Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:12])[C:6]([F:7])=[C:5]([F:8])[C:4]([F:9])=[C:3]([NH2:10])[C:2]=1[F:11].[ClH:13].Cl.[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][CH:31]([CH2:33][NH:34]C(C3C=CC=CC=3)C)[O:30][C:29]2=[O:43])[CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.FC1C=C(N2C[C@H](CN[C@H](C3C=CC=CC=3)C)OC2=O)C=CC=1N1CCOCC1>>[C:1]1([NH2:12])[C:6]([F:7])=[C:5]([F:8])[C:4]([F:9])=[C:3]([NH2:10])[C:2]=1[F:11].[ClH:13].[ClH:13].[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][C@H:31]([CH2:33][NH2:34])[O:30][C:29]2=[O:43])[CH:19]=[CH:20][C:21]=1[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: CC(NCC1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1)c1ccccc1
Agent: C[C@H](NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1)c1ccccc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1

Procedure:
The procedure is the same as in Example 41 except that the dihydrochloride of 3-(3-fluoro-4-morpholinylphenyl)-5-[(1-phenylethyl)aminomethyl]-1,3-oxazolidin-2-one (4a) was replaced by 3-(3-fluoro-4-morpholinylphenyl)-5(S)—[[(S)-1-phenylethyl]aminomethyl]-1,3-oxazolidin-2-one ((S,S)-4b). A white solid of dihydrochloride of 3-(3-fluoro-4-morpholinylphenyl)-5(S)-aminomethyl-1,3-oxazolidin-2-one ((S)-5b) with a melting point >220° C. was obtained and at a yield of 96%; [∝]D20=−53.2° (c 0.1, H2O); 1H NMR (D2O, 400 MHz) δ: 7.48 (d, J=14.0 Hz, 1H, ArH), 7.28 (brs, 2H, ArH), 5.16-5.10 (m, IH, CH), 4.40-4.36 (m, 1H, CH2), 3.97-3.93 (m, 5H, (CH2)2O and CH2), 3.54-3.49 (m, 2H, CH2), 3.17 (brs, 4H, (CH2)2N), NH2 (hidden); TOF-MS (+Q) m/z: 296.15 (Calculated value: 296.14).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>ClCCl>[CH3:17][CH:16]([CH3:18])[C:15]([C:11]1[CH:12]=[CH:13][C:14]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1)=[O:19]
Reactant: c1ccc2c(c1)CCCC2
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)C(=O)c1ccc2c(c1)CCCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Aluminium chloride (28.0 g, 0.21 mole) was suspended in 200 ml of anhydrous dichloromethane (200 ml) and cooled to 0° C. A solution of 1,2,3,4-tetrahydronaphthalene (26.5 g, 0.2 mole) and isobutyryl chloride (21.3 g, 0.20 mole) in 50 ml of anhydrous dichloromethane was slowly added to this suspension. After the addition was completed, the reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was poured onto 300 g of ice water, and the organic layer was separated. The organic layer was successively washed twice with a 5 wt % aqueous hydrochloric acid solution (150 ml) and once with a 2 wt % aqueous sodium bicarbonate solution (150 ml). After drying over anhydrous magnesium sulfate the solution was concentrated under reduced pressure. The yield of 2-methyl-1-(5,6,7,8-tetrahydro-2-naphthalenyl)-1-propanone was 39.7 g or 98%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=2[OH:17])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26]>C(#N)C>[CH2:25]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[C:8]=2[OH:17])[CH2:3][CH2:2]1)[CH3:26]
Reactant: CCI
Reactant: Oc1c(C2CCNCC2)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(c2cccc(C(F)(F)F)c2O)CC1

Procedure:
Preparation according to Example 1: 2-piperidin-4-yl-6-(trifluoromethyl)phenol (0.01 g, 0.04 mmol), acetonitrile (2 ml), potassium carbonate (0.01 g) and iodoethane (0.01 ml). MS m/z (relative intensity, 70 eV) 273 (M+, 37), 259 (15), 258 (bp), 238 (18), 195 (19).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[O:21]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[CH3:8][C:6]1[CH:7]=[C:2]([O:34][C:31]2[CH:30]=[CH:29][C:28]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:33][CH:32]=2)[CH:3]=[C:4]([CH3:12])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1c(C)cc(Cl)cc1C
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(=O)c1c(C)cc(Oc2ccc(Oc3ccccc3)cc2)cc1C
Temperature: 100 °C
Yield: 84.5 %

