Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.[F:19][C:20]([F:28])(S(F)(=O)=O)C(O)=O.CCCCCC.N.CO>C(#N)C.[Cu](I)I.C(OCC)(=O)C>[F:19][CH:20]([F:28])[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:4]1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: O=C(OCc1ccccc1)N1CCCC(CO)C1
Agent: I[Cu]I
Agent: N
Solvent: CO
Solvent: CCCCCC
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCCC(COC(F)F)C1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 60.8 %

Procedure:
Benzyl 3-(hydroxymethyl)piperidine-1-carboxylate (2.49 g, 10.0 mmol) was dissolved in acetonitrile (100 mL), to which copper iodide (I) (2.86 g, 15.0 mmol) and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (2.66 g, 15.0 mmol) were added, followed by stirring at 80° C. for 20 minutes. The mixture was brought down to room temperature, to which adequate amounts of hexane and ethyl acetate were added, followed by neutralization with a 2M ammonia/methanol solution. Impurities were filtered off, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane:ethyl acetate, 100:0-0:100, V/V) to give the desired title compound (1.82 g, yield 61%).
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[N:15][C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][N:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[H-].[Na+].Br[CH2:31][C:32]([NH2:34])=[O:33]>CN(C=O)C>[NH2:34][C:32](=[O:33])[CH2:31][N:20]([C:16]1[N:15]=[C:14]2[CH:13]=[CH:12][N:11]([S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:2])=[O:3])[C:19]2=[N:18][CH:17]=1)[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NC(=O)OC(C)(C)C)cnc32)cc1
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(N(CC(N)=O)C(=O)OC(C)(C)C)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a solution of tert-butyl 5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-ylcarbamate (1.00 g, 2.57 mmol, Example #3 Step E) and DMF (13 mL) under nitrogen at about 0° C. was added NaH (60% dispersion in mineral oil, 0.113 g, 2.83 mmol) in one portion. After about 30 min, 2-bromoacetamide (0.391 g, 2.83 mmol) was added in one portion. After about 30 min, the ice bath was removed and the solution was stirred at ambient temperature for about 2 h. Saturated aqueous NH4Cl/water (1:1, 100 mL) was added. After stirring for about 10 min, the mixture was filtered using water to wash the filter cake. The aqueous phase was extracted with EtOAc (50 mL). The filter cake was dissolved in EtOAc and added to the organic layer. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 20-100% EtOAc/heptane to give tert-butyl 2-amino-2-oxoethyl(5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-yl)carbamate (0.980 g, 82%): LC/MS (Table 1, Method n) Rt=0.70 min; MS m/z 446 (M+H)+.
Reaction SMILES: [OH-].[K+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].I[CH2:11][CH:12]([CH3:14])[CH3:13]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:11]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9])[CH:12]([CH3:14])[CH3:13]
Reactant: O=C1CCCCN1
Reactant: CC(C)CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)CN1CCCCC1=O
Yield: 11.9 %

Procedure:
A suspension of 85% potassium hydroxide (36.6 g), and tetrabutylammonium bromide (9.1 g) in toluene (400 ml) was refluxed overnight in a Dean Stalk apparatus. Then, a solution of 2-piperidone (50.0 g) and iodoisobutane (120.7 g) in toluene (150 ml) was added dropwise at 115° C. to the solution above. After the dropwise addition, the mixture was refluxed further for 2.5 hours, and then cooled, and filtered to remove insoluble matter. The filtrate was washed with water, and the aqueous layer was extracted with toluene. The organic layers were combined and dried over magnesium sulfate. After distilling off the solvent under reduced, the residue was separated and purified by silica gel column chromatography (ethyl acetate) to obtain yellow oil of 1-isobutyl-2-piperidone (9.3 g).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][NH:18][C:19](=[O:45])[NH:20][C:21]4[CH:22]=[CH:23][C:24]([CH3:44])=[C:25]([CH:43]=4)[O:26][C:27](=[O:42])[CH2:28][N:29]4CCN(C(OC(C)(C)C)=O)CC4)[CH:14]=3)[C:9]2=[O:46])[CH2:6][CH2:5][C:4](=[O:47])[NH:3]1.[ClH:48]>C(Cl)Cl.CCOCC>[ClH:48].[NH2:29][CH2:28][C:27]([O:26][C:25]1[CH:43]=[C:21]([NH:20][C:19]([NH:18][CH2:17][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:46])[N:8]([CH:7]2[CH2:6][CH2:5][C:4](=[O:47])[NH:3][C:2]2=[O:1])[CH2:16]3)=[O:45])[CH:22]=[CH:23][C:24]=1[CH3:44])=[O:42]
Reactant: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1OC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1OC(=O)CN
Reaction time: 24 h

