Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][CH:9]1[CH:21]([C:26]1[C:34]2[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[CH2:22][N+:23]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][Si:14]([C:17]([CH3:19])([CH3:18])[CH3:20])([CH3:16])[CH3:15])[CH2:10][CH:9]1[CH:21]([C:26]1[C:34]2[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[CH2:22][NH2:23])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(C[N+](=O)[O-])c1c[nH]c2cc(F)ccc12
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(CN)c1c[nH]c2cc(F)ccc12
Reaction time: 2.5 h
Yield: 97.3 %

Procedure:
To a solution of 78 (10.1 g, 20.0 mmol) in EtOH (150 mL) in a Parr bottle was added an aqueous suspension of Raney Ni (6 pipettes). The bottle was evacuated and flushed with H2 five times, charged to 50 PSI H2 (344.7 KPa) and shaken for 2.5 h. The reaction mixture was filtered through diatomaceous earth (Celite®) and concentrated to afford 79 (9.3 g, 97%) as an off-white powder which was used without further purification. Mass spectrum, m/z [478.2] (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([CH:17]=[CH:18][CH:19]=3)[N:11]=[C:12]([CH3:16])[C:13]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.C(N(CC)CC)C>ClCCl.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[N:10]([CH:17]=[CH:18][CH:19]=3)[N:11]=[C:12]([CH3:16])[C:13]=2[CH:14]=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1nn2cccc2c(-c2ccc(F)cc2)c1CO
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nn2cccc2c(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [4-(4-fluorophenyl)-2-methylpyrrolo-[1,2-b]pyridazin-3-yl]methanol (505 mg) and triethylamine (997 mg) in dichloromethane (4 mL) and dimethyl sulfoxide (2 mL) was added sulfur trioxide pyridine complex (941 mg) in an ice-water bath under nitrogen. After 30 minutes, the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated to about ⅓ volume. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 30 mL) eluted with hexane-chloroform=3-1 and 2-1 to give 4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazine-3-carbaldehyde as an yelow solid (340 mg, 67.9%).
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:40]([O:42][C:43]([C:45]1([NH2:54])[CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46]1)=[O:44])[CH3:41].CCN(C(C)C)C(C)C>CO.C(Cl)Cl.C(Cl)Cl>[CH2:40]([O:42][C:43]([C:45]1([NH:54][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46]1)=[O:44])[CH3:41]
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccccc2C1
Reaction time: 0.08 h
Yield: 133.6 %

Procedure:
A 25 mL vial containing a stirring bar is charged with 2-cyclobutoxy-3-methyl-benzoic acid (1.01 g, 4.87 mmol) and dry DCM (14 mL). Stirring is initiated. HBTU (1.84 g, 4.86 mmol) is added. After 5 min, the 2-aminoindane-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) is added followed by the DIPEA (1.9 mL, 10.92 mmol). The reaction is allowed to stir for 12 days. Analysis by tlc of the reaction mixture (silica, 10% MeOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (70 mL) and transferred to a separatory funnel. This is washed consecutively with dilute aqueous HCl (3%, 35 mL), saturated aqueous NaHCO3 (35 mL) and brine (35 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 2.56 g of an off-white solid. This material is dissolved in 15 mL of DCM. This is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAc in heptanes for 3 column volumes followed by a linear gradient to 50% over 10 column volumes and then 100% EtOAc for 2 column volumes with a ramp of 1 column volume. 25 mL fractions are collected. Fractions 7 through 22 are combined and evaporated in vacuo. Pumping to a constant weight gives amorphous white solid 1.73 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([F:23])=[C:17](F)[C:16]=3[F:25])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28][CH:29]([OH:31])[CH3:30].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([F:23])=[C:17]([O:31][CH:29]([CH3:30])[CH3:28])[C:16]=3[F:25])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)c(F)c(F)cc2c1O
Reactant: CC(C)O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)Oc1c(F)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1F
Temperature: 25 °C

