Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1.Cl[CH2:22][C:23]1[O:27][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:20][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][CH2:22][C:23]2[O:27][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=2)[C:7]=1[C:8]#[C:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: Cc1ncnc(N)c1C#Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CNc2ncnc(C)c2C#Cc2ccc(C(F)(F)F)cc2)o1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
A mixture of 4-amino-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine (2.8 g), ethyl 5-chloromethyl-2-furancarboxylate (1.8 g), potassium carbonate (2.1 g) and N,N-dimethylformamide (120 ml) was heated while stirring at 70° C. for 15 hours. The mixture thus obtained was concentrated under reduced pressure. To the resultant residue, water was added. After extraction was performed with chloroform, an organic phase was dried over anhydrous sodium sulfate and then evaporated. The evaporated residue was purified by column chromatography to obtain a target substance (1 g). The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: C1COCC1.[CH:6]1([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:35])[C:18]([CH2:28][CH2:29][C:30](OCC)=[O:31])=[CH:19][N:20]3[CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][C:14]=2[F:36])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[CH:6]1([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:35])[C:18]([CH2:28][CH2:29][CH2:30][OH:31])=[CH:19][N:20]3[CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][C:14]=2[F:36])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CCOC(=O)CCc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(CCCO)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a 8 ml THF solution of 400 mg of ethyl 3-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]propanoate was added 40 mg of lithium aluminum hydride at 0° C., followed by stirring for 2 hours. Water was added to the reaction mixture, followed by and filtration through celite. After evaporation under a reduced pressure, the resulting residue was purified by silica gel column chromatography to obtain 288 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(3-hydroxypropyl)quinolin-4(1H)-one.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:20][C:21]1[C:22]([CH3:31])=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[C:22]([CH3:31])=[C:23]([S:27]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][C:6]3[CH:16]=[CH:17][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=3)[N:14]=2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-trifluoromethyl-phenoxymethyl)-pyridin-2-ylamine (0.08 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.074 g) as an off-white solid (0.113 g). MS (ESI−): 455.2 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:10][CH:11]([CH2:21][O:22][Si](C(C)(C)C)(C)C)[CH2:12][O:13][Si](C(C)(C)C)(C)C)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.Cl.C(=O)=O.CC(C)=O.N>CCO.CO>[Br:1][C:2]1[N:3]([CH2:10][CH:11]([CH2:21][OH:22])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)Cn1cc([N+](=O)[O-])nc1Br
Agent: Cl
Agent: N
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CO
Solvent: CCO
Product: O=[N+]([O-])c1cn(CC(CO)CO)c(Br)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
A suspension of silyl ether 178 (7.35 g, 14.5 mmol) in a solution of 1% HCl in 95% EtOH (desilylation conditions described by Cunico et al., 1980) (150 mL) was stirred at room temperature for 4 h, and then kept at 4° C. for 12 h. The resulting solution was cooled (CO2/acetone), neutralised by dropwise addition of 7M NH3 in MeOH (9.8 mL) with stirring, and then concentrated to dryness and the residue was chromatographed on silica gel. Elution with 33-75% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 75% EtOAc/petroleum ether and EtOAc gave 2-[(2-bromo-4-nitro-1H-imidazol-1-yl)methyl]-1,3-propanediol (179) (3.42, 85%) as a white solid: mp (MeOH/CH2Cl2/hexane) 110-112° C.; 1H NMR [(CD3)2SO] δ 8.50 (s, 1H), 4.65 (t, J=5.0 Hz, 2H), 4.07 (d, J=7.3 Hz, 2H), 3.41 (m, 4H), 2.06 (m, 1H). Anal. (C7H10BrN3O4) C, H, N.
Reaction SMILES: [F:1][C:2]1([F:24])[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[OH-].[K+]>C(O)(=O)C>[F:24][C:2]1([F:1])[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(F)(F)C(=O)c3ccccc32)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C1c2ccccc2NCCC1(F)F
Temperature: 60 °C

Procedure:
4,4-Difluoro-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (3.00 g) was dissolved in 14 ml of acetic acid, 7 ml of concentrated sulfuric acid was added to the solution and then the resulting mixture was heated at 60° C. for 10 hours. The reaction solution was ice-cooled, adjusted to a basic range with potassium hydroxide and extracted three times with ethyl acetate, and the resulting organic layer was dried over anhydrous potassium carbonate. By evaporating the reaction solvent, 4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one was obtained. This product was used in the following reaction without purification.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH2:58])[S:55][C:45]=2[C:46]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[N:47][CH:48]=1>C1COCC1>[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH:58][C:1](=[O:9])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[S:55][C:45]=2[C:46]([N:49]2[CH2:50][CH2:51][O:52][CH2:53][CH2:54]2)=[N:47][CH:48]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccccc3)nc12

