Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:23][O:22][C:21]2[C:4](=[CH:5][C:6]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][C:7]=3[CH:20]=2)[NH:3]1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:3]1[C:4]2=[CH:5][C:6]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][C:7]=3[CH:20]=[C:21]2[O:22][CH2:23][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)OCC(=O)N3
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(Cc1cccc(F)c1)C(=O)CO3
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 500 mg of t-butyl 3-oxo-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate in 10 ml of DMF were added 250 μl of 1-(bromomethyl)-3-fluorobenzene and 800 mg of cesium carbonate, followed by stirring at 50° C. for 16 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, and water added, followed by extraction with ethyl acetate twice. The combined organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 609 mg of t-butyl 4-(3-fluorobenzyl)-3-oxo-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][C:18]1[C:23]([CH2:24]O)=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=[C:20]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:19]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:24][C:23]3[C:18]([CH3:17])=[N:19][C:20]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:32][CH:31]=4)=[CH:21][C:22]=3[C:26]([F:27])([F:29])[F:28])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)c1CO
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc3C)cc21

Procedure:
In analogy to the procedure described in example 5 f], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 6 b]) was reacted with [2-methyl-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield the title compound as colorless solid.
Reaction SMILES: [C:1]([CH:3]1[C:6]2=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]2[CH2:4]1)#[N:2].[OH-].[K+]>C(O)C.O.CCOCC>[NH2:2][CH2:1][CH2:3][CH2:12][O:11][C:8]1[CH:7]=[C:6]2[CH:3]([CH2:1][N:2]3[CH2:7][CH2:6][CH2:5][CH2:10][CH2:9]3)[CH2:4][C:5]2=[CH:10][CH:9]=1
Reactant: COc1ccc2c(c1)C(C#N)C2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: NCCCOc1ccc2c(c1)C(CN1CCCCC1)C2
Temperature: 25 °C

Procedure:
1-Cyano-5-methoxybenzocyclobutene (29 g) is stirred with saturated KOH in ethanol (180 ml) for about 12 hours under nitrogen at RT. Water (60 ml) is added to the reaction mixture which is refluxed for about 3 hours. The mixture is cooled to RT, diluted with water, washed with ether and the aqueous layer acidified forming an oil. The oil is dissolved in ether and the ethereal solution washed, dried over Na2SO4, filtered and evaporated in vacuo affording the desired product as an oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].N1CCC(C(NC2C=CC=CC=2C(N)=O)=O)CC1.C(OC([N:33]1[CH2:38][CH2:37][CH:36]([C:39]([NH:41][C:42]2[CH:57]=[CH:56][C:55]([CH:58]([OH:60])[CH3:59])=[CH:54][C:43]=2[C:44]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][N:48]=2)=[O:45])=[O:40])[CH2:35][CH2:34]1)=O)(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:53][C:50]1[CH:51]=[CH:52][C:47]([NH:46][C:44](=[O:45])[C:43]2[CH:54]=[C:55]([CH:58]([OH:60])[CH3:59])[CH:56]=[CH:57][C:42]=2[NH:41][C:39]([CH:36]2[CH2:37][CH2:38][NH:33][CH2:34][CH2:35]2)=[O:40])=[N:48][CH:49]=1
Reactant: CC(O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: NC(=O)c1ccccc1NC(=O)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CC(O)c1ccc(NC(=O)C2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1

Procedure:
Using methods substantially equivalent to those described in Example 244-E, N-(5-chloropyridin-2-yl)-5-(1-hydroxyethyl)]-2-[(4-piperidinylcarbonyl)amino]benzamide trifluoroacetate (0.35 g, 86%) was prepared from 2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(1-hydroxyethyl)benzamide.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+].O.C([O-])(O)=O.[Na+]>OS(O)(=O)=O.CCOC(C)=O>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Brc1nccc2ccccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc2c(Br)nccc12

