Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([OH:17])=[CH:10][CH:9]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[N:20]=1.Cl>CS(C)=O.O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([F:18])[N:20]=2)=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14]
Reactant: Fc1cccc(F)n1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cc(Br)ccc1Oc1cccc(F)n1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of cesium carbonate (3.20 mL, 40.0 mmol), 5-bromosalicylic acid (4.34 g, 20.00 mmol) and 2,6-difluoropyridine (5.52 g, 48.0 mmol) in 8 mL of DMSO was stirred at 110° C. for 3 h. After cooling to rt, the reaction mixture was dissolved in water and the pH was adjusted to ˜3 with 1 N HCl. The reaction mixture was extracted with EtOAC (3×25 mL), washed with brine and evaporated to dryness to give crude 5-bromo-2-(6-fluoropyridin-2-yloxy)benzoic acid which was used directly in the next step.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[C:12]([CH3:14])[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]=1[CH3:15])=[C:2]=[S:3].[CH2:16]([NH2:19])[CH2:17][NH2:18]>C1(C)C=CC=CC=1>[NH2:18][CH2:17][CH2:16][NH:19][C:2](=[S:3])[NH:1][C:4]1[CH:13]=[C:12]([CH3:14])[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]=1[CH3:15]
Reactant: Cc1cc(N=C=S)c(C)c2c1OCCO2
Reactant: NCCN
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=S)NCCN)c(C)c2c1OCCO2
Reaction time: 0.08 h

Procedure:
A solution of 2.0 g of 6-isothiocyanato-5,8-dimethyl-1,4-benzodioxane in 40 mL of toluene at 25° C. is added to a solution of 2.42 mL of ethylenediamine in 75 mL of toluene. After five minutes, the mixture is concentrated under reduced pressure to 20 mL at which point a solid precipitates from solution. This solid is collected and dried under vacuum to give 2.6 g of 6-[N'-(2-aminoethyl)thioureido]-5,8-dimethyl-1,4-benzodioxane as a white solid.
Reaction SMILES: [CH2:1](O)[CH2:2][CH3:3].CC1C=CC=C(C)N=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:28]([O:35][NH2:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:28]([O:35][NH:36][CH2:1][CH2:2][CH3:3])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCO
Reactant: NOCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCCNOCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a solution of propan-1-ol (6.25 mL, 83.2 mmol) and 2,6-dimethylpyridine (11.6 mL, 99.8 mmol) in CH2Cl2 (500 mL) under a nitrogen atmosphere at −78° C. was added dropwise trifluoromethanesulfonic anhydride (14.0 mL, 83.2 mmol). After stirring for 30 min at −78° C., a solution of O-benzylhydroxylamine (10.7 ml, 91.5 mmol) in CH2Cl2 (10 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 1 h, then warmed to room temperature, and stirred for additional 2 h. The reaction mixture was diluted with ice water (250 mL) and the organic layer was separated, washed with saturated aq. NaHCO3 (100 mL) and brine (100 mL) The aqueous layers were extracted again with EtOAc (1×200 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (CH2Cl2). To the fraction containing product and 2,6-dimethylpyridine was added 2 M aq KOH (100 mL), that was then washed with MTBE. The aqueous layer was then brought to a pH of ˜5 with 1 M aq HCl and then extracted with MTBE (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford 11.2 g (75%) of O-benzyl-N-propylhydroxylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1)=[O:22]
Reactant: CN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Product: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4Cl)cc23)CC1
Yield: 19.8 %

Procedure:
Beginning with 2.0 gm (8.8 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 1.9 gm (9.7 mMol) 2-chloro-4-fluorobenzoyl chloride, 0.67 gm (19.8%) of the title compound were recovered as a light yellow solid.