Procedure:
To a mixture of tert-butyl 4-(2-(5-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)-2-methylphenoxy)-2-oxoethyl)piperazine-1-carboxylate (0.65 g, 1.0 mmol) in methylene chloride (50 mL) is added 2M HCl in ether (1 mL), and the mixture will be stirred for 24 hrs. The solid precipitate is filtered, rinsed with DCM (10 mL), and dried under vacuum to provide the product.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:10](OCC)(OCC)[O:11][CH2:12][CH3:13].C(OC(=O)C)(=O)C>>[CH2:12]([O:11][CH:10]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(C)=O)C(=O)OCC
Temperature: 135 °C
Yield: 69.7 %

Procedure:
A mixture of ethyl acetoacetate (100 g, 0.77 mol), triethyl orthoformate (130 g, 0.92 mol), and acetic anhydride (150 g, 1.5 mol) was heated at 135° C. for 6-18 h in a round bottomed flask that was equipped with a distillation apparatus to collect the ethanol generated during the reaction. The reaction was cooled, concentrated and the residue was distilled under high vacuum to obtain the desired product (100 g, 70%) as a pale yellow oil: ESI MS m/z 187 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[O:13][C@H]3[C@H:9]([C:10](=[O:14])[NH:11]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O-:18])(O)=O.[Na+]>C(Cl)Cl.CC(C)=CCO>[C:7]([NH:8][C@@H:9]1[C@@H:10]([O:14][CH2:3][CH:2]=[C:1]([CH3:7])[CH3:6])[NH:11][C:15]1=[O:18])(=[O:13])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])O
Reactant: O=C1N[C@H]2OC(c3ccccc3)=N[C@@H]12
Agent: CC(C)=CCO
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)=CCO[C@H]1NC(=O)[C@@H]1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
181 mg (0.96 mmol--1.2 equivalents) of anhydrous tin-II chloride (dried by fusing briefly under a high vacuum) were added all at once, at 0° C., to a suspension of 150 mg (0.78 mmol) of (1R, 5S)-3-phenyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one in 1.3 ml of anhydrous methlene chloride and 0.81 ml (7.8 mmols--10 equivalents) of 3-methyl-2-buten-1-ol. The cooling bath was removed and a clear solution was formed after a few minutes. The reaction mixture was stirred for a further 15 minutes at room temperature, poured into dilute NaHCO3 solution and extracted with methylene chloride and the extract was washed with water and dried over MgSO4. After the solvent had been evaporated off in vacuo and the residue had been filtered on 5 g silica gel (toluene:ethyl acetate 3:7), 153 mg (70%) of the title compound were obtained as colorless crystals, melting point: 92° C., RF : 0.38 (toluene:ethyl acetate 3:7).
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[CH2:27][CH2:28]Br.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C.C(OCC)(=O)C.O>[C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(OCC2CCCNC2)c2ccccc2)cc1
Reactant: COc1cccc(CCBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(CCN2CCCC(COC(c3ccccc3)c3ccccc3)C2)c1
Yield: 53.9 %

