Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:30]([C:33]1[CH:34]=[C:35](O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])[CH3:31]>>[C:30]([C:33]1[CH:38]=[C:37]([CH:36]=[CH:35][CH:34]=1)[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)(=[O:32])[CH3:31]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Cl)cc3)CC2)c1
Product: CC(=O)c1cccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Cl)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-acetylphenol: SMS m/e: 533.1 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:17]([F:18])=[CH:16][C:15](Br)=[C:14]2[C:10]=1[C:11]([CH2:21][C:22]([NH:24][CH3:25])=[O:23])=[CH:12][N:13]2[CH3:20])C1C=CC=CC=1.N1C=CC=CC=1.Cl>CO.[Pd]>[F:18][C:17]1[C:9]([OH:8])=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:20])[CH:12]=[C:11]2[CH2:21][C:22]([NH:24][CH3:25])=[O:23]
Reactant: CNC(=O)Cc1cn(C)c2c(Br)cc(F)c(OCc3ccccc3)c12
Agent: [Pd]
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CNC(=O)Cc1cn(C)c2ccc(F)c(O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
A mixture of 33-5 (1.4 g, 4.5 mmol), pyridine (2 mL) and Pd/C (140 mg, 10%) in methanol (20 mL) was stirred at room temperature overnight under hydrogen atmosphere. The mixture was adjusted with hydrochloric acid to pH=5-6. The solid was filtered off and the filtrate was concentrated. The resulting residue was partitioned between water (20 mL) and ethylacetate (20 mL). The organic layer was separated, washed with brine (3×30 mL), dried over MgSO4, filtered and evaporated to obtain 33-6 (700 mg, 85%) as a brown solid. LRMS: calc 236.1 and found: 237.1 [M+1].
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Br:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[C:15]([NH2:20])=[CH:14][CH:13]=1>C1COCC1>[Br:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][CH:8]=[O:10])=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: COc1nc(Br)ccc1N
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1nc(Br)ccc1NC=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100 %

Procedure:
A mixture of acetic anhydride (8.54 mL, 24.63 mmol) and formic acid (12.8 mL, 24.63 mmol) was stirred at room temperature for 40 min. To this mixture 6-bromo-2-methoxypyridin-3-amine (5.000 g, 24.63 mmol) in 30 mL of THF was added dropwise. The resulting solution was heated at 60° C. with stirring for 16 h. Upon cooling, the reaction mixture was poured into icewater. The resulting precipitate was filtered to give N-(6-bromo-2-methoxypyridin-3-yl)formamide (5.690 g, 24.63 mmol, 100% yield) as light brown solid. LC-MS (M+Na)+=231.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:10][CH2:11][CH2:12][CH2:13]Br>>[Br:10][CH2:11][CH2:12][CH2:13][O:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Oc1cc(F)cc(F)c1
Reactant: BrCCCBr
Product: Fc1cc(F)cc(OCCCBr)c1

Procedure:
Analogously to Example 91b, 0.98 g of 3,5-difluorophenol and 15.2 g of 1,3-dibromopropane are reacted. The title compound is obtained as a colourless oil. Rf=0.70 (1:6 EtOAc-heptane); Rt=5.13.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.CCN(CC)CC.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(Cl)Cl>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:6][CH:1]2[CH2:5][CH:4]=[CH:3][CH2:2]2)=[O:22])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: OC1CC=CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OC1CC=CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a solution of 3-cyclopentene-1-ol (7.0 g, 83.0 mmol) and Et3N (14.5 g, 143.0 mmol) in CH2Cl2 (200 mL) was added 4-nitrobenzoyl chloride (18.5 g, 100.0 mmol) as solid in several portions over a period of 30 min. The resulting suspension was stirred at room temperature over night. The precipitate was filtered off and the filtrate was washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1; column 40M; TLC method: n-hexane/ethyl acetate 9/1; Rf=0.50), affording the title product (15.6 g, yield 81%): 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J=8.9 Hz, 2H), 8.20 (d, J=8.9 Hz, 2H), 5.81 (m, 2H), 5.69 (m, 1H), 2.95 (m, 2H), 2.61 (m, 2H).
Reaction SMILES: C(Br)CBr.Br[C:6]([CH3:8])=[CH2:7].[CH:9](=[O:15])[CH2:10][CH2:11][C:12]#[C:13][CH3:14].[Cl-].[NH4+]>O1CCCC1>[CH3:8][C:6]([CH:9]([OH:15])[CH2:10][CH2:11][C:12]#[C:13][CH3:14])=[CH2:7]
Reactant: C=C(C)Br
Reactant: CC#CCCC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: C=C(C)C(O)CCC#CC
Temperature: 25 °C
Yield: 85 %

