Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[N:3]=1.[CH:24]([O:27][C:28]1[CH:34]=[C:33]([CH:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[C:32]([CH3:42])=[CH:31][C:29]=1[NH2:30])([CH3:26])[CH3:25].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]#[N:10])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[N:3]=[C:2]([NH:30][C:29]2[CH:31]=[C:32]([CH3:42])[C:33]([CH:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[CH:34][C:28]=2[O:27][CH:24]([CH3:26])[CH3:25])[N:7]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc(Cl)c1C#N
Reactant: Cc1cc(N)c(OC(C)C)cc1C1CCN(C)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Cl)c(C#N)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C1CCN(C)CC1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidine-5-carbonitrile (0.5 mmol) and 2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)aniline (0.5 mmol) in 3 mL of isopropanol, was added 4-methylbenzenesulfonic acid (0.5 mmol). The suspension was stirred at 120° C. for 2 hours. Product was obtained after work-up and prep-HPLC. MS (ES+): 597.23 (M+1)+.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[CH3:9][C:10]1[C:14]2[C:15]([CH:19]=[CH2:20])=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][C:11]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([S:36]([NH:39][C@H:40]([C:44]([O:46][CH3:47])=[O:45])[CH:41]([CH3:43])[CH3:42])(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)=[O:22].[OH2:48]>C1COCC1.[Os](=O)(=O)(=O)=O>[OH:48][CH:19]([C:15]1[C:14]2[C:10]([CH3:9])=[C:11]([C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH:35]=[CH:34][C:33]([S:36]([NH:39][C@H:40]([C:44]([O:46][CH3:47])=[O:45])[CH:41]([CH3:43])[CH3:42])(=[O:38])=[O:37])=[CH:32][CH:31]=4)=[CH:28][CH:29]=3)=[O:22])[O:12][C:13]=2[CH:18]=[CH:17][CH:16]=1)[CH2:20][OH:5]
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c12
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(C(O)CO)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a solution of N-methyl morpholine-N-oxide (50% wt solution in water, 0.103 g, 0.44 mmol) in THF and water (1 mL/0.3 mL) was added 0.096 mL (0.38 mmol) of osmium tetroxide (2.5 wt % in t-butanol). To that solution was quickly added 0.21 g (0.38 mmol) of methyl N-[(4′-{[(3-methyl-4-vinyl-1-benzofuran-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valinate (Example 96, Step 2). The reaction was stirred at room temperature for 2 hours and then quenched with excess sodium hydrosulfite in water. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to provide 0.19 g of methyl N-{[4′-({[4-(1,2-dihydroxyethyl)-3-methyl-1-benzofuran-2-yl]carbonyl}amino)-1,1′-biphenyl-4-yl]sulfonyl}-L-valinate. Yield 85.2%. m.p. 90-95° C. MS: 581.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH3:14])[CH:13]=[CH:2][C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccs1
Product: CN(C)C=CC(=O)c1cccs1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A mixture of 2-acetylthiophene (198 mmol) and N,N-dimethylformamide dimethyl acetal (297 mmol) was refluxed overnight and then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure and dried in vacuo to afford 36 g (100% yield) of 3-(dimethylamino)-1-(2-thienyl)prop-2-en-1-one which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([C:12]=2[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.[C:20]([O-:25])(=[O:24])[C:21](C)=[CH2:22].[CH3:26]O>O1CCCC1>[C:20]([CH2:21][CH2:22][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:4]1[CH:1]1[CH2:2][CH2:3]1)([O:25][CH3:26])=[O:24]
Reactant: c1cncc(Cc2c(C3CC3)[nH]c3ccccc23)c1
Reactant: C=C(C)C(=O)[O-]
Reactant: CO
Solvent: C1CCOC1
Product: COC(=O)CCn1c(C2CC2)c(Cc2cccnc2)c2ccccc21

Procedure:
A mixture of 2-cyclopropyl-3-(3-pyridylmethyl)indole (1.98 g), methacrylate (2.06 g) and "Triton B" in methanol (0.5 ml) in tetrahydrofuran (50 ml) was heated under reflux for 4 hours and then evaporated. The residue was dissolved in ethyl acetate and the solution was washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with a mixture of chloroform and petrol (b.p. 40°-60°) (3:1) gave 1-(2-carbomethoxyethyl)-2-cyclopropyl-3-(3-pyridylmethyl)indole as an oil (1.20 g).
