Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([C:12]([NH2:14])=[O:13])=[N:8][CH:9]=[CH:10][N:11]=1)(=O)[CH2:2][CH3:3]>C([O-])([O-])=O.[Na+].[Na+]>[CH2:2]([C:1]1[NH:14][C:12](=[O:13])[C:7]2[C:6](=[N:11][CH:10]=[CH:9][N:8]=2)[N:5]=1)[CH3:3]
Reactant: CCC(=O)Nc1nccnc1C(N)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCc1nc2nccnc2c(=O)[nH]1
Yield: 69.2 %

Procedure:
A mixture of 3-propionylamino-pyrazine-2-carboxylic acid amide (9.7 g, 50 mmol) and Na2CO3 (100 mL, 10%) was refluxed overnight. The water was removed in vacuo and the residue was treated with CH3OH (200 mL). The insoluble salt was filtered and the filtrate was evaporated to give 2-Ethyl-3H-pteridin-4-one as a yellow solid (6.1 g, 69%). 1H NMR (DMSO-d6) δ 8.64 (d, J=2 Hz, 1H), 8.36 (d, J=2 Hz, 1H), 2.52 (q, J=4.5 Hz, 2H), 1.18 (t, J=4.5 Hz, 3H). MS (ESI) m/e (M+1)30: 177.3.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([N:6]1[C:7]2[C:3](=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1cccc2[nH]ccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc2c1ccn2Cc1ccccc1

Procedure:
1-Benzyl-4-bromo-1H-indole was prepared from 4-bromo-1H-indole (1.58 g, 8.06 mmol), sodium hydride (0.680 g of 60% dispersion in oil, 17.0 mmol), and benzyl bromide (2.0 mL, 17 mmol) in DMF (15 mL) according to the procedure described in Step 1 of Example 5. Purification by flash chromatography (Biotage apparatus) using hexane as an eluant yielded a light yellow oil (1.61 g, 70%). 1HNMR (300 MHz, DMSO-d6): δ 7.65 (d, 1H, J=3.8 Hz), 7.5 (d, 1H, J=7.7 Hz), 7.15-7.35 (m, 6H), 7.05 (t, 1H, J=7.7 Hz), 6.45 (d, 1H, J=3.1 Hz), and 5.6 ppm (s, 2H).
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][NH:18][CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14].[C:26]([N:30]=[C:31]=[O:32])([CH3:29])([CH3:28])[CH3:27].ClC1C=C(Cl)C=CC=1C(OC1CN(C(NC(C)(C)C)=O)C1)C1C=CC(Cl)=CC=1>>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][N:18]([C:31]([NH:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14]
Reactant: Fc1cc(Br)ccc1C(OC1CNC1)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)N=C=O
Agent: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(Cl)cc2Cl)C1
Agent: Cl
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Br)cc2F)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-2′-fluoro-4′-bromobenzhydryloxy]azetidine hydrochloride (114) and tert-butyl isocyanate (4.54 mmol) using the procedure described for compound (5) (1.33 g, 58%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:19]=[C:9]2[N:10]=[C:11](S(C)(=O)=O)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[CH3:20][NH:21][CH2:22][CH2:23][NH:24][CH3:25]>CC#N>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:19]=[C:9]2[N:10]=[C:11]([N:21]([CH3:20])[CH2:22][CH2:23][NH:24][CH3:25])[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1
Reactant: CNCCNC
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Solvent: CC#N
Product: CNCCN(C)c1nc(N)n2nc(-c3ccco3)nc2n1
Temperature: 25 °C

Procedure:
2-Furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (18 mmol; see Example 1(a) above) was suspended in 50 mL of CH3CN along with 5 eq. of N,N′-dimethyl-ethane-1,2-diamine. The reaction mixture was stirred under reflux for 2 hours. It was then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in CH2Cl2 and washed with H2O, brine, dried with Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by chromatography (95% CH2Cl2, 4% MeOH, 1% Et3N) to afford 2-furan-2-yl-N5-methyl-N5-(2-methylamino-ethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22](O)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([C:22]([C:16]2([C:13]3[CH:12]=[CH:11][C:10]([S:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:15][CH:14]=3)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:23])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(O)C1(c2ccc(SCCCN3CCCC3)cc2)CCOCC1
Reactant: C1CCNC1
Product: O=C(N1CCCC1)C1(c2ccc(SCCCN3CCCC3)cc2)CCOCC1
Yield: 40 %

