Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH2:31][CH3:32]>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([O:22][CH2:30][CH2:31][CH3:32])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCCBr
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC(F)F
Temperature: 70 °C
Yield: 22.1 %

Procedure:
To a stirring solution of 4-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.75 mmol) and propyl bromide (92 mg, 0.75 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 22%).
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][N:10]([C@@H:13]2[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:17]([O:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:14]2[O:15][CH3:16])[C:9](=[O:39])[N:8]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].CC(C)=[O:42]>O.C(O)(=O)C>[OH:42][C:2]([CH2:3][CH2:4][CH2:5][CH3:6])=[CH:1][C:7]1[CH:12]=[CH:11][N:10]([C@@H:13]2[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@@H:17]([O:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:14]2[O:15][CH3:16])[C:9](=[O:39])[N:8]=1
Reactant: CC(C)=O
Reactant: CCCCC#Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC)c(=O)n1
Solvent: O
Solvent: CC(=O)O
Product: CCCCC(O)=Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC)c(=O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 19 %

Procedure:
4-(1-Hexyn-1-yl)-1-(2-O-methyl-3,5,-di-O-benzoyl-β-D-ribofuranosyl)pyrimidin-2-one was dissolved in acetone (40 ml) and to this solution was added mercuric sulfate dissolved in H2O (10 ml) and acetic acid (10 ml). This solution was stirred at room temperature for 5 hours. The reaction was purified by silica gel column chromatography. Pooling of appropriate fractions and concentration gave 225 mg (19%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:9])=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[NH:10]1[CH2:17][CH2:16]C[C@H:11]1[C:12](O)=[O:13].C(=O)([O-])[O-].[K+].[K+].N1CCOCC1>CS(C)=O.[Cu]I>[F:9][C:3]1[C:2]([NH2:1])=[CH:7][C:6]([N:10]2[CH2:11][CH2:12][O:13][CH2:16][CH2:17]2)=[CH:5][N:4]=1
Reactant: Nc1cc(Br)cnc1F
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1COCCN1
Product: Nc1cc(N2CCOCC2)cnc1F
Temperature: 90 °C
Reaction time: 21.5 h

Procedure:
A stirred mixture of 3-amino-5-bromo-2-fluoropyridine (0.96 g, 5.02 mmol), L-proline (0.12 g, 1.01 mmol), potassium carbonate (1.39 g, 10.1 mmol), copper(I) iodide (0.096 g, 0.50 mmol), and morpholine (1.31 mL, 15.04 mmol) in dry DMSO (3.0 mL) was purged three times with argon and placed under vacuum three times, then the mixture was heated to 90° C. After 21.5 h, the reaction was cooled to rt, then treated with water. After extracting twice with EtOAc, the organics were combined and dried over anhydrous sodium sulfate. After filtration and concentration the residue was purified on basic alumina (10-50% EtOAc in hexanes) to afford a white solid as 2-fluoro-5-morpholinopyridin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.96 (1H, t, J=2.6 Hz), 6.75 (1H, dd, J=9.6, 2.7 Hz), 5.25 (2H, br. s.), 3.80 (4H, m), 3.08 (4H, m). Mass Spectrum ESI (pos.) m/e: 198.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[CH2:18][C:19]#[N:20])#[CH:10]>C(#N)C.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[CH2:18][C:19]#[N:20])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#Cc1ccc(F)cc1CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#CCc1cc(F)ccc1C#Cc1ccnc(Cl)n1
Temperature: 80 °C
Yield: 65.3 %