Reaction SMILES: O=[C:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH:3]1[C:12]([O:14]CC)=O.C(=O)(O)O.[NH2:21][C:22]([NH2:24])=[NH:23]>C(O)(C)(C)C>[NH2:24][C:22]1[N:21]=[C:12]([OH:14])[C:3]2[CH2:4][N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][C:2]=2[N:23]=1
Reactant: CCOC(=O)C1CN(C(=O)OCC)CC1=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(C)(C)O
Product: CCOC(=O)N1Cc2nc(N)nc(O)c2C1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A suspension of intermediate (f) (14.05 g) and guanidine carbonate (g) (16.6 g, 91.9 mmol) was refluxed in t-butanol (147 mL) for about 6 h. The mixture was allowed to cool to ambient temperature for about 2 h. The volatile components were removed under vacuum and water was added. The pH was adjusted to about 6-7 using KHSO4. The resulting slurry was filtered to collect the solids which were washed with water followed by EtOAc. The solids were dried under vacuum to afford intermediate (h) as cream solids (11.9 g, 53.1 mmol) in 87% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 11.01 (s, 1H), 6.97 (s, 0.5H, possible tautomer), 6.70 (s, 2H), 4.25 (s, 4H), 4.13-4.03 (m, 2H), 1.22 (t, 3H). LCMS (M+H)+: 225.2.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[C:8](=[O:25])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=O.[NH3:26].CO>C1COCC1>[OH:24][C:21]([CH3:23])([CH3:22])[C:20]#[C:19][C:16]1[CH:17]=[CH:18][C:11]2[O:10][CH2:9][C:8](=[O:25])[C:7]3[S:6][C:5]([C:3]([NH2:26])=[O:2])=[N:14][C:13]=3[C:12]=2[CH:15]=1
Reactant: COC(=O)c1nc2c(s1)C(=O)COc1ccc(C#CC(C)(C)O)cc1-2
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(=O)CO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 9-(3-Hydroxy-3-methyl-but-1-ynyl)-4-oxo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (81 mg, 0.23 mmol) in THF (4 mL) at room temperature, NH3/CH3OH (self-made, 4 mL) was added. The mixture was stirred at room temperature for 3 h, then concentrated to give 9-(3-Hydroxy-3-methyl-but-1-ynyl)-4-oxo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as a yellow oil, which was used in the next step without any further purification (crude, 80 mg). 1H NMR (400 MHz, DMSO-d6): δ 830 (s, 1H), 8.43 (d, J=2.1 Hz, 1H), 8.18 (s, 1H), 7.50 (dd, J1=8.4 Hz, J2=2.2 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 5.48 (s, 1H), 4.87 (s, 2H), 1.47 (s, 6H); LC-MS (ESI & APCI): 343.2 (M+1).
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:6][NH:5][CH2:4]1.[F:7][C:8]([F:57])([F:56])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][C:41]=5[CH3:50])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=3)[C@H:20]2[CH3:55])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.C(N(CC)CC)C>C1COCC1>[F:17][C:15]([F:16])([F:18])[C:13]1[CH:12]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][C:41]=5[CH3:50])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28]([N:5]4[CH2:6][CH:3]([F:2])[CH2:4]4)[N:27]=3)[C@H:20]2[CH3:55])[CH:10]=[C:9]([C:8]([F:7])([F:57])[F:56])[CH:14]=1
Reactant: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(S(C)(=O)=O)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reactant: FC1CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
3-Fluoroazetidine hydrochloride (159 mg, 1.422 mmol), methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (INTERMEDIATE 46, 350 mg, 0.474 mmol), THF (2.4 mL) and triethylamine (330 μl, 2.369 mmol) were stirred at 100° C. for 10 minutes in the microwave reactor. Once complete, the reaction was partitioned between water and ethyl acetate. The organic was then washed with brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by silica gel chromatography, eluting with 25-100% ethyl acetate/hexanes to give the title compound. 1H NMR (CDCl3, 500 MHz): δ 8.21 (d, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.92 (d, 1H), 7.88 (s, 1H), 7.73 (s, 2H), 7.47 (d, 1H), 7.31 (d, 1H), 5.68 (d, 1H), 5.51 (m, 0.5H), 5.40 (m, 0.5H), 4.72 (d, 1H), 4.47 (m, 3H), 4.30 (m, 2H), 4.00 (d, s, 4H), 3.93 (s, 3H), 2.37 (s, 3H), 0.74 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:23]([CH3:28])([CH3:27])[C:24]([NH2:26])=O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:23]([CH3:28])([CH3:27])[CH2:24][NH2:26])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C(N)=O)C1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CN)C1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCOCC1
Reaction time: 18 h

Procedure:
(h)(i) 2-(4-(1-(4-Fluorophenyl)-1H-indazol-5-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropanamide (23 mg, 0.06 mmol) in 3 mL THF was treated with LiAlH4 (0.2 mL of 1.0 M solution in THF) and stirred for 18 h. The reaction was quenched with EtOAc, TFA was added, and the reaction was purified by HPLC to give 2-(4-(1-(4-fluorophenyl)-1H-indazol-5-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropan-1-amine. (M+H)+=368. This material was coupled to 3,3,3-trifluoropropionic acid using General Coupling Method A. After 16 h, the reaction was purified by HPLC to give 6 mg of 3,3,3-trifluoro-N-(2-(4-(1-(4-fluorophenyl)-1H-indazol-5-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropyl)propanamide. (M+H)+=478.