Procedure:
To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (26-1, 5.00 g, 27.4 mmol), K3PO4 (11.6 g, 54.6 mmol), and 4-phenoxyphenol (6.12 g, 32.9 mmol) in toluene (39.1 mL) was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (349 mg, 0.82 mmol) and Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100° C. for 4.0 h under N2. The solution was cooled to room temperature and filtered through a small pad of diatomaceous earth. The cake was washed with ethyl acetate (50 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc:hexanes=1:10 as eluant) to give 1-(2,6-dimethyl-4-(4-phenoxyphenoxy)phenyl)ethanone (26-2, 7.70 g) as white solids in 85% yield: 1H NMR (500 MHz, CDCl3) δ 7.34-7.37 (m, 2 H), 7.10-7.13 (m, 1 H), 6.99-7.04 (m, 6 H), 6.65 (s, 2 H), 2.49 (s, 3 H), 2.24 (s, 6 H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:17][C:16]2[NH:15][N:14]=[C:13]([CH3:18])[C:12]=2[C:11](=[O:19])[CH2:10]1.[I-].[Li+].N1C(C)=CC(C)=CC=1C>>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:17][C:16]2[NH:15][N:14]=[C:13]([CH3:18])[C:12]=2[C:11](=[O:19])[CH2:10]1
Reactant: COc1ccccc1C1CC(=O)c2c(C)n[nH]c2C1
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: Cc1n[nH]c2c1C(=O)CC(c1ccccc1O)C2
Yield: 18.9 %

Procedure:
A mixture of 6-(2-methoxyphenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.28 g), lithium iodide (0.44 g) and collidine (0.79 g) was refluxed for 5 hours. Under reduced pressure, collidine was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give, the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from acetone-hexane to give colorless crystals of 6-(2-hydroxyphenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.05 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20](O)=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.CCOC(C)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2C(=O)O)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2CO)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 9.4 %

Procedure:
4-(2-Carboxyphenyl)piperidine-1-carboxylic acid t-butyl ester (5.0 g, 160 mmol, 1.0 eq.) and THF (100 mL, 1.0 mol) were combined at room temperature under nitrogen. 1.0M Borane-THF complex in THF (32.7 mL, 32.7 mmol, 2.0 eq.) was added dropwise over 10 minutes (5° C. exotherm, gas evolution). The mixture was stirred at room temperature for 5 minutes, then heated at 50° C. for 1 hour. The mixture was cooled to room temperature, and the reaction was quenched slowly with MeOH (30 mL) (mild exotherm, significant gas evolution), then concentrated by rotary evaporation. The material was azeotroped with MeOH (2×50 mL). The crude product was dissolved in EtOAc (100 mL, 1 mol), washed with NaHCO3 (50 mL), then saturated aqueous NaCl (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield 4-(2-hydroxymethylphenyl)piperidine-1-carboxylic acid t-butyl ester (4.4 g) as a clear, light yellow oil that solidified upon sitting.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH2:7][CH2:6]2.[C:17](=O)(O)[O-].[Na+].IC.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH3:16])[C:13]([O:15][CH3:17])=[O:14])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CC[C@H]2[C@H](C)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)[C@@H](C)[C@@H]1CCc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 83.9 %

Procedure:
A suspension of (2S)-2-[(1S)-5-methoxy-2,3-dihydro-1H-inden-1-yl]propanoic acid (Example 10) (6.45 g, 0.029 mol), sodium bicarbonate (7.380 g, 0.088 mol), and iodomethane (5.5 mL, 0.088 mol) in DMF (60 mL) was stirred at rt for a period of 17 h. The completion of the reaction was achieved by addition of an additional amount of iodomethane (0.93 mL, 0.015 mol) and stirring for another 3 h at rt. The reaction mixture was poured into water (200 mL) and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with NaOH (1 N aqueous solution), water and brine, dried (Na2SO4), filtered, and concentrated to dryness under vacuum to give 5.70 g (84%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 6.96 (d, 1H), 6.77 (d, 1H), 6.67 (dd, 1H), 3.70 (s, 3H), 3.63 (s, 3H), 3.38 (q, 1H), 2.78 (m, 3H), 2.08 (m, 1H), 1.78 (m, 1H); LC-MS RT=3.10 min; (M+H)+ 234.9.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17](SC)[NH:16][CH:15]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([NH:1][CH:2]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]1)[NH:16][CH:15]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)N1
Reactant: NC1CCc2ccccc21
Product: Clc1ccc2c(c1)C(c1ccccc1)NC(NC1CCc3ccccc31)=N2

