Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1[CH:28]=O>C(O)C.N1CCCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[CH:28][C:20]1[NH:19][C:27]2[C:22]([CH:21]=1)=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cc2ccccc2[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(=Cc1cc3ccccc3[nH]1)C(=O)N2
Temperature: 90 °C
Yield: 104.5 %

Procedure:
A mixture of 5-tert-butoxycarbonylamino-2-oxindole (124 mg), indole-2-carbaldehyde (87 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (4 mg) in ethanol (2 mL was heated in a sealed tube at 90° C. for 3 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in oven for overnight to give 196 mg of 5-tert-butoxycarbonylamino-3-(1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one as a bright orange solid. It was then dissolved in trifluoroacetic acid/dichloromethane mixture (2 mL each) and stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was dissolved in water and basified with saturated sodium bicarbonate solution. The solid was collected by vacuum filtration, washed with water and dried in vacuum oven for overnight to give 129 mg of 5-amino-3-(1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one as a brown solid.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[N:11][C:6]2=[N:7][CH:8]=[CH:9][N:10]=[C:5]2[CH:4]=1)=C.CC([OH:17])(C)C.I([O-])(=O)(=O)=O.[Na+]>O1CCOCC1.O.O=[Os](=O)(=O)=O>[N:10]1[CH:9]=[CH:8][N:7]=[C:6]2[N:11]=[CH:12][C:3]([CH:1]=[O:17])=[CH:4][C:5]=12
Reactant: CC(C)(C)O
Reactant: C=Cc1cnc2nccnc2c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cnc2nccnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
7-Vinyl-pyrido[2,3-b]pyrazine (68 mg, 0.43 mmol) was dissolved in dioxane (4 ml) and water (5 ml). OsO4 (0.227 ml of a 2.5% t-BuOH solution, 0.024 mmol) was added, followed by sodium periodate (276 mg, 1.3 mmol). The reaction mixture was allowed to stir at room temperature. After 2 h, the reaction was judged complete by TLC, and the reaction mixture was partitioned between ethyl acetate and brine. The brine was removed and washed one additional time with ethyl acetate. The combined ethyl acetate extracts were washed again with brine, dried using MgSO4, and concentrated under vacuum to yield the title product (65 mg, 95%) as a dark, nearly black, solid. 1H NMR (DMSO-d6): δ=10.37 (s, 1H), 9.55 (d, 1H, J=2.2 Hz,), 9.28 (d, 1H, J=1.7 Hz), 9.21 (d, 1H, J=1.7 Hz), 9.10 (d, 1H, J=2.2 Hz). Calculated mass=159.15, [M+H]+=160. HPLC Method D: 97.5% @ 210-370 nm; 97.9% @ 318 rm; RT=2.4 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH2:16])=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C([O:19][C:20](=[O:26])[CH2:21][C:22]([CH2:24]Cl)=O)C>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:15])[NH:16][C:22]2[CH2:24][O:19][C:20](=[O:26])[CH:21]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(NC(N)=O)cc(OC)c1OC
Reactant: CCOC(=O)CC(=O)CCl
Solvent: C1COCCO1
Product: COc1cc(NC(=O)NC2=CC(=O)OC2)cc(OC)c1OC
Yield: 38.5 %

Procedure:
A mixture of 3,4,5-trimethoxyphenylurea (400 mg) and ethyl-4-chloroacetoacetate (350 mg) in dioxane (0.8 ml) is heated at reflux for 4 hours. After one hour at 25° C. the precipitate is recovered by filtration and recrystallized from methanol (3 ml), to give 210 mg of product.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][CH:6]([CH2:11][N+:12]([O-:14])=[O:13])[CH2:7][CH:8]1[CH2:10][CH2:9]1)C.[OH-].[K+].O>CO>[CH:8]1([CH2:7][CH:6]([CH2:11][N+:12]([O-:14])=[O:13])[CH2:5][C:4]([OH:15])=[O:3])[CH2:9][CH2:10]1
Reactant: CCOC(=O)CC(CC1CC1)C[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC(CC1CC1)C[N+](=O)[O-]
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A solution of 4-cyclopropyl-3-nitromethyl-butanoic acid ethyl ester (1.34 g, 7.27 mmol) in 50 mL of MeOH is added to 10 mL of 10% KOH/H2O at room temperature and stirred overnight. The MeOH is evaporated, and the pH of the solution is adjusted to ca. 7 by the addition of KH2PO4. The aqueous solution is extracted with EtOAc (3×100 mL), and the combined extracts are dried over Na2SO4. Evaporation of the solvents gives 1.3 g of 4-cyclopropyl-3-nitromethyl-butanoic acid as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:23]N1C(=O)CCC1=O.BrBr>C(Cl)(Cl)(Cl)Cl>[Br:23][CH:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:22][CH:21]=2)=[CH:11][CH:12]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
To a mixture of 0.80 g of methyl α-[p-(p-methylsulfonylphenoxy)phenyl]acetate and 0.49 g of N-bromosuccinimide in 12.5 ml of carbon tetrachloride is added several drops of carbon tetrachloride containing bromine. The mixture is stirred and refluxed for 3 days and the solvent removed under vacuum. The residue is dissolved in dichloromethane and filtered through a one inch by five inch column of silica gel. Evaporation of the filtrate gives the product as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[CH:6][CH:7]=1.[C:15]([NH:18][NH2:19])(=O)[CH3:16]>C(O)CCC>[CH3:16][C:15]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[F:14])[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1
Reactant: CC(=O)NN
Reactant: Fc1ccccc1-c1ccc(Cl)nn1
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3ccccc3F)nn12

