Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].ClCCl.CO>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([O-:26])=[O:25].[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH3+:14]
Reactant: CC(C)(C)OC(=O)NCCOCCOCCCCCCCl
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C([O-])C(F)(F)F
Product: [NH3+]CCOCCOCCCCCCCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under argon atmosphere, to a solution of tert-butyl N-[2-{2-(6-chlorohexyloxy)ethoxy}ethyl]carbamate (11) (synthesized by the method described in Non-Patent Document Y. Zhang, M.-k. So, A. M. Loening, H. Yao, S. S. Gambhir, J. Rao, Angew. Chem. Int. Ed., 2006, 118, 4936-4940) (142 mg, 438 μmol) in dichloromethane (3.5 mL) was added trifluoroacetic acid (0.5 mL) at 0° C. After stirring for 2 hours at the same temperature of 0° C., the starting compound 11 completely disappeared as judged from TLC study (RF=0.41, dichloromethane/methanol=9/1). The reaction solution was then concentrated under reduced pressure using an evaporator to give crude 2-[2-(6-chlorohexyloxy)ethoxy]ethylammonium trifluoroacetate (12) as a colorless oil. The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[CH2:12](O)[CH3:13].[OH-].[Na+].O1[CH2:22][CH2:21]OCC1>[Zn]>[C:12]1([CH2:13][NH:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[NH2:9])[C:21]2[C:22](=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCO
Reactant: C1COCCO1
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Product: Cc1ccc(NCc2cccc3ccccc23)c(N)c1
Reaction time: 0.25 h

Procedure:
To (1-naphthyl)methyl)(4-methyl-2-nitro-phenyl)amine (1.0021 g, 3.43 mmol), ethanol (5 ml) and 1,4-dioxane (5 ml) were added, and 2.058 M aqueous sodium hydroxide solution (1 ml) was further added, and refluxed in an oil bath. After 15 minutes, it was removed from the oil bath, and zinc powder (897 mg, 13.72 mmol) was fed thereto in portions. Then it was refluxed again in the oil bath for 2 hours. After 2 hours, it was concentrated under reduced pressure, and dissolved in ethyl acetate (50 ml), and washed twice with saturated saline (25 ml). After drying with magnesium sulfate, it was concentrated under reduced pressure and dried to obtain a brown oil of ((1-naphthyl)methyl)(2-amino-4-methyl-phenyl)amine (943.1 mg).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34]([NH2:36])=O)=[CH:32][N:33]=[C:27]2[N:26]=1>C1(C)C=CC=CC=1>[F:23][C:24]([F:38])([F:37])[C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34](=[S:10])[NH2:36])=[CH:32][N:33]=[C:27]2[N:26]=1
Reactant: NC(=O)c1cnc2nc(C(F)(F)F)ccn12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: NC(=S)c1cnc2nc(C(F)(F)F)ccn12
Yield: 92.8 %

Procedure:
Lawesson's reagent (281 mg, 0.7 mmol) was added to a stirred suspension of the foregoing amide (160 mg, 0.7 mmol) in toluene (16 ml). The resulting mixture was heated at reflux for 2.5 h and then concentrated under reduced pressure while dry loading onto silica. Subsequent purification by column chromatography on silica using firstly diethyl ether and then EtOAc/ether gave 7-trifluoromethylimidazo[1,2-α]pyrimidine-3-carbothioamide (160 mg, 93%): δH (360 MHz, d6-DMSO) δ 7.80 (1H, d, J 7.2), 8.70 (1H, s), 9.73 (1H, s), 9.82 (1H, s), 10.87 (1H, d, J 7.2).
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4]([O:6]CC)=[O:5].C1(C)C=CC(S(O[CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:28][CH2:27]2)(=O)=O)=CC=1.[OH-].[Na+]>C(O)C.O>[CH2:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][CH2:24][CH2:23][CH:3]([C:4]([OH:6])=[O:5])[C:2]([OH:10])=[O:9])[CH2:27][CH2:28]1)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(CCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)O