Procedure:
The title compound (228 mg, 40%) was prepared using 4-{4-[(3-pyrrolidin-1-ylpropyl)thio]phenyl}tetrahydro-2H-pyran-4-carboxylic acid and pyrrolidine similarly to the procedure used for example 149.
Reaction SMILES: [O:1]([C:8]1[S:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:15]Cl=O.[Na+].[OH-].[Na+]>C1COCC1.CC(O)(C)C.O>[O:1]([C:8]1[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccccc2)s1
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.5 %

Procedure:
5-Phenoxy-thiophene-2-carboxaldehyde (325 mg, 1.6 mmol) is dissolved in a mixture of THF (10 mL), t-BuOH (5 mL) and water (5 mL). NaH2PO4 (650 mg, 4.8 mmol) is added followed by NaClO2 (432 mg, 4.8 mmol). The resulting mixture is stirred for 24 hr at rt. Aqueous NaOH (2M, 5 mL) is added, and the organic solvents are removed in vacuo. The resulting aqueous suspension is poured into water (50 mL) and washed with ether (3×50 mL). The aqueous layer is acidified to pH<2 with 25% H2SO4 then washed with CH2Cl2 (3×50 mL). The combined organic washes are dried over Na2SO4, filtered and concentrated in vacuo. The crude product is dissolved in hot aqueous acetone and filtered. The solvents are gradually removed until a precipitate forms. The solid is collected by filtration and dried in vacuo to yield 5-phenoxy-thiophene-2-carboxylic acid (192 mg, 55%). MS for C11H7O3S (ESI) (M+H)+ m/z 219.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Si]([C:21]#[N:22])(C)(C)C.[OH:23]S(O)(=O)=O>C1(C)C=CC=CC=1.O.CC(O)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:21]([NH2:22])=[O:23])=[CH:7][CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: O=S(=O)(O)O
Reactant: O=C1CCOc2cc(Br)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: NC(=O)C1=CCOc2cc(Br)ccc21
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 45 %

Procedure:
To a solution of 7-bromochroman-4-one (2.0 g, 8.8 mmol) and AlCl3 (118 mg, 0.9 mmol) in toluene (10 mL) was added TMSCN (1.3 mL, 9.7 mmol). The solution was stirred at 40° C. for 1.5 h. The reaction was cooled to rt, and H2SO4 (1.0 mL) was added, followed by AcOH (13 mL) and more H2SO4 (4.3 mL). The reaction was heated to 130° C. and stirred for 6 h. The reaction was cooled, poured over H2O (100 mL) and filtered. The filter cake dissolved in THF (50 mL) and filtered. The combined organic solutions were concentrated to give 1.0 g (45%) of the crude title compound as an off-white solid. [M+H] calc'd for C10H8BrNO2, 254, 256. found 254, 256.
Reaction SMILES: [C:1]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH2:2][CH3:3].P(Cl)(Cl)([Cl:18])=O.C(N(CCCC)CCCC)CCC>>[CH2:9]([O:8][C:6](=[O:7])[C:5](=[C:1]([Cl:18])[CH2:2][CH3:3])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10]
Reactant: CCOC(=O)C(C(=O)CC)C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C(C(=O)OCC)=C(Cl)CC
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To diethyl propanoylpropanedioate (5.93 g, 27.4 mmol) was added phosphorus oxychloride (38 mL) and tributylamine (6.5 mL, 27.4 mmol) and the mixture was heated to 115° C. for 6 h then stirred at ambient temperature for 16 h. The mixture was evaporated to dryness and the residue added cautiously to aqueous hydrochloric acid (1M, 80 mL) and extracted twice with diethyl ether. The combined organic layers were washed with aqueous hydrochloric acid (1M), water, aqueous sodium hydroxide (1M) then brine, dried and evaporated to dryness to afford 6.81 g of a brown oil. The product was purified by flash chomatography on silica (250 mL), eluting with ethyl acetate/cyclohexane @1:10 to afford 3.21 g of the title compound. LC-MS m/z 235, 237 (M+H)+, 3.30 min (ret time).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:18]2[CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][C:14](=[O:21])[C:13]=2[CH:12]=[C:11]1[CH3:22])[C:5]#[N:6].[CH2:23]([OH:27])[CH2:24][CH2:25][CH3:26].[H-].[Na+].CN(C=[O:34])C>>[CH2:23]([O:27][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:18]2[CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][C:14](=[O:21])[C:13]=2[CH:12]=[C:11]1[CH3:22])[C:5]([NH2:6])=[O:34])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCO
Reactant: Cc1cc2c(n1-c1ccc(C#N)cc1F)CC(C)(C)CC2=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCCCOc1cc(C(N)=O)ccc1-n1c(C)cc2c1CC(C)(C)CC2=O
Temperature: 100 °C
Yield: 65 %

