Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].[OH2:24]>CO>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:3]1[C:2](=[O:1])[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[C:5](=[O:24])[C:4]=1[CH3:12]
Reactant: COc1cc(C)c(CCCCCCCCCCO)c(O)c1OC
Reactant: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Reaction time: 2 h
Yield: 96.9 %

Procedure:
In methanol (5.4 l) was dissolved 10-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)decan-1-ol (271 g), to which was added an aqueous solution of disodium nitrosodisulfonate (6.7 l, content 0.359 mol./l) synthesized by means of electrolytic oxidation. The mixture was stirred for two hours while keeping the temperatures at 50°±2° C. After confirmation of disappearance of the starting material by thin-layer chromatography, water (8.6 l) was added to the reaction mixture, followed by extraction twice with toluene (5.5 and 2.7 l). The toluene layers were combined and washed with water. The toluene layer was concentrated under reduced pressure to obtain a crude product, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (288 g, content 94.8%, yield 96.9%). This crude product (20 g) was recrystallized from a mixture of toluene (60 ml) and n-hexane (180 ml). The crystals were dissolved in toluene (60 ml), and the solution was allowed to pass through a precoated layer of activated alumina (30 g). The filtrate was concentrated under reduced pressure, and the concentrate was recrystallized again from a mixture of toluene (55 ml) and n-hexane (165 ml). The crystals were further recrystallized from 50% ethanol (108 ml), followed by drying to obtain 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (16.2 g) as orange-yellow crystals, m.p. 54.0° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][C:3]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.C(Br)(Br)(Br)[Br:18].N1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Br:18])=[CH:4][C:3]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(Br)c(OC2CCCCO2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: BrCc1ccc(Br)c(OC2CCCCO2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
The title compound was prepared adapting the method reported by Wada et al.[Wada, 1979] with the following modifications. To a solution of 4-bromo-3-(tetrahydropyran-2-yloxy)benzyl alcohol (3.0 g, 10.45 mmol), carbon tetrabromide (6.93 g, 20.90 mmol) and anhydrous pyridine (0.85 mL, 10.45 mmol) in anhydrous Et2O (50 mL) at 0° C. was added dropwise a solution of triphenylphosphine (5.48 g, 20.90 mmol) in anhydrous Et2O (10 mL). The mixture was stirred at 0° C. for 1 h and then at room temperature overnight. The solvent was removed in vacuo and the residue suspended in n-hexane and filtered. The filtered solid was washed with n-hexane and the combined filtrates concentrated in vacuo to ca. 10 mL. The residue was purified by flash column chromatography [SiO2, EtOAc/n-hexane (5:95)] to give 4-bromo-3-(tetrahydropyran-2-yloxy)benzyl bromide as a pale yellow oil (2.82 g, 77%) which slowly darkened on exposure to light and air; ¤H (270 MHz, CDCl3) 1.58-2.12 (m, 6H), 3.58-3.65 (m, 1H), 3.83-3.92 (m, 1H), 4.41 (d, J=12.6, 2H), 5.53 (m, 1H), 6.89 (dd, J=7.9, 2.0, 1H), 7.16 (d, J=2.2, 1H), 7.48 (d, J=8.2, 1H); LC-MS (APCI−): tR=4.71 min, m/z 266.95 (48, C12H1481Br2O4—C5H8O—H), 264.93 (100, C12H14Br2O4—C5H8O—H), 262.92 (50, C12H1479Br2O4—C5H8O—H); HPLC: tR=3.91 min (94%)
