Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:12]=3[C:13]=2[CH3:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[N:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.O1CCCC1.C(O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:20][C:21]2[N:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=2)[C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:12]=3[C:13]=2[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(F)cc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 12 %

Procedure:
To a mixture of cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methanone (3.00 g) synthesized above, methyl 6-aminopyridine-3-carboxylate (1.93 g), triethylamine (12.8 mL) and methylene chloride (40 mL) was added a 1.0M solution (13.8 mL) of titanium (IV) chloride in methylene chloride at 0° C., and the mixture was stirred under an argon atmosphere at room temperature for 1.5 days. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, methylene chloride was removed by an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a mixture of the obtained oil, ethanol (40 mL) and tetrahydrofuran (20 mL) were added acetic acid (3.29 mL) and sodium cyanoborohydride (3.61 g), and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, the organic solvent was removed by an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% ethyl acetate/hexane) to give the title object compound (547 mg, 12%) as a pale-brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:26]1(=[O:33])(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]1>>[CH3:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][S:26]4(=[O:33])=[O:32])=[CH:9][C:6]=3[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[C:21]([CH3:25])[CH:22]=1
Reactant: O=S1(=O)CCCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3C#N)CC2)c(C)c1
Yield: 79.4 %

Procedure:
Using 5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (399 mg) described in Preparation Example 187 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (360 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.ClCCl.[CH3:34][NH:35][CH2:36][C:37]#[CH:38]>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.[Cu]I.CCN(CC)CC>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:38]=[C:37]([CH2:36][NH:35][CH3:34])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Reactant: C#CCNC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNCc1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 240 h

Procedure:
To a flame-dried flask under a nitrogen atmosphere is added N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (269 mg) of Preparation 26, PdCl2(PPh3)2 (35 mg), and CuI (12 mg). The flask is back-filled with nitrogen gas and charged with dichloromethane (5 mL), Et3N (0.15 mL), and N-methylpropargylamine (0.055 mL). The reaction is stirred at room temperature for 10 days. The reaction is concentrated under reduced pressure, treated with ethanol (5 mL) and heated to 70° C. for 2 days. The reaction is cooled to room temperature and concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed eluting with 2% to 10% methanol in dichloromethane. Product-containing fractions are combined and concentrated under reduced pressure to afford a solid which is crystallized from acetonitrile. The crystals are treated with hydrochloric acid (2 mL, 4N in dioxane). The suspension is diluted with methanol and concentrated under reduced pressure. The residue is triturated with small volumes of methanol-toluene, methanol-ether, toluene, and ether. The solid is treated with dichloromethane and partitioned against saturated aqueous sodium carbonate. The basic aqueous layer is extracted with two additional portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 0.09 g of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=[O:34].[Cl-].[NH4+]>C1COCC1>[F:29][C:30]1[CH:31]=[C:32]([CH:33]([OH:34])[CH:7]2[C:6](=[O:8])[CH:5]=[CH:4][N:3]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH:2]2[CH3:1])[CH:35]=[CH:36][CH:37]=1
Reactant: CC1CC(=O)C=CN1C(=O)OCc1ccccc1
Reactant: O=Cc1cccc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1C(C(O)c2cccc(F)c2)C(=O)C=CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To a solution of phenylmethyl 2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (J. Bioorg. Med. Chem. 2007, 1106-1116) (2.4 g, 9.78 mmol) in THF (35 mL) was added dropwise a 1M solution of lithium bis(trimethylsilyl)amide in THF (11 mL) at −78° C. The solution was warmed up to 0° C., stirred at this temperature for 1 h, then cooled again to −78° C. 3-Fluorobenzaldehyde (1.3 mL, 12.7 mmol) was added in one portion. The reaction was stirred for 4 h while allowing it to slowly warm up to 0° C. Then, saturated ammonium chloride (20 mL) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with saturated sodium chloride (50 mL), dried over sodium sulfate, filtered and concentrated. Column chromatography on silica (gradient 20 to 100% ethyl acetate in hexanes) afforded phenylmethyl 3-[(3-fluorophenyl)(hydroxy)methyl]-2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (2.4 g, 66% yield) as mixture of diastereomers. MS (EI) for C21H20FNO4: 370.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O:13]C)=[O:12])[CH:8]=[C:7]([Cl:15])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].O.O1CCC[CH2:20]1>Cl.C(OCC)(=O)C>[CH3:20][O:6][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=1[Cl:15]
Reactant: COC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(Cl)cc(C(=O)O)cc1Cl
Reaction time: 1 h

