Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[N+:31]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br)([O-:33])=[O:32].P([O-])([O-])([O-])=O>CN(C=O)C>[CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc([N+](=O)[O-])c4)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(2-hydroxyethoxy)hexyl]-1,3-oxazolidin-2-one (0.20 g) in DMF (5 ml) was treated with sodium hydride (60% dispersion in mineral oil, 0.030 g) and the mixture stirred under nitrogen at 20° C. for 15 min. 3-nitrobenzylbromide (0.11 g) was added, and the mixture stirred at 20° C. for a further 3 h. Phosphate buffer (20 ml, pH6.5) was added and the mixture was stirred for 5 min before extracting with EtOAc (3×20 ml). The organic layer was washed with water (3×20 ml), dried over Na2SO4 and filtered. Solvent evaporation gave the crude product which was purified by flash chromatography on silica. Elution with EtOAc-cyclohexane (7:3) followed by solvent evaporation in vacuo gave the title compound (0.10 g). LCMS RT=3.61 min, ES+ve 529 (MH)+.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#[N:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[NH3:9].[NH2:20][CH2:19][C:17]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[C:10]([NH:9][CH2:8][CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:18]=1
Reactant: [H][H]
Reactant: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: [Pd+2]
Agent: N
Agent: [OH-]
Solvent: CCO
Product: NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 30 h
Yield: 153.7 %

Procedure:
A solution of 6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purine-2-carbonitrile (5.70 g, 13.18 mmol) (Preparation 5) in ethanol (200 ml) saturated with ammonia gas was treated with Pearlman's catalyst (1.00 g), pressurised to 414 kPa (60 psi) with hydrogen in a sealed vessel and stirred at room temperature for 30 hours. The suspension was filtered through a pad of Arbocel (trade mark) and the solvent was removed under reduced pressure. The residue was twice azeotroped from dichloromethane and then purified by column chromatography on silica gel eluting with dichloromethane:methanol (95:5 by volume) gradually changing to dichloromethane:methanol:0.88 ammonia (90:10:0.5 by volume) to afford the title compound (4.34 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([O:18][C:19]2[CH:20]=[C:21]([CH2:25][C:26]#[N:27])[CH:22]=[CH:23][CH:24]=2)=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]([Si](C)(C)C)=[N+:30]=[N-:31].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26]3[N:29]=[N:30][NH:31][N:27]=3)[CH:20]=2)=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Oc2cccc(CC#N)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Cc1c(Oc2cccc(Cc3nn[nH]n3)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 90 °C

Procedure:
[3-(1-Benzyl-6-chloro-2-methyl-1H-indol-3-yloxy)-phenyl]-acetonitrile (0.030 g, 0.078 mmol) was dissolved in toluene (1 mL) along with azidotrimethylsilane (44 μL, 0.33 mmol) and dibutyltin(IV) oxide (0.002 g, 0.008 mmol). The reaction was heated to 90° C. for 2 days then concentrated. The crude material was dissolved in DMSO and purified via preparatory HPLC to give the title compound.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=O)[CH3:3].Br[CH2:21]CCBr.[OH-].[K+]>C(O)C.O>[O:4]1[C:5]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]3[N:8]([C:7]=2[CH2:21][CH2:3][CH2:2]1)[CH:13]=[CH:12][CH:11]=[CH:10]3
Reactant: CCOC(=O)Cc1cccc[n+]1CC(=O)OCC
Reactant: BrCCCBr
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c2c(n3ccccc13)CCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1,2-di-[(ethoxycarbonyl)methyl]pyridinium bromide (1.5 g, 0.0045 mole) and 1,3-dibromopropane (0.45 ml, 0.0045 mole) in ethanol (10 ml) was added over 5 minutes to a stirred solution of potassium hydroxide (0.75 g, 0.0134 mole) in ethanol (15 ml) at 5° C. The mixture was then allowed to warm upto room temperature and stir for 20 h. The reaction mixture was diluted with water (150 ml) and extracted with ethyl acetate (2×100 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a brown oil. This was chromatographed on silica gel eluting with ether to afford the title compound as a yellow oil.
