Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)=[O:5]
Reactant: O=C1CCNCC1
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(C(=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
2-Fluorobenzoyl chloride (10.5 g, 66.5 mmol) was added to a stirred solution of 4-piperidone hydrochloride (6.0 g, 60.5 mmol) and DIPEA (3.0 mL, 17.1 mmol) in DCM (150 mL). The mixture was stirred at room temperature for 2 hours and extracted with a 10% solution of citric acid, a saturated solution of Na2CO3 and H2O. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield 1-(2-fluorobenzoyl)-4-piperidinone (5.5 g, 41% yield) that was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.ClC1C=CC(C(N2C3C(=CC(OC)=CC=3)C(CC(O)=O)=C2C)=[O:24])=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:10]1([NH:9][C:8](=[O:24])[NH:7][CH:4]2[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DCC (1.0 g, 4.84 mmol) was added to a stirred solution of the product of Example 13d (0.9 g, 4.40 mmol), 2-{1-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}acetic acid (1.57 g, 4.40 mmol), and DMAP (0.05 g) in CH2Cl2 (30 mL) at room temperature. The resulting suspension was stirred for 1 hour at room temperature. The precipitate was removed by filtration and washed with CH2Cl2 (25 mL). The filtrate was concentrated to give a green oil which was chromatographed on silica gel eluting with 5:95 MeOH:CH2Cl2 to afford a green solid (contaminated with dicyclohexyl urea). The solid was triturated with hexane (50 mL) and filtered. The filtrate was concentrated to give the title compound (1.85 g, 77%) as a viscous green oil. 1H NMR (300 MHz, CDCl3) δ 7.47-7.65 (mult, 4H), 6.84-6.91 (mult, 2H), 6.65 (dd, J=2.5 and 9.0 Hz, 1H), 4.29 (t, J=6.7 Hz, 2H), 3.81 (s, 3H), 3.61 (s, 2H), 2.35 (s, 3H), 2.27 (s, 3H), 2.10-2.70 (mult, 10H); 13C NMR (75 MHz, CDCl3) δ 170.5, 168.2, 156.1, 139.2, 135.9, 133.9, 131.1, 130.7, 130.6, 129.1, 114.9, 112.2, 111.6, 101.3, 61.3, 57.5, 55.7, 51.4 (2C), 46.1, 36.6, 30.3, 13.3; mass spectrum (API-TIS) m/z 544 (M+H).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:22]([C@@H:25]1[C@@H:29]([C:30](=[O:33])[NH:31][CH3:32])[O:28][C@@H:27]([N:34]2[CH:42]=[N:41][C:40]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH:43][CH2:44][C:45]2[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:46]=2[O:47][CH2:48][C:49](O)=[O:50])[C@@H:26]1[OH:57])=[N+:23]=[N-:24].[NH:58]1[CH2:63][CH2:62][NH:61][CH2:60][C:59]1=[O:64]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:32][NH:31][C:30]([C@@H:29]1[C@@H:25]([N:22]=[N+:23]=[N-:24])[C@@H:26]([OH:57])[C@H:27]([N:34]2[CH:42]=[N:41][C:40]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH:43][CH2:44][C:45]2[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:46]=2[O:47][CH2:48][C:49](=[O:50])[N:61]2[CH2:62][CH2:63][NH:58][C:59](=[O:64])[CH2:60]2)[O:28]1)=[O:33]
Reactant: O=C1CNCCN1
Reactant: CNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cc(Cl)ccc4OCC(=O)O)ncnc32)[C@H](O)[C@@H]1N=[N+]=[N-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cc(Cl)ccc4OCC(=O)N4CCNC(=O)C4)ncnc32)[C@H](O)[C@@H]1N=[N+]=[N-]
Reaction time: 20 h