Procedure:
N-((4-Chlorophenyl)methyl)-4-hydroxy-6,7,8-trifluoro-3-quinolinecarboxamide (500 mg) from Example No. 15 and sodium hydride (60% dispersion, 109 mg) are dissolved in DMF (10 mL) and to the mixture is added 2-propanol (115 μL). After being heated for 1 h, additional sodium hydride (50 mg) is added, and the mixture is heated for an additional 1 h. The reaction mixture is allowed to cool to rt, poured into sat. aq. ammonium chloride (25 mL), and is filtered. The crude product is purified by column chromatography (dichloromethane/methanol, 100/1) to afford 62 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]3[CH2:12][CH2:13][O:14][C:15]([CH2:18][C:19](O)=[O:20])([CH2:16][CH3:17])[C:10]=3[NH:9][C:8]=12.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:16]([C:15]1([CH2:18][CH2:19][OH:20])[C:10]2[NH:9][C:8]3[C:7]([C:11]=2[CH2:12][CH2:13][O:14]1)=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:2][CH3:1])[CH3:17]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
A solution of etodolac (2.0 g, 6.97 mmol) in dry THF (5 mL) was added dropwise to 1M LiAlH4 in THF (10.5 mL, 10.5 mmol, 1.5 eq) over five minutes and stirred at room temperature overnight under argon. The resulting mixture was then slowly quenched with EtOAc and poured over water to form an emulsion. The emulsion was filtered, and the aqueous layer was separated and extracted twice with EtOAc. The three organic phases were combined, washed with brine, dried with Na2SO4, concentrated, and purified by column chromatography using 50:50:EtOAc:Hexane to give a yellow oil (1.87 g, 98%): 1HNMR (CDCl3, δ TMS): 0.95 (t, 3H), 1.36 (t, 3H), 1.96 (m, 2H), 2.14 (m, 2H), 2.68 (br, OH), 2.81 (m, 2H), 2.83 (q, 2H), 3.70 (m, 2H), 4.07 (m, 2H), 7.02–7.39 (m, 3H, Ar—H), 7.74 (br, 1H, NH). MS+: m/z 296 (MNa+). MS−: m/z 308 (MCl−), 272 ([M−H]−).
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([OH:33])(=[O:32])[CH2:30][OH:31]>CC(O)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([O-:33])(=[O:32])[CH2:30][OH:31]
Reactant: O=C(O)CO
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CC(C)O
Product: O=C([O-])CO
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Sitagliptin base (150 mg) was suspended in 2-propanol (2.5 mL). Glycolic acid (28 mg) was added and the mixture was stirred for one hour at ambient temperature and 2 hours at 40° C. to give a solution. The mixture was allowed to cool to ambient temperature and stirred for 24 hours at this temperature. The solution was concentrated under vacuum at ambient temperature.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:30])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:9][CH2:10][C:11](OC)=[O:12].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:7][C:8]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:30])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:9][CH2:10][CH2:11][OH:12]
Reactant: COC(=O)CC=C(C)CCCC(C)CCCC(C)CCCC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=CCCO)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
Under a nitrogen atmosphere, 9.8 g (0.26 mol) of lithium aluminum hydride was added little by little at 0° C. to a solution of 35 g (0.10 mol) of methyl 4,8,12,16-tetramethylheptadec-3-enoate in dry tetrahydrofuran (250 mL). After being stirred at 50° C. for 3 hours, the reaction mixture was cooled on ice, followed by careful addition of saturated sodium sulfate aqueous solution until the resulting gray suspension turned white. Sodium sulfate was added to the solution at room temperature for drying. After filtration, the filtrate was concentrated to obtain 28.7 g of the title compound (92% yield) as a colorless transparent liquid. The results of NMR analysis of the obtained compound are as shown below.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([C:15]=2[NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][NH:21]3)[C:13]#[N:14])=[CH:4][CH:3]=1.[CH2:26]([C@H:33]([NH:36]C(=O)OC(C)(C)C)[CH2:34]O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>C1COCC1>[NH2:36][C@@H:33]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:34][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([C:15]=2[NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][NH:21]3)[C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: N#Cc1cncc(-c2ccc(O)cc2)c1Nc1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cncc(-c2ccc(OC[C@@H](N)Cc3ccccc3)cc2)c1Nc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 21 h
Yield: 29.5 %