Reaction SMILES: [Li+].[BH4-].[CH3:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[C:14]([C:16](OCC)=[O:17])[N:15]=[C:5]12>C1COCC1.C(Cl)Cl.O=[Mn]=O>[CH3:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[C:14]([CH:16]=[O:17])[N:15]=[C:5]12
Reactant: CCOC(=O)c1cn2c3ccccc3n(C)c2n1
Agent: O=[Mn]=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1c2ccccc2n2cc(C=O)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To stirred solution of LiBH4 (1.79 g, 82 mmol) in THF at 0° C., ethyl 9-methyl-9H-imidazo[1,2-a]benzimidazole-2-carboxylate (2.5 g, 10.3 mmol) was added drop wise. The reaction mixture was refluxed for 2 hrs and cooled to room temperature. Ti was carefully quenched with icve cold water and acidified with Con. HCl to pH 4. The reaction mixture was stirred at room temperature for 1 hr and basified with K2CO3. The residue was extracted with chloroform;methanol (3:1) and dried over anhydrous MgSO4. It was filtered and concentrated. Yield. 1.3 g (65%). (M+H) 202. The resdue (1.3 g, 6.4 mmol) was oxidised with MnO2 (5.0 g) in CH2Cl2 under refluxing condition. After the completion, reaction mixture was filtered and concentrated. It was purified by SiO2 column chromatography by eluting it with 1:1 ethyl acetate:hexane. Brown solid. Yield. 330 mg (25%); (M+H) 200.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.B>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:13])[CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CC(CC(=O)O)c1ccc(Br)cc1
Agent: B
Solvent: C1CCOC1
Product: CC(CCO)c1ccc(Br)cc1
Yield: 84.2 %

Procedure:
To the solution of 3-(4-bromophenyl)butanoic acid (1 g, 4.1 mmol) in tetrahydrofuran (100 ml) was added borane in tetrahydrofuran (8 ml, 1 mol/L), the solution was stirred at reflux for 2 hours, then the solution was concentrated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give 3-(4-bromophenyl)butan-1-ol (791 mg, 84.6%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[Li]CCCC.[C:18]1([C:24](=[N:31][C:32]2[CH:33]=[N:34][CH:35]=[C:36]([CH:39]=2)[CH:37]=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.CCCCCC>[Cl:1][C:2]1[C:3]2[C:10]([CH:37]([C:36]3[CH:35]=[N:34][CH:33]=[C:32]([N:31]=[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:39]=3)[OH:38])=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cn1cc(I)c2c(Cl)ncnc21
Reactant: O=Cc1cncc(N=C(c2ccccc2)c2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1cc(C(O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2c(Cl)ncnc21
Reaction time: 0.83 h
Yield: 48 %

Procedure:
To stirred solution of 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 226, 6.6 g, 22.7 mmol) in THF (130 mL) was added n-BuLi (18.2 mL of a 2.5M solution in hexane, 45 mmol) at −75° C. under N2, and the mixture was stirred for 50 min. A solution of 5-((diphenylmethylene)amino)nicotinaldehyde (Preparation 106, 6.5 g, 22.7 mmol) in dry THF (50 mL) was added and the mixture was stirred at −70° C. for 80 min. The mixture was quenched with sat. aq. NH4Cl solution and extracted with EtOAc (300 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound as a brown solid in 48% yield, 5.2 g.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].CN(C)C=O.[H-].[Na+].I[CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21]>C(OCC)(=O)C>[CH:20]([O:19][CH2:18][CH2:17][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)([CH3:22])[CH3:21]
Reactant: CC(C)OCCI
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OCCn1ccc([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