Procedure:
In 300 ml of ethanol is dissolved 5.8 g of sodium, and 40 g of diethyl malonate is added to the solution, followed by stirring. 3-(1-Benzyloxycarbonyl-4-piperidyl)propyl p-toluenesulfonate (90.5 g) is added to this mixture followed by refluxing with stirring for 2 hours. After cooling, 1 l of water is added to the reaction solution, which is then extracted with 500 ml of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 5-(1-benzyloxycarbonyl-4-piperidy)-2-ethoxycarbonylvalearate as an oily material. This product is dissolved in 200 ml of ethanol, and a solution of 34 g of sodium hydroxide in 200 ml of water is added dropwise to the solution with stirring. After the addition is completed, 300 ml of water is added to the reaction solution, which is then extracted with a mixture of ether and petroleum ether (1:1, 300 ml). The aqeuous layer is made acidic with conc. hydrochloric acid, followed by extraction with 500 ml of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-(1-benzyloxycarbonyl-4-piperidyl)-2-carboxyvaleric acid as an oily material. This product is heated at 160° to 170° C. with stirring for 45 minutes to give 50 g of 5-(1-benzyloxycarbonyl-4-piperidyl)valeric acid as an oily material.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>C1COCC1>[N:23]1([CH2:22][CH2:21][NH:20][S:17]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:29](=[O:32])[CH:30]=[CH2:31])=[CH:16][CH:15]=2)(=[O:19])=[O:18])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Nc1ccc(S(=O)(=O)NCCN2CCOCC2)cc1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(S(=O)(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.1 %

Procedure:
Diisopropylethylamine (0.09 ml, 0.5 mmol) was added in one portion to a stirred solution of 4-amino-N-(2-morpholin-4-yl-ethyl)-benzenesulfonamide (0.1 g, 0.35 mmol) in THF (3 ml) at room temperature. To this mixture was added acryloyl chloride (0.03 ml, 0.38 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time, the mixture was concentrated under vacuum and the resulting residue purified by Prep HPLC to give the title compound (6 mg, 5% yield) as a white solid.
Reaction SMILES: O[C:2]1([CH2:8][C:9]([O:11]CC)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:14](#[N:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(=O)(=O)(O)[OH:23]>O>[C:14]([NH:21][C:2]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)(=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC1(O)CCCCC1
Reactant: N#Cc1ccccc1
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CC1(NC(=O)c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
To a mixture of ethyl (1-hydroxycyclohexyl)acetate (17.1 g, 92.1 mmol) and benzonitrile (9.5 ml, 92.1 mmol) was added conc. sulfuric acid (50 ml) at 0° C., and the mixture was stirred at room temperature for 12 hrs. Water (200 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, and then with saturated brine and dried over anhydrous MgSO4. After concentration under reduced pressure, ethanol (50 ml) and 50% aqueous potassium hydroxide solution (10 ml) were added to the residue, and the mixture was heated under reflux for 6 hrs. Water (400 ml) was added to the reaction mixture, and the mixture was washed with diethyl ether. The aqueous layer was acidified (pH 2) with 5N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The obtained solid was recrystallized from ethanol-toluene to give the title compound (18.1 g, 75%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([CH:12]=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cn1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(OC)nc1
Temperature: 90 °C