Procedure:
2,4-Dichloropyrimidine (764 mg, 5.13 mmol) is dissolved in degassed acetonitrile (19.700 ml) and triethylamine (19.70 ml). Copper(I) iodide (75 mg, 0.395 mmol) is added, the mixture is degassed again for 10 min., and 2-(2-ethynyl-5-fluorophenyl)acetonitrile (628 mg, 3.95 mmol) and bis(triphenylphosphine)palladium(II) chloride (138 mg, 0.197 mmol) are then added successively to the greenish solution. The reaction phase is warmed at 80° C. for 30 min. The mixture is subsequently worked up, as described above, and the crude mass obtained is purified by chromatography on silica gel (petroleum ether/ethyl acetate=80/20 to 75/25), giving 700 mg of 2-(2-((2-chloropyrimidin-4-yl)ethynyl)-5-fluorophenyl)acetonitrile (2.58 mmol, 65.3% yield) as orange solid;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[CH:23])=[N:20][CH:21]=2)=[CH:12][CH:11]=1.BrCl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:23]#[C:22][C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=3)=[CH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Brc1ccc(I)cc1
Agent: ClBr
Product: Clc1ccc(-c2ccc(C#Cc3ccc(Br)cc3)nc2)cc1

Procedure:
The product was obtained analogously to Example 7.1e starting from 4-bromoiodobenzene and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 7.10 g (90% of theoretical); C19H11BrClN (M=368.654); calc.: molpeak (M+H)+: 368/370/372 (BrCl); found: molpeak (M+H)+: 368/370/372 (BrCl); HPLC-MS: 7.60 minutes (method A).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:42])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:16][N:15]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39](=[O:41])[CH3:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.BrC1(Br)C(=O)NC(=O)NC1=O.[CH2:54]([NH:56][CH2:57][CH3:58])[CH3:55]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:42])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:16][N:15]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39](=[O:41])[CH2:40][N:56]([CH2:57][CH3:58])[CH2:54][CH3:55])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(C)=O)cn3)CC2)C[C@H]1c1ccc(F)cc1
Agent: O=C1NC(=O)C(Br)(Br)C(=O)N1
Solvent: C1COCCO1
Product: CCN(CC)CC(=O)c1ccc(N2CCC(C(=O)N3C[C@@H](N(CC)C(=O)Oc4ccc(F)cc4)[C@H](c4ccc(F)cc4)C3)CC2)nc1
Temperature: 85 °C
Yield: 26.5 %

Procedure:
A mixture of 0.17 g (0.285 mmol) [(3S,4R)-1-(5′-Acetyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester (example 38) and 84.3 mg (0.295 mmol) 5,5-dibromobarbituric acid in 10 mL dioxane was heated to 85° C. for 40 h. At room temperature 0.216 g (2.95 mmol) diethylamine was added and heated to 45° C. for 2 h and evaporated. the residue was taken up in methanol and subjected to preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 49 mg (26%) of the title compound as light brown solid. MS m/e: 648.3 [M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][C@H:4]([NH:7]C(=O)C2C=CC=CC=2)[CH2:3]1.C(O)(=O)C1C=CC=CC=1.[ClH:26]>>[ClH:26].[S:2]1(=[O:16])(=[O:1])[CH2:6][CH2:5][C@H:4]([NH2:7])[CH2:3]1
Reactant: O=C(N[C@H]1CCS(=O)(=O)C1)c1ccccc1
Agent: Cl
Agent: O=C(O)c1ccccc1
Product: N[C@H]1CCS(=O)(=O)C1
Temperature: 130 °C

Procedure:
(S)-(−)-N-(1,1-dioxidotetrahydrothiophen-3-yl)benzamide (I6a) (7.08 g) was suspended in aqueous 5M HCl (250 mL). The mixture was heated at 130° C. for 13 hours. After cooling in an ice-bath solid benzoic acid was removed by filtration and washed with 1M aqueous HCl, the combined filtrates were evaporated to dryness. The residue was re-suspended in 1,4-dioxane (40 mL), the colourless solid subtitle compound was isolated by filtration, washed with dioxane (10 mL) and dried to constant weight. Yield 4.99 g (98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[C:12]([O:16][C:17]([N:19]1[C@@H:23]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH:22]=[C:21](Br)[C:20]1=[O:34])=[O:18])([CH3:15])([CH3:14])[CH3:13].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OC(C)C)(C)C.Cl.O>[C:12]([O:16][C:17]([N:19]1[C@@H:23]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[CH:22]=[C:21]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:20]1=[O:34])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(Br)=C[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C2=C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C2=O)cc1
Yield: 53.1 %

