Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]1[CH2:6][CH:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:30])=[C:16]([NH:18][C:19]([C:21]4[N:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]5=[N:23][CH:22]=4)=[O:20])[CH:17]=3)[N:8]=2)[CH2:4]1)#[N:2].Cl.[NH2:32][OH:33].CCN(C(C)C)C(C)C>C(O)C>[OH:33][N:32]=[C:1]([N:3]1[CH2:4][CH:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:30])=[C:16]([NH:18][C:19]([C:21]4[N:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]5=[N:23][CH:22]=4)=[O:20])[CH:17]=3)[N:8]=2)[CH2:6]1)[NH2:2]
Reactant: Cc1ccc(-c2noc(C3CN(C#N)C3)n2)cc1NC(=O)c1cnc2ccccn12
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(-c2noc(C3CN(C(N)=NO)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 78 °C

Procedure:
A stirring mixture of N-(5-(5-(1-cyanoazetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (82) (50 mg, 0.125 mmol), hydroxylamine HCl (13 mg, 0.188 mmol) and DIEA (44 uL, 0.250 mmol) in ethanol was heated at 78° C. for 2 hours. The solvent was concentrated and dried under high vacuum. Crude N-(5-(5-(1-(N′-hydroxycarbamimidoyl)azetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (83) was used in the next step without further purification. MS m/z 433.17 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22](C(OCC)=O)[CH2:21][CH2:20]2)=[CH:5][CH:4]=1.[OH-].[K+].C(O)(C)C>O>[OH:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccc(CO)o2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: OCc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)o1
Reaction time: 18 h

Procedure:
Combine (1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine (1 mmol), potassium hydroxide (1.2 mmcl), and isopropanol (20 mL). Heat to reflux. After 18 hours, evaporate intcacuo to give a residue. Combine the resczue and water. Extract with dichloromethane. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH:1]1([O:7][CH2:8][C@H:9]2[CH2:14][C@@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[NH2:29]O.Cl>CO.O.C(Cl)Cl>[CH:1]1([O:7][CH2:8][C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:22][NH:29][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](COC2CCCCC2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1COC1CCCCC1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 40.8 %

Procedure:
Cis-methyl 2-(cyclohexyloxymethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.13 g, 3.06 mmol) was dissolved in MeOH (14 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.128 g, 3.21 mmol) dissolved in water (1.400 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.197 mL, 3.21 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (15.80 mL, 94.82 mmol) and the mixture was stirred at 80° C. for 20 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(cyclohexyloxymethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (423 mg, 41%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.12-2.15 (m, 14H), 2.93-3.04 (m, 1H), 3.10-3.31 (m, 2H), 3.35-3.50 (m, 2H), 3.70 (s, 3H), 3.83-3.94 (m, 1H), 4.05-4.15 (m, 1H), 5.75 (s, 1H). MS m/z 339 (M+H)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:29]C)[CH:27]=4)[NH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:2]1.Cl.N1C=CC=CC=1>N1C=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=4)[NH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:2]1
Reactant: COc1ccc2[nH]cc(C3CCN(CCCCc4c[nH]c5ccccc45)CC3)c2c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2[nH]cc(C3CCN(CCCCc4c[nH]c5ccccc45)CC3)c2c1
Reaction time: 3 h