Procedure:
The mixture of 560 mg of 2,6-dichloro-4-methoxycarbonyl benzoic acid, 85 mg of sodium hydroxide, 5 ml of water and 5 ml of tetrahydrofuran was stirred for 1 hour. The mixture was diluted with 1N hydrochloric acid and treated by an ordinary method using ethyl acetate as an extractant to obtain the title compound.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([NH:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C.[Br:36][C:37]1[C:38]([NH2:44])=[N:39][CH:40]=[C:41]([Br:43])[N:42]=1>CN(C)C=O.ClCCl>[Br:36][C:37]1[C:38]([NH:44][C:22](=[O:24])[C:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:26])[CH3:25])=[N:39][CH:40]=[C:41]([Br:43])[N:42]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: Nc1ncc(Br)nc1Br
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)Nc1ncc(Br)nc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.8 %

Procedure:
1,1′-Carbonyldiimidazole (2.63 g, 16.24 mmol) was added to a stirred solution of 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (3.00 g, 14.76 mmol) in N,N-dimethylformamide (4 mL) and dichloromethane (8 mL) at room temperature. The resulting clear colorless mixture was stirred at room temperature under nitrogen for 3 h. N,N-Diisopropylethylamine (3.86 mL, 22.14 mmol) was added followed by 3,5-dibromopyrazin-2-amine (5.60 g, 22.14 mmol). The resulting mixture was heated at 50° C. under a reflux condenser under nitrogen for 71 h. Dichloromethane was removed under reduced pressure. The residue was diluted with ethyl acetate and washed with water. The water layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with 30% ethyl acetate in hexane and solids collected by vacuum filtration. The filtrate was concentrated under reduced pressure and purified using flash chromatography (5-50% ethyl acetate in hexane). Fractions containing the desired product were combined with the solids obtained by filtration and concentrated under reduced pressure. The residue was dried under, high vacuum to give the desired product (2.38 g, 5.43 mmol, 37% yield) as an off-white solid. MS (ESI) m/z 439.3 [M+1]+, 461.1 [M+Na]+.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH3:23])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].[CH:24](N)=O>>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[N:8]=[C:7]2[C:12](=[N:13][CH:24]=[N:6]2)[C:11](=[O:14])[N:10]=1)[CH3:23]
Reactant: NC=O
Reactant: CCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Agent: O=S(=O)(O)O
Product: CCOc1ccccc1C1=NC(=O)C2=NC=NC2=N1

Procedure:
In a similar manner to Example 1 reaction of 4,5-diamino-2-(2-ethoxyphenyl)pyrimidin-6-one sulphate (1.5 g) with formamide (15 ml) afforded the title compound, 0.36 g, m.p. 276°-277° C., (recrystallised from ethanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[C:15]([NH:16][C:17]([NH:19][CH:20]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]3)=S)=[CH:14][N:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1>[Hg]=O.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([NH:19][CH:20]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCCC(NC(=S)Nc2cncnc2NCc2ccc(F)cc2)CC1
Agent: O=[Hg]
Solvent: CCO
Product: CCOC(=O)N1CCCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 46.8 %

Procedure:
A mixture of 74 parts of ethyl 4-[[[[4-[[(4-fluorophenyl)methyl]-amino]-5-pyrimidinyl]amino]thioxomethyl]amino]hexahydro-1H-azepine-1-carboxylate, 39 parts of mercury(II) oxide and 240 parts of ethanol was stirred for 1 hour at reflux temperature. The reaction mixture was filtered while hot over diatomaceous earth and the filtrate was evaporated. The residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 1,1'-oxybisethane and acetonitrile. The product was filtered off and dried, yielding 29 parts (46.8%) of ethyl 4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]hexahydro-1H-azepine-1-carboxylate; mp. 156.7° C. (compound 17).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])N=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1.F[C:38](F)(F)C1C=C(C=C(C(F)(F)F)C=1)C(O)=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:38]=[C:18]([C:26]([F:28])([F:29])[F:27])[CH:17]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)CCN(C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1)c1cnccc1-c1ccccc1F
Product: CS(=O)(=O)CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1F
Yield: 8 %

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-fluoro-phenyl)-pyridin-3-yl]-(2-methanesulfonyl-ethyl)-amine (example 159, intermediate) and 3,5-bis(trifluoromethyl)benzoic acid (CAS RN 725-89-3) after a reaction time of 40 hours. The compound was purified by two silica gel chromatographies using a 10 g column and 5 g column, respectively, on a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The resulting brown solid was suspended in tert-butyl methyl ether, filtered and washed with tert-butyl methyl ether to give the title compound as an off-white solid (8%). MS (ESI): m/z=535.09 [M+H]+.
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[C:3]#[C:4][CH2:5][C@H:6]([C:8]1[C@:9]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][CH:17]=1)[C@@H:13]([OH:18])[CH2:12][CH2:11][CH2:10]2)[CH3:7].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[OH:1][C:2]([CH3:20])([CH3:21])[C:3]#[C:4][CH2:5][C@H:6]([C:8]1[C@:9]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][CH:17]=1)[C:13](=[O:18])[CH2:12][CH2:11][CH2:10]2)[CH3:7]
Reactant: C[C@H](CC#CC(C)(C)O)C1=CCC[C@H]2[C@@H](O)CCC[C@]12C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@H](CC#CC(C)(C)O)C1=CCC[C@H]2C(=O)CCC[C@]12C
Yield: 76.2 %