Procedure:
The diethanolamine complex of 4-methoxyphenyl boronic acid (2.5 grams, 11 mmol) was stirred in a mixture of diisopropyl ether (50 mL) and 1.5M aqueous hydrochloric acid solution (30 mL) for 2 hours. After separation of the aqueous layer, toluene (50 mL) was added and the mixture was concentrated to remove most of the diisopropyl ether. (5R)-3-Bromo-5-(tert-butyl-dimethylsilanyloxymethyl)-2-oxo-2,5-dihydropyrrole-1 -carboxylic acid tert-butyl ester (3.0 grams, 7.38 mmol), toluene (150 mL), and a solution of sodium carbonate (850 mg, 8 mmole) in water (20 mL) were added. After purging the solution of oxygen, tetrakis(triphenylphosphene)palladium (0) (250 mg) was added and the mixture was heated at reflux for 2.5 hours. The mixture was cooled and diluted with toluene and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated to a brown oil. The title compound (1.7 grams, 53%), was isolated by flash chromatography on silica gel eluting with methylene chloride.
Reaction SMILES: [CH2:1]([CH:7]1[C:11](=[O:12])[CH2:10][CH2:9][CH:8]1[C:13]([OH:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:16]O.S(=O)(=O)(O)O>C(Cl)CCl>[CH2:1]([CH:7]1[C:11](=[O:12])[CH2:10][CH2:9][CH:8]1[C:13]([O:15][CH3:16])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1C(=O)CCC1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: CCCCCCC1C(=O)CCC1C(=O)OC

Procedure:
A solution of 17 g of 2-n-hexyl-3-oxo-cyclopentanecarboxylic acid, 10 ml of methanol and 1 g of concentrated sulphuric acid in 50 ml of ethylene chloride, is refluxed for 8 hours. The reaction mixture is then washed with water and sodium carbonate solution and dried over anhydrous sodium sulphate. The solvent is distilled off at a reduced pressure and the residue is distilled through a short Vigreux column. The product, methyl 2-n-hexyl-3-oxo-cyclopentanecarboxylate is collected at 85°C/0,06 mm, yield 17 g (93%), nD20 1.4562.
Reaction SMILES: [CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C@@H:10]([OH:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]3)=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:7]=2[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[O:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O>[CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C@@H:10]([OH:18])[CH2:11][C:12]([CH3:16])([CH3:17])[O:13]3)=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:7]=2[C@H:26]([OH:27])[C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)C[C@H](O)c2c(cc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)cc2)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)C[C@H](O)c2c(cc(C3CCCC3)c([C@H](O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)cc2)O1
Reaction time: 2 h

Procedure:
Under argon, 120 mg (0.23 mmol) of [(4S)-7-cyclopentyl-5-(4-fluorophenyl)-4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl][4-(trifluoromethyl)phenyl]methanone (Example 12A) are initially charged in 2 ml of abs. toluene and cooled to −78° C. At this temperature, 0.59 ml (0.59 mmol) of diisobutylaluminum hydride solution (1 M in toluene) is slowly added dropwise, and stirring of the mixture is then continued at −78° C. for 2 h. Diisobutylaluminum hydride is then added in such an amount that no more starting material can be detected. Saturated potassium sodium tartrate solution is then added, and the mixture is diluted with water and extracted with ethyl acetate. The combined organic phases are washed once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is purified by thick-layer chromatography (mobile phase: cyclohexane/ethyl acetate 5:1), resulting in the separation of the diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][OH:28])[CH2:22]2)[NH:12][C:11]([C:29]2[N:33]=[CH:32][NH:31][N:30]=2)=[N:10]1.[C:34](O)(=[O:37])[CH2:35][CH3:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][O:28][C:34](=[O:37])[CH2:35][CH3:36])[CH2:22]2)[NH:12][C:11]([C:29]2[N:33]=[CH:32][NH:31][N:30]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(CN2CCO[C@@H](CO)C2)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Reactant: CCC(=O)O
Product: CCOC(=O)C1=C(CN2CCO[C@@H](COC(=O)CC)C2)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Yield: 38.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((R)-2-(hydroxymethyl)morpholino)methyl)-2-(1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (2 g, 3.8 mmol) was reacted with propionic acid (0.37 g, 5 mmol) according to the procedure as described in Example 49 to give the title compound as yellow oil (0.84 g, 38%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:42]=[CH:41][C:12]2[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:22][CH:23]=4)[N:18](S(C4C=CC(C)=CC=4)(=O)=O)[C:17]=3[CH3:40])=[N:14][O:15][C:11]=2[CH:10]=1>CO>[CH3:7][O:8][C:9]1[CH:42]=[CH:41][C:12]2[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([O:25][C:26]([F:28])([F:27])[F:29])=[CH:22][CH:23]=4)[NH:18][C:17]=3[CH3:40])=[N:14][O:15][C:11]=2[CH:10]=1
Reactant: COc1ccc2c(-c3c(C)n(S(=O)(=O)c4ccc(C)cc4)c4cc(OC(F)(F)F)ccc34)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc2c(-c3c(C)[nH]c4cc(OC(F)(F)F)ccc34)noc2c1

