cc(O)ccc12
Yield: 22 %

Procedure:
1.98 g of 1-(2,4-dihydroxyphenyl)ethanone oxime (12 mM) and 1 g of potassium hydroxide (18 mM) are refluxed for 4 days in a methanol/water mixture (100 ml/100 ml). The reaction medium is subsequently concentrated under reduced pressure, acidified to pH=1 with 1N HCl, and then extracted with ethyl acetate. The organic phase obtained is dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by silica gel chromatography (methylcyclohexane/ethyl acetate gradient of 70/30 to 30/70; v/v). The expected product is obtained in the form of a white solid (0.39 g) with a yield of 22%.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH3:19])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[C:20](OCCBr)(=[O:22])C>>[CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH2:19][CH2:20][OH:22])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(OC)c2ccn(C3CC3)c2c1
Reactant: CC(=O)OCCBr
Product: CCOC(=O)c1cc(OCCO)c2ccn(C3CC3)c2c1

Procedure:
The compound was prepared according to the procedure for ethyl 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylate but using bromoethyl acetate in place of MeI.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyloxycarbonyl chloride (12.4 ml) was added dropwise to a mixture of 10 g of trans-4-aminocyclohexanol, 13.3 ml of triethylamine and 300 ml of dichloromethane under ice-cooling, and the mixture was stirred at room temperature for one hour. The reaction mixture was washed and dried, and the solvent was removed under reduced pressure. The residue was recrystallized from an ethyl acetate solution to give 5.80 g of N-benzyloxycarbonyl-trans-4-aminocyclohexanol (yield: 27%, melting point: 148°-151° C.).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C:10]([CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14](C(OC(C)(C)C)=O)[CH2:13]1)=[O:11]>C(Cl)Cl>[CH3:8][NH:9][C:10]([CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH2:13]1)=[O:11]
Reactant: CNC(=O)C1CN(C(=O)OC(C)(C)C)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)C1CNc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3 ml of a 25% solution of trifluoroacetic acid in methylene chloride are added to a solution of 216 mg of 1-(tert-butoxycarbonyl)indoline-3(R,S)-carboxylic acid (N-methyl)amide in 1 ml of methylene chloride at 0° C., while stirring. After 90 min, the mixture is allowed to warm to room temperature and stirring is continued for 2 h. Concentration of the mixture and purification of the crude product over 50 g of silica gel (mobile phase K) gives the title compound: Rf (P)=0.52.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:21][CH:20]([CH2:22][O:23][CH3:24])[O:19][C:18]4=[O:25])=[N:15][CH:16]=3)[CH2:7][CH2:6]2)[O:4]CC1.[OH-].[Na+]>O1CCCC1.Cl>[CH3:24][O:23][CH2:22][CH:20]1[O:19][C:18](=[O:25])[N:17]([C:14]2[CH:13]=[CH:12][C:11]([CH:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)=[CH:16][N:15]=2)[CH2:21]1
Reactant: COCC1CN(c2ccc(C3CCC4(CC3)OCCO4)cn2)C(=O)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCC1CN(c2ccc(C3CCC(=O)CC3)cn2)C(=O)O1
Yield: 91.6 %