Procedure:
From benzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 371 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](N(OC)C)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([Mg]Cl)[CH2:24][CH2:25][CH3:26]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17](=[O:18])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)CCc1ccc(OCc2ccccc2)cc1
Reactant: CCCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCCC(=O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound was prepared by treating 3-(4-benzyloxy-phenyl)-N-methoxy-N-methyl-propionamide prepared in Example T (8.5 g, 28 mmol) with n-butyl magnesium chloride (21.4 mL, 2.0M, 42.8 mmol) in 100 mL of THF. The reaction mixture was stirred at room temperature for 1 hour and refluxed for 3 hours. The reaction mixture was cooled to 0° C., quenched with 1N HCl, and extracted with EtOAc. After evaporation of the solvents, the crude product was purified by flash silica gel column chromatography, eluting with EtOAc:hexane (5:95, then switching to 3:7). 1H NMR (CDCl3) δ 0.86 (t, 3 H), 1.27 (m, 2 H), 1.34 (m, 2 H), 2.33 (t, 2 H), 2.64 (t, 2 H), 2.78 (t, 2 H), 5.0 (s, 2 H), 6.85 (d, 2 H), 7.06 (d, 2 H), 7.25 (t, 1 H), 7.31-7.42 (m, 4 H).
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)/[CH:3]=1.[F-].[K+].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[Cl:22][C:23]1[N:24]=[CH:25][C:26]([C:2]2[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]3/[C:10](=[O:19])[NH:11][C:12]4[C:17]/3=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)/[CH:3]=2)=[CH:27][CH:28]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Reactant: OB(O)c1ccc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [F-]
Solvent: C1COCCO1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(Cl)nc1
Temperature: 70 °C
Yield: 60 %

Procedure:
To 240 mL of 1,4-dioxane, were added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (3.0 g, 9.3 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (complex with CH2Cl2, 360 mg, 0.49 mmol), 1M KF aqueous solution (37.5 mL, 37.5 mmol). The resulting mixture was heated at 70° C. under Ar and then 2-chloro-5-pyridineboronic acid (1.57 g, 10.0 mmol) was added in several portions. The reaction was heated at 70° C. under Ar for 22 hours. LC-MS indicated that no starting material molecular peak left; the major peak at 2.59 min with MH+=357.0 was assigned to the product, 3-[4-(6-chloro-pyridin-3-yl)-5,5-dimethyl-5H-furan-(2E)-ylidene]-6-fluoro-1.3-dihydro-indol-2-one (yield>60%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[NH:13]2)=[O:11])=[CH:5][CH:4]=1.[CH2:32]=O>C(O)=O>[O:11]=[C:10]1[N:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:13]2[CH2:32][N:9]1[C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:30])[F:31])=[CH:4][CH:5]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)N1
Reactant: C=O
Solvent: O=CO
Product: O=C1N(c2ccc(C(F)(F)F)cc2)CN2C(c3ccc(Cl)cc3)C(c3ccccc3)CN12

Procedure:
To 1.0 g (2.2 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-phenyl-2,3,4,5-tetrahydro-1H-pyrazole-1-carboxamide in 5 ml of formic acid was added 0.57 g of formalin. The mixture was heated at reflux for 30 minutes and then partitioned between dichloromethane and water. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. Filtration, concentration in vacuo, and chromatography on silica gel using diethyl ether and hexanes gave the expected compound, mp 184°-187° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[S:12][C:13]([C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:14][C:15]=1[NH:16]C(=O)C(F)(F)F)=[O:10].O.C(OCC)(=O)C>CO>[CH3:7][O:8][C:9]([C:11]1[S:12][C:13]([C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:14][C:15]=1[NH2:16])=[O:10]
Reactant: COC(=O)c1sc(C(=O)C2CCCC2)cc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)c1sc(C(=O)C2CCCC2)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (2.275 g) was added to a solution of 5-cyclopentanecarbonyl-3-(2,2,2-trifluoroacetylamino)thiophene-2-carboxylic acid methyl ester (1.150 g) in methanol (17 mL), and the mixture was stirred at room temperature for 2 h. Water and ethyl acetate were added. The 5 organic phase was separated off, and the aqueous phase was re-extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. The product with the molecular weight of 253.32 (C12H15NO3S) was obtained in this way; MS (ESI): 254 (M+H+).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[C:11]([O:14][CH3:15])=[CH:10][N:9]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][C:17]=2[F:27])[N:8]=1)=O.[F:29][C:30]([F:35])([F:34])[CH2:31][NH:32][NH2:33].C(O)(C(F)(F)F)=O>C(O)C>[F:27][C:17]1[CH:18]=[C:19]([N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)[CH:20]=[CH:21][C:16]=1[N:9]1[CH:10]=[C:11]([O:14][CH3:15])[C:12](=[O:13])[C:7]([C:5]2[N:32]([CH2:31][C:30]([F:35])([F:34])[F:29])[N:33]=[CH:3][CH:4]=2)=[N:8]1
Reactant: NNCC(F)(F)F
Reactant: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(=O)C=CN(C)C)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(-c2ccnn2CC(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 3-[3-(dimethylamino)prop-2-enoyl]-5-methoxy-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]pyridazin-4(1H)-one (200 mg) in ethanol (2.0 mL) was added dropwise a solution of 2,2,2-trifluoroethylhydrazine (0.0483 mL) and TFA (0.2 mL) in ethanol (2.0 mL), and the mixture was stirred at room temperature for 48 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (170 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([NH2:19])([CH3:18])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=2)[NH:8][CH:7]=1.[OH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.FC(F)(F)C(O)=O.CO>ClCCl>[CH3:1][O:2][C:3]([C:4]1([CH3:18])[CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=3)[NH:8][C:7]=2[CH:25]([C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([OH:21])[CH:23]=2)[NH:19]1)=[O:20]
Reactant: O=Cc1cccc(O)c1
Reactant: CCOc1ccc2[nH]cc(CC(C)(N)C(=O)OC)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCOc1ccc2[nH]c3c(c2c1)CC(C)(C(=O)OC)NC3c1cccc(O)c1
Reaction time: 6 h
Yield: 92 %