Procedure:
A mixture of 1.6 g of 3-[1-(4-(indol-3-yl)butyl)-4-piperidyl]-5-methoxyindole [which can be prepared according to Example 1], 1.8 g of pyridine hydrochloride and 50 ml of pyridine is boiled for 3 hours. The mixture is cooled, the solvent is evaporated and the residue is worked up in a conventional manner and gives 3-[1-(4-(indol-3-yl)butyl)-4-piperidyl]-5-hydroxyindole, m.p. 178°-180°.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=3[N:3]=[C:2]2[O:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=2)=[CH:13][CH:14]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(C(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (240 mg, 0.649 mmol, intermediate 8) in dimethyl formamide (5 mL) was added 3-(trifluoromethyl)phenol (105 mg, 0.649 mmol) followed by potassium carbonate (107 mg, 0.779 mmol). The resulting mixture was stirred at 80° C. for 6 h. The mixture was diluted with ethyl acetate (15 mL) and extracted with brine and saturated aqueous ammonium chloride solution. Then the organic phase was dried and concentrated to give a crude solid product which was collected and washed with ethanol to give 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione (237 mg, 81.1% yield) as white solid. 1H-NMR (DMSO-d6) δ 11.24 (s, 1H), 7.77 (s, 1H), 7.69-7.71 (m, 3H), 7.43 (s, 4H), 5.42 (s, 2H), 3.22 (s, 3H). LCMS retention time 2.306 min; LCMS MH+ 451.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[CH:25]=[C:26]([CH:31]([OH:33])[CH3:32])[CH:27]=[C:28]([F:30])[CH:29]=1>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([C:31](=[O:33])[CH3:32])[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: CC(O)c1cc(F)cc(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
Dess-Martin periodinane (9.66 g, 22.8 mmol) was added portionwise to a solution of 1-(3,5-difluorophenyl)ethanol (3.00 g, 19.0 mmol) in DCM (40 mL) cooled in an ice bath. The mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure. The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (0-40%). The purification gave 2.06 g (69.6%) of the sub-title compound as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.45 (m, 2H), 7.01 (m, 1H), 2.59 (s, 3H) ppm.
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]([C:18](=O)[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:17]=1)=[O:12])[CH3:9]>FC(F)(F)C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]([CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1ccc(C(=O)CCc2ccccc2)[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(CCCc2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylsilane (0.977 mL, 6.14 mmol) was added to a stirring, room temperature solution of 5-(3-phenylpropionyl)1H-pyrrole-2-carboxylic acid ethyl ester (175) (0.5374 g, 1.98 mmol) in trifluoroacetic acid (TFA) (4.72 mL, 0.42 M) under N2. The reaction was judged complete by HPLC after stirring at room temperature overnight. The TFA was removed under vacuum, and the crude product was purified by preparative reverse phase HPLC with the following conditions: 35:65 H2O:CH3CN; 20 mL/min.; λ=254 nM. HPLC: 11.12 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O.C(O)(=O)C.C([BH3-])#N.[Na+].C1COCC1>C1COCC1.CO>[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6]
Reactant: COC(=O)CN
Reactant: O=Cc1cccc(O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)CNCc1cccc(O)c1
Temperature: 25 °C
Yield: 45 %

Procedure:
Glycine methyl ester (500 mg, 4 mmol) and 3-hydroxybenzaldehyde (480 mg, 4 mmol) were dissolved in 5 mL THF/Methanol (1:1). Acetic acid (240 mg, 4 mmol), and 1M sodium cyanoborohydride in THF (4.8 mL, 4.8 mmol) were slowly added into the reaction. The reaction was irradiated in the microwave reactor at 85° C. for 15 minutes, cooled to room temperature and the salts were removed by filtration. The clear solution was concentrated and the residue was purified by reversed phase HPLC (10 to 95% Acetonitrile in H2O:25 minute gradient) to give the title compound as a clear gel. Yield 45%. MS M+H calculated 196.1; found 196.1.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[C:49]1[O:53][N:52]=[CH:51][C:50]=1[C:54](O)=[O:55]>CN(C=O)C>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:3]2[CH2:4][CH2:5][N:1]([C:54]([C:50]3[CH:51]=[N:52][O:53][C:49]=3[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][N:43]=3)=[O:55])[CH2:2]2)[CH:7]=1
Reactant: O=C(O)c1cnoc1-c1ccccn1
Reactant: c1cncc(C2CCNC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cnoc1-c1ccccn1)N1CCC(c2cccnc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-pyrrolidin-3-yl-pyridine (15 mg, 0.1 mmol), TBTU (48 mg, 0.15 mmol, 1.5 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.1 mmol) in DMF (0.6 mL) was added to 5-pyridin-2-ylisoxazole-4-carboxylic acid (19 mg, 0.1 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound as (12 mg). MS (ESI, pos. ion) m/z calcd for C18H16N4O2: 320.1273, found 320.1273.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([I:10])[C:7]([I:11])=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13])([O-])=O.N>C(O)C>[N+:12]([C:5]1[CH:6]=[C:7]([I:11])[C:8]([I:10])=[CH:9][C:4]=1[NH2:1])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(I)c(I)cc1[N+](=O)[O-]
Agent: N
Solvent: CCO
Product: Nc1cc(I)c(I)cc1[N+](=O)[O-]

