Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[CH2:9]>CO>[CH3:12][O:11][C:7](=[O:10])[CH2:8][CH2:9][NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCNC1CCCC1
Yield: 64.8 %

Procedure:
A mixture of 59.605 g (0.70 mole) cyclopentylamine (Aldrich), 72.299 g (0.84 mole) of methyl acrylate (Aldrich) and 250 mL of methanol was heated at reflux under an argon atmosphere for 14 hours, then ca 200 mL of solvent was distilled out at atmospheric pressure. The residue was distilled under vacuum (12 mm Hg, bp 112-114 degrees) to give 77.616 g (64%) of 3-cyclopentylamino-propanoic acid methyl ester.
Reaction SMILES: [C:1]1([S:7]([CH2:9][Br:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[C:13]=1[CH3:20].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[H+].[B-:37]([F:41])([F:40])([F:39])[F:38]>C(OCC)C>[F:38][B-:37]([F:41])([F:40])[F:39].[Br:10][CH2:9][S+:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:17]1[CH:16]=[C:15]([CH3:18])[C:14]([CH3:19])=[C:13]([CH3:20])[C:12]=1[CH3:11]
Reactant: Cc1ccc(C)c(C)c1C
Reactant: O=S(CBr)c1ccccc1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: Cc1cc([S+](CBr)c2ccccc2)c(C)c(C)c1C
Reaction time: 3 h

Procedure:
Bromomethyl phenyl sulfoxide (1 g, 4.58 mmol) of example 32 was dissolved in dry diethyl ether (30 mL) under an argon atmosphere. 1,2,3,4-tetramethylbenzene (0.678 g, 1.09 eq) was added to the previous solution and then the mixture was cooled to a temperature below −60° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (0.77 mL, 1 eq) was added slowly, maintaining the same temperature. The mixture was stirred until the reaction was complete. After 3 hours at −60° C., HBF4 in diethyl ether was added (54%, 1.11 mL, 1.75 eq). The resulting suspension was stirred for 30 minutes. The precipitated tetrafluoroborate salt formed was isolated by filtration and dried under vacuum. 1.24 g (62%) of the desired product was obtained as a white solid. mp: 140-142° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[OH-].[Na+].S(OC)(O[CH3:17])(=O)=O>C(O)C.O>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:17])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(C)=O)cc1

Procedure:
In 200 ml of ethanol was dissolved 30.0 g of 4-hydroxyacetophenone, and a solution of 11.3 g (1.28 eq.) of sodium hydroxide in 60 ml of water and 33.9 g (1.22 eq.) of dimethyl sulfate were added dropwise consecutively. After the reaction mixture was refluxed for 30 minutes', a solution of 2.8 g (0.32 eq.) of sodium hydroxide dissolved in 10 ml of water was added, followed by heating under for 3 hours' reflux. After the solvent was distilled off, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried. Then, the solvent was distilled off. The resulting crystals were collected by filtration with hexane.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[C:32]1([S:42]([NH2:45])(=[O:44])=[O:43])[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([NH2:41])(=[O:40])=[O:39])[CH:33]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:45][S:42]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([NH2:41])(=[O:40])=[O:39])[CH:33]=3)(=[O:44])=[O:43])=[O:31])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1cccc(S(N)(=O)=O)c1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3cccc(S(N)(=O)=O)c3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 1,3-benzenedisulfonamide: 1H-NMR (CDCl3) δ 8.47 (1H, s), 8.05-7.95 (2H, m), 7.52-7.09 (10H, m), 6.27 (1H, br.s), 3.37-3.28 (2H, m), 2.75-2.64 (2H, m), 2.17 (3H, s), 2.13 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:14][C:15]#[CH:16])[C:8](=[O:13])[CH:9]([S:11][CH3:12])[CH3:10])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.[OH:23]O>>[Cl:1][C:2]1[C:6]([N:7]([CH2:14][C:15]#[CH:16])[C:8](=[O:13])[CH:9]([S:11]([CH3:12])=[O:23])[CH3:10])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: C#CCN(C(=O)C(C)SC)c1cn(-c2cccnc2)nc1Cl
Reactant: OO
Product: C#CCN(C(=O)C(C)S(C)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-(methylthio)-N-(prop-2-yn-1-yl)propanamide (0.1 g, 0.30 mmol) in hexafluoroisoproanol (2.0 ml) was added hydrogen peroxide (35 wt %, 0.08 ml, 0.90 mmol) and the reaction mixture was stirred vigorously at ambient temperature. The reaction was complete after 1 h. The reaction was quenched with saturated sodium sulfite solution and the organic layer was extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified using silica gel chromatography (0-20% methanol (MeOH)/DCM) to afford the title compound as an off-white foam (82 mg, 0.21 mmol, 78%): 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.65 (d, J=4.6 Hz, 1H), 8.23 (s, 1H), 8.11-7.97 (m, 1H), 7.51-7.41 (m, 1H), 4.88 (br s, 1H), 4.14 (br s, 1H), 2.64 (s, 1.2H), 2.55 (s, 1.8H), 2.33-2.27 (m, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.42 (br s, 1H); 13C NMR (101 MHz, CDCl3) δ 168.11, 148.95, 148.78, 140.45, 140.33, 140.20, 135.56, 126.54, 124.10, 121.68, 121.58, 121.48, 77.69, 73.49, 38.60; ESIMS m/z 351 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[S:20])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C.O>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([C:10]2[S:20][C:7]3[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[N:9]=2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: COc1ccc(NC(=S)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Temperature: 90 °C
Yield: 28.8 %