Procedure:
The starting material was prepared by reaction of 1-bromoisoquinoline in concentrated H2SO4 at 0° with KNO3. The reaction mixture was worked up with water, NaHCO3 and EtOAc to give 1-bromo-5-nitro isoquinoline, m.p. 187°-8°. Reaction of this compound with trimethyloxonium tetrafluoroborate in CH2Cl2 gave impure 1-bromo-2-methyl-5-nitroisoquinolinium tetrafluoroborate which was used as such. n.m.r in solvent A: 3.5(s, 3H); 7.7-8.7(m, 5H).
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:10]([CH3:22])[CH2:9]1)C1C=CC=CC=1.C(O)=O>CO.[C].[Pd]>[CH3:22][C@@H:10]1[CH2:9][NH:8][C@@H:13]([CH3:14])[CH2:12][N:11]1[C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: C[C@@H]1CN[C@@H](C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.8 %

Procedure:
Under an argon atmosphere, (2R,5S)-tert-butyl 4-benzyl-2,5-dimethylpiperazine-1-carboxylate (2.0 g, 6.57 mmol) was dissolved in methanol (60 mL), and added 10% palladium carbon (670 mg) and formic acid (1.5 g, 32.9 mmol). The mixture was stirred at room temperature for 2 hours. Then, the reaction solution was filtered through a pad of celite, and concentrated in vacuo. The obtained residue was added chloroform and a saturated aqueous solution of sodium hydrogen carbonate, extracted with chloroform, dried over sodium sulfate, concentrated in vacuo, and the title compound (1.56 g, >100%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:26])=[CH:12][C:13]([C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:14][C:4]=2[O:3]1.[ClH:28].[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])[CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:28].[CH3:27][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:26][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][N:32]3[CH2:31][CH2:30][O:29][CH2:34][CH2:33]3)=[CH:12][C:13]([C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:14][C:4]=2[O:3]1
Reactant: CCCC(C)(c1ccccc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Reactant: O=C(O)CCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCC(C)(c1ccccc1)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
1.0 g. (3.5 mmoles) of 4,4-dimethyl-9-hydroxy-7-(phenyl-1-methylbutyl)-1,2,3,4-tetrahydrocyclopenta[c][1]benzopyran, 0.76 g. (3.63 mmoles) of γ-morpholinobutyric acid hydrochloride and 0.76 g. (3.70 mmoles) of dicyclohexylcarbodiimide are combined in 75 ml. of methylene chloride and stirred at room temperature for 24 hours. The insoluble by-product of dicyclohexylurea is removed by filtration and the methylene chloride solution is concentrated to 20 ml. Cyclohexane is added until the desired compound is obtained as a colorless solid. Recrystallization from methylene chloride/cyclohexane gives the desired crystalline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].I[CH3:14]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH3:14])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (207 mg, 1.05 mmol), sodium hydride (29 mg, 1.21 mmol) in tetrahydrofuran (5 mL) was added iodomethane (164 mg, 1.15 mol) then stirred for 2 h at room temperature. The reaction mixture was carefully quenched with water then extracted with ethyl acetate (3×). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give 5-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine. MS (EI) for C8H7BrN2: 209, 211 (MH+, Br pattern).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:9]=1[CH2:10][C:11]1[CH:15]=[CH:14][N:13]([CH2:16][CH:17](O)[CH3:18])[C:12]=12.C(N(CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+]>ClCCl.C(OCC)C.CN(C)C=O.O>[N:31]([CH:17]([CH3:18])[CH2:16][N:13]1[CH:14]=[CH:15][C:11]2[CH2:10][C:9]3[C:20]([C:12]1=2)=[CH:21][CH:22]=[CH:23][C:8]=3[O:7][CH3:6])=[N+:32]=[N-:33]
Reactant: COc1cccc2c1Cc1ccn(CC(C)O)c1-2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc2c1Cc1ccn(CC(C)N=[N+]=[N-])c1-2
Yield: 71.2 %