Procedure:
To a suspension of 5-(4-hydroxyphenyl)-4-(1H-indol-4-ylamino)nicotinonitrile 225 (100 mg, 0.31 mmol), tert-butyl (1S)-1-benzyl-2-hydroxyethylcarbamate (77 mg, 0.31 mmol), and Ph3P (97 mg, 0.37 mmol) in THF (2.0 mL) was added diethyl azodicarboxylate (64 mg, 0.37 mmol) via a syringe over 6 min. The resulting mixture was stirred at r.t. for 21 h and treated with concentrated HCl (˜200 mg). After heating at 60° C. for one h, the reaction mixture was partitioned between saturated NaHCO3 and CH2Cl2. The combined organics were dried over Na2SO4, concentrated and purified by silica gel flash column chromatography (eluting with 4% MeOH/CH2Cl2) to give 42 mg (30%) of 5-(4-{[(2S)-2-amino-3-phenylpropyl]oxy}phenyl)-4-(1H-indol-4-ylamino)nicotinonitrile 226 as a white solid. MS: 460.4 (M+H); melting range: 83-85° C.
Reaction SMILES: C(O)CO.[S:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14](C(OCC)=O)[C:15]([O:17]CC)=[O:16])=[CH:13][C:8]=2[CH:7]=[CH:6]1.[OH-].[K+].O>C1(C)C=CC=CC=1>[S:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][C:15]([OH:17])=[O:16])=[CH:13][C:8]=2[CH:7]=[CH:6]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc2sccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: OCCO
Product: O=C(O)Cc1ccc2sccc2c1
Yield: 12.2 %

Procedure:
To ethylene glycol (1.0 mL) suspension of 0.25 g of diethyl 2-(1-benzothiophen-5-yl)malonate were added 1.0 mL of 40% (w/w) potassium hydroxide aqueous solution and 0.3 mL of water, which was then refluxed for 2 hours. To the reaction mixture were added water and toluene, and the aqueous layer was separated. The pH was adjusted to 2 with 6 mol/L hydrochloric acid, and thereto was added ethyl acetate. The organic layer was separated, and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was suspended to 5 mL of xylene, and thereto was added 0.01 g of p-toluenesulfonic acid monohydrate, which was then refluxed for 30 minutes. The solvent was distilled off under reduced pressure, and to the resultant residue were added toluene and cyclohexane. The precipitate was collected by filtration to provide 0.02 g of 2-(1-benzothiophen-5-yl)acetic acid as pale yellow solid form.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(N(CC)CC)C.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]([NH:11][S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Nc1cc(Br)c2cc[nH]c2c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cc(Br)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
4-Bromo-6-amino indole (100 mg, 0.47 mmol) and triethylamine (0.1 ml, 0.71 mmol) were stirred together in pyridine at 0° C. Mesyl chloride (54 mg, 0.47 mmol) was then added and the mixture stirred for 1 hour, then allowed to warm to room temperature. The mixture was loaded directly onto an aminopropyl cartridge (10 g) and eluted with methanol. Solvent was evaporated and the residue was further purified by chromatography on silica (20 g cartridge) eluting with 0-25% methanol in DCM over 20 mins to afford the title compound as a orange/brown gum (110 mg).
Reaction SMILES: [CH3:1][C:2]1[N+:7]([O-:8])=[C:6]([CH3:9])[CH:5]=[C:4](Cl)[N:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH3:1][C:2]1[N+:7]([O-:8])=[C:6]([CH3:9])[CH:5]=[C:4]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=1
Reactant: C1CCNCC1
Reactant: Cc1cc(Cl)nc(C)[n+]1[O-]
Product: Cc1cc(N2CCCCC2)nc(C)[n+]1[O-]

