Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH:18]1([CH2:24][CH2:25][CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:23][CH2:22][CH:21]=[CH:20][CH2:19]1.C1(C)C=CC=CC=1.C1CCCCC1>CN(C)C=O.O1CCCC1.O>[C:14]([O:13][C:11](=[O:12])[N:10]([CH2:26][CH2:25][CH2:24][CH:18]1[CH2:23][CH2:22][CH:21]=[CH:20][CH2:19]1)[C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCCC2CC=CCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCC1CC=CCC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 86.6 %

Procedure:
Sodium hydride (60% in mineral oil, 2.5 g, 62.5 mmol, corrected) was added in several portions over a period of 15 min to an ice-cold mixture of di-tert-butyl-iminodicarboxylate (22.0 g, 100 mmol) in 60 ml of dimethyl formamide and 180 ml of tetrahydrofuran under stirring. A solution of toluene-4-sulfonic acid 3-cyclohex-3-enyl-propyl ester (Marvell, E.; Sturmer, D.; Kunston, R. Journal of Organic Chemistry 1968, 33, 2991-2993) (14.8 g, 50.0 mmol) in a mixture of 15 ml of dimethyl formamide and 45 ml of tetrahydrofuran was charged to it dropwise over 30 minutes. The mixture was stirred for 7 hours at 70° C. and 16 hours at room temperature, diluted with water and extracted with tert-butyl methyl ether. The organic extract was washed with water, brine and stripped of the solvent to give a mixture. After chromatography of the mixture (silica, toluene/cyclohexane=75/25) the title compound (ethyl acetate/toluene=15/85, Rf=0.19, 14.7 g, 86% yield, uncorrected) was obtained as clear yellow oil.
Reaction SMILES: [Si]([N:8]1[CH:11]([CH2:12][C:13](=[O:25])[CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:10]([N:26]=[N+:27]=[N-:28])[C:9]1=[O:29])(C(C)(C)C)(C)C.Cl>CO.O>[N:26]([CH:10]1[CH:11]([CH2:12][C:13](=[O:25])[CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[NH:8][C:9]1=[O:29])=[N+:27]=[N-:28]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CC(=O)CC(=O)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NC1C(=O)NC1CC(=O)CC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of N-(t-butyldimethylsilyl)-3-azido-4-(3-benzyloxycarbonyl-2-oxopropyl)azetidin-2-one (1.0 g) in methanol (10 ml) is treated with conc. hydrochloric acid (0.1 ml) and left at room temperature for 2 hr. The solution is diluted with water and extracted with ethyl acetate. The extracts are washed with 5% sodium bicarbonate solution and brine, dried, and evaporated under vacuum. The residue is chromatographed on silica gel to give 3-azido-4-(3-benzyloxycarbonyl-2-oxopropyl)-azetidin-2-one.
Reaction SMILES: [CH3:1][C:2]1([C:9]([OH:11])=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:14])=O>>[CH3:1][C:2]1([C:9]([Cl:14])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CC1(C(=O)O)CCCCCC1
Product: CC1(C(=O)Cl)CCCCCC1
Yield: 99 %

Procedure:
A solution of 1-methyl-cycloheptanecarboxylic acid (156 mg, 0.998 mmol) (Journal of Organic Chemistry (1982), 47(17), 3242-7) in thionyl chloride (5 ml) was stirred at room temperature for 2 days and then concentrated on high vacuum giving 174 mg (99%) of 1-methyl-cycloheptanecarbonyl chloride as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH:14][C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1
Reactant: Cn1cc(N)cn1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Br)cc1Cl
Solvent: c1ccncc1
Product: Cn1cc(NS(=O)(=O)c2c(Cl)cc(Br)cc2Cl)cn1
Yield: 83.8 %