Procedure:
N-(4-Methoxyphenyl)-4-nitrobenzothioamide (39, 6.0 g, 20.81 mmol) was drenched in ethanol (1 mL) and 30% NaOH aqueous solution (6.66 g, 166.48 mmol) was added. The resulting reaction mixture was diluted with water (60 mL) and K3Fe(CN)6 (18.0 g, 41.62 mmol) dissolved in water (50 mL) was slowly added at 90° C. After heating the reaction mixture for 1 hour at 90° C. and cooling to room temperature, the produced precipitate was filtered and washed with water. After dissolving the remaining precipitate in ethyl acetate and removing drying over sodium sulfate, column chromatography yielded the target compound 2-(4-nitrophenyl)-6-methoxybenzothiazole (41, 1.718 g, 30%) as a yellow solid.
Reaction SMILES: C(N(CC)C(C1C=CC2N(C3CC4N(C)C(CC4)C3)C3C(OC=2C=1)=CC=CC=3)=O)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32].[CH2:38]([N:40]([CH2:75][CH3:76])[C:41]([C:43]1[CH:44]=[CH:45][C:46]2[N:47]([CH:59]3[CH2:65][CH:64]4[N:66]([CH2:67]CC5C=CC=CC=5)[CH:61]([CH2:62][CH2:63]4)[CH2:60]3)[C:48]3[C:53]([O:54][C:55]=2[CH:56]=1)=[C:52]([O:57][CH3:58])[CH:51]=[CH:50][CH:49]=3)=[O:42])[CH3:39].C(#N)C>O>[CH2:75]([N:40]([CH2:38][CH3:39])[C:41]([C:43]1[CH:44]=[CH:45][C:46]2[N:47]([CH:59]3[CH2:60][CH:61]4[N:66]([CH3:67])[CH:64]([CH2:63][CH2:62]4)[CH2:65]3)[C:48]3[C:53]([O:54][C:55]=2[CH:56]=1)=[C:52]([O:57][CH3:58])[CH:51]=[CH:50][CH:49]=3)=[O:42])[CH3:76].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(OC)cccc1N2C1CC2CCC(C1)N2CCc1ccccc1
Agent: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1N2C1CC2CCC(C1)N2C
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(OC)cccc1N2C1CC2CCC(C1)N2C

