Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])([CH3:21])[CH3:20].C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:25]([C:24]3[CH:28]=[C:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=[CH:31][C:23]=3[O:22][CH:19]([CH3:21])[CH3:20])=[O:26])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 (b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a yellowish foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][C:4]=1[CH3:13].C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH2:28]([C@@H:35]1[CH2:39][O:38][C:37](=[O:40])[NH:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([Li])CCC>O1CCCC1>[CH2:28]([C@@H:35]1[CH2:39][O:38][C:37](=[O:40])[N:36]1[C:10](=[O:12])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:13])[CH:5]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: COc1ccc(CC(=O)O)cc1C
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of (4-methoxy-3-methyl-phenyl)-acetic acid (5.04 g, 27.97 mmol) and triethylamine (3.9 mL, 27.97 mmol) in anhydrous tetrahydrofuran (100 mL) under nitrogen at −78° C. was added trimethylacetyl chloride (3.44 mL, 27.97 mmol). The reaction mixture was stirred at −78° C. for 10 minutes, 0° C. for 1 hour, then re-cooled to −78° C. At the same time, to a separate flask charged with a solution of (R)-(+)-4-benzyl-2-oxazolidinone (4.96 g, 27.97 mmol) in anhydrous tetrahydrofuran (100 mL) under nitrogen at −78° C. was added dropwise a solution of n-butyllithium (14 mL, 28 mmol, 2 M in hexanes). The second reaction mixture was stirred at −78° C. for 20 minutes, then transferred via cannula into the first reaction flask containing the mixed anhydride at −78° C. The reaction mixture was stirred at 0° C. for 1 hour, then warmed to room temperature and stirred for 18 hours. The mixture was quenched with saturated aqueous ammonium chloride solution (200 mL), concentrated to about half of its original volume under reduced pressure to remove tetrahydrofuran. The remaining mixture was extracted with ethyl acetate (2×250 mL). The organic layers were separated, combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography over silica gel eluted with 1:1 ethyl acetate/hexanes to give (R)-4-benzyl-3-[2-(4-methoxy-3-methyl-phenyl)-acetyl]-oxazolidin-2-one as a pale yellow oil (8.5 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:5][C:6]1O[C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][C:20]([CH3:22])=[N:19][CH:18]=3)=[C:13]([O:23][CH3:24])[CH:12]=2)=[N:9][N:10]=1.[H-].[Na+].[C:31]([Si:35]([O:38][CH:39]([CH2:42]I)[CH2:40]Cl)([CH3:37])[CH3:36])([CH3:34])([CH3:33])[CH3:32].[Cl-].[NH4+:45]>CN(C=O)C>[Si:35]([O:38][CH:39]1[CH2:42][N:45]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH3:22])=[N:19][CH:18]=4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[N:9][N:10]=[C:6]2[CH:5]([C:4]2[CH:25]=[CH:26][C:27]([F:28])=[C:2]([F:1])[CH:3]=2)[CH2:40]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OC(CCl)CI
Reactant: COc1cc(-c2nnc(Cc3ccc(F)c(F)c3)o2)ccc1-c1cnc(C)o1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3n2CC(O[Si](C)(C)C(C)(C)C)CC3c2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(3,4-difluorobenzyl)-5-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-1,3,4-oxadiazole (2.41 g) in DMF (45 mL) was added sodium hydride (60%, 264 mg) at 0° C., and the mixture was stirred for 10 min. tert-Butyl[2-chloro-1-(iodomethyl)ethoxy]dimethylsilane (2.52 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane). To a mixture of the purified product in DMSO (7.6 mL) was added sodium azide (199 mg), and the mixture was stirred at 100° C. for 10 hr. The reaction mixture was diluted with ethyl acetate/brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). To a mixture of the purified product in THF (46 mL) were added diphenylphosphino-polystyrene (1.99 mmol/g, 4.58 g) and water (4.6 mL), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, the precipitate was filtered off, and the filtrate was evaporated under reduced pressure. Toluene (46 mL) was added to the residue, and the mixture was stirred under heating with reflux for 1 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (415 mg).
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[CH:15]C(CO)=C[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CCCC.[BrH:19].[C:20]1([CH3:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Br:19][CH2:12][CH:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16][CH2:15][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccccc1
Reactant: CCCCCCCCCCc1ccc(CO)cc1
Reactant: Br
Product: CCCCCCC(CBr)CCCc1ccccc1
Temperature: 90 °C