Procedure:
EDCI (44 mg, 0.23 mmol), HOBT (30 mg, 0.22 mmol) and DMAP (40 mg) were added to a mixture of (2R,3R,4S,5S)(2-{[9-(4-Azido-3-hydroxy-5-methylcarbamoyl-tetrahydro-furan-2-yl)-9H-purin-6-ylamino]-methyl}-4-chloro-phenoxy)-acetic acid (60 mg, 0.116 mmol) and piperizin-2-one (35 mg, 0.35 mmol) in anhydrous DMF (3 mL). After 20 hours at room temperature, the mixture was concentrated, pre-adsorbed onto silica gel and purified by flash chromatography (6-8% methanol/dichloromethane) to afford the title compound as a colorless solid. MS: 600 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].CO>N1C=CC=CC=1>[S:23]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)=[O:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1)([CH3:22])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccc(CN2CCC(O)CC2)o1)N1CCCCC1
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CCN(Cc2ccc(C(=O)N3CCCCC3)o2)CC1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 91.8 %

Procedure:
In 70 ml of pyridine was dissolved 3.47 g (11.88 mmol) of Compound t and with ice-cooling, 1.9 ml (23.77 mmol) of methanesulfonyl chloride was added dropwise. The mixture was stirred at 0° C. for 4.5 hours and, after addition of 5 ml of methanol, stirred at room temperature for 30 minutes. The solvent was then distilled off under reduced pressure and the residue was dissolved in 100 ml of methylene chloride. This solution was washed with 3 portions of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 4.04 g (91.8%) of 1-[5-(4-mesyloxypiperidinomethyl)-2-furancarbonyl]piperidine (Compound u) as red-brown oil.
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.[CH:10]1([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:28])=[C:20]([F:27])[C:21]=3[O:23][CH:24]([F:26])[F:25])[C:16](=[O:29])[C:15]([C:30]([O:32]CC)=[O:31])=[CH:14]2)[CH2:12][CH2:11]1>O>[CH:10]1([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:28])=[C:20]([F:27])[C:21]=3[O:23][CH:24]([F:25])[F:26])[C:16](=[O:29])[C:15]([C:30]([OH:32])=[O:31])=[CH:14]2)[CH2:11][CH2:12]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Temperature: 25 °C
Yield: 84.4 %

Procedure:
9 ml of acetic acid, 1.2 ml of concentrated sulfuric acid and 7 ml of water were added to 1.40 g (0.0039 moles) of ethyl 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate [(XX), R1 =--OCHF2, R3' =H, R17 =, C2H5, X=F] (prepared as described in Preparation 6), and the mixture was heated under reflux for 1 hour. At the end of this time, it was cooled to room temperature and poured into ice-water. The precipitated crystals were collected by filtration and washed with water and with diethyl ether, in that order, to give 1.09 g of 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as colorless needles, melting at 202°-207° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:11][OH:12].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[N:11]/[OH:12]
Reactant: NO
Reactant: O=Cc1ccccc1O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O/N=C/c1ccccc1O
Temperature: 95 °C
Reaction time: 5 h

Procedure:
Into a 500 mL round bottom flask was placed a solution of 2-hydroxybenzaldehyde (20 g, 163.93 mmol) in ethanol (200 mL). To this was added (H2NOH HCl) hydroxylamine hydrochloride (14 g, 197.18 mmol). To the mixture was added triethylamine (19.2 g, 190.10 mmol) slowly. The resulting solution was allowed to react, with stirring, for 5 hours while the temperature was maintained at 95° C. in a bath of oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The mixture was concentrated by evaporation. The resulting solution was extracted two times with 150 mL of ethyl acetate and water. The resulting mixture was washed 3 times with 150 mL of water. The mixture was dried over MgSO4 and concentrated by evaporator. The residue was purified by eluting through a column with a 1:100 ethyl acetate/petroleum ether solvent system. This resulted in 10 g (43%) of (E)-2-hydroxybenzaldehyde oxime as a white solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1[N:28]=[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([CH:26]=O)[N:20]2[N:19]=1.O>O1CCCC1>[CH3:17][C:18]1[N:28]=[C:21]2[CH:22]=[CH:23][CH:24]=[C:25](/[CH:26]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:20]2[N:19]=1
Reactant: Cc1nc2cccc(C=O)n2n1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cccc2nc(C)nn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
To a suspension of sodium hydride (0.570 g, 13.0 mmol) in tetrahydrofuran (50 mL) was added a solution of ethyl diethylphosphonoacetate (2.36 mL, 11.8 mmol) in tetrahydrofuran (10 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2-methyl[1,2,4]triazolo[1,5-a]pyridine-5-carbaldehyde (1.90 g, 11.8 mmol) in tetrahydrofuran (58 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (2.50 g, yield 92%).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][CH:5]2[CH:4]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:3]1.[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C>[Br:19][C:10]1[CH:9]=[CH:8][C:7]2[N:6]3[C:2](=[O:1])[O:3][CH:4]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH:5]3[CH2:13][C:12]=2[CH:11]=1
Reactant: CC(=O)NCC1OC(=O)N2c3ccccc3CC12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CC(=O)NCC1OC(=O)N2c3ccc(Br)cc3CC12