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])(=O)=O.[F:22][C:23]1[CH:45]=[CH:44][C:26]([C:27]([C:29]2[C:38](O)=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:34]3)=[O:28])=[CH:25][CH:24]=1.S(=O)(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[C:38]([O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15])=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:34]3)=[O:28])=[CH:44][CH:45]=1
Reactant: CS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(O)ccc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reaction time: 0.5 h
Yield: 108.6 %

Procedure:
Pyridine (0.38 ml, 4.65 mmol) and trifluoromethanesulfonic anhydride (0.39 ml, 2.32 mmol) were added to a solution of 5-(4-fluorobenzoyl)-6-hydroxy-2-methylsulfonylnaphthalene (0.4 g, 1.16 mmol), [prepared as described in Example 2, step 3 above], in methylene chloride (10 ml) at 0° C. After 0.5 h, additional amounts of pyridine (0.38 ml, 4.65 mmol) and trifluoromethanesulfonic anhydride (0.39 ml, 2.32 mmol) were added and stirring was continued. After 0.5 h, 1N sodium bisulfate was added and the stirring was continued for an additional 30 minutes. The organic layer was separated, washed with brine, and dried over sodium sulfate. The solvent was removed in vacuo to give 0.6 g of 5-(4-fluorobenzoyl)-6-trifluoromethylsulfonyloxy-2-methylsulfonylnaphthalene as an oil (90% yield).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:13]([OH:15])=[O:14])=[CH:8]2.Br.[C:17](O)(=O)C>>[OH:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:13]([O:15][CH3:17])=[O:14])=[CH:8]2
Reactant: COc1cccc2cc(C(=O)O)ccc12
Reactant: CC(=O)O
Agent: Br
Product: COC(=O)c1ccc2c(O)cccc2c1

Procedure:
5-Methoxy-2-naphthoic acid (49 7 g; 0 246 mol, J Med Chem 1993, 36, 2485) in glacial acetic acid (450 ml) and in 48% strength aqueous hydrobromic acid solution (450 ml) is heated to reflux for 15 h After cooling, the reaction mixture is concentrated in vacuo and is extracted with dichloromethane after addition to water The organic phase is washed with water, dried over MgSO4 and concentrated in vacuo. The residue is dissolved in MeOH (1.6 l) The solution is saturated with hydrogen chloride (about 1 h), the reaction mixture heating to reflux temperature. The solvent is then stripped off in vacuo, the residue is taken up in ethyl acetate, and the mixture is washed with satd NaCl solution, dried (MgSO4) and concentrated in vacuo. The residue is chromatographed on silica gel using dichloromethane:ethyl acetate (20:1). The product thus obtained is stirred with dichloromethane/petroleum ether, filtered off with suction and dried in vacuo.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1.CS(C)=[O:15]>C(OCC)C>[ClH:1].[ClH:1].[NH2:12][C:9]1[NH:8][C:7](=[CH:6][CH2:5][CH2:4][NH2:3])[C:11](=[O:15])[N:10]=1
Reactant: NCCCc1c[nH]c(N)n1
Reactant: CS(C)=O
Agent: Cl
Solvent: CCOCC
Product: NCCC=C1NC(N)=NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3-amino-propyl)-1H-imidazol-2-ylamine 16 (0.200 g, 0.930 mmol) was dissolved in anhydrous dimethyl sulfoxide (6 mL) Bromine (0.047 mL, 0.930 mmol) was added drop-wise and the solution was stirred at room temperature for 1 h. Diethyl ether (7 mL) was added and the organics were then decanted. The residue was purified by column chromatography (MeOH sat. with NH3) to yield the desired product as its free base. Addition of concentrated hydrochloric acid to a methanol solution (8 mL) of the free base followed by evaporation under reduced pressure afforded the target compound ((Z)-isomer exclusively) (0.141 g, 67%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 12.10 (br s, 1H), 9.20 (br s, 2H), 8.18 (br s, 2H), 5.92 (t, 1H, J=7.8 Hz), 2.96 (m, 2H), 2.66 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 164.13, 156.63, 130.88, 113.70, 37.57, 24.94; HRMS (FAB) calcd for C6H10N4O (MH+) 155.0933, found 155.0943.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([OH:25])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C2C=CC=CC=2C(O)=O)C=CC=CC=1.ClCl.C1(C(Cl)(Cl)[Cl:50])C=CC=CC=1>[Hg]>[C:1]([O:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:17]([Cl:50])(=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClC(Cl)(Cl)c1ccccc1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccccc1
Agent: ClCl
Agent: O=C(O)c1ccccc1-c1ccccc1
Agent: [Hg]
Product: O=C(Cl)c1ccccc1
Product: O=C(OC(=O)c1ccccc1)c1ccccc1
Reaction time: 5 h

Procedure:
1,000 g of a distillate prepared as described above (74.2% of benzyl benzoate, 13.4% of benzoic acid and 10.0% of phenylbenzoic acid) are chlorinated at 160° C. under irradiation with UV light (mercury vapour lamp). After 5 hours, the mixture has increased in weight by approx. 260 g by absorption of chlorine. 330 g of benzotrichloride and 1,1 g of FeCl3 are added dropwise to the mixture at 150° C. to convert benzoic acid which is still present and benzoic acid anhydride which has been formed into benzoyl chloride. After the evolution of hydrogen chloride has ended, the mixture is fractionally distilled in vacuo. 1,265 g of pure benzoyl chloride (yield greater than 92%, relative to benzoic acid, benzyl benzoate, phenylbenzoic acid and benzotrichloride added) are obtained in this distillation. 250 g remain in the distillation residue.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.C([Mg]Cl)(C)C.[Cl:24][CH2:25][C:26](N(OC)C)=[O:27]>CCOCC.C1COCC1>[Cl:24][CH2:25][C:26]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12)=[O:27]
Reactant: CON(C)C(=O)CCl
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(C(=O)CCl)ccnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
To a solution of 4-bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (2.05 g, 0.00626 mol) in THF (10 mL, 0.123 mol) at 0° C. was added dropwise a solution of isopropylmagnesium chloride in ether (2.0 M, 9.4 mL). The mixture was allowed to warm to room temperature and stirred for 4 hours. This mixture was then transferred via cannula to a solution of 2-chloro-N-methoxy-N-methylacetamide (2.84 g, 0.0207 mol) in THF (10 ml). After 30 minutes reaction time, the solution was quenched by the addition of saturated ammonium chloride aqueous solution. The product was extracted with ethyl acetate, the combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (0-20% ethyl acetate/hexanes) to afford 2-chloro-1-(1-[2-(trimethylsilyl)-ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)ethanone (711 mg, 35%). 1H NMR (400 MHz, CDCl3): δ 8.56 (d, 1H), 7.66 (d, 1H), 7.60 (d, 1H), 7.23 (d, 1H), 5.80 (s, 2H), 4.91 (s, 2H), 3.60 (dd, 2H), 0.98 (dd, 2H), 0.01 (s, 9H); MS(ES): 325 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](OB(O)O)=[CH:27][CH:26]=1)[CH3:20].C(N(CC)CC)C>ClCCl>[CH2:19]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:27][CH:26]=1)[CH3:20]
Reactant: CCOCCCc1ccc(OB(O)O)cc1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCCCc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.4 g), 4-(3-ethoxypropyl)phenylboric acid (0.65 g), cupric acetate (0.27 g) and molecular sieves 4A (0.8 g) suspended in dichloromethane (15 ml) was added triethylamine (1.0 ml), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the filtrate was evaporated to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain methyl 7-[4-(3-ethoxypropyl)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.28 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].Cl.[N:11]([O-])=O.[Na+].[CH3:15][C:16]1[CH:17]=[C:18]([OH:23])[CH:19]=[C:20]([CH3:22])[CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CC#N>[OH:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1/[N:1]=[N:11]/[C:21]1[C:20]([CH3:22])=[CH:19][C:18]([OH:23])=[CH:17][C:16]=1[CH3:15]
Reactant: O=N[O-]
Reactant: Nc1ccccc1CO
Reactant: Cc1cc(C)cc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(O)cc(C)c1/N=N/c1ccccc1CO
Temperature: -5 °C
Reaction time: 0.42 h

Procedure:
(2-aminophenyl)methanol (4000 mg, 32.48 mmol) was dissolved in water (25 mL) with concentrated HCl (6 N, 7.00 mL, 42.2 mmol) and the solution was cooled in an ice/NaCl bath to −5° C., afterward sodium nitrite (2420 mg, 39 mmol) in 20 mL of water was added dropwise over 20 minutes. Solids precipitated out. The organic mixture/suspension was stirred at −5° C.->0° C. for 25 minutes. 5 mL CH3CN was added. The solution of 3,5-dimethylphenol (3970 mg, 32.5 mmol) in CH3CN (10 mL) was mixed with a solution of Na2CO3 (13.8 g, 130 mmol) in H2O (20 mL). The mixed solution was added to the above diazonium solution slowly at −5° C.->0° C. The mixture was stirred at −5° C.->0° C. for 2 hours. Brownish solids precipitated out. The mixture was neutralized with conc. HCl (12 N) and diluted with EtOAc. The suspension filtered through celite and washed with EtOAc which was used for extraction. After four extractions, the combine dark brownish organic layers were washed with brine, dried over Na2SO4 and concentrated, leading to dark brownish solids. The crude was dissolved in EtOAc and loaded to the column and purified by ISCO (120 g silica gel, EtOAc/Heptane: 0->45%), leading the desired product as orange solids. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 6H) 4.96 (d, J=5.66 Hz, 2H) 5.14-5.25 (m, 1H) 6.58 (s, 2H) 7.29-7.36 (m, 1H) 7.41-7.50 (m, 2H) 7.65 (d, J=0.78 Hz, 1H) 9.92 (s, 1H). LCMS: m/z=257.3 [M+H].