Procedure:
0.45 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 0.7 g of (RS)-1-(5-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 1.6 ml of triethylamine in 20 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 200 ml of diethyl ether, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 140 ml of diethyl ether. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 20 ml of anhydrous dimethylformamide, treated with 366 mg of sodium azide and the reaction mixture was heated to 60° while stirring for 18 hours. After cooling, the solution was poured into 140 ml of water and extracted twice with 140 ml of diethyl ether each time. The combined organic phases were washed once with 140 ml of water and once with 140 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 0.55 g (73%) of (RS)-1-(2-azido-propyl)-5-methoxy-1,4-dihydro-indeno[1,2-b]-pyrrole was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)[S:10][C:11]=2[C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1.CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)[S:10][C:11]=2[C:12]([N:14]=[CH:26][N:27]([CH3:29])[CH3:28])=[O:13])=[CH:22][CH:23]=1
Reactant: NC(=O)c1sc(-c2ccnc(Cl)c2)nc1Cc1ccc(Cl)cc1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=NC(=O)c1sc(-c2ccnc(Cl)c2)nc1Cc1ccc(Cl)cc1

Procedure:
A solution of 4-(4-chlorobenzyl)-2-(2-chloropyridin-4-yl)thiazole-5-carboxamide (128 mg, 0.351 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.467 mL, 3.51 mmol) in toluene (3.75 mL) was heated at 100° C. for 1 hour. The reaction was cooled and concentrated in vacuo to give the intermediate, 4-(4-chlorobenzyl)-2-(2-chloropyridin-4-yl)-N-((dimethylamino)methylene)thiazole-5-carboxamide, as a solid. LC/MS (FA) ES+ 419, 421. The intermediate was dissolved in acetic acid (3.60 mL). Hydrazine hydrate (0.0855 mL, 1.76 mmol) was added and the resulting solution was heated at 90° C. for 2 hours. The mixture was cooled and concentrated in vacuo, and the residue was azeotroped with toluene. The residue was slurried in DCM (30 mL) and saturated sodium bicarbonate (20 mL). Some undissolved solids were filtered to give one batch of desired product. The layers of the filtrate were separated and the aqueous layer was extracted with DCM (2×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give another batch of desired product. The two product batches were combined and purified by silica gel chromatography (methanol/DCM=0/100→20/80) to give 85 mg of the title compound as a beige solid (62% yield). LC/MS (FA) ES+ 388, 390. 1H NMR (300 MHz, d6-DMSO) δ: 14.48 (bs, 1H), 8.76 (s, 1H), 8.54-8.51 (m, 1H), 7.96-7.95 (m, 1H), 7.92-7.89 (m, 1H), 7.38-7.30 (m, 4H), 4.65 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[CH:4][N:3]=1.[CH3:11][Mg]Br>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([OH:10])[CH3:11])=[CH:4][N:3]=1
Reactant: O=Cc1cnc(Cl)nc1Cl
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cnc(Cl)nc1Cl
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2,4-dichloro-pyrimidine-5-carbaldehyde (Example 17, 1.01 g, 5.7 mmol) in THF (10 mL), methyl magnesium bromide (Aldrich, 3 M in ether, 6.27 mmol, 2.1 mL) was added slowly at −78° C. The mixture was stirred for an additional 2 hours at −78° C. and the reaction was quenched with 1N HCl (10 mL). The resulting mixture was extracted with EtOAc and the extract was dried with sodium sulfate. Removal of solvent gave a brown solid. 1.07 g, 97%. MS (M+H)+, 193.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9](O)[N:8]=1.C(=O)([O-])O.[Na+]>O>[Cl:3][C:9]1[N:8]=[C:7]([CH3:6])[CH:12]=[C:11]([CH3:13])[N:10]=1
Reactant: Cc1cc(C)nc(O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, phosphorus oxychloride (2 ml) was added to 4,6-dimethyl-2-hydroxypyrimidine (400 mg), and the resulting mixture was stirred for 1 hour while heating the mixture to reflux. The reaction solution was cooled to room temperature, and the cooled solution was added in small portions to water. After adding sodium hydrogen carbonate in small portions to the resulting mixture to neutralize it, the mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to obtain 2-chloro-4,6-dimethylpyrimidine (350 mg). (2) In the same manner as in Reference Example 8, 4-iodophenol (223 mg) and 2-chloro-4,6-dimethylpyrimidine (157 mg) were reacted by using sodium hydride to obtain 2-(4-iodophenoxy)-4,6-dimethylpyrimidine (226 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7])([O-:3])=[O:2].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1.C(O)(=O)C>O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][N:7]1[CH:14]=[CH:18][CH:17]=[CH:16]1)([O-:3])=[O:2]
Reactant: COC1CCC(OC)O1
Reactant: NCc1ccccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccccc1Cn1cccc1