Procedure:
The title compound (MS: m/e=374.1 [M+H+]) was prepared in analogy to example 1 (b) from (+/−)-1-aminoindan and 6-chloro-2-methylsulfanyl-4-phenyl-3,4-dihydro-quinazoline. 6-Chloro-2-methylsulfanyl-4-phenyl-3,4-dihydro-quinazoline can be prepared by the method of Richter, P.; Oertel, F. Pharmazie 1990, 45(10), 721-724.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[C:8]([O:11][CH:12]=[CH:13][CH2:14][CH2:15][CH3:16])(=[O:10])[CH3:9].C([O-])(O)=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[C:8]([O:11][C@@H:12]1[NH:5][C:6](=[O:7])[C@H:13]1[CH2:14][CH2:15][CH3:16])(=[O:10])[CH3:9]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCCC=COC(C)=O
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCC[C@@H]1C(=O)N[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 120 h
Yield: 3.4 %

Procedure:
Eight hundred microliters of chlorosulfonyl isocyanate was added to a solution of 1.28 g (10 mM) pent-1-enyl acetate in 5 ml methylene chloride at 0° under nitrogen. After stirring at 0° 5 days, the reaction mixture was added dropwise to a mixture of 5 g ice, 1.15 ml water, 2.82 g NaHCO3 and 1.0 g Na2SO3 and stirred at 0° for 30 minutes. The mixture was extracted with 2×25 ml methylene choride and the combined organic phases washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel in hexane/ethyl acetate to yield 60 mg trans 4-acetoxy-3-n-propylazetidin-2-one (3.4%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.[Br:12][C:13]1[C:18]([CH2:19]Cl)=[CH:17][CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:12][C:13]1[C:18]([CH2:19][O:1][C:2]2[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: ClCc1cccnc1Br
Reactant: COc1cc(C=O)c(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)c(OCc2cccnc2Br)cn1
Temperature: 50 °C
Yield: 85 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (306 mg, 2 mmol, 1 eq.), 2-bromo-3-(chloromethyl)pyridine (crude above, 2 mmol), and K2CO3 (828 mg, 6 mmol, 3 eq.) in DMF (1.0 mL) was heated at 50° C. for 2 h. The mixture was cooled and added to water (50 mL) dropwise. The precipitate was filtered, washed with water, dried under high vacuo to give 5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (350 mg, 85%) as an yellow solid. 1H NMR (400 MHz; CDCl3) δ=10.51 (s, 1H), 8.42 (dd, 1H), 8.09 (s, 1H) 7.91 (d, 1H), 7.40 (dd, 1H), 7.15 (s, 1H), 5.27 (s, 2H), 3.95 (s, 3H). LRMS (M+H+) m/z 323.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26]([O-])=[O:27])=[CH:24][N:23]=1.ClC1C=C[C:35]([NH:38]C(=O)C2C=CC(C(F)(F)F)=NC=2C)=CC=1C1C=CC(C(O)=O)=CN=1.Cl.CN>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26](=[O:27])[NH:38][CH3:35])=[CH:24][N:23]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(C(=O)[O-])cn2)c1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(C(=O)O)cn2)c1
Agent: CN
Agent: Cl
Product: CNC(=O)c1ccc(-c2cc(NC(=O)c3ccc(C(F)(F)F)nc3C)ccc2Cl)nc1

Procedure:
120 mg of 6-(2-chloro-5-(2-methyl-6-(trifluoromethyl)nicotinamido)phenyl)nicotinate was hydrolyzed via Procedure M. 112 mg of 6-(2-chloro-5-(2-methyl-6-(trifluoromethyl)nicotinamido)phenyl)nicotinic acid was coupled to Methylamine Hydrochloride via Procedure G and purified by reverse phase HPLC to give pure N-(4-chloro-3-(5-(methylcarbamoyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide. MS (Q1) 449 (M)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[CH2:13][C@@H:12]2[CH2:14][O:15][C:16]2[C:21]([CH2:22][OH:23])=[CH:20][N:19]=[C:18]([CH3:24])[N:17]=2)=[N:9][CH:10]=1.Cl[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[CH2:13][C@@H:12]2[CH2:14][O:15][C:16]2[C:21]([CH2:22][O:23][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:20][N:19]=[C:18]([CH3:24])[N:17]=2)=[N:9][CH:10]=1
Reactant: Clc1ccccn1
Reactant: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2CO)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2COc2ccccn2)nc1
Temperature: 100 °C