Reaction SMILES: CN(C)[C:3](=[O:22])[CH:4]([CH2:19][CH:20]=[CH2:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1COCC1.[OH2:29].[I:30]I>C(OCC)(=O)C>[I:30][CH2:21][C@H:20]1[CH2:19][C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:3](=[O:22])[O:29]1
Reactant: C=CCC(CCCCCCCCCCCCCC)C(=O)N(C)C
Reactant: II
Reactant: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCC[C@H]1C[C@H](CI)OC1=O
Reaction time: 72 h

Procedure:
To a solution of 8.25 g (25.5 mmol) of N,N-dimethyl-2-allylhexadecanamide in THF/ H2O (1:3 v/v, 120 mL) 9.69 g (38.2 mmol) of iodine was added at room temperature and the reaction mixture was stirred for 3 days. Then, the mixture was diluted with 200 mL of ethyl acetate, washed twice with 10% sodium thiosulfate and extracted twice with ethyl acetate. The combined organic layers were dried with sodium sulfate and after evaporation of the solvent it was obtained 11.3 g of a solid that was purified by column chromatography (silica gel, hexane: ethyl acetate 7%) to give 6.98 g of the trans isomer, 0.91 g of a mixture of the cis and trans isomers and 0.42 g of the cis isomer (overall yield 87%).
Reaction SMILES: [CH:1]1([C:6]2[C:7]([OH:19])=[CH:8][C:9]([N+:16]([O-:18])=[O:17])=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH3:24]O>ClCCl>[CH:1]1([C:6]2[C:7]([OH:19])=[CH:8][C:9]([N+:16]([O-:18])=[O:17])=[C:10]([CH2:12][C:13]([O:15][CH3:24])=[O:14])[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)Cc1cc(C2CCCC2)c(O)cc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Cc1cc(C2CCCC2)c(O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 2-(5-cyclopentyl-4-hydroxy-2-nitro-phenyl)acetic acid (270 mg, 1.02 mmol) in methanol was added thionyl chloride (149 μL, 2.04 mmol) dropwise at 25° C. The mixture was stirred at room temperature for 1 h. The reaction was diluted with dichloromethane and washed with 50% saturated NaHCO3 (2×50 mL), brine, dried over Na2SO4, and concentrated in vacuo to afford methyl 2-(5-cyclopentyl-4-hydroxy-2-nitro-phenyl)acetate as clear brown oil (180 g, 63% yield). LC/MS m/z 280.0 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16](O)[CH:17]2[CH2:21][O:20][N:19]([CH3:22])[C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])[CH:16]=[C:17]1[CH2:21][O:20][N:19]([CH3:22])[C:18]1=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1OCC(C(O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CN1OCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O

Procedure:
A mixture of 20 g (60 mmol) of 4-[(3,5-di-tert-butyl-4-hydroxyphenyl)hydroxymethyl]-2-methyl-3-isoxazolidinone and 0.4 g of p-toluenesulfonic acid monohydrate in 300 ml of benzene was refluxed for 5 hours. The reaction mixture was concentrated and the concentrate triturated in 150 ml of ether to yield 10 g of the E-isomer of 4-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-methyl-3-isoxazolidinone having a melting point of 194°-196° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:34]=[CH:35][CH:36]=2)[CH2:27][CH2:26]1.Cl>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:12][C:3]1[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=1[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:34]=[CH:35][CH:36]=2)[CH2:27][CH2:26]1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccccc3F)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[5-(2-fluorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.89 (s, br, 1H), 7.72-6.88 (m, 11H), 5.59-5.48 (m, 1H), 3.70-3.48 (br, 2H), 3.05-2.84 (br, 2H), 2.82-2.58 (m, br, 4H), 2.58-2.40 (m, br, 2H), 2.22-1.82 (m, br, 6H), 1.71-1.42 (m, br, 2H), 1.25 (d, 6H, J=6.4 Hz); ESMS m/e: 589.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[C:13]([C:23]([OH:25])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]2[C:34]3([CH2:40][O:41][C:30]=2[CH:29]=1)[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[C:13]([C:23]([N:37]3[CH2:38][CH2:39][C:34]4([C:31]5[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=5[O:41][CH2:40]4)[CH2:35][CH2:36]3)=[O:25])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(Nc3ccc(C)cc3)c(C(=O)O)cnc12