Reaction SMILES: C(O[C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:17])C.[CH3:20][C:21]([CH3:26])([CH3:25])[C@H:22]([NH2:24])[CH3:23].C(OCC)(=O)C>CCCCCC>[CH3:20][C:21]([CH3:26])([CH3:25])[C@H:22]([NH:24][C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:17])[CH3:23]
Reactant: C[C@@H](N)C(C)(C)C
Reactant: CCOc1c(Nc2c(O)cccc2C#N)c(=O)c1=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@@H](Nc1c(Nc2c(O)cccc2C#N)c(=O)c1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-ethoxy-4-(2-hydroxy-6-cyanophenyl)amino-3-cyclobutene-1,2-dione (0.250 g, 0.00097 mol) and (R)-2,2,1-trimethylpropylamine (0.2M in ethanol, 9.7 ml, 0.0019 mol) was stirred at room temperature for two days. TLC (2:1 ethyl acetate:hexane) indicates a loss of starting material. The reaction is evaporated on a rotary evaporator. The residue is taken up in ethyl acetate and extracted well with 0.25N HCl. The organic layer is washed once with distilled water, dried (Na2SO4), and evaporated to a solid. The solid is collected and washed with diethyl ether with several drops of ethyl acetate to give 3-[(R)-2,2,1-trimethylpropylamino]-4-(2-hydroxy-6-cyanophenyl)amino-3-cyclobutene-1,2-dione, 0.230 g (0.00073 mol, 76%)
Reaction SMILES: [CH:1](=[C:8]1/[CH2:9][CH2:10][C@H:11]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[C@@H:12]([C:14]([O:16]C)=[O:15])[CH2:13]/1)/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Li+].O.OO>>[CH:1](=[C:8]1/[CH2:9][CH2:10][C@H:11]([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)=[O:19])[C@@H:12]([C:14]([OH:16])=[O:15])[CH2:13]/1)/[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1C/C(=C/c2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1C/C(=C/c2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of methyl (1S,2S,5E)-5-benzylidene-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxylate (116 mg, 0.000277 mol) in tetrahydrofuran (6.0 mL, 0.074 mol) at rt was added a solution of lithium hydroxide (102 mg, 0.00416 mol) in water (2.0 mL, 0.11 mol). The resulting cloudy solution was stirred at rt for 17 h. LCMS showed that there was only 40% conversion. The reaction mixture was cooled to 0° C., hydrogen peroxide (0.113 mL, 0.00111 mol) was then added. The reaction mixture was stirred at 0° C. for 2 h. LCMS showed that there was little change. The reaction mixture was then stirred at rt over the weekend. LCMS showed the reaction was done. The reaction was quenched with 10% Na2S2O3 (10 mL), acidified with 1 N HCl (5 mL) to pH=4, extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product as a colorless solid. (112 mg, 100% in yield). MS (ESI): (M+H)+=405.1.