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[CH:3]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.CNC.[C:35]([S:39](Cl)=[O:40])([F:38])([F:37])[F:36]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[CH:11][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:39]([C:35]([F:38])([F:37])[F:36])=[O:40]
Reactant: N#Cc1cc(N)n(-c2c(F)cc(C(F)(F)F)cc2Cl)n1
Reactant: O=S(Cl)C(F)(F)F
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#Cc1nn(-c2c(F)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Temperature: 40 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
To a solution of 5-amino-1-(2-chloro-6-fluoro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile (140 g, 459.6 mmol, 1.00 eq.) and dimethylamine tosylate (151.8 g, 698.6 mmol, 1.52 eq.) in toluene (840 mL) was added CF3SOCl (89.7 g, 588.3 mmol, 1.28 eq.). After the mixture was stirred at 40° C. for 16 h, nitrogen was bubbled through the solution and the solution was cooled to rt. Then the mixture was poured into 2 L ice/water and stirred at 0° C. for 1 h. The precipitated solid was isolated by filtration and dried under vacuum. The solid was recrystallized with toluene to give 5-amino-1-(2-chloro-6-fluoro-4-(trifluoromethyl)phenyl)-4-(trifluoromethylsulfinyl)-1H-pyrazole-3-carbonitrile (125 g, 64%) as yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[C:13](OC(=O)C)(=[O:15])[CH3:14].O>N1C=CC=CC=1>[C:13]([O:11][C:10]1[C:9]([CH3:12])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[CH3:1])(=[O:15])[CH3:14]
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
To a solution of 3,5-dimethyl-4-hydroxy-benzoic acid (3.0 g, 18.05 mmol) in pyridine (7 mL) was added acetic anhydride (2.05 mL, 21.66 mmol) and the reaction mixture was stirred at room temperature for 16 h. Water was added and the mixture was extracted with ethyl acetate, washed with water, brine and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo to obtain 4-acetoxy-3,5-dimethyl-benzoic acid (3.52 g, 94%). To a solution of 4-acetoxy-3,5-dimethyl-benzoic acid (6.02 g, 28.91 mmol) in CH2Cl2 (80 mL), oxalyl chloride (5.04 mL, 57.83 mmol) was added slowly, followed by a drop of dimethyl formamide. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed and acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester was dried under vacuum (6.37 g, 97%). To a solution of N,N,N,N-tetramethyl guanidine (2.77 mL, 22.078 mmol) in CH3CN (50 mL), a solution of 6,8-dimethoxy-isochroman-1,3-dione (4.46 g, 20.07 mmol) in CH3CN (100 mL) was added slowly at <0° C. (bath temperature −20° C.) in 30 min. Then, Et3N was added in one portion, followed by a solution of acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester (6.37 g, 28.1 mmol) in CH3CN (50 mL) and stirred for 30 min. at <0° C. The reaction mixture was stirred at room temperature for 16 h, then heated to reflux for 3 h. After cooling to room temperature, the reaction mixture was quenched with 1 N HCl. The precipitated solid was filtered off to give a mixture of acetic acid 4-(6,8-dimethoxy-1,3-dioxo-isochroman-4-carbonyl)-2,6-dimethyl-phenyl ester and acetic acid 4-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl)-2,6-dimethyl-phenyl ester (6.0 g).