Procedure:
(±) (1S,9aS/1R,9aR) N-[(9,9a-Dihydro-3-oxo-1H,3H-oxazolo[3,4-a]indol-1-yl)methyl]acetamide (X, diastereomer B, [SS,RR-trans], EXAMPLE 11, 299 mg) is dissolved in acetonitrile (10 ml). To this mixture N-bromosuccinimide (235 mg) and a catalytic amount of benzoylperoxide are added as solids to the mixture at 20°-25°. The mixture is stirred at 20°-25° in a sealed flask over night. Then a small portion is removed and examined by NMR. The mixture was then concentrated under reduced pressure to give the title compound, NMR (CDCl3, 300 MHz) 7.30, 6.49, 4.63, 4.52, 3.72, 3.29, 3.12, 2.76 and 2.06 δ.
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[BH3-][C:20]#N.[Na+]>CC(O)=O.CO>[Cl:3][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][CH3:20])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
Formaldehyde (108 mg, 1.33 mmol, 37% wt solution in H2O) was added to a solution of 1-(4-chlorobenzyl)-4-(aminomethyl)piperidine (318 mg, 1.33 mmol) and NaBH3CN (668 mg) in 10% CH3COOH/CH3OH (3 mL). The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was loaded on DOWEX™ 50W×2 column (10 mL) and washed with CH3OH (100 mL). Product was eluted off using 2 N NH3 in CH3OH (100 mL) and concentrated to afford 173 mg of crude 1-(4-chlorobenzyl)-4-{(methylamino)methyl}piperidine as a colorless oil used without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9](I)=[CH:10]3)[C:6]=2[CH:16]=1.CC[Mg+].[Br-].[C:21](=[O:23])=[O:22].Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:21]([OH:23])=[O:22])=[CH:10]3)[C:6]=2[CH:16]=1
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Reactant: O=C=O
Agent: CC[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: -30 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Into a 20 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 9-Bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (700 g, 1.79 mol, 1.00 equiv) in tetrahydrofuran (13 L), followed by the addition of EtMgBr (1400 mL) dropwise with stirring at −30° C. over 60 min. To the above an excess of CO2 (gas) was introduced in over 3 h at −78° C. The resulting solution was warmed to room temperature naturally. The pH value of the solution was adjusted to 3 with hydrogen chloride (2 mol/L). The precipitates were collected by filtration, washed with 2×100 mL of EA and dried in a vacuum oven to afford 410 g (74%) of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid as a white solid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[OH:18])[CH2:7][CH2:6]2)[O:4]CC1.O.[NH+]1C=CC=CC=1>CC(C)=O>[OH:18][C:12]1[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=1[CH:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1
Reactant: Oc1ccc(C2CCC3(CC2)OCCO3)c(O)c1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(c2ccc(O)cc2O)CC1
Yield: 99.9 %

Procedure:
A round bottomed flask was charged with 4-(1,4-dioxaspiro[4.5]dec8-yl)-1,3-benzenediol (11.3 g), acetone (250 ml) and water (50 ml). To the stirred solution was added pyridinium ptoluenesulfonate (1.14 g) in one portion and the reaction mixture was then heated to reflux temperature for 8 hr. After allowing the reaction mixture to cool to room temperature, most of the acetone was removed in vacuo and the remaining mixture was partitioned between ethyl acetate (200 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (3×50 ml) and the combined organic layers were washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford an off white powder. After washing the powder with dichloromethane (100 ml) and removing excess solvent under reduced pressure, the title compound (9.30 g, 100%) was obtained as an off-white powder. m/z (ES+) 207 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[C:12]([C:13](=O)[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[C:16]1([S:22]([N:25]=C=O)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[C:16]1([S:22]([N:25]=[C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:14]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: COC(=O)c1cc(=O)c2ccccc2o1
Solvent: CC#N
Product: COC(=O)c1cc(=NS(=O)(=O)c2ccccc2)c2ccccc2o1
Reaction time: 24 h