Procedure:
100 ml of piperidine are introduced into a 250 ml three-necked flask fitted with a thermometer, a condenser and a magnetic stirrer and 13.5 g (8.51×10-2 mol) of 2,4-dimethyl-6-chloropyrimidine 3-oxide are then added, in solid portions, in a manner such that exothermic heat does not develop beyond 60° C. The reaction mixture is then allowed to return to ambient temperature; the piperidinium hydrochloride is then removed from the mixture by filtration and the filtrate is evaporated to dryness. The crude oil obtained crystallises rapidly at ambient temperature. The crystalline mass is dissolved in a minimum of ethanol and ethyl ether is then added cold until precipitation occurs. The mixture is stirred for half an hour and the precipitate is then filtered off and drained. A final filtration through silica gel using the dichloromethane/methanol (90/10) eluent system allows white crystals to be obtained.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:15]([NH2:19])(=[O:18])[CH:16]=[CH2:17].[Cl-].[Al+3].[Cl-].[Cl-].Cl.C(NC(=O)C=C)CCCCCCCCCCCCCCC>CC(C)=O>[C:1]([NH:19][C:15](=[O:18])[CH:16]=[CH2:17])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=CC(N)=O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: C=CC(=O)NCCCCCCCCCCCCCCCC
Agent: Cl
Agent: [Al+3]
Solvent: CC(C)=O
Product: C=CC(=O)NC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a 250 ml capacity conical flask 10.9 g dodecanoyl chloride (0.05 M), 3.5 g acrylamide (0.05 M) and 50 ml acetone were placed to obtain a clear solution. The solution was stirred with a magnetic needle at room temperature. 6.5 g anhydrous aluminium chloride (0.05 M) was added and the reaction mixture was stirred at room temperature. After 5 to 10 minutes of stirring, vigorous evolution of hydrogen chloride took place which ceased after about 5 minutes. The product was isolated following the procedure described for synthesis of N-cetylacrylamide.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:18]([O:20]CC)=O)[CH2:10][CH:9]2[CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:2]1([C:8]2([C:18]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:20])[CH2:10][CH:9]2[CH2:11][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(c2ccccc2)CC1CN1CCOCC1
Reactant: C1CCNC1
Agent: Cl
Product: O=C(N1CCCC1)C1(c2ccccc2)CC1CN1CCOCC1

Procedure:
In a manner similar to that described in Example 1, but hydrolyzing the hydrochloride of 1-phenyl 1-ethoxycarbonyl 2-morpholinomethyl cyclopropane (Z) and then treating the intermediate acid chloride with pyrrolidine, there is obtained the product of the formula ##STR15##
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].N([O-])=O.[Na+].[I-:14].[K+]>Cl.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([I:14])[CH:7]=1
Reactant: [I-]
Reactant: Nc1cc(Cl)ccc1O
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Oc1ccc(Cl)cc1I
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
2-Amino-4-chlorophenol (50 g, 0.35 mol) was dissolved in 500 ml of 2.5N HCl. The resulting solution was cooled to 0° C., at which a solution of 25.25 g (0.37 mol) of sodium nitrite in 50 ml of water was added slowly. After stirring for 30 minutes, a chilled solution of 70 g (0.42 mol) of potassium iodide in 100 ml of water was added slowly. The temperature of the reaction mixture was allowed to rise to room temperature, at which the reaction mixture was stirred overnight. The reaction mixture was extracted with ethyl acetate and the solvent was distilled off under reduced pressure, whereby 89.7 g of 4-chloro-2-iodophenol were obtained (yield: 99%). Next, 85 g (0.33 mol) of the 4-chloro-2-iodophenol and 32.5 g (0.36 mol) of copper cyanide were dissolved in 150 ml of DMF. After the resultant solution was heated under reflux for 2 hours, the DMF was distilled off under reduced pressure. The residue was extracted with ethyl acetate and the extract was then washed with water. An insoluble matter was filtered off. The solvent was then distilled off under reduced pressure, whereby 40.4 g of 5-chloro-2-hydroxybenzonitrile were obtained (yield: 80%) (melting point: 150.3-152.6° C.).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:16]=[CH:15][C:14]=3[S:23]([NH2:26])(=[O:25])=[O:24])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1(C2C=CC=CN=2)CCCC1.Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:40].N1(CC2C=CC(C3C=C(CC(C)C)C=CC=3S(NC(C)(C)C)(=O)=O)=CC=2)C=CN=C1>N1C=CC=CC=1>[CH2:42]([O:41][C:39]([NH:26][S:23]([C:14]1[CH:15]=[CH:16][C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:18][C:13]=1[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:12][CH:11]=1)(=[O:24])=[O:25])=[O:40])[CH2:43][CH2:44][CH3:45]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1ccc(S(N)(=O)=O)c(-c2ccc(Cn3ccnc3)cc2)c1
Agent: CC(C)Cc1ccc(S(=O)(=O)NC(C)(C)C)c(-c2ccc(Cn3ccnc3)cc2)c1
Agent: c1ccc(N2CCCC2)nc1
Solvent: c1ccncc1
Product: CCCCOC(=O)NS(=O)(=O)c1ccc(CC(C)C)cc1-c1ccc(Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 68 %