Reaction SMILES: [CH2:1]([N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:10](=O)[C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:20]([NH:28][NH2:29])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)/[C:10](=[N:29]/[NH:28][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)/[C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Reactant: NNC(=O)c1ccccc1
Product: CCCCCCN1C(=O)/C(=N\NC(=O)c2ccccc2)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-hexyl-6-methoxy-isatin and benzhydrazide according to the synthetic method E. NMR (CDCl3): δ 0.88 (t, 3H), 1.28 to 1.39 (m, 6H), 1.68-1.74 (m, 2H), 3.73 (t, 2H), 3.87 (s, 3H), 6.44 (d, 1H), 6.64 (dd, 1H), 7.51 (t, 2H), 7.59 (t, 1H), 7.80 (d, 1H), 8.00 (d, 1H), 13.98 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[CH2:10][C:9]1([CH3:19])[C:16](O)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23].CCN=C=NCCCN(C)C.Cl>>[CH3:31][O:30][C:28]([C:27]1[CH:32]=[CH:33][C:24]([C@@H:22]([NH:21][C:16]([C:9]2([CH3:19])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:15][CH2:14][C:11]3([CH2:12][CH2:13]3)[CH2:10]2)=[O:17])[CH3:23])=[CH:25][CH:26]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)CC1(C)C(=O)O
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2(C)CC3(CCN2C(=O)OC(C)(C)C)CC3)cc1
Yield: 27.4 %

Procedure:
The title compound (D57) (25 mg) was prepared according to the general procedure for amides preparation (Method A) starting from 6-(tert-butoxycarbonyl)-5-methyl-6-azaspiro[2.5]octane-5-carboxylic acid (D6) (57 mg) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (46 mg). EDC.HCl: 1.1 eq, Reaction time: 48 hrs.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=O.[N+:11]([CH2:14][C:15](OCC)=[O:16])([O-:13])=[O:12].N1CCCCC1>CC1C=CC=CC=1C>[I:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][C:15](=[O:16])[C:14]([N+:11]([O-:13])=[O:12])=[CH:4]2
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: Nc1ccc(I)cc1C=O
Solvent: Cc1ccccc1C
Solvent: C1CCNCC1
Product: O=c1[nH]c2ccc(I)cc2cc1[N+](=O)[O-]

Procedure:
A stirred mixture of 2-amino-5-iodobenzaldehyde (2.0 g), ethyl nitroacetate (4.2 g), and piperidine (0.7 g) was heated under reflux for 1.5 hours in o-xylene (100 cm3). The cooled solution was then concentrated in vacuo and the solid residue was recrystallised from chloroform-isopropanol to afford 6-iodo-3-nitro-2-(1H)-quinolone, m.p. 279°-282°, (1.14 g).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([C:10]([O:12]C)=[O:11])[C:7]([CH3:14])=[CH:6][CH:5]=1.CO>C1COCC1>[Cl:3][C:4]1[N:9]=[C:8]([C:10]([OH:12])=[O:11])[C:7]([CH3:14])=[CH:6][CH:5]=1
Reactant: COC(=O)c1nc(Cl)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(Cl)nc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
A solution of aqueous 1N NaOH (10 ml) is added to a stirred solution of methyl 6-chloro-3-methyl-pyridine-2-carboxylate (1.0 g, 5.39 mmoles) in THF:MeOH (10 ml:2 ml). The mixture is stirred at room temperature for 3 hours. The organic solvent is removed under reduced pressure and the semi-solid is dissolved in water and acidified to pH 1-2 with aqueous 1N HCl. The resulting precipitate is filtered, washed with water, and dried at 40° C. in a vacuum oven for 12 hours to give the title compound as a white solid (780 mg, 84%). Mass spectrum (m/z): 172.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH3:13]I>CS(C)=O>[OH:10][C:9]1[C:2]([O:1][CH3:13])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: CI
Reactant: O=Cc1cccc(O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(O)cccc1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,3-dihydroxybenzaldehyde (20.0 g) in dimethylsulfoxide (80 ml) was added sodium hydride (5.79 g), and the mixture was stirred at room temperature for 1 hr. Methyl iodide (9.0 ml) was added, and the mixture was further stirred at room temperature for 20 hrs. The obtained reaction mixture was partitioned between ethyl acetate (1000 ml) and water (500 ml). The aqueous layer was further extracted with ethyl acetate (1000 ml). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography and crystallized from diisopropyl ether and hexane to give 3-hydroxy-2-methoxybenzaldehyde (11.5 g) as pale-brown crystals.