Procedure:
NaH (4 mg, 0.10 mmol, 60% disp.) was added in one portion to a stirring solution of (4-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-2-methylpyrimidin-5-yl)methanol (15 mg, 0.05 mmol) and 2-chloropyridine (11.3 mg, 0.1 mmol) in THF (0.33 mL) in a small pressure vessel. The vessel was sealed and then heated to 100° C. for 2 h. The reaction mixture was cooled to room temperature and then quenched by addition of 2 drops of saturated aqueous NaHCO3. The reaction mixture was diluted with EtOAc (5 mL) and washed sequentially with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organics were dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-95% acetonitrile in water with 0.1% TFA modifier) to afford the title compound as a white solid. 1H NMR (500 MHz, DMSO): δ 8.44 (s, 1 H), 8.13-8.16 (m, 2H), 7.57 (td, J=7.2, 2.0 Hz, 1 H), 7.07 (dd, J=8.5, 2.9 Hz, 1 H), 7.02 (d, J=8.6 Hz, 1 H), 6.88 (dd, J=6.4, 5.4 Hz, 1 H), 6.77 (d, J=8.3 Hz, 1 H), 5.34 (s, 2H), 4.10-4.49 (m, 2 H), 3.82 (s, 3 H), 2.52 (s, 3 H), 2.06 (dt, J=8.3, 4.9 Hz, 1 H), 1.80-1.85 (m, 1 H), 1.26 (dt, J=8.6, 5.1 Hz, 1 H), 1.03 (dt, J=8.6, 4.9 Hz, 1 H); LRMS m/z (M+H) 379.4 found, 379.2 required.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH:15]1[CH2:30][NH:29][CH2:28][CH2:27][C:16]21[O:20][N:19]=[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:17]2.Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:29]2[CH2:28][CH2:27][C:16]3([O:20][N:19]=[C:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:17]3)[CH:15]([CH3:14])[CH2:30]2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: CC1CNCCC12CC(c1ccccc1)=NO2
Agent: Cl
Solvent: C1CCOC1
Product: CC1CN(C(=O)Nc2ccc(C(C)(C)C)cc2)CCC12CC(c1ccccc1)=NO2
Reaction time: 2 h