Procedure:
Magnesium (14.4 g, 0.6 g atom) was dried in a 250 ml flask fitted with reflux condenser, mechanical stirrer and addition funnel. After initiation of reaction under dry N2 with about one ml ethylene dibromide in 70 ml tetrahydrofuran, 36.0 g (0.30 mole) 2-bromopropene was added dropwise at such a rate as to maintain reflux without external heating. The Grignard solution was then stirred until it cooled to room temperature (30 minutes-1hour). It was then cooled further to -15° in ice-salt, and the total crude 4-hexynal from part (c) above was added dropwise over 15 minutes. The reaction mixture was stirred for 2 hours at room temperature, saturated ammonium chloride solution was added and the product was extracted with ether. There was obtained 23.50 g of 2-methyloct-1-en-6-yn-3-ol (85%, based on 4-methyl hexynoate) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:19])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18].C(N(CC)CC)C.C([O:29][C:30](=O)[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])C>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:19])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:30](=[O:29])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33]
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Reactant: Cc1nc2cccc3n(CCCCCN)c(=O)c1n23
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc2cccc3n(CCCCCNC(=O)C(F)(F)C(F)(F)F)c(=O)c1n23
Temperature: 25 °C
Yield: 50.5 %

Procedure:
To a solution of 2.58 g (10.0 mmol) of 3-methyl-1-[5-(amino)pentan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one and 1.81 ml (13.0 mmol) of triethylamine in 100 ml of acetonitrile was added, while stirring at room temperature, 2.31 g (12.0 mmol) of pentafluoropropionic acid ethyl ester. The mixture was stirred for 4 hours at the same temperature. The solvent was distilled off. To the residue was added methylene chloride, and the mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to afford 2.04 g of the desired compound (50.4%, a pale yellow solid).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([CH3:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([CH3:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(C)c(Cl)ccc23)c1
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3c(C)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-Chloro-2,7-dimethyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:18])[CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:20][N:21]1[CH:25]=[C:24]([NH2:26])[CH:23]=[N:22]1.C(N(C(C)C)C(C)C)C>CCCCO>[CH3:18][N:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:26][C:24]2[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=2)[N:7]=1)[CH:9]1[CH:13]2[O:14][CH2:15][CH:16]([OH:17])[CH:12]2[O:11][CH2:10]1
Reactant: Cn1cc(N)cn1
Reactant: CN(c1ccnc(Cl)n1)C1COC2C(O)COC21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(c1ccnc(Nc2cnn(C)c2)n1)C1COC2C(O)COC21
Temperature: 150 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a suspension of 6-((2-chloropyrimidin-4-yl)(methyl)amino)hexahydrofuro[3,2-b]furan-3-ol (358.0 mg, 1.32 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (178.6 mg, 1.34 mmol) in n-BuOH (5 mL) was added N-ethyldiisopropylamine (434.6 mg, 3.36 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as a beige solid (300 mg, 68.4%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[F:11].[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:11])[CH:4]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Br)c(F)c1