Procedure:
4-Decylphenylmethanol (3.91 g) was dissolved in toluene (40 ml) and thereto was added 48% hydrobromic acid (40 ml). The mixture was refluxed under heating at 90° C. for 6 hours. After cooling, the organic layer was separated and washed with saturated brine and a sodium hydrogencarbonate solution. The mixture was dried over anhydrous sodium sulfate and the solvent was distilled away to give 4.9 g of the oily subject compound.
Reaction SMILES: BrC[C:3]1[C:8]([CH2:9]Br)=[N:7][CH:6]=[CH:5][N:4]=1.[C:11](N)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[CH3:32][N:33](C)C=O>>[C:11]([N:7]1[C:8]2=[CH:9][CH:32]=[N:33][C:3]2=[N:4][CH:5]=[CH:6]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1nccnc1CBr
Reactant: CN(C)C=O
Solvent: O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc3nccc2-3)cc1
Temperature: 25 °C

Procedure:
To a solution of 2,3-dimethylpyrazine (1.33 g, 12.3 mmol) in tetrachloromethane (30 mL) was added N-bromosuccinimide (6.6 g, 37 mmol)) and 2,2′-azobis(2-methylpropionitrile) (0.2 g, 1.2 mmol). After refluxing under nitrogen for 16 h, the mixture was filtered, and washed with tetrachloromethane. The filtrate was concentrated, and the residue was purified on Biotage silica gel cartridge (gradient 2-20% ethyl acetate in hexanes) to yield 2,3-di(bromomethyl)pyrazine. A solution of 2,3-di(bromomethyl)pyrazine (2.0 g, 7.7 mmol) in N,N-dimethylformamide (100 mL) at 0° C. was mixed with a solution of tritylamine (6.0 g, 23.0 mmol) in N,N-dimethylformamide. The resulting mixture was stirred at room temperature for one h, heated at 60° C. for 3 h, and then poured into water and extracted with ethyl acetate (2×200 mL). The organic layers were washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified on Biotage silica gel cartridge (gradient 2-50% ethyl acetate in hexanes) to yield the N-trityl-pyrrolopyrazine. A portion of this product (420 mg, 1.2 mmol) was treated with 4N of hydrochloric acid in methanol for 2 h. After solvent was removed, the residue was purified on Biotage silica gel cartridge (gradient 0-12% methanol containing 1% ammonium hydroxide in dichloromethane) to yield Intermediate 17.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:17])[NH:6][C:7]1[CH:8]=N[C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=1.[S:20]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH:28]=[CH:29][CH:30]=2)=[CH:21]1.[CH:37](N(C(C)C)CC)(C)C.O>CS(C)=O>[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:5]([N:34]2[CH2:35][CH2:36][N:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:22]4[CH:23]=[CH:24][S:20][CH:21]=4)[CH:26]=3)[CH2:32][CH2:33]2)=[O:17])=[CH:8][CH:37]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Reactant: c1cc(-c2ccsc2)cc(N2CCNCC2)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3cccc(-c4ccsc4)c3)CC2)cc1
Yield: 49.7 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl[6-(acetylamino)pyridin-3-yl]carbamate (147 mg, 0.450 mmol), 1-[3-(3-thienyl)phenyl]piperazine (100 mg, 0.409 mmol) and diisopropylethylamine (0.143 ml, 0.818 mmol) in dimethylsulfoxide (1.5 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the titled compound 85.5 mg (51.5%) as solid product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([F:24])[CH:3]=2)[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(F)c2)C1=O
Yield: 53.9 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (235 mg) described in Preparation Example 114 and 1-acetylimidazolidin-2-one (115 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (142 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]([N:6]1[Si:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][Si:7]1([CH3:14])[CH3:13])([CH3:5])[C:3]#[CH:4].[CH2:15]([Li])CCC.[OH2:20]>O1CCCC1>[CH3:5][C:2]([N:6]1[Si:7]([CH3:14])([CH3:13])[CH2:8][CH2:9][Si:10]1([CH3:11])[CH3:12])([CH3:1])[C:3]#[C:4][CH2:15][OH:20]
Reactant: C#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Reactant: O
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CCO)N1[Si](C)(C)CC[Si]1(C)C
Temperature: -20 °C