Reaction SMILES: C[O:2][S:3]([CH2:6][C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][N:8]=1)(=O)=[O:4].C1(C)C=CC=CC=1.C[N:24](C=O)C.C(Cl)(=O)C(Cl)=O>O>[CH:13]1[CH:14]=[CH:15][C:10]2[O:9][N:8]=[C:7]([CH2:6][S:3]([OH:2])(=[O:4])=[NH:24])[C:11]=2[CH:12]=1
Reactant: CN(C)C=O
Reactant: COS(=O)(=O)Cc1noc2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: N=S(=O)(O)Cc1noc2ccccc12
Temperature: 10 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
A 250 ml three necked flask, equipped with mechanical stirrer, Dean-Stark trap and condenser, was charged with 1,2-benzisoxazole-3-methanesulfonic acid methyl ester (10 grams, 0.044 mole, obtained from a commercial vendor) and toluene (100 ml). The suspension was heated to reflux while azeotropic distillation of water was performed, during 2 hours. The mixture was thereafter cooled under nitrogen atmosphere to 10° C. and DMF (0.36 ml, 0.0044 mole, 0.1 molar equivalent) was added to the mixture. Oxalyl chloride (4.1 ml, 0.047 mole, 1.07 molar equivalent) was then added drop-wise at 10-15° C. during 30 minutes and the reaction mixture was heated to 40° C. and was kept at this temperature for 4 hours. Ammonia (gas) (3.0 grams, 4 molar equivalents) was then bubbled into the reaction mixture at 10-18° C. during 2 hours and the reaction mixture was kept at ambient temperature overnight. The obtained precipitate was collected by filtration and slurried in 25% ammonium hydroxide (40 ml) at ambient temperature for 2 hours. The obtained solid was collected by filtration, washed with water and dried under reduced pressure at 50° C., overnight to obtain crude zonisamide (7.4 grams, 80.4% yield) having a purity of 98.7%, as determined by HPLC.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C:12]1[CH:23]=[C:22]([OH:24])[C:21]([I:25])=[CH:20][C:13]=1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].IC.[CH3:28]N1CCCN(C)C1=O>C1COCC1>[Si:3]([O:10][CH2:11][C:12]1[CH:23]=[C:22]([O:24][CH3:28])[C:21]([I:25])=[CH:20][C:13]=1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:5])[CH3:4]
Reactant: CN1CCCN(C)C1=O
Reactant: COC(=O)CCc1cc(I)c(O)cc1CO[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)CCc1cc(I)c(OC)cc1CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h

Procedure:
A suspension of 60% sodium hydride in mineral (1.2 g) in THF (56 ml) is cooled to -20° C. and of solution of methyl 2-tert-butyldimethylsilyloxymethyl-4-hydroxy-5-iodohydrocinnamate (12.6 g), iodomethane (5 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (8 ml) in THF (20 ml) is added. The cold bath is removed, the mixture stirred for about 2 hours, and diluted with ether. The ether solution is washed with 0.1M HCl, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography, eluting with 10% ether in hexanes, to give the desired product.
Reaction SMILES: CO[C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:24][NH:25][C:26]([NH2:28])=[O:27].C[O-].[Mg+2].C[O-].CO>>[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:16][C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([NH:28][C:26]([NH:25][CH3:24])=[O:27])=[O:23])=[CH:12][CH:13]=1
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 13.6 %

Procedure:
A mixture of 2-biphenyl-4-yl-3-cyclopentylpropionic acid methyl ester (987.4 mg, 3.20 mmol) and methyl urea (948.7 mg, 12.80 mmol) was treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 18 mL, 12.80 mmol). The resulting reaction mixture was then heated under reflux for 19 h. The reaction mixture was allowed to cool to 25° C. and then filtered through celite. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 1-(2-biphenyl-4-yl-3-cyclopentyl-propionyl)-3-methyl urea (152.5 mg, 14%) as a white solid: mp 195-197° C.; EI-HRMS m/e calcd for C22H26N2O2 (M+) 350.1994, found 350.2004.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[CH3:1][O:2][C@H:3]([CH3:13])[CH2:4][N:5]([CH3:16])[C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10]
Reactant: CI