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(Br)c(F)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 0° C. solution containing 2.4 g of 1-(4-bromo-3-fluorophenyl)ethanone (11.1 mmols) in 56 mL of CHCl3 was added dropwise 0.57 mL of bromine (11.1 mmols). The reaction was stirred at 0° C. for three hours and then allowed to warm to ambient temperature. The reaction mixture was quenched with 10 mL of saturated aqueous Na2S2O3. The layers were separated, and the organics were dried over MgSO4, filtered through a frit, and concentrated to a yellow solid which was used without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([NH:4][C:5](=[O:25])[C:6]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[CH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C=C(C(=O)NC2CC2)c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=Cc2ccc(C(=O)O)cc2)C(=O)NC2CC2)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of methyl 4-(3-(cyclopropylamino)-2-(4-methylphenyl)-3-oxoprop-1-en-1-yl)benzoate (4 g, 12 mmol) in methanol (10 mL), a solution of NaOH (1.4 g, 36 mmol) in water (1 mL) was added. The reaction mixture was refluxed for two hours at 70° C. The solvent was removed by evaporation, poured to ice cold water. The aqueous layer was acidified to pH 3 with citric acid and allowed to stand at 4° C. for 30 minutes the solid precipitated out was filtered and dried under vacuum to get a pale yellow solid (3.2 g, 83% yield).
Reaction SMILES: [F:1][CH:2]([F:56])[C:3]1[C:11]2[C:10]([F:13])([F:12])[CH2:9][CH2:8][C:7]([F:15])([F:14])[C:6]=2[N:5]([CH2:16][C:17]([NH:19][C@H:20]([C:30]2[C:35]([C:36]3[CH:37]=[CH:38][C:39]([F:45])=[C:40]([CH:44]=3)[C:41]([NH2:43])=[O:42])=[CH:34][N:33]=[C:32]([N:46]3[CH2:55][CH2:54][C:49]4(OCC[O:50]4)[CH2:48][CH2:47]3)[N:31]=2)[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)=[O:18])[N:4]=1.Cl>C1COCC1>[F:56][CH:2]([F:1])[C:3]1[C:11]2[C:10]([F:12])([F:13])[CH2:9][CH2:8][C:7]([F:14])([F:15])[C:6]=2[N:5]([CH2:16][C:17]([NH:19][C@H:20]([C:30]2[C:35]([C:36]3[CH:37]=[CH:38][C:39]([F:45])=[C:40]([CH:44]=3)[C:41]([NH2:43])=[O:42])=[CH:34][N:33]=[C:32]([N:46]3[CH2:47][CH2:48][C:49](=[O:50])[CH2:54][CH2:55]3)[N:31]=2)[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)=[O:18])[N:4]=1
Reactant: NC(=O)c1cc(-c2cnc(N3CCC4(CC3)OCCO4)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F
Agent: Cl
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2cnc(N3CCC(=O)CC3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Compound 19B (40 mg, 0.05 mmol) was dissolved in 2 mL of THF and to it was added 1 mL of 6N HCl. The mixtures was stirred at ambient temperature for 16 hours and then extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC eluting with acetonitrile/water (with 0.1% TFA) to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.71 (d, J=5.0 Hz, 1H), 7.46 (s, 1H), 7.33 (m, 1H), 7.30-7.18 (m, 1H), 7.11 (d, J=11.0 Hz, 1H), 6.98 (m, 1H), 6.78 (t, J=53.6 Hz, 1H), 6.58 (m, 1H), 6.20 (d, J=6.2 Hz, 2H), 5.37 (d, J=7.4 Hz, 1H), 5.11-4.89 (m, 2H), 4.22-3.98 (m, 4H), 2.83 (m, 2H), 2.54 (m, 8H). MS (m/z) 754.11 [M+H]+.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8])(=O)C.[OH-].[Na+].Cl>CO>[SH:4][CH2:5][CH:6]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8]
Reactant: CC(=O)SCC(Cc1ccc(N(C)C)cc1)C(=O)Nc1cccc(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1ccc(CC(CS)C(=O)Nc2cccc(C(=O)O)c2)cc1
Reaction time: 1 h
Yield: 30.1 %