Procedure:
As in Example 36, a mixture of 2.5 g. of 3-chloro-6-(o-fluorophenyl)-pyridazine and 1.76 g. of acetylhydrazine in 50 ml. of n-butanol is refluxed for 48 hrs. to give 2.0 g. of product as off-white crystals, m.p. 147°-149° C.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][OH:29]>>[OH:29][CH2:28][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: COc1ccc(COC(=O)c2ccc(O)cc2)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(COC(=O)c2ccc(OCCO)cc2)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 4-methoxybenzyl 4-hydroxybenzoate (7.0 g, 27 mmole) in dry NN-dimethylformamide (50 ml) was added potassium carbonate (4.15 g, 30 mmole) and 2-bromoethanol. The mixture was stirred 48 hours at 80° C., evaporated under reduced pressure and ethyl acetate and water were added. The organic phase was washed five times with water and dried with sodium sulfate. The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography with hexane/ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:11]([N:16]=1)=[N:12][CH:13]=[CH:14][CH:15]=2.[OH:17]O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:11]([N:16]=1)=[N+:12]([O-:17])[CH:13]=[CH:14][CH:15]=2
Reactant: OO
Reactant: Fc1ccccc1-c1nc2ncccc2o1
Solvent: CC(=O)O
Product: [O-][n+]1cccc2oc(-c3ccccc3F)nc21
Temperature: 0 °C

Procedure:
A solution of 1 g. of 2-(2-fluorophenyl)oxazolo[4,5-b]pyridine (from Example 6) in 10 ml. of acetic acid was treated with 2 ml. of 30% hydrogen peroxide and heated on the steam bath for 16 hours. After cooling the mixture was diluted with ice-water. The precipitate was collected and recrystallized from dioxane-ether to give 2-(2-fluorophenyl)oxazolo[4,5-b]pyridine-4-oxide, m.p. 214°-216° C.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:13]([C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=1[OH:26])[C:20](O)=[O:21])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:30][C:27]([C:24]1[CH:23]=[C:19]([CH:18]=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:25]=1[OH:26])[C:20]([NH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:12][CH:11]=1)=[O:21])([CH3:28])[CH3:29]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 74 %

Procedure:
1.88 g (10 mmoles) of p-nitrobenzylamine hydrochloride, 2.5 g (10 mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid, 1.38 ml (10 mmoles) of triethylamine and 2.26 g (11 mmoles) of dicyclohexylcarbodiimide are introduced into a 250 ml flask containing 25 ml of THF. The reaction medium is agitated for 15 hours at ambient temperature, the precipitate which appears is filtered out and rinsed with the minimum quantity of ethyl acetate. After concentration of the solution under reduced pressure, the residue is precipitated from a mixture of ethyl acetate/diethyl ether (1/4) and filtered. The crystals are washed abundantly with diethyl ether in order to finally produce, after drying, a white powder with a yield of 74% (2.85 g). Melting point: 230-231° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[CH2:29][O:30][C:31](=[O:35])[N:32]([CH3:34])[CH3:33])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:28][C:24]1[CH:23]=[C:22]([S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[C:14]([CH:15]=2)[CH2:29][O:30][C:31](=[O:35])[N:32]([CH3:34])[CH3:33])(=[O:20])=[O:21])[CH:27]=[CH:26][CH:25]=1
Reactant: CN(C)C(=O)OCc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)OCc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCNC1
Reaction time: 5 h

Procedure:
3-[2-Dimethylcarbamoyloxymethyl-4-(3-fluoro-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (83 mg, 1.638 mmol) was dissolved in 3 ml of CH2Cl2. TFA (0.5 ml) was added and the mixture was stirred for 5 hours. The solution was concentrated under reduced pressure to give dimethyl-carbamic acid 5-(3-fluoro-benzenesulfonyl)-2-pyrrolidin-3-yl-benzyl ester, MS (M+H)=407.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cccc3F)ccc2c1
Temperature: 80 °C
Yield: 57.4 %