Procedure:
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (500 mg, 1.54 mmol) and 4-amino-1-methyl-1H-pyrazole (206 mg, 1.54 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a white solid (496 mg, 1.29 mmol, 84%). δH (D-6 DMSO, 300K) 7.64 (2H, s), 7.45 (1H, s), 7.18 (1H, s), 7.01 (1H, s), 3.85 (3H, s). m/z (ES+, 70V) 385.9 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][CH:19]([N:26](C)[C:27](=O)OC(C)(C)C)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:9]1(=[O:36])=[O:35].Cl>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][CH:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:26][CH3:27])[S:9]1(=[O:36])=[O:35]
Reactant: CN(C(=O)OC(C)(C)C)C(CCN1c2ccccc2N(c2ccccc2F)S1(=O)=O)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CNC(CCN1c2ccccc2N(c2ccccc2F)S1(=O)=O)c1ccccc1
Yield: 60.8 %

Procedure:
tert-butyl {3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-phenylpropyl}methylcarbamate (0.11 g, 0.22 mmol) was treated with an excess of 2N HCl in ether. The precipitated amine salt was collected to give 55 mg of 3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-1-phenylpropan-1-amine.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:29])[C:15](=[O:28])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=1)=[CH:7]2.[CH3:30][O:31][C:32](=[O:49])[CH:33](OS(C(F)(F)F)(=O)=O)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:30][O:31][C:32](=[O:49])[CH:33]([O:12][C:11]1[CH:10]=[CH:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([CH2:13][N:14]([C:15](=[O:28])[C:16]3[CH:17]=[CH:18][C:19]([CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:20][CH:21]=3)[CH3:29])[CH:7]=2)[C:2]=1[Br:1])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)C(Cc1ccccc1)OS(=O)(=O)C(F)(F)F
Reactant: CN(Cc1ccc2c(Br)c(O)ccc2c1)C(=O)c1ccc(C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(CN(C)C(=O)c3ccc(C4CCCCC4)cc3)ccc2c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A mixture of N-(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-4-cyclohexyl-N-methyl-benzamide (799 mg, 1.51 mmol), prepared in the previous step, 3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester (1.66 mmol), prepared in step 2 of Example 7, and cesium carbonate (985 mg, 3.0 mmol) in acetone was stirred at room temperature for 3 h. The reaction was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted three times with ethyl acetate. The combined extracts were dried (Na2SO4) and the solvent removed under reduced pressure. Purification of the residue by column chromatography using 10%-20% ethyl acetate-hexanes as the eluent gave 2-(1-bromo-6-{[(4-cyclohexyl-benzoyl)-methyl-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester (445 mg, 48%), LCMS ES+(Calc'd: 613.2; Found: 614.3).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:4][CH3:5].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=3)=[N:26][N:25]=[N:24]2)C=CC=CC=1>CN(C=O)C>[CH2:3]([O:6][C:7]1[N:8]([CH2:40][C:37]2[CH:38]=[CH:39][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[C:27]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:35][CH:36]=2)[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:4][CH3:5]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCOc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.24 g) was added to a stirred solution of 2-propoxybenzimidazole (0.71 g) in DMF (10 ml) under ice-cooling. The mixture was stirred for 20 minutes, to which was added N-triphenylmethyl-5-(4'-bromomethylbiphenyl-2-yl)tetrazole (2.3 g), followed by stirring at room temperature for 5 hours. To the reaction mixture was added ice-water, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was dissolved in methanol (50 ml), to which was added 1N-HCl (15 ml), followed by stirring at 60° C. for 2 hours. The reaction mixture was concentrated, to which were added water (15 ml) and ethyl acetate (15 ml). The mixture was made alkaline with 1N NaOH and shaken. The aqueous layer was adjusted to pH 3-4 with 1N-HCl and then extracted with chloroform. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was purified by column chromatography on silica gel to yield crystals. Recrystallization from ethyl acetate-methanol gave colorless crystals (0.58 g, 35%), m.p. 177°-179° C. (decomp.).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.CN([CH:18]=[O:19])C>>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:18]=[O:19])=[CH:7]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a 500 mL round bottom flask containing 250 mL of DMF at 0° C. was added 105 mL (1.12 mol) of phosphorous oxychloride dropwise via an addition funnel. The reaction mixture was stirred for 30 min at 0° C. and then indole (0.51 mol) was added as a solid. The reaction mixture was heated to 80° C. for 6 h and then cooled in an ice bath. The cold solidified reaction was quenched with water (Q2 L) until all the solid had dissolved. The solution was kept cool and the pH was adjusted to ˜11 by the addition of 50% NaOH. The precipitate was filtered and washed with water. The filter cake was dried in vacuo in the presence of P2O5 to yield crude indole-3-carboxaldehyde (90-95% yield).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[In+3].C([SiH](CC)CC)C.[CH3:12][O:13][C:14](=[O:33])[CH2:15][C:16]1[C:25]([C:26]#[CH:27])=[C:24]([O:28][C:29](=[O:31])[CH3:30])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:32])[CH:22]=2)[CH:17]=1.C(B(CC)CC)C>C(#N)C.O>[CH3:12][O:13][C:14](=[O:33])[CH2:15][C:16]1[C:25]([CH:26]=[CH2:27])=[C:24]([O:28][C:29](=[O:31])[CH3:30])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:32])[CH:22]=2)[CH:17]=1
Reactant: C#Cc1c(CC(=O)OC)cc2ccc(F)cc2c1OC(C)=O
Agent: CCB(CC)CC
Agent: CC[SiH](CC)CC
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: C=Cc1c(CC(=O)OC)cc2ccc(F)cc2c1OC(C)=O
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 62.9 %