Reactant: CO[C@H](C)CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H](C)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [(2R)-2-methoxypropyl]carbamate (2.72 g) in DMF (41 ml) was added NaH (862 mg; 60% oil suspension) under nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. MeI (1.79 ml) was added to the mixture, and the whole was stirred for 3 hours at the same temperature. Water was added, and the whole was extracted with EtOAc and the extract was washed with water and brine and dried over MgSO4. Concentration under reduced pressure gave a residual oil, which was purified with silica gel column eluting with EtOAc:n-hexane=1:5 to give tert-butyl [(2R)-2-methoxypropyl]methylcarbamate (1.94 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:32][CH2:33]SC)[C:13]([NH:15][C@H:16]1[CH2:22][CH2:21][C@@H:20]2[CH2:23][C@H:17]1[C:18](=[O:31])[N:19]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>IC.CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:32][CH2:33][N:15]([C@H:16]2[CH2:22][CH2:21][C@@H:20]3[CH2:23][C@H:17]2[C:18](=[O:31])[N:19]3[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:13]1=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CC[C@@H]2C[C@H]1C(=O)N2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.3 %

Procedure:
Preparation A3, Step 3: (1R,2S,5R)-Tert-butyl 2-((S)-2-(benzyloxycarbonylamino)-4-(methylthio)butanamido)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (5.1 g) was dissolved in iodomethane (40 mL). The resulting solution was stirred at rt for 12 h before being concentrated in vacuo. The residue was dissolved in methylene chloride, and the resulting solution was concentrated; this was repeated to afford the salt. This material was dissolved in DMF (30 mL) and the solution was charged with Cs2CO3 (6.6 g). After 12 h, the reaction was partitioned between EtOAc and brine. The organic phase was dried (MgSO4), filtered, and concentrated. The resulting residue was purified by flash chromatography to afford (1R,2S,5R)-tert-butyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (2.0 g). MS found: (M+H)+=458.6.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH2:16](O)[CH3:17]>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:16][CH3:17])=[O:5]
Reactant: CCO
Reactant: Nc1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccccc1N
Yield: 78 %

Procedure:
To a solution of 2-aminobenzoic acid (7.29 mmol, 1.0 g) in ethanol (20 ml), H2SO4 (45 mmol, 2.5 ml) was added and the mixture was refluxed for 20 hours. The solvent was evaporated and the crude residue was dissolved in water. The solution neutralised with 6N NaOH aqueous solution and extracted with CHCl3. The organic phase was evaporated affording 0.939 g (yield 78%) of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([S:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29].C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:7])=[C:4]([S:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)Sc1cc(Br)ccc1C(=O)O
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)Sc1cc(Br)ccc1C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of 4-bromo-2-(isopropylthio)benzoic acid (47.90 g) in N,N-dimethylformamide (480 ml) was added 1,1′-carbonyldiimidazole (31.00 g) and stirred for 30 minutes at room temperature under nitrogen atmosphere. To the mixture were added methanesulfonamide (18.17 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (39.10 ml) and then stirred at room temperature overnight. The reaction mixture was poured into hydrochloric acid aqueous solution (1N, 2 l) and extracted with ethyl acetate (2 l). The separated organic layer was washed with water (2 l) and brine (2 l), dried over magnesium sulfate and concentrated in vacuo. Then the residue was dried to give 4-bromo-2-(isopropylthio)-N-(methylsulfonyl)benzamide (60.00 g) as a white solid.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([NH:7]N)=[CH:3][CH:2]=1.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[C:14]([CH3:29])([CH2:19][CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13]1>>[CH3:11][N:12]1[CH2:17][C:16]2[C:3]3[CH:2]=[C:1]([CH3:9])[CH:6]=[CH:5][C:4]=3[N:7]3[C:15]=2[C:14]([CH3:29])([CH2:19][CH:20]=[C:21]3[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13]1
Reactant: CN1CCC(=O)C(C)(CCC(=O)c2ccccc2)C1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2c(c1)c1c3n2C(c2ccccc2)=CCC3(C)CN(C)C1

Procedure:
A solution of p-tolylhydrazine.HCl (13 mg, 0.084 mmol) and 1,3-dimethyl-3-(3-oxo-3-phenyl-propyl)-piperidin-4-one (22 mg, 0.084 mmol) in ethanolic-HCl (5 mL) was stirred at 84° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was basified with saturated aqueous NaHCO3 solution. The product was extracted with EtOAc (3×15 mL), organic layer dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to obtain 2,3a,10-trimethyl-6-phenyl-2,3,3a,4-tetrahydro-1H-indolo[3,2,1-ij][1,6]naphthyridine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7](Cl)(=[O:9])=[O:8])[N:4]=[CH:3]1.[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:13][CH2:12]1.ClCCl>C(#N)C>[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][S:7]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)(=[O:9])=[O:8])[CH2:13][CH2:12]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: NCCCN1CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: Cn1cnc(S(=O)(=O)NCCCN2CCOCC2)c1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of 30 g (0.17 mol) of 1-methylimidazole-4-sulfonyl chloride from Example C-1 in 150 ml of acetonitrile is added dropwise to a solution of 24 ml (0.17 mol) of 3-morpholinopropylamine in 50 ml of acetonitrile (or dichloromethane). The temperature of the reaction mixture is kept at room temperature or below by external cooling with ice-water. Stirring is continued for 6 h at room temperature. The precipitate deposited is filtered off with suction and recrystallized from acetonitrile in order to give 46 g (85% of theory) of the title compound (hydrochloride) of melting point 207°-208° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:21](O)[CH3:22]>>[CH2:21]([O:18][C:17](=[O:19])[CH2:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[CH:15]=1)[CH3:22]
Reactant: O=C(O)Cc1ccc2nc(-c3ccccc3)oc2c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1ccc2nc(-c3ccccc3)oc2c1

Procedure:
A solution of 2-phenyl-6-benzoxazolylacetic acid (20 gm) in ethanol (200 ml) was heated under reflux for 6 hr., during which time dry hydrogen chloride gas was passed through the solution. The residual oil on evaporation of the solution was extracted with ether and this solution was evaporated to dryness. The solid formed was recrystallised from toluene/petroleum ether to yield while crystals of ethyl-2-phenyl-6-benzoxazolylacetate, m.p. 76° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1OCC)OCC
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1OCC)OCC

Procedure:
In analogy to the procedure described in example 1 f], [rac]-2-ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester (example 47 c]) was reacted with 4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole (example 2 b]) in N,N-dimethylformamide in the presence of potassium carbonate to yield [rac]-2-ethoxy-3-{2-ethoxy-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 1 g], to yield [rac]-2-ethoxy-3-{2-ethoxy-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic acid as colorless solid, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]2)[CH:9]=1.[I:39]N1C(=O)CCC1=O>C(#N)C>[CH3:34][Si:33]([CH3:36])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:37])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:39])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Solvent: CC#N
Product: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
A 50 mL roundbottom flask was charged ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)-methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (381 mg, 0.68 mmol) and acetonitrile (10 mL). To this solution was added N-Iodosuccinimide (167 mg, 0.74 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude oil was purified via silica gel chromatography (0% to 30% ethyl acetate in hexanes gradient) to yield ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (335 mg, 0.49 mmol, 72% yield) as clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].Cl[Sn]Cl.O.[CH3:15][CH2:16][O:17]C(C)=O>ClCCCl>[C:16]([C:6]1[C:2]([Cl:1])=[C:3]([C:7]([O:9][CH3:10])=[O:8])[NH:4][CH:5]=1)(=[O:17])[CH3:15]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1[nH]ccc1Cl
Agent: Cl[Sn]Cl
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1[nH]cc(C(C)=O)c1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
A solution of methyl 3-chloro-1H-pyrrole-2-carboxylate (0.100 g, 0.627 mmol) in DCE (3 mL) was added to a suspension of SnCl2 (0.238 g, 1.25 mmol) and methyl 3-chloro-1H-pyrrole-2-carboxylate (0.100 g, 0.627 mmol) in DCE (3 mL) at 0° C. The reaction was stirred for 10 min. at 0° C. then warmed to room temp over 2 hours. The reaction mixture was poured into water and EtOAc. The organic layer was separated, washed with 1N sodium hydroxide, dried over MgSO4, filtered and evaporated to a residue. Purification was accomplished on silica with EtOAc and hexanes to afford the title compound (0.034 g, 26%) as a solid, along with methyl 4-acetyl-3-chloro-1H-pyrrole-2-carboxylate (0.047 g, 37%) as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.19 (br. s., 1H), 7.34-7.84 (m, 1H), 3.90 (s, 3H), 2.52 (s, 3 H). LCMS: m/z 200.0 (M−1).