Procedure:
Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-yl ester (1.50 g, 2.86 mmol) in 50 mL of acetonitrile and add 2,6-difluorophenyl boronic acid (0.90 g, 5.73 mmol), tetrakis(triphenylphosphine)palladium(0) (0.66 g, 0.57 mmol). Next add potassium phosphate (3.64 g, 17.16 mmol) and heat to 80° C. for one hour. Add Celite and filter. Concentrate the solvent under vacuum to a dark oil, dissolve in methanol and purify on an SCX cartridge, eluting with 2N ammonia/methanol. Purify further on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient. Evaporate the solvent to yield 800 mg (58%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([F:7])[F:6])[CH3:2].I[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1>[Cu].CS(C)=O>[CH2:1]([O:3][C:4](=[O:9])[C:5]([F:7])([F:6])[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH3:2]
Reactant: Ic1ncccn1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of copper bronze (Aldrich) (5.88 g, 92.5 mmol), DMSO (10 mL), and bromo-difluoro-acetic acid ethyl ester (Advanced Synthesis Technologies) (6.46 mL, 50.4 mmol) was evacuated and flushed with argon three times, and was then stirred at rt for 1 h. Upon standing, the supernatant was dark green. Solid 2-iodopyrimidine (8.76 g, 42.5 mmol) (J. Org. Chem. 67:6550, 2002) was then added, the flask was again evacuated and flushed with argon three times, and stirred at rt for 14 h (mild initial warming of flask spontaneously occurred). The resulting immobile dark brown paste was diluted with saturated NH4Cl (175 mL) and EtOAc (150 mL), the mixture was filtered through a pad of Celite, and the filter cake washed with EtOAc (2×50 mL). The blue aqueous layer filtrate was extracted with EtOAc (1×50 mL), and the combined filtrate clear yellow organic layers were washed with saturated NH4Cl (2×100 mL), 10% w/v EDTA trisodium (1×100 mL; saturated NaBr needed to break phases), saturated NaCl (1×50 mL), saturated NaBr (1×20 mL), dried (2×Na2SO4), and concentrated under reduced pressure. Silica flash chromatography of the greenish residue (1:1 hexanes/EtOAc eluent) provided the title compound as a nearly colorless oil with a greenish precipitate (1.75 g, 20%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:11][NH2:12]>C(O)CCC>[NH2:5][C:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[NH:12][N:11]=1
Reactant: N#Cc1ccccc1F
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Nc1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 44 %

Procedure:
2-Fluorobenzonitrile (605 mg, 5 mmol) and 85% aqueous hydrazine hydrate (352 mg, 6 mmol) were mixed with 1-butanol (3 mL). The mixture was heated at reflux with stirring for 5 h then cooled to room temperature. The resulting precipitate was collected by filtration and washed with dichloromethane and the filter cake was dried in vacuo to give 3-amino benzpyrazole (293 mg, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:34]=1.[N:35]1([C@@H:41]2[CH2:45][CH2:44][CH2:43][C@H:42]2[OH:46])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[N:35]1([C@@H:41]2[CH2:45][CH2:44][CH2:43][C@H:42]2[O:46][C:16]2[CH:17]=[CH:18][C:13]([C:11]([C:10]3[C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:34][C:7]=4[S:8][C:9]=3[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)=[O:12])=[CH:14][CH:15]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COc1ccc2c(C(=O)c3ccc(F)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reactant: O[C@@H]1CCC[C@H]1N1CCCCC1
Product: COc1ccc2c(C(=O)c3ccc(O[C@@H]4CCC[C@H]4N4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield by essentially following the procedures outlined in Example 72, Part E, from 4-fluorophenyl 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (Example 59, Part A) and (±)-trans-2-(1-piperidyl)cyclopentanol (Part A).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH3:4].[Si]([O:46][CH:47]1[CH2:52][CH2:51][CH:50](O)[CH2:49][CH2:48]1)(C(C)(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C@H:50]3[CH2:51][CH2:52][C@@H:47]([OH:46])[CH2:48][CH2:49]3)=[CH:14][CH:13]=2)[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(-c2ccc(O[C@H]3CC[C@@H](O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h

Procedure:
To a solution of 6-butyl-3-(4-hydroxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (1.2 g), 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanol (1.2 g) and triphenylphosphine (1.4 g) in tetrahydrofuran (12 mL) was added dropwise diisopropyl azodicarboxylate (1.9 M toluene solution, 2.8 mL). After stirring for 2 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and a mixture of the residue, hydroxylammonium chloride (0.87 g), sodium hydrogen carbonate (1.3 g) and dimethyl sulfoxide (9 mL) was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (9 mL). N,N′-carbonyldiimidazole (0.3 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 30 min. Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 2.5 mL) was added, and the mixture was stirred overnight at 50° C. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.37 g, 28%) as an amorphous solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[CH:17])[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[CH2:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH2:15][C:16]#[CH:17]
Reactant: C#CCCN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CCCN1CCNCC1
Yield: 95 %