Procedure:
A round-bottom flask (5 mL) charged with indium trichloride (88 mg, 0.40 mmol) was heated at 100° C. under reduced pressure for 1 h, and filled with nitrogen. A solution of triethylsilane (46 mg, 0.4 mmol) in acetonitrile (4 mL), which was cooled to 0° C., was added by means of syringe. After the mixture was stirred at 0° C. for 5 minutes, (4-acetoxy-3-ethynyl-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (60 mg, 0.20 mmol) and a solution of triethylborane (1M solution in tetrahydrofuran, 20 μL, 0.02 mmol) were added. The resulting mixture was stirred at 0° C. for 3 hours, then poured into water (10 mL), and extracted with ethyl acetate (10 mL×3). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column (elution with 10% ethyl acetate in petroleum ether) to afford (4-acetoxy-6-fluoro-3-vinyl-naphthalen-2-yl)-acetic acid methyl ester (38 mg, 62.9%) as a pale solid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-].[Na+:9].C(O)(=[O:13])C=C.C(N)(=O)C=C.OO>>[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:13])=[O:5].[Na+:9].[Na+:9]
Reactant: C=CC(=O)O
Reactant: O=C1C=CC(=O)O1
Agent: C=CC(N)=O
Agent: OO
Agent: [Na+]
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
An aqueous sodium maleate solution was prepared by neutralizing maleic anhydride with an aqueous sodium hydroxide solution in a four-necked flask. The aqueous solution polymerization of this solution, an aqueous acrylic acid solution and acrylamide was effected in the presence of hydrogen peroxide and sodium hydroxide at 100° C. for 6 h. After neutralization with an aqueous sodium hydroxide solution, a dyeability-improving agent comprising the salt of the copolymer and containing 3% of acrylamide as a third component was obtained.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)C=1C(O)=O)([OH:3])=[O:2].[C:29](Cl)(=[O:31])[CH3:30]>>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:15][C:16]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=1)[C:30]1[C:29](=[O:31])[O:3][C:1](=[O:2])[CH2:4][C:5]2=1
Reactant: CC(=O)Cl
Reactant: O=C(O)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12
Product: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1

Procedure:
34.1 A mixture of 3-carboxymethyl-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid (from example 34, 0.5 g) in acetylchloride (6.2 ml) was heated to reflux for 5 h. The solution was evaporated and the residue triturated with diethylether to give 6-fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione as a pale yellow solid. MS: 377.4 ([M+NH4]+).
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:15][C@H:16]([C:24]([OH:26])=O)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl.[CH3:28][NH:29][O:30][CH3:31].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:31][O:30][N:29]([CH3:28])[C:24](=[O:26])[C@@H:16]([NH:15][C:8](=[O:9])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 81.2 %