Procedure:
A solution of 0.5 g of (RS)-3-[5-(1,4-dioxa-spiro[4,5]decan-8-yl)-pyridin-2-yl]-5-methoxymethyl-oxazolidin-2-one in 20 ml of tetrahydrofuran and 5 ml of 2N hydrochloric acid was stirred at room temperature for 4 h. Then, 10 ml of 2N sodium hydroxide solution were added and the mixture was extracted several times with ethyl acetate. The organic phases were combined, dried with magnesium sulfate and concentrated. After chromatography with ethyl acetate on silica gel there was obtained 0.4 g of (RS)-5-methoxymethyl-3-[5-(4-oxo-cyclohexyl)-pyridin-2-yl]-oxazolidin-2-one. 1H-nmr (CDCl3) ppm: 8.22 (s, 1H), 8.18 (d,1H), 7.58 (d, 1H), 4.78 (m,1H), 4.27 (t, 1H), 4.09 (t, 1H), 3.64 (m, 2H), 3.43 (s, 3H), 3.08 (m, 1H), 2.51 (m, 4H), 2.04 (bm, 4H).
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][C:4]=1[C:20]([F:23])([F:22])[F:21].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:4]([C:20]([F:21])([F:22])[F:23])=[CH:5][C:6]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CCOC(=O)CCc1cc(C(F)(F)F)c(OC)c(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(C(F)(F)F)c(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 3-[4-methoxy-3,5-bis(trifluoromethyl)phenyl]propanoate (270 mg, 0.78 mmol, 1.00 equiv), dichloromethane (5.0 mL). That was followed by adding BBr3 (1N in dichloromethane) (1.57 mL) dropwise at −78 degree C. The resulting solution was warmed to room temperature and stirred for 2 h at 25° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 5 mL of water, extracted with 3×10 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 0.15 g (58%) of ethyl 3-[4-hydroxy-3,5-bis(trifluoromethyl)phenyl]propanoate as yellow oil. Mass spectrum (ESI, m/z): Calcd. for C13H12F6O3, 329.1 (M−H). found 329.1.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)(=O)=O.[I-:21].[Na+].O>CC(C)=O>[C:11]1([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][I:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: [I-]
Reactant: CS(=O)(=O)OCCCCCc1cccc2ccccc12
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: ICCCCCc1cccc2ccccc12
Yield: 85.9 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 4.1 grams (0.014 mole) of 1-methylsulfonyloxy-5-(naphth-1-yl)pentane, and 4.2 grams (0.028 mole) of sodium iodide in 150 mL of acetone was heated at reflux for 2.5 hours. The reaction mixture was poured into 400 mL of water, and the mixture was extracted with two 100 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 3.9 grams of 5-(naphth-1-yl)pentyl iodide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][O:10][CH2:11][CH2:12][C:13](O)=O.Cl.N>>[CH3:9][O:10][CH2:11][CH2:12][C:13]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: COCCC(=O)O
Reactant: Nc1ccccc1N
Agent: Cl
Agent: N
Product: COCCc1nc2ccccc2[nH]1
Yield: 91.8 %

Procedure:
A mixture of 3.17 g (29.3 mmols) of o-phenylenediamine, 3.75 g (36.0 mmols) of 3-methoxypropionic acid [J. Am. Chem. Soc., 70, 1004 (1948)]and 32 ml of a 4 normal aqueous hydrochloric acid solution was heated under reflux for 14 hours. After cooling, the mixture was neutralized with a 28-30% aqueous ammonia solution. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol =20/1) to afford 4.74 g (yield: 92%) of 2-(2-methoxyethyl)benzimidazole.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=1.[F:23][C:24]([F:31])([F:30])[CH2:25][S:26](Cl)(=[O:28])=[O:27]>>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([N:11]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[S:26]([CH2:25][C:24]([F:31])([F:30])[F:23])(=[O:28])=[O:27])[CH:8]=[CH:9][CH:10]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Fc1ccccc1Oc1cccc(NCc2cccnc2)c1
Product: O=S(=O)(CC(F)(F)F)N(Cc1cccnc1)c1cccc(Oc2ccccc2F)c1

Procedure:
Using the method of Example 342 using N-(3-(2-fluorophenoxy)phenyl)pyridin-3-ylmethylamine and 2,2,2-trifluoroethanesulfonyl chloride and purifying via radial chromatography eluting with 40:60 to 50:50 THF/hexanes gave the title compound. Anal Calcd for C20H16F4N2O3S: C, 54.54; H, 3.66; N, 6.36. Found: C, 54.23; H, 3.40; N, 6.31. MS found 441.2 [M+H]+