Procedure:
A mixture of (+/−)-2-amino-3-(5-ethoxy-1H-indol-3-yl)-2-methyl-propionic acid methyl ester (829 mg, 3 mmol), 3-hydroxybenzaldehyde (439 mg, 3.6 mmol) and trifluoroacetic acid (223 μl, 3 mmol) in dry dichloromethane (40 ml) is stirred for 6 h under argon. Methanol (2 ml) is added to dissolve the precipitated product and the mixture is diluted with dichloromethane (150 ml). It is washed with saturated aqueous NaHCO3 (2×50 ml) and water (2×50 ml), is dried, and the solvent is removed under reduced pressure. The residue is purified by column chromatography (dichloromethane-ethyl acetate, 7:1→4:1) to provide (1RS,3SR)-1-(3-hydroxy-phenyl)-6-ethoxy-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester (1.05 g, 93%). M.p. 173-175° C. (from ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:47])[NH:24][C@H:25]([C@H:33]([N:36](C)[C:37](OCC[Si](C)(C)C)=O)[CH2:34][CH3:35])[CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>>[OH:57][C:51]([C:53]([F:56])([F:55])[F:54])=[O:52].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:47])[NH:24][C@H:25]([C@H:33]([NH:36][CH3:37])[CH2:34][CH3:35])[CH2:26][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H]([C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cccc(Cl)c2)C1)N(C)C(=O)OCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](NC)[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cccc(Cl)c2)C1
Reaction time: 0.5 h

Procedure:
Methyl 2-((R)-(3-chlorophenyl)((R)-1-((2S,3R)-1-cyclohexyl-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)pentan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate (17 mg) was dissolved in DCM/TFA (4/1 mL) and stirred for 30 min. After concentrated, the slurry was purified through preparative HPLC to afford methyl 2-((R)-(3-chlorophenyl)((R)-1-((2S,3R)-1-cyclohexyl-3-(methylamino)pentan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate TFA salt (11.9 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26][C:27]([F:30])([F:28])[F:29])=[CH:22][CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: FC(F)(F)Sc1ccc(CBr)cc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(SC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available (4-(bromomethyl)phenyl)(trifluoromethyl)sulfane. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.83 min.; [M+H]+: 426.20 g/mol.
Reaction SMILES: BrC1C=CC2[C:6](C3C=CC(O)=CC=3)=[N:7]OC=2C=1.BrCCCCCCBr.[Br:26][C:27]1[CH:49]=[CH:48][C:30]2[C:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]Br)=[CH:36][CH:35]=3)=[N:32][O:33][C:29]=2[CH:28]=1.C(NC)C=C>>[Br:26][C:27]1[CH:49]=[CH:48][C:30]2[C:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:7][CH3:6])=[CH:36][CH:35]=3)=[N:32][O:33][C:29]=2[CH:28]=1
Reactant: Oc1ccc(-c2noc3cc(Br)ccc23)cc1
Reactant: BrCCCCCCOc1ccc(-c2noc3cc(Br)ccc23)cc1
Agent: BrCCCCCCBr
Agent: C=CCNC
Product: CNCCCCCCOc1ccc(-c2noc3cc(Br)ccc23)cc1