Procedure:
A mixture of 3-(diphenylmethoxymethyl)piperidine (1.40 g, 5.0 mmol--see Preparation 1), 3-methoxyphenethyl bromide (1.08 g, 5.0 mmol), sodium carbonate (1.08 g) and sodium iodide (0.10 g) in acetonitrile (30 ml) was heated under reflux for 18 hours, diluted with ethyl acetate and water and the layers separated. The organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-3% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (1.12 g) as a colourless oil which was characterised containing a third of an equivalent of water.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]([CH:10]([F:12])[F:11])([F:9])[F:8])([F:4])([F:3])[F:2].[Br:13]Br.C(=O)=O>>[C:1]([CH:5]([O:6][C:7]([CH:10]([F:11])[F:12])([F:8])[F:9])[Br:13])([F:4])([F:3])[F:2]
Reactant: BrBr
Reactant: FC(F)C(F)(F)OCC(F)(F)F
Agent: O=C=O
Product: FC(F)C(F)(F)OC(Br)C(F)(F)F
Temperature: 475 °C

Procedure:
CF3CH2OCF2CF2H (110 g.) was reacted with bromine (125 g.) by passing a mixture of the two diluted with a stream of nitrogen through a 12 inch × 1 inch glass tube heated to 475° C. The effluent product was condensed in a "Dry Ice" trap and purified by fractional distillation and preparative gas chromatography to give CF3CHBrOCF2CF2H., b.p. 80° C., nD25 1.3155. This product analyzed as follows:
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[NH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[OH:25]>>[OH:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[NH:18][C:15]([C:5]1[CH:4]=[N:3][C:2]([Br:1])=[C:7]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[N:6]=1)=[O:17]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 19e, using 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid, and (1R,2R)-2-amino-cyclohexanol (commercially available) as starting materials to give the title compound as a light yellow solid, MS (ISP): 410.0, 412.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2>CS(C)=O.O>[N:1]1([C:8]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[N:13]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)c2cccnc12
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c2cccnc12
Temperature: 100 °C
Yield: 80.4 %

Procedure:
Morpholine (251.6 μl, 2.88 mmol) was added to a solution of 5-chloro-8-nitro-quinoline 27 (200 mg, 0.96 mmol) in DMSO (2 ml) and the mixture was heated at 100° C. in a sealed tube for 18 h. After cooling, the mixture was diluted with water (10 ml) and the resulting precipitate was collected by filtration. The solid was dried in vacuo to give the title compound (200 mg, 81%) which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[C:4]([O:18][CH3:19])[CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl.O>[CH2:10]([C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Br:1])=[CH:3][C:4]=1[O:18][CH3:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc(C(=O)c2ccccc2)c(OC)cc1Br
Agent: CC[SiH](CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1cc(Cc2ccccc2)c(OC)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of (4-bromo-2,5-dimethoxyphenyl)(phenyl)methanone (100 mg, 0.311 mmol) in 0.2 mL of anhydrous DCM (C=1.5M), were successively added dropwise trifluoroacetic acid (0.24 mL, 10 eq) and triethylsilane (0.2 mL, 4 eq). After 16 h of stirring at r.t., the reaction mixture was hydrolyzed with a saturated NH4Cl solution (5 mL). The layers were diluted with 20 mL of DCM and 20 mL of water and then separated. The aqueous layer was extracted twice with DCM (2×10 mL) The combined organic phase was washed twice with a saturated NaHCO3 solution (2×20 mL), brine (2×20 mL), dried over MgSO4, filtered and concentrated in vacuo. The product was obtained pure enough for further reaction in 98% yield (93.4 mg). 1H NMR (300 MHz, CDCl3) δ 7.34-7.25 (m, 2H), 7.24-7.17 (m, 3H), 7.08 (s, 1H), 6.69 (s, 1H), 3.95 (s, 2H), 3.78 (s, 3H), 3.78 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 151.9 (C), 150.1 (C), 140.4 (C), 129.9 (C), 128.9 (CH), 128.5 (CH), 126.1 (CH), 116.1 (CH), 115.0 (CH), 109.1 (C), 57.0 (OCH3), 56.3 (OCH3), 35.9 (CH2Bn); MS (ESI) m/z: 324.5, 326.1 [M+NH4, 79Br, 81Br]+; 630.3, 632.0, 634.2 [2M+NH4, 79Br, 81Br]+.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@@H:13](O)[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[F:17]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C>C1COCC1.O.CCOC(C)=O.CCCCCCC>[F:17][C@@H:13]([C@H:12]1[CH2:11][O:10][C:9](=[O:16])[N:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[N:7]=1)[CH3:14]
Reactant: C[C@H](O)[C@H]1COC(=O)N1c1ccnc(F)n1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C[C@@H](F)[C@H]1COC(=O)N1c1ccnc(F)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 28.8 %