Procedure:
3-Fluoro-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrile (148 mg, 0.5 mmol) and 1-butanol (185.3 mg, 2.5 mmol) were dissolved in anhydrous DMF (1.5 mL). To this solution was added NaH (24.0 mg, 1 mmol). After purging the reaction vessel (Personal Chemistry Microwave Vial) with nitrogen, the reaction vessel was sealed and heated to 100° C. for 300 seconds in an Emyrs Optimizer Microwave. After cooling, the reaction mixture was diluted with H2O and extracted into EtOAc (×2). The combined organics were washed with brine (×2), dried over Na2SO4, and concentrated to dryness. The yellow residue (3-Butoxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrile) was then dissolved in EtOH (3 mL) and treated with 1 mL of 1 N NaOH (aq) and a catalytic amount of H2O2. Quantitative conversion of the nitrile to the amide occurred after heating this solution at 65° C. for 3 hours. Column chromatography on silica eluting with EtOAc gave the product as a white solid (119.9 mg, 65%). (100% clean by LC/MS, product M+H=369.2).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7]1[C:8]([C:12]2[N:16]([CH2:17][C:18]3[O:19][CH:20]=[C:21]([Br:23])[CH:22]=3)[C:15](=[O:24])[O:14][N:13]=2)=[N:9][O:10][N:11]=1)=[N+]=[N-].[I-:25].[Na+].Cl[Si](C)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO.O>[IH:25].[NH2:1][CH2:4][CH2:5][NH:6][C:7]1[C:8]([C:12]2[N:16]([CH2:17][C:18]3[O:19][CH:20]=[C:21]([Br:23])[CH:22]=3)[C:15](=[O:24])[O:14][N:13]=2)=[N:9][O:10][N:11]=1
Reactant: [I-]
Reactant: [N-]=[N+]=NCCNc1nonc1-c1noc(=O)n1Cc1cc(Br)co1
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CO
Product: I
Product: NCCNc1nonc1-c1noc(=O)n1Cc1cc(Br)co1
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
To a solution of 3-{4-[(2-azidoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-[(4-bromo-2-furyl)methyl]-1,2,4-oxadiazol-5(4H)-one (7.7 g, 19 mmol) in methanol (80 mL) was added sodium iodide (17.4 g, 116 mmol). After stirring for 10 minutes, a solution of chlorotrimethylsilane (14.8 mL, 116 mmol) was added dropwise over 5 minutes. The reaction continued to stir for 1 hour, at which time it was slowly added to a solution of sodium thiosulfate (23.0 g, 145 mmol) in water (800 mL) at 0° C., resulting in a precipitate. The flask was rinsed with methanol (10 mL) and the precipitate was collected through vacuum filtration. The solid was rinsed with cold water (2×25 mL) and was dried under vacuum to give the desired product (5.8 g, 60%) as the hydroiodide salt. LCMS calculated for C11H12BrN6O4 (M+H)+: m/z=370.9, 372.8. 1H NMR (400 MHz, DMSO-d6): δ 7.86 (s, 1 H), 7.36 (br s, 3 H), 6.68 (t, J=5.8 Hz, 1 H), 6.65 (s, 1 H), 5.07 (s, 2 H), 3.45 (q, J=5.8 Hz, 2 H), 2.98 (t, J=5.8 Hz, 2 H).
Reaction SMILES: Br[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5]Br.[CH2:8]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CCOC(C)=O>[CH2:8]([C:16]1[CH:17]=[CH:18][C:19]([N:20]2[CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]2)=[CH:21][CH:22]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: OC(CBr)CCBr
Reactant: CCCCCCCCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCc1ccc(N2CCC(O)C2)cc1
Temperature: 120 °C
Yield: 537.2 %

Procedure:
To 10 microwave vials were added 1,4-dibromobutan-2-ol (0.375 mL, 2.75 mmol), 4-octylaniline (0.572 mL, 2.5 mmol), potassium carbonate (0.380 g, 2.75 mmol) and water (3 mL). Each vial was heated in a CEM microwave at 100 watt, 120° C., 150 psi, ramp time 5 min and hold time 20 min. After cooling to room temperature EtOAc (1 mL) was added to each vial. After thorough mixing the organic layers were removed, combined and concentrated in vacuo. The product was purified by flash chromatography on silica gel (eluting with EtOAc/Hep) to provide 1-(4-octylphenyl)pyrrolidin-3-ol (3.7 g, 13.43 mmol, 53.7% yield) as a white solid which was stored under nitrogen in a sealed flask.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O.C(Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ccnc(N)n1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Nc1ncc(Br)c(N)n1
Reaction time: 12 h
Yield: 81.6 %