Procedure:
A solution of the 5-bromo-2-methoxypyridine 16-2 (74.3 g, 0.4 mol), ethyl acrylate (150 mL, 1.4 mol), triethylamine (150 mL, 1.08 mol), palladium acetate (10 g, 0.045 mol) and tri-o-tolylphosphine (20 g, 0.066 mol) in 100 mL acetonitrile was degassed with argon for 10 minutes. The mixture was heated at 90° C. for 12 hr, then the volatiles were removed in vacuo. Toluene (300 mL) was added and the mixture concentrated again. Diethyl ether (300 mL) was added and the mixture filtered through a pad of silica gel eluting with 800 mL of diethyl ether. After removal of the diethyl ether, the residue was chromatographed on silica gel eluting with EtOAc/hexane, 1:19 then 1:14 then 1:9 to give 16-3 as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([NH:9][C@H:10]1[C@H:15]([O:16][CH3:17])[CH2:14][CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H][H]>CO.[Pd]>[CH3:17][O:16][C@@H:15]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[NH:9][P:4](=[O:5])([O:6][CH2:7][CH3:8])[O:3][CH2:1][CH3:2]
Reactant: [H][H]
Reactant: CCOP(=O)(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1OC)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(N[C@@H]1CNCC[C@H]1OC)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A mixture of trans-benzyl 3-(diethoxyphosphorylamino)-4-methoxypiperidine-1-carboxylate (2.00 g, 4.99 mmol) and 10% Pd/C (0.27 g, 0.25 mmol) in methanol (30 mL) was charged with 1 atmosphere hydrogen and stirred at room temperature for 1 hour. The catalyst was removed by filtration and washed with methanol (20 mL). The filtrate was concentrated in vacuo to give diethyl trans-4-methoxypiperidin-3-ylphosphoramidate (1.30 g, 98%) as an oil.
Reaction SMILES: [CH3:1][Mg]Br.[C:4]1([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:12]=[C:11]2[CH:19]=[O:20])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[NH4+]>C1COCC1>[C:4]1([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:12]=[C:11]2[CH:19]([OH:20])[CH3:1])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1nc2cnccc2n1-c1ccccc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nc2cnccc2n1-c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
Methylmagnesium bromide (3.0M in diethyl ether, 2.1 mL, 6.36 mmol) was added to a stirred solution of 1-phenyl-1H-imidazo[4,5-c]pyridine-2-carbaldehyde (0.71 g, 3.18 mmol) in THF (25 mL) at −78° C. under nitrogen. The resulting mixture was stirred at −78° C. for 2 h then at −10° C. for 20 minutes, then re-cooled to −78° C. and additional methyl magnesium bromide (3.0M in diethyl ether, 1 mL, 3.00 mmol) added. The resultant mixture was stirred at −10° C. for 30 minutes then poured into saturated aqueous ammonium chloride solution (25 mL) and extracted with EtOAc (3×50 mL). The combined EtOAc extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was dissolved in THF (25 mL) and cooled to −78° C. and methyl magnesium bromide (3.0M in diethyl ether, 2.1 mL, 6.36 mmol) added, then stirred at −78° C. for 30 minutes followed by −10° C. for 1 h. The mixture was then poured into saturated aqueous ammonium chloride solution (25 mL) and extracted with EtOAc (3×50 mL). The combined EtOAc extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by chromatography (SiO2 0-10% (2M ammonia in methanol) in DCM) to give the title compound as a yellow oil (0.36 g, 47%). LCMS (method H): Rt 1.42 min, [M+H]+ 240.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:5][C:4]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:3]1.[Cl:21][C:22]1[CH:27]=[C:26]([CH:28]=O)[CH:25]=[C:24]([Cl:30])[C:23]=1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[F:38].C(O)(=O)C.C([BH3-])#N>CN(C=O)C>[ClH:21].[Cl:21][C:22]1[C:23]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])=[C:24]([Cl:30])[CH:25]=[C:26]([CH2:28][N:18]2[CH2:17][CH2:16][C:4]3([O:3][C:2](=[O:1])[N:6]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:14][CH:15]=4)[CH2:5]3)[CH2:20][CH2:19]2)[CH:27]=1
Reactant: O=Cc1cc(Cl)c(-c2ccc(F)cc2F)c(Cl)c1
Reactant: O=C(O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Agent: [BH3-]C#N
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cl
Product: O=C(O)c1ccc(N2CC3(CCN(Cc4cc(Cl)c(-c5ccc(F)cc5F)c(Cl)c4)CC3)OC2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 132.1 %

Procedure:
To a solution of 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoic acid (27 mg, 0.087 mmol) (from Example 5-1, Step 4) and 2,6-dichloro-2′,4′-difluorobiphenyl-4-carboxaldehyde (20 mg, 0.070 mmol) (from Step 3) in DMF (2 mL) in a 20 mL scintillation vial was added acetic acid (13 uL, 0.209 mmol) and MP-cyanoborohydride resin (56 mg, 0.140 mmol, 2.49 mmol/g). The mixture was shaken at room temperature for 20 hours and then was filtered to remove the resin and washed with acetonitrile/water. The mixture was acidified with TFA and used directly for reverse phase (C-18) HPLC chromatography (10-55% acetonitrile/water gradient, 0.1% TFA) to afford the desired title compound (27 mg) as a solid TFA salt. The TFA salt was converted to the title compound hydrochloride salt by taking up in DCM and addition of excess 2M hydrogen chloride in ether and evaporation (twice) followed by trituration with ether to give the HCl salt (24 mg) as a white solid.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[C:8]([CH:11]=1)[CH:9]=O>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[C:8]([CH:11]=1)[CH2:9][NH:2][CH3:1]
Reactant: CN
Reactant: O=Cc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: CNCc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Reaction time: 0.08 h