Procedure:
K2CO3 (3 eq) and 10 (2.5 g, 4.8 mmol) were heated to reflux in aqueous methanol for 2 hours at which time starting material had been consumed. The reaction mixture was concentrated, diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified via flash chromatography eluding with 20% EtOAc/hexanes to provide the product as a pale green solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:16]=1)[C:11](O)=[O:12])#[N:2].[C:29]([O:33][C:34](=[O:43])[NH:35][CH:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:43])[NH:35][CH:36]1[CH2:37][CH2:38][CH:39]([NH:42][C:11](=[O:12])[C:10]2[CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=[C:8]([O:7][CH2:6][C:5]3[CH:26]=[CH:27][CH:28]=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:9]=2)[CH2:40][CH2:41]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: N#Cc1ccc(Oc2cc(OCc3cccc(C#N)c3)cc(C(=O)O)c2)cc1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCc3cccc(C#N)c3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 74 %

Procedure:
Following the procedure of Example 5(c) 3-(3-cyano benzyloxy)-5-(4-cyano phenoxy)benzoic acid 0.46 g (1.24 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.265 g, 1.24 mmol) were used to afford 0.52 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.40 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 5.25 (2H, s), 6.74 (1H, d), 7.02 (1H, s), 7.32 (2H, d), 7.22 (1H, s), 7.44 (1H, s), 7.64 (1H, m), 7.84 (4H, m), 7.95 (1H, s), 8.3 (1H, d).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC([O:24][CH:25](C)[CH3:26])=O.[CH:34]([C@H:47]1[N:52]2[CH2:53][C@H:54]([OH:56])[CH2:55][C@H:51]2[CH2:50][N:49]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:48]1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(O)(=O)C>[C:25]([O:56][C@@H:54]1[CH2:53][N:52]2[C@H:47]([CH:34]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:48][N:49]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:50][C@@H:51]2[CH2:55]1)(=[O:24])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H](O)CN2[C@H](C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1C[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](C(c3ccccc3)c3ccccc3)N2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triphenylphosphine (860 mg), acetic acid (159 mg) and diisopropyl azodicarboxylate were added successively into a solution of tert-butyl (4R,7R,8aS)-4-benzhydryl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (670 mg) in tetrahydrofuran (10 ml) at room temperature. After being stirred for 1 hour at room temperature, the reaction mixture was poured into aqueous saturated sodium hydrogen carbonate. The whole was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a mixture of hexane and ethyl acetate (2:1-3:2) as an eluent to give tert-butyl (4R,7S,8aS)-7-acetoxy-4-benzhydrylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]3[S:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[C:10](=[O:25])[N:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl.O>[CH3:33][S:34]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]3[S:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=3)[C:10](=[O:25])[N:9]=2)[CH2:6][CH2:7]1)(=[O:36])=[O:35]
Reactant: Cc1nc(N2CCC(O)CC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1nc(N2CCC(OS(C)(=O)=O)CC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Yield: 100.1 %