Procedure:
590 mg (2.03 mmol) of (1S,4aS,8aR)-5-[(R)-5-Hydroxy-1,5-dimethyl-hex-3-ynyl]-4a-methyl-1,2,3,4,4a,7,8,8a-octahydro-naphthalen-1-ol was dissolved in 10 ml of abs. CH2Cl2 and oxidized with 1.91 g (5.08 mmol) of pyridinium dichromate during 2 h at ambient temperature. Filtration over Celite, evaporation to dryness, and flash chromatography (SiO2, Hexane/AcOEt=7/3) produced 446 mg of the title compound as colorless oil.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:26])=[C:21](F)[C:22]=3[Cl:24])[C:17](=[O:27])[C:16]([C:28]([OH:30])=[O:29])=[CH:15]2)[CH:8]=1.Cl.Cl.[NH2:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:33][CH:34]1[CH2:37][N:36]([C:21]2[C:22]([Cl:24])=[C:23]3[C:18]([C:17](=[O:27])[C:16]([C:28]([OH:30])=[O:29])=[CH:15][N:14]3[C:9]3[CH:8]=[C:7]([NH2:6])[C:12]([F:13])=[CH:11][N:10]=3)=[CH:19][C:20]=2[F:26])[CH2:35]1
Reactant: NC1CNC1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ncc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)ncc1F
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 87.6 %

Procedure:
To 110 mg of N,N-dimethylformamide were added 23 mg of 1-(4-amino-5-fluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 20 mg of 3-aminoazetidine dihydrochloride, and 50 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 20 minutes. After adding 500 mg of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 23 mg of the title compound as a colorless powder.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])[CH2:3]1.OC1C(O)C2C(=CC=CC=2)CC1C1CCN(C)C1>>[OH:1][CH:2]1[CH2:11][C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])[CH2:3]1
Reactant: CN1CCCC1C1CC(O)Cc2ccccc21
Agent: CN1CCC(C2Cc3ccccc3C(O)C2O)C1
Product: CN1CCCC1C1CC(O)CC2=C1CC=CC2

Procedure:
Following the procedure of Example 6, part D, but substituting the 2-(3-hydroxy-1,2,3,4-tetrahydronaphthalenyl)-1-methylpyrrolidine for the 3-(3,4-dihydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1-methylpyrrolidine, the title C compound is obtained.
Reaction SMILES: P([O-])([O-])([O-])=O.[O:6]=[C:7]1[CH2:12][CH2:11][CH:10]2[CH:8]1[CH:9]2[C:13]([O:15]CC)=[O:14]>CCCCCC>[O:6]=[C:7]1[CH2:12][CH2:11][C@@H:10]2[C@H:8]1[C@H:9]2[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C1C2CCC(=O)C21
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCC
Product: O=C(O)[C@H]1[C@@H]2CCC(=O)[C@@H]21
Temperature: 40 °C