Procedure:
Triethyl amine (40 g, 0.4 mol) was added to a suspension of Boc-L-phenylalanine (90 g, 0.34 mol) and N,O-dimethylhydroxylamine hydrochloride (36.5 g, 0.37 mol) in DCM (500 mL) at 0° C. with stirring. The suspension was stirred for 10 min and EDCI (HCl salt, 72 g, 0.37 mol) was added. The suspension was stirred for further 3 hours at 0° C. The mixture was quenched with saturated aqueous NaHCO3 (1 L). The layers were separated, and the aqueous phase was re-extracted with DCM (500 mL×3). The combined organic phases were washed with water (1 L×3), 5% KHSO4 aqueous (1 L×3), saturated aqueous NaHCO3 (1 L×3), and brine (1 L×1), was dried (Na2SO4), and was concentrated to dryness. The crude material was further purified by flash chromatography (silica gel, EtOAc/Hexane=1:1) and afforded (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxo-3-phenylpropan-2-ylcarbamate (85.1 g, 81% yield) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.1-57.26 (m, 5H), 5.25 (bs, 1H), 4.95 (m, 1H), 3.63 (s, 3H), 3.14 (s, 3H), 2.83-3.07 (m, 2H), 1.37 (s, 9H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18](=[S:20])[NH2:19])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23](=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:20][CH:22]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:19]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1ccc(-c2c(C(N)=S)cnn2C(C)(C)C)cc1
Solvent: CCO
Product: CCOC(=O)c1csc(-c2cnn(C(C)(C)C)c2-c2ccc(OC)cc2)n1
Yield: 76.9 %

Procedure:
A solution of 1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazole-4-carbothioamide (1.24 g, 4.28 mmol) and ethyl bromopyruvate (0.647 mL, 5.14 mmol) in ethanol (24 mL) was stirred at 90° C. for 14 hr. The reaction mixture was concentrated under reduced pressure, and hexane was added thereto to give ethyl 2-(1-(tert-butyl)-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)thiazole-4-carboxylate (1.27 g, 3.29 mmol, 77%) as a white powder.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].[NH2:16][C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[OH:9][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH2:5][C:6]([CH3:8])=[CH2:7])[CH2:3][CH2:2][NH:16][C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)CC(O)(CCN[C@H]1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Yield: 94.1 %

Procedure:
A mixture of 1-chloro-5-methyl-3-phenylhex-5-en-3-ol (5.16g, 23mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (6.9 g, 1.5 equiv), KI (4.0 g, 1.05 equiv), K2CO3 (4.77 g, 1.5 equiv) were mixed with acetonitrile (100 mL) and heated to reflux for 20 h. The mixture was filtered through a pad of Celite, concentrated and purified by chromatography on a 120 g silica gel column, eluted with a 0-10% methanol in CH2Cl2 gradient, to afford (3S)-tert-butyl 3-(3-hydroxy-5-methyl-3-phenylhex-5-enylamino)piperidine-1-carboxylate (8.41 g, 94% yield). LC-MS Method 1 tR=1.56 min., m/z 389 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:6]([C@H:7]2[O:20][CH2:19][C@@H:14]([O:15]C(=O)C)[C@@H:9]([O:10]C(=O)C)[CH2:8]2)[C:5]2[CH:21]=[C:22]([Cl:26])[C:23]([Cl:25])=[CH:24][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:1][C:2]1[N:6]([C@H:7]2[O:20][CH2:19][C@@H:14]([OH:15])[C@@H:9]([OH:10])[CH2:8]2)[C:5]2[CH:21]=[C:22]([Cl:26])[C:23]([Cl:25])=[CH:24][C:4]=2[N:3]=1
Reactant: CC(=O)O[C@H]1C[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)OC[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O[C@@H]1CO[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
An ethanolic solution of 2-bromo-5,6-dichloro-1-(3,4-di-O-acetyl-2-deoxy-alpha-D-erythro-pentopyranosyl)-1H-benzimidazole (0.21 g, 0.45 mmol) was deprotected in a modification of General Procedure VI with 0.12 g (1.17 mmol) of sodium carbonate in 1 ml of water. After stirring overnight at ambient temperature, the mixture was treated as described in General Procedure VI. The crude product was triturated in ethyl acetate to give 0.11 g (0.29 mmol, 65% yield) of 2-bromo-5,6-dichloro-1-(2-deoxy-alpha-D-erythro-pentopyranosyl)-1H-benzimidazole. 1H NMR (DMSO-d6) δ8.15 (s, 1H), 7.96 (s, 1H), 5.80-5.77 (d, 1H), 5.12 (bs, 1H), 4.97 (m, 1H), 3.97-3.90 (m, 2H), 3.78-3.70 (m, 2H), 2.42-2.35 (m, 1H), 1.83-1.79 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[C:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: NCc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(NCc2cccc(F)c2)CC1
Yield: 91.4 %