Procedure:
To a dichloromethane solution (2.0 mL) of 4-(4-hydroxypiperidin-1-yl)-6-methyl-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (374 mg, 1.00 mmol) synthesized in Reference Synthesis Example 348 and triethylamine (557 μL, 4.00 mmol), methanesulfonyl chloride (155 μL, 2.00 mmol) was added dropwise at 0° C. and the resultant mixture was stirred at room temperature for 1 hour. After the reaction, water was added to the reaction solution and extraction from the resultant mixture with dichloromethane was performed. The obtained organic layer was dried over anhydrous sodium sulfate and thereafter concentrated under reduced pressure to obtain the title compound (453 mg, yield 100%).
Reaction SMILES: NCC(O)=O.[OH-].[Na+].[C@@H:8]1([CH2:16][OH:17])[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][OH:15].COC1C=CC(C=O)=CC=1>O.C(O)C.C(OCC)(=O)C.C(Cl)Cl>[C@H:9]12[CH2:14][O:15][C:16](=[O:17])[C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10]2
Reactant: OC[C@@H]1CCCC[C@@H]1CO
Agent: COc1ccc(C=O)cc1
Agent: NCC(=O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1OC[C@@H]2CCCC[C@H]12
Yield: 92.6 %

Procedure:
Glycine (18.8 grams) is dissolved in 2 liters of deionized water, and the pH is adjusted by the addition of 10% sodium hydroxide to 9.0. Cis-1,2-cyclohexane dimethanol (10.0 grams) is added to the glycine solution with stirring until dissolution occurs, followed by the addition of βNAD+ (Sigma, 2 grams) and flavin mononucleotide (Sigma, 30 grams). To the resulting dear orange solution is added horse liver alcohol dehydrogenase (Sigma, 250 mg, approximately 400 units). After the enzyme has dissolved the pH is readjusted to 9.0 with 10% sodium hydroxide, and the reaction mixture is stirred at 30° C. During the reaction, the pH is maintained at 9.0 with a pH-stat by the addition of 10% sodium hydroxide. Progress of the reaction is monitored by thin layer chromatography (Silica gel plates, eluent 1:1 ethyl acetate-methylene chloride; visualization by dipping in a solution of 5% anisaldehyde in ethanol and heating). When the reaction is complete as judged by thin layer chromatography, the reaction mixture is adjusted to a pH of 13 with 10 M sodium hydroxide and then extracted 3 times with 250 ml of methylene chloride. The pH of the aqueous mixture is then adjusted to 3 with concentrated HCl, followed by continuous extraction with 1 liter of ethyl acetate for 24 hours. The ethyl acetate extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield (1R,6S)-(+)-8-oxabicylo[4.3.0]nonan-7-one (9 grams) as an orange oil. The product may be further purified by distillation at reduced pressure to yield a colorless oil, [∂]D =+46° c=1.1, chloroform. The enantiomeric excess is 98% as determined by chiral gas chromatography (Lipodex D column, column temperature 165° C., injection temperature 180° C., detector temperature 260° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH:16]([CH2:20][OH:21])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:29]([C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1)([O-:31])=[O:30]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH:16]([CH2:20][O:21][S:38]([C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=4)(=[O:39])=[O:40])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OCC1CN(C2CCN(c3ccc(Cl)cc3)CC2)CCO1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CN(C3CCN(c4ccc(Cl)cc4)CC3)CCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a solution of {4-[1-(4-chlorophenyl)-4-piperidinyl]-2-morpholinyl}methanol obtained from step (vi) (125 mg, 0.384 mmol) in dichloromethane (CH2Cl2) (2 mL) was added triethylamine (0.240 mL, 1.72 mmol) followed by 3-nitrobenzenesulfonyl chloride (127.5 mg, 0.575 mmol) and the reaction mixture kept on stirring at room temperature overnight. The volatiles were removed in vacuo, residue dissolved in chloroform, washed sucessively with saturated aqueous sodium hydrogen carbonate (NaHCO3) and water (H2O). The organic layer was dried over sodium sulphate (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash chromatography to give the subtitled compound (163 mg).