Procedure:
1-(1,1-Dimethyl-2-propynyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (22.6 g) in dry tetrahydrofuran (250 ml) was cooled to −50° C. under an atmosphere of nitrogen with stirring and a solution of n-butyl lithium (44 ml, 2.5M solution in hexanes) was added dropwise over 10 minutes. The mixture was stirred for 0.5 hour, allowed to warm to −20° C. and formaldehyde gas bubbled through the mixture until no starting material remained, as determined by glc analysis. On completion of the reaction, the mixture was treated with water, the ether phase separated, the aqueous phase extracted with ethyl acetate (twice) and the organic extracts combined and washed with water (three times). The combined organic extract was dried over magnesium sulphate and evaporated under reduced pressure to give 4-methyl-4-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)pent-2-yn-1-ol (24.96 g) as a pale yellow liquid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.[N+:7]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)([O-:9])=[O:8].F[P-](F)(F)(F)(F)F.ClC1N(C)C=C[N+]=1C.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][CH2:3][C:4]([NH:14][C:13]1[CH:15]=[CH:16][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1)=[O:6]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: COCC(=O)O
Agent: Cn1cc[n+](C)c1Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1ccc([N+](=O)[O-])cc1
Yield: 71.4 %

Procedure:
To a mixture solution of 384 μL (5.0 mmol) of methoxyacetic acid and 691 mg (5.0 mmol) of p-nitroaniline in 10 mL of dichloromethane were added 1.53 mg (5.5 mmol) of 2-chloro-1,3-dimethylimidazoliumhexafluorophosphate and 1.53 mL (111.0 mmol) of triethylamine, and the mixture was refluxed for 7 hours. Then, the reaction mixture was extracted with ethyl acetate, the extract was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=2/1) to give 750 mg (71%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][N:14]1[C:18]2=[N:19][CH:20]=[C:21]([CH2:23][NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:22]=[C:17]2[CH:16]=[CH:15]1>>[Cl:8][C:7]1[C:2]([N:24]([CH2:23][C:21]2[CH:22]=[C:17]3[CH:16]=[CH:15][N:14]([CH3:13])[C:18]3=[N:19][CH:20]=2)[S:25]([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)(=[O:26])=[O:27])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2cnc3c(ccn3C)c2)cc1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2cnc3c(ccn3C)c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 37).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[O:9].[C:19]([O:23][C:24]([NH:26][C@@H:27]([CH2:31][CH3:32])[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[Br:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:28](=[O:29])[C@@H:27]([NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:31][CH3:32])[C:3]=1[C:8](=[O:9])[NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1
Reactant: Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Yield: 14 %

Procedure:
The title compound was prepared from 1-amino-3-bromo-N-(3,5-difluorophenyl)-1H-pyrrole-2-carboxamide (1 g, 3.16 mmol) and (S)-2-(tert-butoxycarbonylamino)butanoic acid following the experimental procedure described in Preparation 45a. 0.26 g (14% yield) of the desired compound were obtained.
Reaction SMILES: [C:1](=[O:4])([O-])[OH:2].[Na+].Cl.NO.[C:9]([C:11]1[C:12](=[O:40])[N:13]([CH2:17][C@H:18]2[C@H:24]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[O:23][CH2:22][CH2:21][N:20]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:19]2)[CH:14]=[CH:15][CH:16]=1)#[N:10].C1(C2CCCCCCCCCC=2)CCCCCCCCN[N:42]=1>CS(C)=O.O.C1COCC1>[Cl:32][C:27]1[CH:26]=[C:25]([C@@H:24]2[O:23][CH2:22][CH2:21][N:20]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:19][C@H:18]2[CH2:17][N:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:9]3[NH:42][C:1](=[O:4])[O:2][N:10]=3)[C:12]2=[O:40])[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](Cn2cccc(C#N)c2=O)C1
Reactant: O=C([O-])O
Reactant: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](Cn2cccc(-c3noc(=O)[nH]3)c2=O)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 72.6 %

Procedure:
Sodium hydrogen carbonate (829 mg, 9.87 mmol) and hydroxylamine hydrochloride (686 mg, 9.87 mmol) were added to a solution of tert-butyl (6R,7R)-6-[(3-cyano-2-oxopyridin-1(2H)-yl)methyl]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (590 mg, 1.23 mmol) in DMSO (4 mL), and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was diluted with THF (10 mL), diazabicycloundecene (0.184 mL, 1.23 mmol) and carbonyl-1,1′-bisimidazole (299 mg, 1.85 mmol) were added, and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was acidified with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and recrystallized from ethanol-hexane to give the title compound (480 mg, 0.893 mmol, 72.6%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH3:24][N:25]1[CH:29]=[C:28]([CH:30]([NH2:32])[CH3:31])[CH:27]=[N:26]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][CH:30]([C:28]4[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=4)[CH3:31])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Reactant: CC(N)c1cnn(C)c1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(NC(C)c3cnn(C)c3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 25 °C
Yield: 83 %