In a round bottom flask was placed 3-nitro-1H-pyrazole (prepared in example 3, 315 mg, 2.79 mmol) and dry N,N-dimethylformamide (5 mL). This solution was then treated with sodium hydride (95%, 80 mg, 3.35 mmol) and gas evolution occurred. It was then stirred another 15 min at 25° C. 2-(2-Iodo-ethoxy)-propane (896 mg, 4.18 mmol) was then added to the reaction mixture and the reaction was stirred at 25° C. for 6 h. The reaction was then diluted with ethyl acetate (10 mL) and washed with water (2×10 mL). The aqueous layers were then combined and extracted with ethyl acetate (2×10 mL). The organic layers were combined and washed with a saturated aqueous brine solution (10 mL) and then dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 25% ethyl acetate/hexanes to 35% ethyl acetate/hexanes) afforded 1-(2-isopropoxy-ethyl)-3-nitro-1H-pyrazole (428 mg, 77%) as a light yellow oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][CH:19]1[O:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[OH:21][CH:19]([CH2:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH3:9])[CH2:20][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: O=C1CCNCC1
Reactant: COc1ccccc1OCC1CO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1ccccc1OCC(O)CN1CCC(=O)CC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
The starting material can be prepared as follows: A mixture of 20 g of the hydrate of 4-piperidone-hydrochloride, 46.8 g of 1-(2-methoxyphenyloxy)-2,3-epoxy-propane, 18 g of potassium carbonate and 250 ml of isopropanol is stirred for 6 hours at a reaction temperature of 60° C. After cooling, the suspension is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in 100 ml of 6 N hydrochloric acid and washed with four 75 ml portions of ethyl acetate. The aqueous acid solution is adjusted with a 2 N sodium carbonate solution to a pH of 10 and extracted with three 75 ml portions of ethyl acetate. The organic extracts are dried over sodium sulphate and concentrated under reduced pressure. The red residue is dissolved in methanol and the solution is boiled for 30 minutes with the addition of activated charcoal. The solution is filtered and the filtrate is concentrated under reduced pressure. The residue is treated with toluene and recrystallised from a mixture of ethyl acetate and petroleum ether to give 1-[2-hydroxy-(2-methoxyphenyloxy)-propyl]-piperidin-4-one with a melting point of 77°-78° C.
Reaction SMILES: COC1C=CC(C[N:10]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([S:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:19]=2)[S:11]([N:14]2[CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][O:24][C:22]1[N:21]=[C:20]([S:26][CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:19]=[C:18]([NH:10][S:11]([N:14]2[CH2:17][CH2:16][CH2:15]2)(=[O:12])=[O:13])[CH:23]=1
Reactant: COc1ccc(CN(c2cc(OC)nc(SCCc3ccccc3)n2)S(=O)(=O)N2CCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)N2CCC2)nc(SCCc2ccccc2)n1

Procedure:
A solution of N-[(4-methoxyphenyl)methyl]-N-[6-methoxy-2-[(2-phenylethyl)thio]pyrimidin-4-yl]azetidine-1-sulfonamide (the product of step iii, 0.17 g) in DCM (1 ml) and TFA (2 ml) was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure. The residue was recrystallised from EtOAc and iso-hexane to give the title product as a white solid. Yield: 50 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:17])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16])[C:5]([NH2:7])=[O:6].CO[C:20](OC)([N:22](C)C)[CH3:21].Cl.NO>>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][N:22]=[C:20]([CH3:21])[N:7]=2)[CH:8]=[C:9]([CH3:17])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16]
Reactant: C#CCCCOc1c(C)cc(C(N)=O)cc1C
Reactant: COC(C)(OC)N(C)C
Agent: Cl
Agent: NO
Product: C#CCCCOc1c(C)cc(-c2nc(C)no2)cc1C

Procedure:
5-[3,5-Dimethyl-4-(3-ethynylpropoxy)phenyl]-3-methyl-1,2,4-oxadiazole [XIV; Y=(CH2)3, R1 and R2 =3,5-(CH3)2, R8 =CH3 ] was prepared from 4.7 g 3,5-dimethyl-4-(3-ethynylpropoxy)benzamide, 31 ml dimethylacetamide dimethyl acetal and 1.7 g hydroxylamine hydrochloride according to the procedure of Example 2, part (b), and was obtained (4.4 g) in the form of a viscous oil used directly in the next reaction. A sample when crystallized from isopropyl acetate/hexane had the m.p. 38°-40° C.