Procedure:
Under N2, a solution of methylamine (2.9 mL, 5.8 mmol, 2.0 M solution in CH3OH) in 20 mL of ethanol was treated with titanium (IV) isopropoxide (1.7 mL, 5.8 mmol) at room temperature. After 5 min., a suspension of 5-bromo-2-(3,4-dichlorophenoxy)-benzaldehyde (1.0 g, 2.9 mmol, the title compound of Preparation 1) in 20 mL of ethanol was added and stirred for 16 hr at room temperature. Sodium borohydride (0.165 g, 4.4 mmol) was then added and stirring was continued for an additional 24 hr, at which time the reaction was quenched by the addition of 5 mL of 6 N HCl and 5 mL of water, stirred for 30 min and made basic by the addition of saturated aqueous Na2CO3. The resulting mixture was extracted with EtOAc, and the organic extracts were clarified by filtration throught diatomaceous earth (d.e.), washed with saturated NaCl, dried over Na2CO3 and concentrated in vacuo to a clear oil, 0.987 mg.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]Cl)[CH2:10][CH:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CC(C)=O>[Cl:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[CH2:10][CH:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1
Reactant: CCNCC
Reactant: ClCCN1CCN(Cc2ccc(Cl)cc2)C(c2ccccc2)C1
Agent: Cl
Solvent: CC(C)=O
Product: CCN(CC)CCN1CCN(Cc2ccc(Cl)cc2)C(c2ccccc2)C1

Procedure:
20 g. of 1-(4'-chloro benzyl)-2-phenyl-4-(β-chloro ethyl) piperazine hydrochloride, 14 g. of diethylamine and 200 cc. of acetone are boiled under reflux for 12 hours. After cooling, the precipitated diethylamino hydrochloride is filtered off with suction and the solvent of the filtrate is evaporated in a vacuum. The residue is distilled in a vacuum. 15 g. of a light yellow oil having a boiling point of 190° C./0.06 mm. Hg are obtained. This product is identical with the product as obtained according to Example 1 B.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[C:5]#[N:6].Cl.[NH2:15][OH:16].CCN(C(C)C)C(C)C>CCO>[OH:16][NH:15][C:5](=[NH:6])[C:4]1[CH:7]=[CH:8][C:9]([O:10][CH:11]([CH3:12])[CH3:13])=[C:2]([I:1])[CH:3]=1
Reactant: NO
Reactant: CC(C)Oc1ccc(C#N)cc1I
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)Oc1ccc(C(=N)NO)cc1I
Temperature: 50 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A suspension of 3-iodo-4-isopropoxybenzonitrile (0.576 g; 2 mmol), HCl×NH2OH (0.276 g; 4 mmol) and DIPEA (0.69 ml; 4 mmol) in EtOH (50 ml) was stirred for 18 h at 50° C. The solvent was distilled off and the residue was diluted to 50 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was distilled off to give the title product (0.61 g; 95%), as colourless solid. 1H-NMR (CDCl3) 8.0 (d, 1H, J=2.22 Hz); 7.55 (dd, 1H, J=9.54, 2.28 Hz); 6.77 (d, 1H, J=8.7 Hz); 4.95 (b, 2H); 4.69-4.63 (m, 1H); 1.42 (d, 6H).
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:30](=O)[CH2:31][CH2:32][CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(Cl)(Cl)Cl>[CH2:30]([N:27]1[CH2:28][CH2:29][CH:24]([O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:12])=[O:13])[CH2:25][CH2:26]1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCC=O
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNCC3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCCN1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
A suspension of 3-(1-naphthylsulfonyl)-5-(piperidin-4-yloxy)-1H-indazole (56.5 mg, 0.138 mmol) in 1,2-dichloroethane was treated sequentially with butyraldehyde (0.1 mL, 1 mmol) and acetic acid (0.1 mL, 2 mmol), stirred at ambient temperature for 3 hours, treated with sodium triacetoxyborohydride (46.5 mg, 0.220 mmol), stirred for 1 hour, 20 minutes under nitrogen at ambient temperatures, diluted with chloroform and poured into excess 1.0 N sodium hydroxide. The phases were separated. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was twice purified by flash chromatography using 0.25-0.5% ammonium hydroxide/2.5-5.0% methanol in chloroform to afford 5-(1-butylpiperidin-4-yloxy)-3-(1-naphthylsulfonyl)-1H-indazole as a light orange foam, 25.6 mg (40.0% yield). The foam was dispersed in methanol, treated with ethereal HCl and concentrated in vacuo at 83° C. for 25 hours to give the title product as an orange foam, 22.0 mg, Mass spectrum (+EI, [M+H]+) m/z 464. 1HNMR (500 MHz, DMSO-d6): δ14.16 (d, 1H, J=4.15 Hz), 9.86-9.98 (m*, 1H), 8.73 (dd, 1H, J=15.74 Hz and 8.42 Hz), 8.54-8.56 (m, 1H), 8.27 (d, 1H, J=8.29 Hz), 8.02-8.05 (m, 1H), 7.70-7.75 (m, 1H), 7.54-7.63 (m, 3H), 7.28-7.38 (s* and s*, 1H), 7.09-7.20 (m*, 1H), 4.60-4.80 (m*, 1H), 3.52-3.55 (m, 1H), 3.32-3.35 (m, 1H), 3.00-3.16 (m, 4H), 2.06-2.16 (m, 2H), 1.97-2.00 (m, 1H), 1.79-1.88 (m, 1H), 1.60-1.67 (m, 2H), 1.25-1.34 (m, 2H), 0.92-0.87 ppm (m, 3H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:11].[NH:12]1[CH2:16][CH2:15][NH:14][C:13]1=[S:17].[I:18]I.[I-].[K+]>CO.O>[IH:18].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:17][C:13]2[NH:14][CH2:15][CH2:16][N:12]=2)=[C:3]1[CH3:11]
Reactant: S=C1NCCN1
Reactant: II
Reactant: Cc1cc2ccccc2n1C
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(SC2=NCCN2)c2ccccc2n1C
Product: I
Reaction time: 1 h