Procedure:
To a solution of 23 (1.02 g, 5.47 mmol) triethylamine (762 μL, 5.47 mmol) and NaI (23 mg, 0.153 mmol) in DMSO but-3-ynyl mesylate (810 mg, 5.47 mmol) is dropwise added. The mixture is heated at 50° C. overnight, then water is added. The aqueous phase is treated with Et2O, and the organic phase is washed with brine, and dried over sodium sulfate. After solvent evaporation, 4-but-3-ynyl-piperazine-1-carboxylic acid t-butyl ester (24) (1.10 g, 4.62 mmol, 84%) is obtained as a yellow oil. 1H NMR (CDCl3, 200 MHz) δ 3.38 (t, J=4.8 Hz, 4H), 2.55 (m, 2H), 2.41-2.28 (m, 6H), 1.94 (t, J=2.6 Hz, 1H), 1.40 (s, 9H) ppm; 13C NMR (CDCl3, 50 MHz) δ 154.3 (s), 82.3 (s), 79.5 (s), 69.1 (d), 56.9 (t), 52.6 (t), 43.5 (t), 28.4 (q), 16.7 (t) ppm. Compound 24 (1.10 g, 4.62 mmol) is left reacting for 16 h in the presence of a 1:1 mixture of CH2Cl2/TFA (2 mL/mmol). After solvent evaporation, the residue is taken up in MeOH, and eluted through a column containing Amberlyst A-21, thus giving pure 1-but-3-ynyl-piperazine (25) (606 mg, 4.39 mmol) in 95% yield. 1H NMR (CDCl3, 200 MHz) δ 6.98 (br, 1H), 3.06-3.01 (m, 4H), 2.62-2.55 (m, 6H), 2.38-2.29 (m, 2H), 1.96 (t, J=2.6 Hz, 1H) ppm; 13C NMR (CDCl3, 50 MHz) δ 82.1 (s), 69.4 (d), 56.6 (t), 50.6 (t), 44.1 (t), 16.8 (t). MS m/z 138 (M+, 7), 99 (100), 70 (48), 56 (98) ppm. To a solution of N,N′-di-Boc-N″-trifluoromethanesulfonylguanidine (1.52 g, 3.88 mmol) in anhydrous CH2Cl2 (18 mL) triethylamine (595 μL, 4.27 mmol) and 25 (590 mg, 4.27 mmol) are added. The mixture is left reacting for 16 h at room temperature, and then the solvent is evaporated. The residue is taken up in EtOAc and treated with a saturated aqueous NaHCO3 solution and brine. Crude product is purified by flash chromatography (CH2Cl2-MeOH 12:1, Rf=0.50), giving pure 5 as a white solid (1.10 g, 2.25 mmol) in 58% yield. 1H NMR (CDCl3, 200 MHz) δ 3.58 (m, 4H), 2.63-2.51 (m, 6H), 2.39-2.33 (m, 2H), 1.96 (t, J=2.6 Hz, 1H) ppm; 13C NMR (CDCl3, 50 MHz) δ 154.7 (s), 151.2 (s), 115.9 (s), 85.9 (s), 82.3 (s), 69.2 (d), 56.6 (t), 52.3 (t), 46.7 (t), 28.0 (q), 27.8 (q), 16.8 (t); MS m/z 380 (M+, 0.11), 160 (17), 121 (79), 57 (100) ppm.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:18]([N:25]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[NH:28][CH:27]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:26]1=[O:42])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:8]1([S:14]([N:32]2[CH2:33][CH2:34][C:29]3([N:25]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:26](=[O:42])[CH:27]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[NH:28]3)[CH2:30][CH2:31]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C(Cc2ccccc2)NC2(CCN(S(=O)(=O)c3ccccc3)CC2)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
Triethylamine (0.12 ml, 0.89 mmol) and subsequently benzenesulfonyl chloride (0.19 ml, 0.26 mmol) were added to a solution of 1,3-dibenzyl-1,4,8-triazaspiro-[4,5]decan-2-one (250 mg, 0.75 mmol) in CH2Cl2 (6.7 ml) with stirring under a blanket of nitrogen at RT. The reaction mixture was stirred overnight. The organic phase was rendered alkaline using saturated aqueous sodium carbonate solution (20 ml), and the aqueous phase was extracted with CH2Cl2 (15 ml). The combined organic phases were dried over Na2SO4. After filtration, removal of the solvent, and column chromatography, the desired product 8-benzenesulfonyl-1,3-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 259 mg (73% of theory).