Procedure:
A solution was prepared from 3 gms. of 1,2-dinitro-4,5-diiodobenzene in 150 ml. of ethanol. Gaseous ammonia was passed into the solution while heating to refluxing temperature. This procedure was continued until TLC indicated that all starting material had reacted (about 8 hours). The volume of the solution was then reduced to 1/3 of the original volume and the solution was cooled. 2-nitro-4,5-diiodoaniline formed in the above reaction precipitated and was collected by filtration; mp=196°-7° C.; yield=1.70 g.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O:8]=[S:9]1(=[O:38])[C:15]2[CH:16]=[C:17]([OH:22])[C:18]([S:20][CH3:21])=[CH:19][C:14]=2[N:13]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:12][C:11]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:10]1.C([O-])([O-])=O.[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[O:38]=[S:9]1(=[O:8])[C:15]2[CH:16]=[C:17]([O:22][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:18]([S:20][CH3:21])=[CH:19][C:14]=2[N:13]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:12][C:11]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:10]1
Reactant: CCCCC1(CCCC)CN(c2ccc(Cl)cc2)c2cc(SC)c(O)cc2S(=O)(=O)C1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CCCCC1(CCCC)CN(c2ccc(Cl)cc2)c2cc(SC)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Yield: 86.2 %

Procedure:
Ethyl bromoacetate (0.101 g, 0.604 mmol) was added to a mixture of 1,1-dioxo-3,3-dibutyl-5-(4-chlorophenyl)-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 99; 0.194 g, 0.402 mmol), anhydrous Na2CO3 (0.192 g, 1.81 mmol) and tetrabutylammonium bromide in MeCN (5 ml). The reaction mixture was refluxed for 3.5 hours. The solvent was evaporated under reduced pressure and the residue was extracted with DCM/water. The organic layer was separated, dried and evaporated under reduced pressure. The crude product was purified by column chromatography using DCM/EtOAc (100:5 and 100:10) as eluent to give the title compound 0.197 g (86%). NMR (300 MHz) 0.80–0.89 (m, 6H), 1.0–1.45 (m, 15H), 2.34 (s, 3H), 3.16 (s, 2H), 3.68 (s, 2H), 4.30 (q, 2H), 4.71 (s, 2H), 7.05–7.11 (m, 3H), 7.19 (s, 1H), 7.29–7.35 (m, 2H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:16]([O:7][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:8])[CH:1]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(OC(=O)c2ccccc2)c1
Temperature: 25 °C