Procedure:
Using an adaptation of Procedure 16, and substituting the TFA salt of 10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide, 4e for TFA salt of 6-methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide, 6e, the title compound 6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide, 8e was obtained as a TFA salt and as a mixture of endo and exo isomers after reverse phase chromatography (eluent gradient: acetonitrile in water containing 0.1% TFA). MS m/z (MH+) 422.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)[CH2:2][CH2:3][CH3:4].O.O.O.[F:14][C:15]([F:23])([F:22])[C:16]([C:18]([F:21])([F:20])[F:19])=[O:17]>CCOC(C)=O>[CH2:1]([NH:5][C:6]1[S:7][C:8]([C:16]([OH:17])([C:18]([F:21])([F:20])[F:19])[C:15]([F:23])([F:22])[F:14])=[CH:9][N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nccs1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCNc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Temperature: 100 °C

Procedure:
A catalytic amount of molecular sieves powder (4A) was added to the mixture of 2-butylaminothiazole (1 g 6.41 mmol) prepared above and hexafluoroacetone trihydrate (2.86 g 13 mmol). The mixture was heated to gently reflux at 100° C. overnight. EtOAc is added and the mixture was filtered. Solvent was evaporated under reduced pressure. The residue was recrystallized in THF and hexanes to afford the title compound as a white solid. (1.68 g). 1H NMR δ0.95 (t, 3H), 1.40 (m, 2H), 1.6 (m, 2H), 3.20 (t, 2H), 7.3 (s, 1H); ESIMS: m/z 323 (M+H).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]2=[N:6][CH:7]=[N:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[H-].[Na+].[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[NH:28][C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[CH2:39][N:38]([C:41]1[S:42][C:43]([CH2:51][CH2:52][CH2:53]I)=[C:44]([C:46]([O:48]CC)=[O:47])[N:45]=1)[CH2:37][CH2:36]2)=[O:30].[OH-].[Na+]>CN(C=O)C.CO.C1COCC1>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:53][CH2:52][CH2:51][C:43]3[S:42][C:41]([N:38]4[CH2:37][CH2:36][C:35]5[C:40](=[C:31]([C:29](=[O:30])[NH:28][C:20]6[S:19][C:23]7[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=7[N:21]=6)[CH:32]=[CH:33][CH:34]=5)[CH2:39]4)=[N:45][C:44]=3[C:46]([OH:48])=[O:47])=[CH:14][CH:15]=2)[C:5]2=[N:6][CH:7]=[N:8][CH:9]=[C:4]2[CH:3]=[N:2]1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Reactant: Oc1ccc(-n2ncc3cncnc32)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCCOc3ccc(-n4ncc5cncnc54)cc3)s1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 21D (106 mg, 0.498 mmol) in DMF (5 mL) was added sodium hydride (56.9 mg, 1.423 mmol). The resulting mixture was stirred at rt for 30 minutes and compound 2C (300 mg, 0.474 mmol) was added. The reaction mixture was stirred for 1 hour and 10% sodium hydroxide (1.897 mL, 4.74 mmol), THF (5 mL) and MeOH (3 mL) was added. The resulting mixture was stirred at 70° C. overnight, cooled, and filtered. The filtrate was acidified by HCl to pH 4. The precipitate was collected and dried to provide the desired product: 1H NMR (400 MHz, DMSO-D6) δ ppm 12.85 (1H, s), 9.45 (1H, s), 9.10 (1H, s), 8.61 (1H, s), 7.98-8.06 (3H, m), 7.78 (1H, d), 7.67 (1H, d), 7.42-7.50 (2H, m), 7.32-7.40 (2H, m), 7.09-7.16 (2H, m), 4.84 (2H, s), 4.06 (2H, t), 3.73 (2H, t), 3.14-3.24 (2H, m), 3.03 (2H, t), 1.98-2.12 (2H, m); LCMS (APCI): m/z 687 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=2)=[N:5][S:4][N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[N:5][S:4][N:3]=1
Reactant: COc1ccc(-c2nsnc2Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2nsnc2Cl)cc1
Yield: 87.1 %