Procedure:
Analogously to Example 1, from 4-(6-bromo-benzo[d]isoxazol3-yl)-phenol and 1,6-dibromohexane via 6-bromo-3-[4-(6-bromo-hexyloxy)-phenyl]-benzo[d]isoxazole and by reaction with N-allyl-methyl-amine there is obtained allyl-[6-[4-(6-bromo-benzo[d]-isoxazol-3-yl)-phenoxy]-hexyl-methyl-amine which is converted into the fumarate, MS: m/e 442 (M+H+, 1 Br).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.B.C1COCC1>O1CCCC1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:20][OH:21])[CH2:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
(R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-tert-butoxy-4-oxobutanoic acid (8.2 g) in tetrahydrofuran (2 mL) was treated with BH3-THF (39.9 mL) overnight. The reaction mixture was quenched with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography, eluting with 30% ethyl acetate in petroleum ether, to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=[O:11])[S:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH:19]=[CH2:20]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:20][CH:19]=[CH2:18])[C:9](=[O:11])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: C=CCI
Reactant: O=c1[nH]c2cc(F)cnc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)sc2ncc(F)cc21
Temperature: 100 °C
Yield: 70.6 %

Procedure:
6-Fluoro[1,3]thiazolo[5,4-b]pyridin-2(1H)-one (0.045 g, 0.31 mmol) was dissolved in DMF (3 ml) and treated with potassium carbonate (0.043 g, 0.31 mmol) and allyl iodide (0.03 ml, 0.33 mmol) then heated at 100° C. for 18 hrs. The solvent was then removed in-vacuo and the residue partitioned between water and ethyl acetate. The organic layer was washed with saturated brine, separated and dried. Chromatography on silica gel eluting with a gradient of 10-50% ethyl acetate/40-60 petroleum ether gave the title compound (0.046 g, 83%) as an oil.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17](CC3C=CC=CC=3)[CH:16]=[N:15][C:14]=2[N:13]([CH3:28])[C:11]1=[O:12])(=[O:3])[CH3:2].[H][H]>[Pd].C(O)(=O)C>[C:1]([O:4][C@H:5]([CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][CH:16]=[N:15][C:14]=2[N:13]([CH3:28])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]cnc2n(C)c1=O
Yield: 95.5 %

Procedure:
A mixture of (R)-1-(5-acetoxyhexyl)-7-benzyl-3-methylxanthine (13.0 g, 32.6 mmol) and 10% palladium on carbon (50% water, 3.6 g) in glacial acetic acid (160 ml) was treated with hydrogen gas (50 psi) on a Parr shaker for 16 hours. After filtering through a pad of celite, the filtrate was concentrated under reduced pressure to provide (R)-1-(5-acetoxyhexyl)-3-methylxanthine (9.6 g, 96% yield) as a white colored solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH:11]([F:13])[F:12].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C>[N:14]([C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH:11]([F:13])[F:12])=[N+:15]=[N-:16]
Reactant: FC(F)Oc1c(Br)cc(Br)nc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(Br)nc(Cl)c1OC(F)F
Temperature: 65 °C
Yield: 48.4 %

Procedure:
4,6-Dibromo-2-chloro-3-(difluoromethoxy)pyridine (780 mg, 2.312 mmol) was dissolved in DMF (5 mL), and sodium azide (180 mg, 2.77 mmol) was added. The reaction mixture was heated at 65° C. for 2 h and the progress of the reaction was checked by liquid chromatography-mass spectrometry (LC-MS). The reaction appeared to be mostly complete. The product was partitioned between Et2O and H2O. The aqueous phase was then extracted twice more with Et2O. The organic extracts were combined, diluted with petroleum ether, washed twice with H2O, dried, and concentrated. The product was purified by column chromatography (SiO2, EtOAc/hexane gradient) to yield 4-azido-6-bromo-2-chloro-3-(difluoromethoxy)-pyridine (0.335 g, 48.4%): 1H NMR (300 MHz, CDCl3) δ 7.26 (s, 1H), 6.59 (t, J=73.6, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH2:13][C@@H:14]2[CH2:19][N:18]([CH3:20])[C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[O:15]2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:28])=O>CN(C)C=O.COCCOC>[CH3:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH2:13][C@@H:14]2[CH2:19][N:18]([CH3:20])[C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[O:15]2)[CH:8]=[CH:7][C:3]=1[C:4]([Cl:28])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(OC[C@@H]2CN(C)c3ccccc3O2)ccc(C(=O)O)c1C
Solvent: COCCOC
Solvent: CN(C)C=O
Product: Cc1c(OC[C@@H]2CN(C)c3ccccc3O2)ccc(C(=O)Cl)c1C
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Under argon atmosphere, the compound (400 mg) prepared in Example 9 was dissolved to 1,2-dimethoxyethane (6.0 mL). Anhydrous N,N-dimethylformamide (one drop) and oxalyl chloride (0.22 mL) were added to the reaction mixture, which was stirred for 30 minutes at 40° C. The title compound was obtained by concentrating the reaction mixture.