Procedure:
4-(4-Chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethylisoxazole (200 mg, 0.599 mmol, for preparation see Intermediate 8) and [1-(1-methyl-1H-pyrazol-4-yl)ethyl]amine (113 mg, 0.9 mmol) were heated in a mixture of DIPEA (0.324 ml, 1.858 mmol) and NMP (15 ml) at 120° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with water (300 ml) and extracted with EtOAc (2×200 ml). The combined organic phase was washed with water (300 ml) and brine (200 ml), dried with sodium sulphate and evaporated. The resulting gum was dissolved in DCM (3 ml) loaded onto a 100 g silica cartridge and eluted with 2M methanolic ammonia/DCM (0-12%). The product-containing fractions were evaporated in vacuo to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)-3-nitroquinolin-4-amine (0.21 g, 0.497 mmol, 83% yield) which was used in the subsequent step without further purification. LCMS (formate) Rt 0.87 min, MH+ 423.
Reaction SMILES: [CH3:1][CH:2]([CH2:6]C)C(=O)C.[C-:8]#[N:9].[K+].C([O:14][CH:15]([CH3:17])[CH3:16])(C)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH:14][C@@:15]([CH3:16])([CH2:17][CH:2]([CH3:6])[CH3:1])[C:8]#[N:9]
Reactant: [C-]#N
Reactant: CCC(C)C(C)=O
Reactant: CC(C)OC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Product: CC(C)C[C@](C)(O)C#N
Temperature: 2.5 °C
Yield: 38 %

Procedure:
500 μl of 3-methyl-2-pentanone (4 mmol) were dissolved in 15 ml of diisopropyl ether with stirring, the mixture was cooled to 0-5° C. and an aqueous solution of 520 mg. of potassium cyanide in 20 ml of 0.5 M citric acid was added. After addition of 2 ml of enzyme solution (1000 IU/ml), the reaction vessel was sealed pressure-tight and the mixture was stirred at 0-5° C. for 5 hours. The mixture was then diluted with 30 ml of diisopropyl ether and the reaction mixture was extracted. After separation of the organic phase, the aqueous phase was extracted a second time by shaking with 30 ml of diisopropyl ether. The aqueous phase was discarded, the combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. After column chromatography, 193 mg of (S)-2-hydroxy-2,4-dimethylpentanenitrile (38%) were obtained.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][OH:29])[O:25][C:24]4=[O:30])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][O:29][S:39]([CH3:38])(=[O:41])=[O:40])[O:25][C:24]4=[O:30])=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CC=C(c2ccc(N3C[C@H](CO)OC3=O)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCN(C(=O)OCc4ccccc4)CC3)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (R)-(-)-3,6-dihydro-4-[4-[5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]phenyl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester (EXAMPLE 17, Step 3, 970 mg) and triethylamine (0.50 mL) in dry methylene chloride (9.5 mL) at 0° C. under N2 is treated with methanesulfonyl chloride (0.20 mL) dropwise. The resulting mixture is stirred at 0° C. for one hour, diluted with methylene chloride (40 mL), washed with water (10 mL), saturated aqueous sodium bicarbonate (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, mp 166-168° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH2:18][NH:19][C:20]4[CH:21]=[CH:22][N:23]=[C:24]5[C:29]=4[N:28]=[CH:27][C:26]([C:30]4(O)[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)=[CH:25]5)=[N:16][N:17]=3)[N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(S(F)(F)[F:50])CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH2:18][NH:19][C:20]4[C:29]5[C:24](=[CH:25][C:26]([C:30]6([F:50])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]6)=[CH:27][N:28]=5)[N:23]=[CH:22][CH:21]=4)=[N:16][N:17]=3)[N:14]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cnc3c(NCc4nnc5ccc(-c6cc(F)cc(F)c6)nn45)ccnc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc(F)cc(-c2ccc3nnc(CNc4ccnc5cc(C6(F)CCNCC6)cnc45)n3n2)c1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of tert-butyl 4-(8-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (30 mg, 51 μmol) in 0.5 mL of DCM was cooled to −78 C. Then added DAST (13 μl, 102 μmol) and let stir to room temperature over 30 min. TFA was then added to the reaction mixture and stirred for 30 min. The solvent was then removed by rotary evaporation and the residue was redissolved in MeOH and free based through a cation exchange column. Purification via MPLC (DCM/MeOH+1% NH4OH) yielded the title compound (15 mg, 60% yield). M/Z=491.2 [M+H], calc 490.18 for C25H21F3N8.