Reactant: Fc1ccc2c(c1)OCC21CCNCC1
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3ccc(C)cc3)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 89.1 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(4-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.060 g, 0.176 mmol) obtained in step 2 and 6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.040 mg, 0.194 mmol), the title compound (0.083 g, 89%) was obtained.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C@H:5](O)[C:6]([O:8][CH3:9])=[O:7].Cl.O1CCOCC1.S(Cl)([Cl:20])=O>N1C=CC=CC=1>[ClH:20].[NH2:2][CH2:3][CH2:4][C@@H:5]([Cl:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)[C@@H](O)CCN
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cl)CCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To methyl (S)-4-amino-2-hydroxybutyrate hydrochloride (170.1 mg; 133.5 mg when calculated as methyl (S)-4-amino-2-hydroxybutyrate) was added 3 ml of 4 N-HCl/dioxane, followed by further addition of 189.1 mg of thionyl chloride. The mixture was stirred at room temperature for 1 hour. Thereafter, 2.5 mg of pyridine was added, and the mixture was further stirred at 50° C. for 6 hours. After confirmation of disappearance of the starting material by TLC, the solvent was distilled off under reduced pressure to give methyl (R)-4-amino-2-chlorobutyrate hydrochloride. To this were added 10 ml of chloroform and 5 ml of a saturated aqueous solution of sodium hydrogen carbonate, and the aqueous layer was further extracted six times with chloroform. The organic layer was dried over sodium sulfate and the solvent was distilled off to give 120.7 mg of (R)-3-chloro-2-pyrrolidinone (yield quantitative, optical purity 93.9% ee) The optical purity was determined by high performance liquid chromatography using a chiral column (Chiralcel OB-H (Daicel)).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([C:16]([O:18][CH3:19])=[O:17])[CH2:4]2)[CH2:2]1.[Li+].[CH3:21]C([N-]C(C)C)C.C1COCC1.CCCCCCC.IC.[NH4+].[Cl-]>C1COCC1>[CH3:21][C:5]1([C:16]([O:18][CH3:19])=[O:17])[N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:7][CH2:8][C:3]2([CH2:2][CH2:1]2)[CH2:4]1
Reactant: COC(=O)C1CC2(CCN1C(=O)OC(C)(C)C)CC2
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CI
Product: COC(=O)C1(C)CC2(CCN1C(=O)OC(C)(C)C)CC2
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
6-tert-butyl 5-methyl 6-azaspiro[2.5]octane-5,6-dicarboxylate (D4) (420 mg, 1.56 mmol) was dissolved in THF (25 ml) and the solution was cooled at −78° C. prior addition of LDA 2M sol in THF/heptane (1.16 ml, 2.34 mmol). The red solution was left stirring at −78° C. for 40 min before adding iodomethane (0.146 ml, 2.34 mmol). The reaction was allowed to warm to RT and left stirring for 3 hrs. The resulting yellow-orange solution was treated with NH4Cl sat. sol. (5 ml) and extracted with Et2O (3×50 ml). Collected organic phases were washed with NaCl sat. sol. and dried over Na2SO4. Collected organics after solvent evaporation, afforded a residue which was purified by Biotage SNAP-Si (25 g) eluting with DCM. Collected fractions after solvent evaporation afforded the title compound (D5) (320 mg)