Procedure:
By the method described in `Advanced Organic Synthesis, Methods and Techniques` Academic Press, p 66 (1971), incorporated herein by reference, 2.0 g (0.0088 mole) of 3-chloro-(4-methoxy-phenyl)-1,2,5-thiadiazole (prepared in manner of Example 2) was reacted with 11.0 g (0.044 mole) of boron tribromide in 60 ml of methylene chloride to produce 1.63 g of 3-chloro-4-(4-hydroxyphenyl)-1,2,5-thiadiazole (m.p. 135°-136.5° C.).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Amino-3-nitrobenzoic acid may be prepared as described in Chapman, E. and Stephen, H., "Preparation of phthalmic acids and their conversion to anthranilic acids," J. Chem. Soc., (1925), 1151. To a mixture of this acid (14.00 g, 76.9 mmol) and cesium carbonate (20.00 g, 61.5 mmol) in dimethylformamide (150 mL) at 0° C. methyl iodide (12.00 g, 84.5 mmol) was added with stirring. After 20 minutes, it was warmed to room temperature and stirred for 3 hours. Most of the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (250 mL) and water (100 mL). The organic layer was separated, the aqueous layer was washed with ethyl acetate (250 mL) and the combined organic extract was dried over magnesium sulfate. After concentrating, the residue was triturated with ether to obtain the first crop of product as a yellow solid (3.20 g). The filtrate solution was concentrated, and the residue was passed through a flash column on silica gel eluting with 4:1 hexane:ethyl acetate to afford a slightly impure product. This material was triturated with methanol to obtain a pure second crop of product (9.10 g); total 12.3 g in 82% yield.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:9][C@H:8]2[C@H:6]([CH2:7]2)[CH2:5][N:4]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C1CCCCC1.CCOC(C)=O>C(Cl)Cl>[CH:2]([C@@H:3]1[CH2:9][C@H:8]2[C@H:6]([CH2:7]2)[CH2:5][N:4]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:1]
Reactant: O=C(OCc1ccccc1)N1C[C@H]2C[C@H]2C[C@H]1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: O=C[C@@H]1C[C@@H]2C[C@@H]2CN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of phenylmethyl (1S,4S,6S)-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate D9 (0.447 g) in DCM (13 ml) was added NaHCO3 (0.575 g, 6.84 mmol) and Dess-Martin periodinane (0.798 g, 1.882 mmol) and stirred at room temperature. TLC (Cyclohexane/EtOAc 1/1,2,4-dinitrophenylidrazine) showed the absence of starting material, so a solution of saturated NaHCO3/5% Na2S2O3 (60 ml) and DCM (10 ml) were added to the reaction mixture and it was left stirring for 30 minutes. The aqueous phase was back extracted with DCM (3×10 mls) and the biphasic system was passed through a phase separator cartridge. The organic solvent was evaporated under reduced pressure to yield a yellowish oil purified via Biotage SP4 (silica gel, SNAP 25 g; Cy/EtOAc, 25 CV from 1/0 to 7/3). Collected fractions gave the title compound D10 (0.370 g). MS: (ES/+) m/z: 260 (M+1), C15H17NO3 requires 259. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.50-9.38 (m, 1 H), 7.48-7.18 (m, 5 H), 5.19-4.93 (m, 2 H), 4.31-3.83 (m, 2 H), 3.28-2.90 (m, 1 H), 2.30-2.15 (m, 1H), 1.77-1.30 (m, 1 H), 1.21-0.84 (m, 2 H), 0.56-0.75 (m, 1 H), 0.22-0.03 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([O:25]C)=[O:24])(=[O:16])=[O:15])=[O:12])[N:4]=1.[OH-].[K+].Cl>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([OH:25])=[O:24])(=[O:16])=[O:15])=[O:12])[N:4]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)n1
Reaction time: 24 h