Procedure:
To a stirred solution of 3.6 g 1,2-dimethylindole and 2.55 g 2-imidazolidinethione in 80 ml methanol is added a solution of 6.35 g iodine and 13 g potassium iodide in 50 ml water. After 1 hour at room temperature, the solution is concentrated in vacuo until crystals separate, then cooled and filtered. The precipitate is washed with water and ether and is recrystallized from alcohol to give 1,2-dimethyl-3-(2-imidazolin-2-ylthio)-indole hydriodide melting at 203°-205° (with decomposition).
Reaction SMILES: P(O[C:18]([CH3:48])=[C:19]([N:33]1[C:39](=[O:40])[CH:38]2[CH:34]1[S:35][C:36]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[N:37]2)[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.O>C(#N)C>[CH2:41]([C:36]1[S:35][CH:34]2[CH:38]([C:39](=[O:40])[N:33]2[C:19](=[C:18]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[CH3:48])[C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])[N:37]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: C1COCCN1
Reactant: CC(OP(=O)(Oc1ccccc1)Oc1ccccc1)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Solvent: CC#N
Solvent: O
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(Cc3ccccc3)SC21)N1CCOCC1
Reaction time: 2 h

Procedure:
To a solution of diphenyl 1-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate (6.86 g) in acetonitrile (50 ml) at 0°-5° C. was added morpholine (1.83 ml) dropwise and the reaction mixture stirred at this temperature for 2 hours. Water (50 ml) was added and the mixture was extracted with ethyl acetate (40 ml). The organic layer was separated, washed with water (30 ml) and saturated sodium chloride solution (30 ml), dried with magnesium sulphate, filtered and evaporated to give the title compound as a yellow foam in almost quantitative yield. The product obtained was a mixture of geometric isomers (ca. 1:1.4) about the enamine double bond and was identical to that produced in Example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[Br:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38]O)[CH:34]=[CH:35][CH:36]=1>>[ClH:1].[Br:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][O:24][C:23]([C:18]2([C:20]([O:22][CH2:38][CH2:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([Br:30])[CH:32]=3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH:34]=[CH:35][CH:36]=1
Reactant: OCCc1cccc(Br)c1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCCc1cccc(Br)c1)(C(=O)OCCc1cccc(Br)c1)O2)NC[C@H](O)c1cccc(Cl)c1
Product: Cl

Procedure:
The title compound was prepared as a brown oil from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-(3-bromophenyl)ethanol according to the procedure of Example 1; 1H NMR (300 MHz, CDCl3): δ 1.12 (m, J=6.3 Hz, 3H), 2.79 (m, 8H), 3.5 (m 2H), 4.18 (s, 1H, OH), 5.56 (m, 1H), 6.8 (m, 3H), 7.0 (m, 4H), 7.33 (m, 4H), 7.5 (m, 4H), 8.5 (m, 1H, NH); MS (ES) m/z (relative intensity): 788 (M+ +H, 100).