Procedure:
To a round bottom flask containing a solution of (R)-3-(2-fluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (348 mg, 1.53 mmol) in THF (5.1 mL) was added perfluorobutanesulfonyl fluoride (0.83 mL, 4.60 mmol) followed by the addition of triethylamine trihydrofluoride (0.75 mL, 4.60 mmol) and triethylamine (1.9 mL, 13.8 mmol). The resulting reaction mixture allowed to stir at room temperature for 6 hr. The reaction mixture was diluted with water and the aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 60%) provided a viscous oil of (R)-4-((R)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (125 mg, 0.44 mmol, 28% yield) which crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.34 (dd, J=24.26, 6.65 Hz, 3H) 4.45-4.55 (m, 1H) 4.61-4.68 (m, 1H) 5.11 (dt, J=7.63, 4.01 Hz, 1H) 5.30-5.52 (m, 1H) 8.13-8.17 (m, 1H) 8.52 (d, J=5.87 Hz, 1H). LCMS m/z 230.0 (M+H)+, Rt 0.66 min.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2.C1C2C(=CC=CC=2)CCC21CCC(=O)CC2.[NH2:32][OH:33].[OH-].[Na+]>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[CH2:14][CH2:13][C:12](=[N:32][OH:33])[CH2:11][CH2:10]2
Reactant: NO
Reactant: O=C1CCC2(CC1)Cc1ccccc1C2
Agent: O=C1CCC2(CC1)CCc1ccccc1C2
Agent: [Na+]
Agent: [OH-]
Product: ON=C1CCC2(CC1)Cc1ccccc1C2

Procedure:
The first step of the process comprises reacting a spiro (cyclohexane-1,2'-indan)-4-one (II) or a 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one (II) with an acid addition salt of hydroxylamine and an alkali metal hydroxide such as sodium hydroxide at reflux temperature for from about 4 to about 8 hours to obtain the corresponding spiro(cyclohexane-1,2'-indan)-4-one oxime (III) or the corresponding 3',4'-dihydrospiro[cyclohexane-1,2'-(1'H)naphthalen]-4-one oxime (III), respectively.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3(C)[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[C:21](Cl)(=[O:23])[CH3:22]>C(O)(=O)C>[NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][O:19][C:16](=[O:17])[CH3:18])[C@@H:14]([O:15][C:14](=[O:15])[CH2:12][CH3:11])[C@H:12]3[O:13][C:21](=[O:23])[CH3:22])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Reactant: CC(=O)Cl
Solvent: CC(=O)O
Product: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2ccc3c(N)ncnc32)O[C@@H]1COC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step 3 (1.10 g, 3.92 mmol) in glacial acetic acid (8 mL) was added acetyl chloride (3 mL) and the mixture stirred at room temp overnight. The reaction was concentrated in vacuo and the residue was plated onto silica gel column with dichloromethane and eluded by ramping to 5% methanol in dichloromethane to give 1.5 g (94%);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[N:10][C:9]=2[O:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[N:20]1[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[N:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:26]([C:24]3[CH:25]=[N:20][CH:21]=[N:22][CH:23]=3)=[O:27])[CH:11]=[N:10][C:9]=2[O:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cncnc1
Reactant: Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)n1
Product: O=C(Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)n1)c1cncnc1

Procedure:
The title compound was synthesized in analogy to Example 42g, using 6-(4-chloro-phenyl)-5-cyclobutoxy-pyrazin-2-ylamine (example 50c) and 5-pyrimidinecarboxylic acid (CAN 4595-61-3) as starting materials; LC-MS (UV peak area/ESI) 96.3%, 482.1073 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:5]=2[N:6]=1.[CH3:13][C:14]1[S:18][C:17]([C:19](Cl)=[O:20])=[CH:16][CH:15]=1>>[F:12][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:19]([C:17]3[S:18][C:14]([CH3:13])=[CH:15][CH:16]=3)=[O:20])[S:3][C:4]=2[CH:10]=[C:9]([F:11])[CH:8]=1
Reactant: Nc1nc2c(F)cc(F)cc2s1
Reactant: Cc1ccc(C(=O)Cl)s1
Product: Cc1ccc(C(=O)Nc2nc3c(F)cc(F)cc3s2)s1