Procedure:
Each of the various commercial enzymes shown in Table 3 was added in an amount shown in Table 4 to 1 ml of 100 mM phosphate buffer (pH 7.0) and dissolved therein. 10 mg of racemic ethyl(1SR,5RS,6SR)-2-oxobicyclo [3.1.0]hexane-6-carboxylate was dissolved in 1 ml n-hexane, then added to the enzyme solution, and heated to 40° C. and the mixture was stirred. After the time shown as the reaction time in Table 4 elapsed, an aliquot of the reaction solution was removed and analyzed in the same manner as in Examples 1 to 8 to determine the optical purity and reaction yield of the formed 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid. (+)-(1S,5R, 6S)-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid was obtained in excess. The results are shown in Table 4.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH:3]=1.[NH4+].[Cl-].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[C:17]1([CH:15]([C:4]2[CH:3]=[C:2]([OH:1])[N:6]([C:7]3[CH:12]=[C:11]([C:13]4[NH:27][N:26]=[N:25][N:14]=4)[CH:10]=[CH:9][N:8]=3)[N:5]=2)[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(c1ccccc1)c1cc(O)n(-c2cc(C#N)ccn2)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccccc1)c1cc(O)n(-c2cc(-c3nnn[nH]3)ccn2)n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a suspension of 2-[5-hydroxy-3-(1-phenylethyl)pyrazol-1-yl]pyridine-4-carbonitrile (150 mg, 0.5 mmol), NH4Cl (278 mg, 5.2 mmol) in DMF (5 mL) was added NaN3 (338 mg, 5.2 mmol) at r.t. The reaction mixture was stirred at 110° C. for 2 h in a microwave oven. The reaction mixture was then filtered and purified by pre-HPLC to give the title compound (100 mg, 58%) as a brown solid. 1H NMR (400 MHz, CD3OD): δ 1.64 (3H, d, J=7.2 Hz), 4.07-4.12 (1H, m), 7.17-7.19 (1H, m), 7.20-7.35 (4H, m), 7.83 (1H, dd, J=1.2, 5.2 Hz), 8.43 (1H, d, J=5.2 Hz), 8.74 (1H, s). [M+H] Calc'd for C17H15N7O, 334; Found, 334.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[N+:7]([C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].[OH-].[Na+]>N1C=CC=CC=1>[S:3]1[CH:4]=[N:5][N:6]=[C:2]1[NH:1][S:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1)(=[O:17])=[O:18]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1nncs1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nncs2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
To a stirred suspension of 2-amino-1,3,4-thiadiazole (1.5 g, 15 mmol) in anhydrous pyridine (6 ml) at 0° C., under nitrogen, was added 3-nitrobenzenesulphonyl chloride (3.5 g, 16 mmol) portionwise. The mixture turned yellow and set solid. The mixture was then heated at 120° C. for 1 h before aqueous sodium hydroxide (20% (w/w), 3.3 ml) was added cautiously. Heating was continued for a further 15 min then the solution allowed to cool to ambient temperature. The mixture was evaporated in vacuo and the residue evaporated with water (2×50 ml) followed by toluene (2×50 ml). The residue was then taken up in water and the resultant brown solid collected by filtration. This was then recrystallised from glacial acetic acid. The title compound (1.4 g, 37%) was isolated as a yellow solid, which contained one mole of acetic acid. mp 189°-192° C. 1H NMR (250 MHz, D6 -DMSO) δ 7.88 (1H, dd, J=8 and 8 Hz), 8.23 (1H, dd, J=8 and 1 Hz), 8.45 (2H, m), 8.83 (1H, s).
Reaction SMILES: [P:1]([CH:5]1[CH2:9][CH2:8][CH:7](P(O)(O)=O)[O:6]1)([OH:4])([OH:3])=[O:2].P([O-])(OC)[O:15][CH3:16].[H-].[Na+]>COC1CCC(OC)O1>[P:1]([CH:5]1[CH2:9][CH2:8][CH:7]([O:15][CH3:16])[O:6]1)([OH:4])([OH:3])=[O:2]
Reactant: COP([O-])OC
Reactant: O=P(O)(O)C1CCC(P(=O)(O)O)O1
Agent: COC1CCC(OC)O1
Agent: [H-]
Agent: [Na+]
Product: COC1CCC(P(=O)(O)O)O1

Procedure:
To make 2,5-diphosphonotetrahydrofuran (i.e. n is 2), step (a) is suitably accomplished by adding dimethyl phosphite to a cool slurry of sodium hydride in 2,5-dimethoxytetrahydrofuran under an inert atmosphere such as nitrogen or argon and heating the resulting reaction mixture to form 2-phosphono-5-methoxytetrahydrofuran as a first intermediate. Step (b) is suitably accomplished by adding bromotrimethyl silane to said first intermediate and stirring the resulting mixture under an inert atmosphere such as nitrogen or argon, thereby forming di-(trimethylsilyl)2-phosphono-5-bromotetrahydrofuran as a second intermediate. Step (c) is suitably accomplished by adding triisopropyl phosphite to said second intermediate and heating the mixture under an inert atmosphere such as nitrogen or argon, thereby forming 2-(di-(trimethyl silyl)phosphono)-5-(diisopropylphosphono)-tetrahydrofuran. Diphosphonotetrahydrofuran may be produced by adding a concentrated acid, such as hydrochloric acid to the 2-(di-(trimethyl silyl)phosphono)-5-(diisopropylphosphono)-tetrahydrofuran and refluxing the acid solution. 2,6-Diphosphonotetrahydropyran (i.e. n is 3) and 2,7-Diphosphonooxepane (i.e. n is 4) may be produced in similar fashion, respectively using 2,6-dimethoxytetrahydropyran and 2,7-dimethoxyoxepane rather than 2,5-dimethoxytetrahydrofuran as a starting material.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[CH3:2].[Cl:24][CH2:25][C:26](Cl)=[O:27]>>[Cl:24][CH2:25][C:26]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)=[O:27]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: O=C(Cl)CCl
Product: CCN(C(=O)CCl)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from ethyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (100 mg) and chloroacetyl chloride (0.04 ml) according to an analogous synthetic method to Preparation Example 87, the title compound (133 mg) was obtained.