Procedure:
To a solution of 2,4-diaminopyrimidine (1.0 g, 9.1 mmol) in chloroform (30 mL) was added N-bromosuccinimide (1.62 g, 9.08 mmol). The solution was stirred in the dark for 12 hours, at which time it was added to CH2Cl2 (150 mL) and 1N NaOH (50 mL). The solid that formed was filtered, rinsed with water and concentrated in vacuo, yielding 1.4 g (74%) of 5-bromopyrimidine-2,4-diamine. LCMS (m/z): 189/191 (MH+). 1H NMR (DMSO-d6): δ 7.78 (s, 1H), 6.58 (bs, 2H), 6.08 (bs, 2H).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH3:7])[C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH:14]=1>ClCCl>[Br:1][CH:2]([CH2:6][CH3:7])[C:3]([C:18]1[S:17][C:16]2[CH:20]=[CH:21][C:13]([Cl:12])=[CH:14][C:15]=2[CH:19]=1)=[O:4]
Reactant: Clc1ccc2sccc2c1
Reactant: CCC(Br)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(Br)C(=O)c1cc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromobutyryl chloride (8 g) in dichloromethane (15 ml) was added dropwise under nitrogen at ambient temperature to a stirred suspension of anhydrous aluminium chloride (12 g) in dichloromethane (100 ml). When the addition was complete, a solution of 5-chlorobenzo[b]thiophene (5 g; prepared in a manner similar to that described in J. Heterocyclic Chem., 1988, 25, 1271) in dichloromethane (30 ml) was added dropwise, then the mixture was stirred at ambient temperature for 1 hour and added to ice-cold water (500 ml). The mixture was stirred at ambient temperature for 30 minutes then the product was extracted into dichloromethane (100 ml). The extract was washed with water (2×30 ml) and saturated aqueous sodium chloride solution (2×30 ml), then it was dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by repeated (5-fold) flash chromatography over silica using a 19:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 2-bromo-1-(5-chlorobenzo[b]thiophen-2-yl)butan-1-one (1.04 g) as an off-white solid which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([CH3:38])[C:17]2[C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])=[CH:19][C:20]([NH:23][C:24]([CH2:26][O:27]C(=O)C)=[O:25])=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+].C(OCC)(=O)C>O1CCCC1>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([C:17]2[CH:22]=[N:21][C:20]([NH:23][C:24](=[O:25])[CH2:26][OH:27])=[CH:19][C:18]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[CH3:38])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(=O)OCC(=O)Nc1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(NC(=O)CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 54.2 %

Procedure:
To a solution of 30 mg (0.05 mmol) acetic acid (5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-ylcarbamoyl)-methyl ester in 2 ml tetrahydrofuran were added 2 ml 1 N sodium hydroxide solution at room temperature. After stirring for 15 min, ethyl acetate was added, the aqueous phase was separated and the organic layer was dried (sodium sulfate). After evaporation the residue was purified by flash-chromatography to give 15 mg (54%) of the title compound as white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:29][CH2:30][CH:25]([C:16]4[CH:17]=[CH:18][C:19]5[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:15]=4)[CH2:26][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: c1ccc2cc(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)ccc2c1

Procedure:
The title compound was prepared in similar fashion from 1-chloro-3-(1H-indole-4-oxy)propane and 4-(2-naphthyl)-piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 57% overall yield as a white solid. mp. 145°-146° C. FDMS m/e=384 (M+ of free base).
Reaction SMILES: [CH2:1]([Sn:11]([CH2:26][C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:29])[CH3:28])(C1C=CC(F)=CC=1)[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl:36]Cl>C(Cl)(Cl)Cl>[CH2:1]([Sn:11]([Cl:36])([CH2:26][C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:29])[CH3:28])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C[Sn](CC(C)(C)c1ccccc1)(c1ccc(F)cc1)c1ccc(F)cc1)c1ccccc1
Reactant: ClCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C[Sn](Cl)(CC(C)(C)c1ccccc1)c1ccc(F)cc1)c1ccccc1
Yield: 101.3 %