Procedure:
The starting material is prepared as follows: The mixture of 3,078 g of o-nitrobenzylamine and 2,670 g of 2,5-dimethoxytetrahydrofuran is added rapidly to 10,000 ml of glacial acetic acid at 86° while stirring under nitrogen. The mixture is stirred at 95° for 1.25 hours, cooled to 25° and combined with 30,000 ml of water. It is extracted with ethyl acetate, the extract is washed with 10% aqueous sodium hydroxide and 10% aqueous sodium chloride, filtered and evaporated to yield the 1-(o-nitrobenzyl)-pyrrole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1)#[N:2].[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17]3)=[O:13])=[CH:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](N)CC1
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Product: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](NC(=O)c2cc3cc(C#N)ccc3o2)CC1

Procedure:
The same method as in Example 18 was employed. That is, 5-cyano-2-benzofurancarboxylic acid (749 mg, 4.00 mmol) and t-butyl trans-(4-aminocyclohexyloxy)acetate (917 mg, 4.00 mmol) were condensed to give 1.24 g of t-butyl trans-[4-[(5-cyano-2-benzofuranyl)carbonylamino]cyclohexyloxy]acetate as a colorless solid (78%).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].C(O[CH:10]([O:21]CCCC)[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-])=O)CCC.[Cl-].[NH4+]>O1CCCC1>[F:17][C:15]1[CH:14]=[C:13]2[C:12](=[C:11]([CH:10]=[O:21])[CH:16]=1)[NH:18][CH:2]=[CH:1]2
Reactant: CCCCOC(OCCCC)c1cc(F)ccc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1cc(F)cc2cc[nH]c12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 56.1 %

Procedure:
Add vinylmagnesium bromide (1 M in tetrahydrofuran, 85.2 mL, 85.2 mmol) dropwise to a solution of 2-dibutoxymethyl-4-fluoro-1-nitro-benzene (8.5 g, 28.4 mmol) in tetrahydrofuran (250 mL) at −78° C. Warm the reaction mixture −45° C. to −50° C. for 30 minutes, cool to −78° C., and add vinylmagnesium bromide (1 M in tetrahydrofuran, 85.2 mL, 85.2 mmol) drop wise. Warm the reaction mixture to −45° C. to −50° C. for 20 minutes, then add saturated aqueous ammonium chloride (300 mL). Warm the mixture to room temperature and extract with diethyl ether (200 mL×2). Wash the combined organic phases with saturated aqueous sodium chloride (400 mL×2), dry over sodium sulfate, and concentrate under reduced pressure. Dissolve the residue in tetrahydrofuran (100 mL), add 0.5 N HCl (10 mL), and stir for 20 minutes. Dilute the mixture with diethyl ether (200 mL), wash sequentially with saturated aqueous sodium bicarbonate (200 mL×3) and saturated aqueous sodium chloride (200 mL×2). Dry the organic phase over sodium sulfate and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 5% to 10% ethyl acetate in hexanes to provide the desired compound as a pale yellow solid (2.6 g, 56%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].S=[CH:30][C:31]([O-:33])=[O:32].COC1C=CC([Te](C2C=CC(OC)=CC=2)=O)=CC=1>>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1].[C:31]([O-:33])(=[O:32])[CH3:30]
Reactant: O=C([O-])C=S
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: COc1ccc([Te](=O)c2ccc(OC)cc2)cc1
Product: CC(=O)[O-]