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.O[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]=[C:17]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH:16]=1.[O:39]1[CH2:43][CH2:42][NH:41][C:40]1=[O:44].[H-].[Na+]>C(Cl)Cl>[O:44]=[C:40]1[N:41]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[N:18]=[C:17]([O:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:30][CH2:31]3)[CH:16]=2)[CH2:42][CH2:43][O:39]1
Reactant: O=C1NCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(CO)cc(C(F)(F)F)n2)CC1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(CN3CCOC3=O)cc(C(F)(F)F)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (220 μL, 1.6 mmol) and then methanesulfonyl chloride (82 μL, 1.1 mmol) were added to a solution of tert-butyl 4-{[4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (0.20 g, 0.53 mmol, from Step 2) in methylene chloride (2 mL) at 0° C. After stirring at this temperature for 30 minutes, the reaction mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude mesylate intermediate was dissolved in N,N-dimethylformamide (2.0 mL), and oxazolidin-2-one (230 mg, 2.6 mmol) was added. The mixture was cooled to 0° C. and sodium hydride (53 mg, 1.3 mmol, 60% in mineral oil) was added. The reaction was warmed to room temperature and stirred for 40 minutes, then was quenched with water, and extracted with EtOAc. The organic extract was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-70% EtOAc in hexanes afforded product (95 mg, 40%). 1H NMR (400 MHz, CDCl3) δ 7.14 (s, 1H), 6.79 (s, 1H), 5.27 (tt, J=7.7, 4.1 Hz, 1H), 4.44 (s, 2H), 4.44-4.38 (m, 2H), 3.80-3.68 (m, 2H), 3.58-3.47 (m, 2H), 3.31 (ddd, J=13.6, 8.5, 3.6 Hz, 2H), 1.99 (ddt, J=13.2, 6.3, 3.0 Hz, 2H), 1.78-1.67 (m, 2H), 1.47 (s, 9H); 19F NMR (376 MHz, CDCl3) 5-68.89 (s); LCMS (M+Na)+: 468.0.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]/[C:4]([O:6]CC)=O.[H-].[Na+].[F:15][C:16]1([F:34])[O:21][C:20]2[CH:22]=[C:23]([F:29])[C:24]([N:26]=[C:27]=[O:28])=[CH:25][C:19]=2[N:18]([CH2:30][C:31]#[CH:32])[C:17]1=[O:33]>CN(C=O)C.C1(C)C=CC=CC=1>[F:12][C:9]([F:10])([F:11])[C:2]1[NH:1][C:27](=[O:28])[N:26]([C:24]2[C:23]([F:29])=[CH:22][C:20]3[O:21][C:16]([F:15])([F:34])[C:17](=[O:33])[N:18]([CH2:30][C:31]#[CH:32])[C:19]=3[CH:25]=2)[C:4](=[O:6])[CH:3]=1
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N=C=O)cc21
Reactant: CCOC(=O)/C=C(/N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (E)-ethyl 3-amino-4,4,4-trifluorobut-2-enoate (4.24 g, 23.2 mmol) was added dropwise at 5° C. under N2 to a stirred solution of sodium hydride (1.01 g of a 55% suspension in mineral oil, 23.2 mmol) in dry DMF. The light yellow suspension was stirred for 1 hour, while allowing the reaction mixture to warm to room temperature. After that period, a solution of 2,2,7-trifluoro-6-isocyanato-4-(prop-2-ynyl)-2Hbenzo[b][1,4]oxazin-3(4H)-one (6.54 g, 23.2 mmol) in toluene was added dropwise, after which the mixture was heated at 80° C. overnight under nitrogen. As LC/MS indicated that the reaction was not fully complete, heating was continued for a further 3 hours at 100° C., after which the light brown solution was concentrated in vacuo. The dark residue was partitioned between ethyl acetate and aqueous ammonium chloride solution, and the aqueous phase was extracted with additional ethyl acetate. The combined organic fractions were washed with brine and dried over Na2SO4. Filtration and evaporation of the solvent gave 10.68 g crude brown oil. This was purified by column chromatography (EtOAc:heptane, 20-60%) to give three fractions in which the desired product was the major component (present as a mixture of keto and enol tautomers). These three fractions were combined and further purified by column chromatography, eluting with di-isopropyl ether, to give the product (3.0 g) as an off-white fluffy solid (94% purity according to NMR, with ca. 20% existing as the enol tautomer).