Procedure:
Dineophyl-di(parafluorophenyl)tin (62.1 g, 0.108 mol) prepared above was dissolved in chloroform (200 g). While the resulting solution was maintained at -15° to -20° C., chlorine gas (7.6 g, 0.216 gram atom) was introduced. The mixture was then concentrated under reduced pressure to give 56 g of dineophyl-parafluorophenyltin chloride as a pale-yellow liquid. Gas chromatography analysis indicated 87.5% purity of the desired product.
Reaction SMILES: [NH2:1][N+:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH2:9].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=O>N1C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][N:2]2[N:1]=[C:28]([C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([O:24][CH3:23])[CH:26]=3)[N:9]=[C:3]2[CH:4]=1
Reactant: Nc1cc(Br)cc[n+]1N
Reactant: COc1cccc(C(=O)Cl)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: c1ccncc1
Product: COc1cccc(-c2nc3cc(Br)ccn3n2)c1
Temperature: 85 °C

Procedure:
To a solution of 1,2-diamino-4-bromo-pyridinium-2,4,6-trimethyl-benzenesulfonate (Example 1, step a) (8 g, 20.7 mmol) in pyridine (50 ml) was added 3-methoxybenzoyl chloride (6 ml, 41.3 mmol). The reaction mixture was heated at 85° C. for 3 h. Volatiles were removed in vacuum, and the resultant residue was diluted with EtOAc (300 ml). The organic layer was washed successively with water (2×250 ml) and brine (100 ml), dried over anhydrous Na2SO4, filtered, and evaporated in vacuum. The crude material thus obtained was purified by column chromatography over silica gel (10-15% EtOAc/hexane) to afford 7-bromo-2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (8 g, quant) as white solid. LC-MS: m/z=303.8 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].[CH3:18][CH:19]([CH3:23])[CH2:20][CH2:21]O.O>S(=O)(=O)(O)O.C1C=CC=CC=1>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][CH2:21][CH2:20][CH:19]([CH3:23])[CH3:18])[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: CC(C)CCO
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CC(C)CCOC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C
Yield: 85.3 %

Procedure:
A mixture of 2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran-5-yl methanesulphonate (13g, 0.05 mole), 3-methyl-1-butanol (4.4g, 0.05 mole) and concentrated sulphuric acid (4 drops) in benzene (50 ml) was heated at reflux under a Dean and Stark trap until 0.9 ml water (0.05 mole) had been eliminated. The reaction mixture was cooled, washed with dilute aqueous sodium hydroxide solution and with water (twice) and dried over sodium sulphate. The benzene was then distilled off under reduced pressure to give 2,3-dihydro-3,3-dimethyl-2-(3-methylbutoxy)-5-benzofuranyl methanesulphonate as a yellow oil (14 g, 86% yield) which slowly solidified (melting point 35°-38° C.).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH3:15])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14].Cl.O.[OH-].[Na+]>CO>[CH3:1][O:2][NH:3][CH:4]([CH3:15])[CH2:5][C:6]1[C:7]([Cl:14])=[CH:8][C:9]([Cl:13])=[CH:10][C:11]=1[Cl:12]
Reactant: CON=C(C)Cc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CONC(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To 1-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime prepared as described in example P4 (53.9 g; assay 99%; 0.20 mol) in methanol (100 g) was added hydrogen chloride gas (22.0 g; 0.60 mol), whereas internal temperature in maintained at 20-30° C. by external cooling. A colourless suspension was obtained. The reaction mixture was cooled to 15° C. and triethylamino borane (borane triethylamine complex; 27.6 g; assay 96%; 0.23 mol) was dosed in during 60 min maintaining internal temperature at 15° C. The reaction mass was stirred for another 2 hours allowing the mixture to warm to ambient temperature. Thereafter almost no starting material can be detected by HPLC. The reaction mixture was then added to preheated (85° C.) water (126 g) during 30 min. A steady stream of gas was evolved; at the same time solvent was distilled. Heating was continued and the temperature maintained at 85-90° C. for another 1 hour. Finally gas was no longer produced. The resulting mixture was cooled to 20-25° C. Sodium hydroxide (30% aqueous solution; 56.5 g; 0.42 mol) was carefully added in order to bring pH to 7.2-7.7. The resulting mixture was extracted with tert-butyl methyl ether (125 ml). Phases were allowed to separate. The (lower) aqueous phase was split of. The (upper) organic phase was washed with water (2×100 g) and evaporated. Crude O-Methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (53.9 g; assay 97.8%; yield 98.0%) was obtained as clear oil.