Reaction SMILES: [CH:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][C:2]=1[CH2:11][OH:12].[H][H]>O1CCCC1.[C].[Pd]>[CH2:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH:2]1[CH2:11][OH:12]
Reactant: [H][H]
Reactant: OCC1=CC2(CCCCC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: OCC1CCC2(CCCCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a solution of spiro[4.5]dec-1-en-2-yl-methanol (50 mg) obtained in Step 5 of Example 15 in tetrahydrofuran (1 mL) was added 5% palladium carbon (5 mg), followed by stirring the reaction mixture under normal pressure in an atmosphere of hydrogen at room temperature for 20 hours. Then, the reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was dissolved in methanol (1 mL). To the solution was added sodium borohydride (10 mg), followed by stirring the reaction mixture at room temperature for 1 hour. Then, after addition of 1N aqueous hydrochloric acid solution, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to give spiro[4.5]dec-2-yl-methanol (30 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12]Br)[CH:6]=1)[CH3:2].[CH2:15]([O:22][C:23](=[O:27])[NH:24][CH2:25][CH3:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12][N:24]([C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:27])[CH2:25][CH3:26])[CH:6]=1)[CH3:2]
Reactant: CCNC(=O)OCc1ccccc1
Reactant: CCOC(=O)c1ccc(Br)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(CN(CC)C(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4-Bromo-3-bromomethyl-benzoic acid ethyl ester (2.95 g, 9.2 mmol) and ethyl-carbamic acid benzyl ester (3.30 g, 18.4 mmol) were combined in DMF (100 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil; 0.772 g, 19.3 mmol) was added slowly, and the reaction was stirred at room temperature for 10 minutes. The mixture was quenched with H2O and 1N aqueous HCl (20 mL), and then extracted with 1:1 EtOAc:hexanes three times. The organic layer was washed with brine, and then dried and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give 3-[(N-benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-bromo-benzoic acid ethyl ester, as well as the hydrolyzed product, which was combined with the product from the next step.
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]1[CH2:11][CH2:10][N:9]([S:12]([NH:15][C:16]([C:18]2[N:19]=[C:20]([CH2:23][N:24]([C:34](=[O:46])[C:35]3[CH:40]=[C:39]([O:41][CH3:42])[C:38]([CH3:43])=[C:37]([O:44][CH3:45])[CH:36]=3)[CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:21][CH:22]=2)=[O:17])(=[O:14])=[O:13])[CH2:8]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1COCC1>[CH3:42][O:41][C:39]1[CH:40]=[C:35]([CH:36]=[C:37]([O:44][CH3:45])[C:38]=1[CH3:43])[C:34]([N:24]([CH2:23][C:20]1[S:21][CH:22]=[C:18]([C:16]([NH:15][S:12]([N:9]2[CH2:10][CH2:11][CH:7]([OH:6])[CH2:8]2)(=[O:14])=[O:13])=[O:17])[N:19]=1)[CH2:25][CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:46]
Reactant: COc1cc(C(=O)N(CCCc2ccccc2)Cc2nc(C(=O)NS(=O)(=O)N3CCC(O[Si](C)(C)C(C)(C)C)C3)cs2)cc(OC)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)N(CCCc2ccccc2)Cc2nc(C(=O)NS(=O)(=O)N3CCC(O)C3)cs2)cc(OC)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
N-[(3-{[tert-Butyl (dimethyl)silyl]oxy}pyrrolidin-1-yl)sulfonyl]-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-1,3-thiazole-4-carboxamide (580 mg) was added to THF (10 mL), and subsequently, a 1 M TBAF/THF solution (2.02 mL) was added dropwise thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was neutralized by the addition of an appropriate amount of 1 M hydrochloric acid, and then extracted with CHCl3 several times. The organic layer was washed with brine and dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3:MeOH=20:1) to obtain 2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(3-hydroxypyrrolidin-1-yl)sulfonyl]-1,3-thiazole-4-carboxamide (383 mg) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:33](=[O:35])[CH3:34])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (22 mg, 48 mmol) was dissolved in abs. pyridine (5 ml). At room temperature, acetic anhydride (98 mg, 960 μmol, 20 eq.) was added. Once analysis of the reaction by TLC showed substantial conversion (a few hours), the reaction mixture was concentrated under reduced pressure and directly purified by preparative HPLC (Reprosil C18 column, 30×200 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (20.6 mg, 93% of theory).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2]C.I[CH2:26]CC>>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)([CH3:26])[CH3:2]