Procedure:
The crude product from step (d) above was dissolved in pyridine (2 mL, dried over 4 Å molecular sieve). Pyrrolidinopyridine (36 mg, 0.024 mmol) and butyl chloroformate (276 μL, 2.23 mmol) were added to the mixture, which was then stirred for 30 h under N2 (g) at room temperature. The solvent was removed in vacuo and then co-evaporated with acetonitrile. Purification using column chromatography with CHCl3: MeOH (10:1) as eluent yielded the title compound (66.7 mg, 0.142 mmol) in 68% yield (from 2-(4-imidazol-1-ylmethylphenyl)-4-iso-butyl-N-tert-butylbenzene-sulfonamide).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([CH:11]=O)[CH:3]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21][C:22]#[N:23].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:14]3[C:15](=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[C:21]([C:22]#[N:23])=[CH:11][C:4]=2[CH:3]=1
Reactant: O=Cc1cc(Cl)ccc1B(O)O
Reactant: N#CCc1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cc2cc(Cl)ccc2c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 20.2 %

Procedure:
To a microwave vial was added 4-chloro-2-formylphenylboronic acid (480 mg, 2.6 mmol), 2-(2-bromo-5-chlorophenyl)acetonitrile (500 mg, 2 mmol), tetrakis(triphenyl phosphine)palladium (0) (100 mg, 0.085 mmol) and cesium carbonate (2.12 g, 6.5 mmol) sequentially. The mixture was suspended in toluene (10 mL) and methanol (5 mL). Then the reaction vial was sealed and place in a microwave reactor and irradiated at 150° C. for 10 minutes. The reaction was cooled to room temperature, diluted with ethyl acetate, and filtered through a short celite pad. The solution was concentrated. The crude residue was purified by flash chromatography to yield 2,7-dichlorophenanthrene-9-carbonitrile (110 mg, 19%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH:23]1([CH2:29][C@H:30]([NH:43][C:44](=O)[O:45]C2C=CC([N+]([O-])=O)=CC=2)[CH2:31][N:32]([CH3:42])[C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:44](=[O:45])[NH:43][C@H:30]([CH2:31][N:32]([CH3:42])[C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])[CH2:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:18]2)([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CO[C@@](C)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Reactant: CN(C[C@H](CC1CCCCC1)NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)OCC[Si](C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CO[C@@](C)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
A mixture of ethyl 2-((R)-1-(3-chlorophenyl)-1-((R)-piperidin-3-yl)ethoxy)acetate, (S)-4-nitrophenyl 1-cyclohexyl-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)propan-2-ylcarbamate (0.096 g, 0.20 mmol), and DIPEA (1 mL) in CH2Cl2 was stirred at rt for 24 h. After the reaction mixture was evaporated under reduced pressure, the crude product was purified by reversed-phase HPLC to afford 0.0425 g (47% in two steps) of ethyl 2-((R)-1-(3-chlorophenyl)-1-((R)-1-((S)-1-cyclohexyl-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)propan-2-ylcarbamoyl)piperidin-3-yl)ethoxy)acetate. MS ESI +ve m/z 668 (M+H).
Reaction SMILES: [CH2:1]([CH:8]([NH2:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH2:36][C:37](O)=[O:38])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:23]>>[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH2:36][C:37]([NH:21][CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:38])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:23]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: NC(Cc1ccccc1)c1ccccc1N1CCCCC1
Product: CCOC(=O)c1ccc(CC(=O)NC(Cc2ccccc2)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
Prepared analogously to Example 47 from α-benzyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.