Procedure:
5-Cholesten-3β-ol-thionoacetate (111 mg, 0.25 mmol), was reacted with bis-(p-methoxyphenyl)-telluroxide for 0.25 h. 5-Cholesten-3β-ol-acetate (107 mg, 100%) was obtained after P.l.c. (petroleum ether-ethyl acetate 9:1. The product obtained was recrystallized from acetone (90 mg, 84%), m.p. 113°-114° (lit., 114°-115°).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C1CCCCC1>[N:29]1([C:14]([C@@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:16])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2CCCC2)C1
Temperature: 21.5 °C
Reaction time: 3 h

Procedure:
(R)-1-(tert-Butoxycarbonyl)piperidine-3-carboxylic acid (6.0 kg, 26 mol) was added in portions to a mixture of 1,1′-carbonyldiimidazole (5.1 kg, 31 mol) in tetrahydrofuran (48 L) at a temperature of 18-22° C. The mixture was held at this temperature for 3 h, then pyrrolidine (2.28 kg, 32 mol) was added while maintaining a temperature of 18-25° C., and the resulting reaction mixture was held at this temperature for 2 h. Cyclohexane (48 L) and aqueous potassium carbonate solution (prepared from 4.8 kg potassium carbonate and 48 L water) were then added sequentially, and the mixture was stirred for 30 min before separation of the layers. The organic layer was then washed with another portion of aqueous potassium carbonate solution (prepared from 4.8 kg potassium carbonate and 48 L water). The combined aqueous layers were extracted with cyclohexane (30 L). The combined organic layers were then washed with aqueous sodium chloride solution (prepared from 3.0 kg sodium chloride and 30 L water). The organic layer was dried over sodium sulfate (2.0 kg), then the cyclohexane was removed by distillation under reduced pressure at 45° C. Isopropanol (43 L) was added and the mixture was stirred for 30 min. The presence of (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate was confirmed by HPLC analysis: HPLC retention time: 5.98 min (Column: Halo C18, 4.6×150 mm, 2.7 μm; Mobile Phase A: 0.1% orthophosphoric acid and 2% acetonitrile in water, Mobile Phase B: acetonitrile; Gradient: 20% B to 90% B over 7 min, then held for 3 min; Flow: 0.8 mL/min; Temperature: 25° C.; UV detection at 210 and 226 nM). This material was used in the next step without further purification.
Reaction SMILES: [CH:1]1([NH:7][NH:8][C:9](=[O:19])[C:10]2[C:15](I)=[CH:14][CH:13]=[N:12][C:11]=2[O:17][CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.[Cu]I>[CH:1]1([N:7]2[C:15]3[CH:14]=[CH:13][N:12]=[C:11]([O:17][CH3:18])[C:10]=3[C:9](=[O:19])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nccc(I)c1C(=O)NNC1CCCCC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: COc1nccc2c1c(=O)[nH]n2C1CCCCC1
Yield: 69 %

Procedure:
A solution of N′-cyclohexyl-4-iodo-2-methoxynicotinohydrazide (220 mg), L-proline (13.5 mg), potassium carbonate (162 mg) and copper(I) iodide (11.2 mg) in DMSO (6 mL) was stirred overnight under nitrogen atmosphere at room temperature. To the reaction mixture was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was removed, to the obtained aqueous layer was added 1N hydrochloric acid (1.5 mL) under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (100 mg).
Reaction SMILES: [CH2:1]([C:4]([P:10]([OH:13])([OH:12])=[O:11])([P:6]([OH:9])([OH:8])=[O:7])[OH:5])[CH2:2]N.C[CH2:15][N:16](CC)CC>O>[CH2:2]([CH2:15][NH2:16])[CH2:1][C:4]([P:10]([OH:13])([OH:12])=[O:11])([P:6]([OH:9])([OH:8])=[O:7])[OH:5]
Reactant: CCN(CC)CC
Reactant: NCCC(O)(P(=O)(O)O)P(=O)(O)O
Solvent: O
Product: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The NHS ester (0.35 g, 0.62 mmol) was dissolved in H2O (30 mL), and pamidronate (0.52 g, 2.23 mmol) and Et3N (1.7 mL, 12.4 mmol) were added. The reaction solution was stirred for 24 h at room temperature. Subsequently, the H2O was removed in the vacuum. The product obtained was purified by means of HPLC.