Reactant: CCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Reactant: CCCI
Product: CC(C)Oc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3

Procedure:
Following the procedure for the preparation of 10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole and substituting 2-iodopropane for 1-iodopropane while making non-critical variations the title compound was obtained as 236 mg (56%) of a brown oil: 1H NMR (400 MHz, CDCl3) δ 7.88 (br s, 1H), 7.36-7.26 (m, 3H), 7.16-7.12 (m, 1H), 7.05-7.00 (m, 2H), 6.95 (d, J=7.2 Hz, 1H), 4.33-4.27 (m, 1H), 3.11-3.03 (m, 2H), 2.96-2.94 (m, 2H), 2.87-2.81 (m, 2H), 2.48-2.35 (m, 2H), 1.15-1.08 (m, 6H); HRMS (FAB) calcd for C21H24N2O+H1: 321.1967 found 321.1949.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:31](=[O:32])[CH2:30][C:28]#[N:29])[CH2:26][CH2:27]2)=[CH:19][CH:20]=1
Reactant: N#CCC(=O)O
Reactant: Clc1c(-c2ccc(CN3CCNCC3)cc2)ccc2c1nnn2CC1CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CCC(=O)N1CCN(Cc2ccc(-c3ccc4c(nnn4CC4CC4)c3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-chloro-1-(cyclopropylmethyl)-5-[4-(piperazin-1-ylmethyl)phenyl]-1H-benzotriazole (Example 71, 15 mg, 0.039 mmol) in dichloromethane (530 uL) was added cyanoacetic acid (6.7 mg, 0.079 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (31 mg, 0.059 mmol) and diisopropylethylamine (34 uL, 0.20 mmol). After stirring for 2 hours at ambient temperature, the mixture was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (95:5 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid) to afford the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 8.01 (1H, d, J=8.5 Hz), 7.66 (2H, d, J=7.7 Hz), 7.62 (2H, d, J=7.7 Hz), 7.60 (1H, d, J=8.6 Hz), 4.68 (2H, d, J=7.4 Hz), 4.39 (1H, br s), 2.57-2.46 (10H, m), 1.75-1.72 (2H, m), 1.49-1.38 (1H, m), 0.60-0.56 (2H, m), 0.52-0.49 (2H, m) ppm high resolution mass spectrometry (ES+) m/z 449.1862 [(M+H)+; calculated for C24H26ClN6O: 449.1851].
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:11]1([C:14]#[CH:15])[CH2:13][CH2:12]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@:26]23[C:32]([CH3:34])([CH3:33])[C@@:29]([CH3:35])([CH2:30][CH2:31]2)[C:28](=[O:36])[O:27]3)=[O:25])=[C:19]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])[CH:18]=1>C1COCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@:26]23[C:32]([CH3:33])([CH3:34])[C@@:29]([CH3:35])([CH2:30][CH2:31]2)[C:28](=[O:36])[O:27]3)=[O:25])=[C:19]([C@@:37]([OH:42])([C:15]#[C:14][CH:11]2[CH2:13][CH2:12]2)[C:38]([F:39])([F:40])[F:41])[CH:18]=1
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1C(=O)C(F)(F)F)OC2=O
Reactant: C#CC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)OC2=O
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
1M LiHMDS (7.4 mL, 7.4 mmol) was added slowly to a solution of cyclopropyl acetylene (0.49 g, 7.4 mmol) in THF (4 mL) in an ice-salt bath under argon, and then (1S, 4R)-N-(4-chloro-2-(2,2,2-trifluoroacetyl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (9, 1 g., 2.48 mmol) in THF (1.5 mL) was added slowly. The mixture was stirred at −15° C. for 20 minutes. TLC showed the formation of the product. The reaction mixture was worked up similarly to the example 6, and (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10) was isolated as an off-white solid. 1H NMR spectrum of the product was identical to that of Example 5.