Procedure:
4-Tert-butylphenyl isocyanate [260 mg, 1.48 mmol, dissolved in abs. THF (1 ml)] was added to a solution of compound U (320 mg crude product, approx. 1.39 mmol) in abs. THF (20 ml) under argon at RT within 10 min. The mixture was stirred for two hours and then mixed with 2N HCl solution (10 ml). The acidic reaction mixture was stirred for 10 min and then extracted with EtOAc (3×20 ml). The combined organic phases were washed with sat. NaHCO3 solution (10 ml), dried over Na2SO4 and concentrated to dryness under vacuum. The residue obtained was purified by flash chromatography (mobile solvent:cyclohexane/EtOAc=7:3). 6-Methyl-3-phenyl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylic acid-(4-tert-butylphenyl)amide was thus obtained as a diastereoisomer mixture (melting point from 65° C.) in a yield of 170 mg (30%).
Reaction SMILES: [CH2:1]([C:3]1([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]([C:34]#[C:35][CH2:36][OH:37])[C:18]4[S:22][C:21]([N:23]5[CH2:28][N:27]([CH3:29])[CH2:26][N:25]([CH2:30][CH3:31])[C:24]5=[O:32])=[N:20][C:19]=4[CH:33]=3)=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52]>C(Cl)Cl.O>[CH2:1]([C:3]1([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:4][CH2:5][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]([C:34]#[C:35][CH2:36][O:37][S:51]([CH3:50])(=[O:53])=[O:52])[C:18]4[S:22][C:21]([N:23]5[CH2:28][N:27]([CH3:29])[CH2:26][N:25]([CH2:30][CH3:31])[C:24]5=[O:32])=[N:20][C:19]=4[CH:33]=3)=[CH:11][N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(C#CCO)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(C#CCOS(C)(=O)=O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Ethyl 4-ethyl-1-[5-[2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-7-(3-hydroxyprop-1-ynyl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]piperidine-4-carboxylate (325 mg, 0.55 mmol) was dissolved in anhydrous DCM (32 mL) under argon and the solution cooled to 0° C. Triethylamine (0.19 mL, 1.40 mmol) was added followed by methanesulfonyl chloride (0.064 mL, 0.82 mmol) and the mixture allowed to warm to rt and stirred for 45 minutes. The mixture was diluted with water, extracted into DCM (3×20 mL) and the combined organic layer washed with brine, dried over Na2SO4 and concentrated to dryness under reduced pressure. The desired compound was obtained as a yellow oil which was used without further purification in the next step. MS: 670.09 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[C:14]1([CH3:24])[C:15]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=1>ClCCl>[C:14]1([CH3:24])[C:15]([S:20]([O:1][CH2:2][C:3]([O:5][CH3:6])=[O:4])(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COS(=O)(=O)c1ccccc1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
18 g (0.2 mol) of methyl hydroxyacetate and 20.2 g (0.2 mol) of triethylamine are first introduced into 300 ml of dichloromethane at 0° C. 41.9 g (0.22 mol) of toluenesulfonyl chloride are then added at this temperature in small portions. Stirring of the batch at 0° C. is continued overnight. Ice water is added, the phases are separated, and the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed once with water, dried, and the solvent is removed on a rotary evaporator. 48 g (98% of theory) of methyl toluenesulfonyloxyacetate having a GC content of 96% are isolated as a colorless solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][CH:9]([O:17][CH3:18])[CH2:10][CH2:11][CH2:12][C:13](OC)=[O:14].CCCCCC.C(OCC)(=O)C>O1CCCC1>[CH3:7][O:8][CH:9]([O:17][CH3:18])[CH2:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: COC(=O)CCCC(OC)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(CCCCO)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
To a suspension of LAH (0.4 g, 11 mmol) in tetrahydrofuran (20 ml) was added dropwise at 0° C. methyl 5,5-dimethoxyvalerate (3.5 g, 20 mmol) dissolved in tetrahydrofuran (30 ml), which was then stirred for 2 hours. After the reaction was completed, the mixture was poured into ice-water (50 ml) and then extracted with ether. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate-2:1) to give 5,5-dimethoxypentanol (1.02 g, yield 34%). Methanesulfonylchloride (3.2 g, 28 mmol) and triethylamine (3.0 g, 30 mmol) dissolved in dichloromethane (50 ml) were added thereto, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was poured into water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product (2.36 g). While, 4,4,5,5,5-pentafluoropentyl thioacetate (5.7 g, 24 mmol) prepared in Step 1 was dissolved in methanol (10 ml), sodium methoxide (23 mg, 23 mmol, 11.0 mol/l) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. To this solution was added dropwise the crude product prepared above (0.90 g) dissolved in tetrahydrofuran (10 ml), which was then stirred at room temperature for 5 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=20:1) to give 5,5-dimethoxy-1-(4,4,5,5,5-pentafluoropentylthio)pentane (460 mg).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].C1COCC1.[CH2:14]([CH:16]([C:19]1[C:20]2[N:21]([C:26](I)=[C:27]([CH3:29])[N:28]=2)[N:22]=[C:23]([CH3:25])[CH:24]=1)[CH2:17][CH3:18])[CH3:15]>CCOC(C)=O.[Zn].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]>[CH2:14]([CH:16]([C:19]1[C:20]2[N:21]([C:26]([C:2]3[S:3][CH:4]=[CH:5][C:6]=3[C:7]#[N:8])=[C:27]([CH3:29])[N:28]=2)[N:22]=[C:23]([CH3:25])[CH:24]=1)[CH2:17][CH3:18])[CH3:15]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: N#Cc1ccsc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sccc3C#N)c(C)nc12
Temperature: 25 °C
Yield: 42.5 %

Procedure:
To a solution 0.05 g/mL of Reike® Zn (31 mL, 23.93 mmol) is added 2-bromo-thiophene-3-carbonitrile (Fournari, P. et al. Bull. Soc. Chim. Fr., 1967, 4115) (2.25 g, 11.96 mmol) and THF (5 mL). The solution is heated at a reflux for 2 hours, cooled to ambient temperature and the excess Zn allowed to settle. The solution is transferred via a cannula into a flask of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (2.5 g, 7.98 mmol) and PdCl2(dppf) (0.29 g, 0.040 mmol). The mixture is heated at 65° C. overnight, diluted with EtOAc (75 mL), washed with sat. NH4Cl (2×75 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (10%-20% EtOAc/hexane gradient) furnish the title compound (1.10 g, 3.39 mmol, 42%). 1H NMR (CDCl3) δ 0.86 (t, J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 2.55 (s, 3H), 2.61 (s, 3H), 3.25-3.34 (m, 1H), 6.75 (s, 1H), 7.35 (d, J=5.2 Hz, 1H), 7.53 (d, J=5.2 Hz, 1H). LC/MS (m/z): calcd. for C18H20N4S (M+H)+: 325.5; found: 325.2.