Procedure:
To a chilled (0°-5° C.) solution of 5.0 g (0.046 mol) of m-cresol in 20 mL of methylene chloride containing 5.16 g (0.051 mol) of triethylamine was added dropwise a solution containing 6.47 g (0.046 mol) of benzoyl chloride in 20 mL of methylene chloride. A precipitate formed upon addition. The reaction mixture was stirred several hours at room temperature and was then filtered. The filtrate was washed with water (25 mL) and then with brine (25 mL). The organic phase was removed and dried over magnesium sulfate, filtered and evaporated to dryness in a rotary evaporator. The crude product amounted to 9.66 g. An analytical sample (m.p. 51°-54° C.) was obtained by recrystallization from petroleum ether.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=4)[CH:17]=3)[O:12][C:11]([CH3:33])([CH3:32])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CCO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=4)[CH:17]=3)[O:12][C:11]([CH3:32])([CH3:33])[CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)O3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc(C2=CC(C)(C)Oc3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 35 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of ethyl 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-chromen-6-yl]-ethynyl]-benzoate (Compound 267, 82.0 mg, 0.188 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). The resulting solution was heated to 35° C., cooled to room temperature and stirred overnight. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before the solvent was removed under reduced pressure. The residual solid was recrystallized from CH3CN to give 65.0 mg (85%) the title compound as a colorless solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.01 (2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.4 Hz), 7.40 (1H, dd, J=2.0, 8.3 Hz), 7.35-7.25 (4H, m), 7.17 (1H, d, J=2.0 Hz), 6.90 (1H, d, J=8.3 Hz), 5.77 (1H,s), 2.69 (2H, q, J=7.6 Hz), 1.49 (6H, s), 1.24 (2H, t, J=7.6 Hz).
Reaction SMILES: C[C@H]1O[C@@H]([O:8][C@:9]23[C:24](=[CH2:25])[CH2:23][C@:21]4([CH2:22]2)[C@H:12]([C@@:13]2([CH3:41])[C@H:18]([CH2:19][CH2:20]4)[C@@:17]([C:27]([O:29][C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)=[O:28])([CH3:26])[CH2:16][CH2:15][CH2:14]2)[CH2:11][CH2:10]3)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H]2O)[C@@H](O)[C@@H]1O.[K].P([O-])([O-])([O-])=O.SC[C@H]([C@@H](CS)O)O.O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O>OP([O-])(O)=O.[K+].CC#N.C(Cl)(Cl)Cl.CO.O>[CH3:41][C@:13]12[C@@H:12]3[CH2:11][CH2:10][C@@:9]4([OH:8])[C:24]([CH2:23][C@@:21]3([CH2:22]4)[CH2:20][CH2:19][C@@H:18]1[C@@:17]([C:27]([OH:29])=[O:28])([CH3:26])[CH2:16][CH2:15][CH2:14]2)=[CH2:25]
Reactant: C=C1C[C@@]23CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@@H]2CC[C@]1(O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O)[C@@H]1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1O)C3
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])[O-]
Agent: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CC#N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=C1C[C@@]23CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)O)[C@@H]2CC[C@]1(O)C3

Procedure:
Rebaudioside C, 3-sulfopropyl ester, potassium salt prepared as in Part B. was incubated anaerobically for three days at 37° C. with 5% fresh rat cecal contents at concentrations of 0.25, 0.5, and 1.0 mg/ml, in sterile Krebs-Ringer 0.25 M phosphate buffer (pH 7.4) containing 0.25 mg/ml dithiothreitol and 0.25 mg/ml α-D-glucose. TLC [silica gel F-254; CHCl3 :CH3OH:H2O (15:10:2)] and HPLC [30 cm C-18 on μ-Bondapak; 15 min linear gradient of 10-40% CH3CN in 0.005 M KH2PO4 (pH 3.45); 200 nm] analysis showed all the rebaudioside C, 4-sulfopropyl ester (Rf =0.42; tR =14.0 min) to have been consumed within 24 h to yield apparently only the sulfopropyl ester of steviol, (Rf =0.63; tR =16.3 min). No steviol (Rf =0.95; tR =31.3 min) was detected. After 3 days the bacterial cells were sedimented by centrifugation. The sediment was extracted (THF), as was the lyophilized supernatant. HPLC analysis for steviol of the two THF extracts showed none to be detectable. With a detection limit of 0.05 μg, as little as 0.03 and 0.13 percent degradation to steviol could have been detected for the sediment and supernatant fractions, respectively.
Reaction SMILES: CN1[C@@H](CC2C3C=C(CCS(C4C=CC=CC=4)(=O)=O)C=CC=3NC=2)CCC1.[C:28]([N:31]1[C:39]2[C:34](=[CH:35][C:36]([CH2:40][CH2:41][S:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)(=[O:44])=[O:43])=[CH:37][CH:38]=2)[C:33]([CH2:51][C@H:52]2[CH2:56][CH2:55][CH2:54][N:53]2[CH3:57])=[CH:32]1)(=[O:30])[CH3:29].BrC1C=C2C(=CC=1)NC=C2C[C@H]1CCCN1C.C(N1C2C(=CC(Br)=CC=2)C(C[C@H]2CCCN2C)=C1)(=O)C.C(S(C1C=CC=CC=1)(=O)=O)=C>[Pd]>[C:28]([N:31]1[C:39]2[C:34](=[CH:35][C:36]([CH:40]=[CH:41][S:42]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)(=[O:43])=[O:44])=[CH:37][CH:38]=2)[C:33]([CH2:51][C@H:52]2[CH2:56][CH2:55][CH2:54][N:53]2[CH3:57])=[CH:32]1)(=[O:30])[CH3:29]
Reactant: CC(=O)n1cc(C[C@H]2CCCN2C)c2cc(CCS(=O)(=O)c3ccccc3)ccc21
Agent: [Pd]
Agent: C=CS(=O)(=O)c1ccccc1
Agent: CC(=O)n1cc(C[C@H]2CCCN2C)c2cc(Br)ccc21
Product: CC(=O)n1cc(C[C@H]2CCCN2C)c2cc(C=CS(=O)(=O)c3ccccc3)ccc21