Procedure:
4.0 g of N-[(4-methoxy-6-methylpyrimidin-2-yl)-aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide was dissolved in a mixture of 20 ml of absolute ethanol, 2.5 ml of water and 2.5 g of potassium hydroxide. After stirring at 25° for 24 hours the mixture had become a semi-solid mass. Enough cold water was added to dissolve the solid and the solution was acidified to pH 3 with concentrated hydrochloric acid. The resultant precipitate was isolated by filtration and washed with cold water. The precipitate was dried to afford 3.7 g of the title compound, melting at 195°-200°. The nuclear magnetic resonance spectrum exhibited resonances for the methyl and methoxy substituents on the pyrimidine ring at 2.67 ppm and 4.20 ppm respectively.
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:25](O)=[O:26])[CH2:11]2)=[CH:6][CH:5]=1.O[N:30]=[C:31]([O:33][CH2:34][CH3:35])[NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][CH:2]([F:28])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH:12]([C:25]3[O:26][N:32]=[C:31]([O:33][CH2:34][CH3:35])[N:30]=3)[CH2:13][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:15]2)=[CH:8][CH:9]=1
Reactant: CCOC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)CC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1noc(C2CC(c3ccc(OC(F)F)cc3)CN(C(=O)N3CCS(=O)CC3)C2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
185 mg (0.37 mmol) of the compound from Example 42A and 50 mg (0.48 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] were initially charged in 1.0 ml of DMF and reacted with 210 mg (0.55 mmol) of HATU and 0.19 ml (143 mg, 1.1 mmol) of N,N-diisopropylethylamine. The mixture was stirred at RT for 15 minutes and then the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in 2.0 ml of acetic acid and heated to reflux for 1 h. The reaction mixture was purified by means of preparative HPLC. Yield: 62 mg (33% of theory)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[CH2:20][CH2:19][N:18]([C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.O>ClC(Cl)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:20][CH2:19][N:18]([C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](c1ccccc1)N1CCC(O)(c2ccc(OCc3ccccc3)cc2)CC1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CC(Cl)Cl
Product: C[C@H](c1ccccc1)N1CC=C(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 32.5 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
121.7 g crude (R)-4-(4-benzyloxy-phenyl)-1-(1-phenyl-ethyl)-piperidin-4-ol was dissolved at 40° C. in 1.21 L dichloroethane. 59.4 g (471 mmol) oxalic acid (Merck 492) was added. The mixture was boiled for 3 h, while 20 mL of water was separated. The reaction mixture was washed at room temperature with 1.2 L 10% Na2CO3. The precipitate (52 g) was separated from filtrate A and added to a mixture of 250 mL 2 N NaOH and 300 mL dichloromethane, where it was dissolved after stirring for 30 min at 30-35° C. The organic phase was separated and washed with a half-saturated NaCl solution. The resulting precipitate was separated and dissolved in 200 mL dichloromethane and 60 mL methanol. The combined organic phases were concentrated after drying over Na2SO4. 80 mL ethyl acetate was added to the residue and stirred for 2 h. The crystals were separated, washed with pentane, and dried to yield 36.5 g of (R)-4-(4-benzyloxy-phenyl)-1-(1-phenyl-ethyl)-1,2,3,6-tetrahydropyridine.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[I:13][CH2:14][C:15](=O)[CH3:16].B(F)(F)F.CCOCC>C1C=CC=CC=1>[I:13][CH2:14][C:15]1([CH3:16])[C:2]2[CH2:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[CH2:10][CH2:11][O:12]1
Reactant: OCCC1=CCc2ccccc21
Reactant: CC(=O)CI
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC1(CI)OCCC2=C1Cc1ccccc12

Procedure:
To a solution of indene-3-ethanol (15 g) in 150 ml of benzene, iodoacetone (12 g) is added. The mixture is heated at reflux with 5 ml of boron trifluoride-etherate and hydrated alkali-aluminum silicate (Molecular Sieves No. 4). After a total of 2 hours the reaction is cooled, filtered and washed with 5% sodium bicarbonate, water and dried over sodium sulfate. Evaporation under reduced pressure affords an oil. This oil is purified by chromatography on silica gel. Elution with benzene and concentration of the eluate gives the title compound, identical to the compound of the same name described in Example 463.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:24]=[CH:23][C:15]([O:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)COc1ccc(OCCCCc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)COc1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.8 %

Procedure:
A mixture of ethyl [4-(4-phenylbutoxy)phenoxy]acetate (0.59 g, 1.8 mmol), lithium hydroxide monohydrate (0.15 g, 3.6 mmol), tetrahydrofuran (5 mL), methanol (1 mL) and water (3 mL) was stirred at room temperature for 48 hrs. The mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (0.48 g, yield 89%).