Procedure:
Using general procedure A, 3-fluorobenzylamine (0.25 mL, 2.2 mmol) and 1-Boc-4-piperidone (482 mg, 2.4 mmol) afforded 4-(3-fluoro-benzylamino)-piperidine-1-carboxylic acid tert-butyl ester as a colourless oil (620 mg, 91%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:39]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.Cl[CH2:42][C:43]1[N:47]([CH2:48][CH2:49][CH3:50])[CH:46]=[N:45][N:44]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([O:38][CH2:42][C:43]5[N:47]([CH2:48][CH2:49][CH3:50])[CH:46]=[N:45][N:44]=5)=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:39]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(O)cc2)CCN3CC(C)C)cc1
Reactant: CCCn1cnnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(OCc4nncn4CCC)cc2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-(4-hydroxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.5 g), 3-chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (0.22 g) and potassium carbonate (0.4 g), N,N-dimethylformamide (10 ml) was added, and the mixture was stirred overnight under nitrogen atmosphere at room temperature. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-propyl-4H-1,2,4-triazol-3-yl)methoxy]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 26) (0.47 g) as pale yellow amorphous.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:17]([C:19]1[N:20]([CH2:32][C:33]#[CH:34])[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:31]=1)[CH3:18]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH2:17]([C:19]1[N:20]([CH2:32][C:33]#[C:34][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[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:31]=1)[CH3:18]
Reactant: C#CCn1c(CC)nc2cnc3ccccc3c21
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1nc2cnc3ccccc3c2n1CC#Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.3 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (64 mg, 0.03 eq.), 4-iodoanisole (531 mg, 1.1 eq.), triethylamine (862 μL, 3.0 eq.), and copper (I) iodide (23.6 mg, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinoline (485 mg, 2.06 mmol, 1.0 eq.) in DMF (10 mL). The reaction mixture was stirred at ambient temperature for 3 hour and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 2/98 methanol/chloroform) to provide 0.34 g of 2-ethyl-1-[3-(4-methoxyphenyl)-2-propynyl]-1H-imidazo[4,5-c]quinoline as a clear oil that partially crystallized on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[NH2:17][C:18]1[CH:35]=[CH:34][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:26]2)=[C:20]([O:36][CH3:37])[CH:19]=1.ClCCl.CO.N>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([NH:17][C:18]1[CH:35]=[CH:34][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:26]2)=[C:20]([O:36][CH3:37])[CH:19]=1)=[O:16]
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: COc1cc(N)ccc1OCCN1CCC(C(N)=O)CC1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN1CCC(C(N)=O)CC1

Procedure:
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid and 194 mg (0.66 mmol) of 1-[2-(4-amino-2-methoxyphenoxy)ethyl]piperidine-4-carboxylic acid amide. Yield: 310 mg (98% of theory); melting point: 150° C.; C25H25ClF3N3O4 (M=523.93); calc.: molecular ion peak (M+H)+: 524/526 (Cl); found: molecular ion peak (M+H)+: 524/526 (Cl); Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).