Procedure:
Using 2-amino-4,6-difluoro-benzothiazole and 5-methyl-thiophene-carboxylicacid chloride the title compound was prepared as a yellow solid (74% yield), MS: m/e=310 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(CC(O)C(F)(F)F)c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(CC(O)C(F)(F)F)c2=O)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
An amount of 280 mg (0.61 mmol) of the compound from Example 24A was dissolved in 4 ml of a 1:1 mixture of methanol and THF and admixed with 0.61 ml of 2 N sodium hydroxide solution. It was stirred at 80° C. for 1 h. For working out, it was admixed with 5 ml of water and extracted with 5 ml of ethyl acetate. The aqueous phase was acidified to a pH of 1 using 1 N hydrochloric acid and extracted with twice 5 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. This gave 275 mg (100% of theory) of the target compound.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10]O)[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:18]>ClCCl>[Br:18][CH2:10][C:8]1[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=1
Reactant: CCOC(=O)c1nn(C(C)(C)C)cc1CO
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1nn(C(C)(C)C)cc1CBr
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a 0° C. solution of ethyl 1-tert-butyl-4-(hydroxymethyl)-1H-pyrazole-3-carboxylate (3.9 g, 17.24 mmol) in dichloromethane (120 mL) was added phosphorus tribromide (4.91 mL, 51.7 mmol), and the resultant mixture was stirred 30 minutes at 0° C. and then 1 hour at room temperature. The mixture was quenched with 50 mL water, neutralized with saturated aqueous sodium bicarbonate, stirred 30 minutes, and then extracted with dichloromethane (2×150 mL). The combined organic extracts were washed with 100 mL brine, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography (7-60% ethyl acetate/heptanes, 50 g silica gel) to yield ethyl 4-(bromomethyl)-1-tert-butyl-1H-pyrazole-3-carboxylate (4.12 g) as a clear oil. +APCI (M+H) 289.1; 1H NMR (400 MHz, CDCl3, δ): 7.61 (s, 1H), 4.70 (s, 2H), 4.41 (q, J=7.2 Hz, 2H), 1.60 (s, 9H), 1.40 (t, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][C:31]1=[O:35]>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([NH:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][C:31]2=[O:35])=[N:3][CH:4]=1
Reactant: NCCCN1CCCC1=O
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: C1COCCO1
Product: O=C1CCCN1CCCNc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 27 %

Procedure:
A 1,4-dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (200 mg, 0.48 mmol) obtained in Example 54 and 1-(3-aminopropyl)pyrrolidin-2-one (400 μl) was stirred at 120° C. for 17 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (68 mg, 27%) as an oil.
Reaction SMILES: [C@@H:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)([CH2:3][CH3:4])[CH3:2].Cl.[F:20][C:21]([F:34])([F:33])[C:22]1[S:26][C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][CH:23]=1>>[C@@H:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([N:30]1[CH2:31][CH2:32][N:27]([C:25]2[S:26][C:22]([C:21]([F:34])([F:20])[F:33])=[CH:23][N:24]=2)[CH2:28][CH2:29]1)=[O:10])([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@H](C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC[C@H](C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1
Yield: 13 %

Procedure:
Prepared in analogy to example 1 (b) from 2-((S)-sec-butoxy)-5-methanesulfonyl-benzoic acid (Example A21) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by reversed phase HPLC (acetonitrile/water) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 13%). MS (m/e): 492.4 (M+H+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:24])=[CH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)nc1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2cccc(F)c2)nc1

Procedure:
Using the procedure outlined in Example 104, the title compound was prepared from 7-aminoquinoline (D55) (28 mg, 0.19 mmol) and 6-(3-fluorophenyl)-nicotinic acid (D73) (50 mg, 0.23 mmol) as a yellow solid. MS(ES): MH+ 344, M-H+ 342