Procedure:
As a result of this difficulty, we have now developed an alternative route to eletriptan which avoids the use of a precursor which is prone to dimerisation. Specifically, the process of the invention comprises the preparation of eletriptan by the hydrolysis of (R)1-acetyl-5-(2-benzenesuiphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole, which compound may conveniently be prepared by (i) N-acetylating (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole, (ii) reacting the resulting (R)-1-acetyl-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole with phenyl vinyl sulphone in the presence of a palladium catalyst, a triarylphosphine and a base to give (R)-1-acetyl-5-(2-benzenesulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1 H-indole and (iii) catalytically reducing same.
Reaction SMILES: [CH2:1]([C:5]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH:3]=C.[BH4-].[Na+].ClCCl.C[OH:34]>>[OH:34][CH2:3][CH2:2][CH2:1][C:5]1([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][CH2:6]1
Reactant: C=CCCC1(C(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCCO)(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A solution of 1-(1,1-dimethylethyl) 4-phenylmethyl 4-(3-butenyl)-1,4-piperidinedicarboxylate (Description 135, 1.06 g, 2.84 mmol) in dichloromethane/methanol (50:50, 20 mL) was cooled to −78° C. and oxygen was bubbled through the mixture for 10 minutes. Ozone was bubbled through the mixture until a blue coloration persisted. Oxygen was bubbled through the mixture for 10 minutes, then nitrogen for 10 minutes. Sodium borohydride (1.1 g, 28.9 mmol) was added over 5 minutes and the mixture was allowed to warm to room temperature. The solvent was evaporated under reduced pressure and water (40 mL) was added. The mixture was extracted with ethyl acetate (3×40 mL), the combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (1.06 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.4–7.3 (5H, m), 5.15 (2H, s), 3.95–3.75 (2H, m), 3.52 (2H, t, J 7 Hz), 2.95–2.80 (2H, m), 2.12 (2H, br d, J 10 Hz), 1.65–1.30 (7H, m), and 1.44 (9H, s).
Reaction SMILES: Cl.NNC(N[N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=N.FC(F)([O:21]C1C=CC(C=NO)=CC=1)C(F)F>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]=[N:7][OH:21])=[CH:10][CH:11]=1
Reactant: N=C(NN)NN=Cc1ccc(Cl)cc1
Reactant: ON=Cc1ccc(OC(F)(F)C(F)F)cc1
Agent: Cl
Product: ON=Cc1ccc(Cl)cc1

Procedure:
Using a similar procedure, 1-amino-3-p{[p-(1,1,2,2-tetrafluoroethoxy)benzylidene]amino}guanidine hydrochloride (white solid, mp 205°-212° C.); 1-amino-3-{p-(trifluoroethoxy)benzylidene]amino}guanidine hydrochloride (white powder; mp 235°-238° C.); and 1-amino-3-(p-chlorobenzylideneamino)guanidine hydrochloride may be prepared. The second products of the reactions, p-(1,1,2,2-tetrafluoroethoxy)benzaldehyde oxime (pinkish white solid, mp 47°-53.5° C.); α,α,α-trifluoro-p-anilaldehyde oxime (off-white solid, mp 46°-49.5° C.) and p-chlorbenzaldehyde oxime may also be isolated from the reactions.