Procedure:
3-[[2-Acetylthiomethyl-3-(4-dimethylaminophenyl)-propionyl]amino]benzoic acid (compound of Example 45) (2.6 g) is dissolved in 50% aqueous methanol (30 ml), and the mixture is adjusted to pH 12.0 with 10% aqueous sodium hydroxide solution under nitrogen. After reacting at room temperature for one hour, the reaction mixture is adjusted to pH 4.5 with 10% hydrochloric acid, and methanol is distilled off. The resulting aqueous solution is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected, and acetonitrile is distilled off and the residue is lyophilized to give the title compound (0.7 g).
Reaction SMILES: [NH2:1][C:2]1([C:15]([OH:17])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl.[CH2:19]([O:26][C:27](ON1C(=O)CCC1=O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[OH-].[Na+].COCCOC>[CH2:19]([O:26][C:27]([NH:1][C:2]1([C:15]([OH:17])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)O)CC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(=O)O)CC1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
4-Amino-1-tert-butoxycarbonylpiperidine-4-carboxylic acid (18.0 g) was dissolved in 0.03M aqueous sodium hydroxide (750 mL), and 1,2-dimethoxyethane (100 mL). The pH was adjusted to 9.5 with dilute hydrochloric acid, and the suspension was added to an ice-cold solution of N-(benzyloxycarbonyloxy)succinimide (28.8 g) in 1,2-dimethoxyethane (100 mL). The pH was kept at 9.5 by addition of aq. sodium hydroxide, and the mixture was stirred at room temperature. More N-(benzyloxycarbonyloxy)succinimide (3 g) was added after 7 h, then stirring continued overnight. After evaporation to remove the 1,2-dimethoxyethane, the aqueus residue was extracted with ether then acidified to pH4 and extracted with ethyl acetate. This extract was washed with dilute hydrochloric acid, water and brine, dried and evaporated. Trituration of the oily residue gave 4-benzyloxycarbonylamino-1-tert-butoxycarbonylpiperidine-4-carboxylic acid (23 g). This acid (9.62 g) was esterified by treatment with allyl bromide (2.2 mL), potassium carbonate (7.04 g) and potassium iodide (catalytic) in acetone (100 mL) under reflux for 20 h. Evaporation, partitioning of the residue between dichloromethane and water and evaporation of the organic phase gave the allyl ester (10.2 g). This was then treated with trifluoroacetic acid in dichloromethane (1.5 h, room temp.) to give, after basification of the triflate salt and extraction with dichloromethane/methanol, the piperidine free base (6.58 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:12]12[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:17]C(=O)O[C:13]2=[O:14]>>[C:13]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)(=[O:14])[C:12]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH2:17]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: CC(C)(C)c1ccc(OC(=O)c2ccccc2N)cc1

Procedure:
To 112.5 g. of p-tert-butylphenol heated at 100°-120° C. there was added in portions 123 g. of isatoic anhydride during about 0.75 hour. The reaction mixture was allowed to cool and was then extracted with hot ethyl alcohol from which the crude ester crystallized upon cooling. Recrystallization from n-heptane afforded the crystalline ester mp 142°-143° C.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23](Cl)[C:22]=1[NH2:32])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH2:13]([N:20]1[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:32]=[C:1]1[OH:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1ccccc1
Solvent: C1CCOC1
Product: Oc1nc2cnc3ccccc3c2n1Cc1ccccc1
Temperature: 50 °C
Yield: 70.2 %

Procedure:
1,1′-Carbonyldiimidazole (2.9 g, 18 mmol) was added to a solution of N4-benzyl-2-chloroquinoline-3,4-diamine (5.0 g, 18 mmol) in tetrahydrofuran (THF) (50 mL), and the reaction was heated at 50° C. for three days. An analysis by liquid chromatography/mass spectrometry (LC/MS) indicated the presence of starting material, and additional 1,1′-carbonyldiimidazole (1.5 g, 9.2 mmol) was added. The reaction was stirred for several hours at 80° C., and additional 1,1′-carbonyldiimidazole (2.9 g, 18 mmol) was added. The reaction was stirred for one hour at 80° C. and overnight at 50° C. A solid was present and was isolated by filtration, washed with diethyl ether, and dried under vacuum to provide 3.48 g of 1-benzyl-1H-imidazo[4,5-c]quinolin-2-ol as a fluffy, white solid. Diethyl ether was added to the filtrate, and the resulting mixture was stirred for 20 minutes. A solid was present and was isolated by filtration and dried under vacuum to provide 0.95 g of 1-benzyl-4-chloro-1H-imidazo[4,5-c]quinolin-2-ol as a fluffy, beige solid.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[C@H:10]([OH:16])[CH2:9]1)=O)(C)(C)C.[ClH:17].CC(OC)(C)C>CCO>[ClH:17].[CH2:12]1[C:11]2([CH2:14][CH2:15][NH:8][CH2:9][C@H:10]2[OH:16])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@H](O)C1
Agent: Cl
Solvent: CCO
Solvent: COC(C)(C)C
Product: O[C@@H]1CNCCC12CC2
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of (S)-4-hydroxy-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (3.26 g, 14.3 mmol) in EtOH (10 ml) was treated at RT with HCl solution (4 M in 1,4-dioxane, 30 ml), then after 1 h TBME (40 ml) was added. The suspension was stirred for 1 h, then the precipitate was collected by filtration to afford the title compound (2.11 g, 90%). White solid, MS: 128.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH:14]([N:17]=[C:18]=S)([CH3:16])[CH3:15]>C(OCC)(=O)C>[Cl:8][C:6]1[C:5]([F:9])=[CH:4][C:3]2[S:10](=[O:12])(=[O:11])[N:13]=[C:18]([NH:17][CH:14]([CH3:16])[CH3:15])[NH:1][C:2]=2[CH:7]=1
Reactant: CC(C)N=C=S
Reactant: Nc1cc(Cl)c(F)cc1S(N)(=O)=O
Solvent: CCOC(C)=O
Product: CC(C)NC1=NS(=O)(=O)c2cc(F)c(Cl)cc2N1

Procedure:
The title compound was prepared from 2-amino-4-chloro-5-fluorobenzenesulfonamide and isopropyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 282-285° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 1.17 (d, 6H, CH(CH3)2), 3.92 (m, 1H, CH(CH3)2), 7.34 (br., 1H, NH), 7.45 (d, 1H, ArH), 7.76 (d, 1H, ArH), 10.44 (br.s, 1H, NH); MS: m/e 291/293 (M+); (C10H11N3Cl1F1O2S1) calc. C, 41.17; H, 3.80; N, 14.40; found C, 41.3; H, 3.8; N, 14.4.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.O>[C:13]1([CH2:12][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=Cc1ccc(OCc2ccccc2)cc1

Procedure:
To a solution of 36.6 g (0.3 mol) of 4-hydroxybenzaldehyde in 100 ml of ethanol were added dropwise, one after another, a solution of 12.0 g (0.3 mol) of sodium hydroxide in 100 ml of water and a solution of 36.5 ml of (0.307 mol) of benzylbromide in 100 ml of ethanol and the mixture was then kept for 1 hour at 50° C. The ethanol was extensively distilled off, finally in vacuo, the remaining aqueous emulsion was divided between water and ethyl acetate. The ethyl acetate phase was dried over sodium sulphate and evaporated down in vacuo. The residue remaining crystallised on trituration with petroleum ether and was recrystallised from diisopropylether. 48.0 g (75.4% of theory) of colourless crystals of melting point 118-122° C. were obtained.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[CH:26])[CH2:20][CH2:19][C:18]4([O:24][CH2:23][CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>N1CCCCC1.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:20][CH2:19][C:18]4([O:21][CH2:22][CH2:23][O:24]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Brc1ccncc1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC2(CC1)OCCO2
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: O
Product: COc1ccc(C2(C#Cc3ccncc3)CCC3(CC2)OCCO3)cc1OC1CCCC1
Yield: 90.6 %

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-1,1-(ethylenedioxy)cyclohexane (0.10 g, 0.28 mmol) and 4-bromopyridine (0.54 g, 2.8 mmol) in piperidine (1.5 mL) under an argon atmosphere were added tetrakis(triphenyl-phosphine)palladium(0) (0.013 g, 4%), copper(I) iodide (0.004 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80°-85° C. for 0.5 h. Water was added, the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate),and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)-1,1-(ethylenedioxy)cyclohexane as a pale yellow oil (0.11 g, 93%). 1H-NMR (400 MHz, CDCl3) δ 8.56 (d, J=5.3 Hz, 2H), 7.33 (d, J=5.3 Hz, 2H), 7.16 (d, J=2.2 Hz, 1H), 7.09 (dd, J=8.5, 2.2 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.80 (m, 1H), 4.00 (m, 4H), 3.85 (s, 3H), 2.0-2.2 (m, 6H), 1.8-2.0 (m, 8H), 1.59 (m, 2H).