Procedure:
Combine chromone-2-carboxylic acid methyl ester (0.341 g, 1.66 mmol) and benzenesulfonyl isocyanate (0.365 g, 1.88 mmol) in acetonitrile (5.0 mL) and reflux. After 24 hours, quench the reaction with methanol (1 mL). Concentrate in vacuo and triturate with hexane. Filter to obtain a paste. Recrystallize the paste from methanol to obtain a solid. Recrystallize from methanol to give the title compound as a solid: mp; 144°-146° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20].O1CCCC1.[H-].[Na+].Cl[C:29]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[O:30]>C(OCC)C>[CH2:32]([O:31][C:29]([O:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20])=[O:30])[CH:33]([CH3:35])[CH3:34]
Reactant: COC1C(O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reactant: CC(C)COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC1C(OC(=O)OCC(C)C)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Yield: 26.7 %

Procedure:
To a solution of 6-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (14.1 mg) in freshly distilled tetrahydrofuran (0.5 ml) was added sodium hydride (6.0 mg, 60% oil dispersion) in one portion at 5° C. The mixture was stirred for half an hour at the same temperature and then isobutyl chloroformate (7 mg) was added thereto. The reaction mixture was stirred for 2 hours at ambient temperature and then diluted with diethyl ether. The organic layer was washed with brine, dried, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (elution by diethyl ether/n-hexane =1/3) to yield 6-isobutoxycarbonyloxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (5.1 mg) as an oil.
Reaction SMILES: [Na].C[O:3][CH2:4][C:5]([O:7][CH2:8]C)=O.[CH3:10][C:11]([CH3:13])=[O:12].COC(C)(C)C>C1(C)C=CC=CC=1>[CH3:8][O:7][CH2:5][C:4](=[O:3])[CH2:10][C:11](=[O:12])[CH3:13]
Reactant: CCOC(=O)COC
Reactant: CC(C)=O
Agent: [Na]
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: COCC(=O)CC(C)=O
Reaction time: 3 h
Yield: 36.9 %

Procedure:
To a solution of sodium (5.83 g, 243.3 mmol) in dry toluene (62.5 mL) was added ethyl (methyloxy)acetate (24 g, 203.4 mmol) at −5° C. After stirring for 3 h, acetone (14 g, 231.4 mmol) was slowly added, upon which the mixture became brown and viscous. Next added 72 mL of tert-butyl methyl ether, and the reaction mixture was stirred at room temperature for 12 h, after which time the sodium salt precipitated. After collection and washing with additional tert-butyl methyl ether, the sodium salt was dissolved in 46 mL of 20% H2SO4. The contents were extracted with tert-butyl methyl ether and the organic layers concentrated to afford 1-(methyloxy)-2,4-pentanedione (9.76 g, 36.9%). 1H NMR (400 MHz, CDCl3-d3) δ 5.76 (s, 1H), 3.96 (s, 2H), 3.38 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([C@H:8]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:7]=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C=O)C.CCOC(C)=O>[N:31]([CH2:24][CH2:23][O:22][C@@H:8]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH3:30])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[N+:32]=[N-:33]
Reactant: Cc1ccc(Cl)cc1[C@H](OCCOS(C)(=O)=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1[C@H](OCCN=[N+]=[N-])[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Yield: 93.5 %

Procedure:
(R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (8.4 g, 18.3 mmol) was dissolved in anhydrous DMF (150 mL), solid NaN3 (3.56 g, 54.8 mmol.) was added and the reaction mixture was heated to 60° C. for overnight. The reaction mixture was cooled to rt and diluted with EtOAc (500 mL), the organic phase was washed with water (5×50 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo to give (R)-tert-butyl 3-((R)-(2-azidoethoxy)(5-chloro-2-methylphenyl)methyl)piperidine-1-carboxylate (7 g).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH2:33])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:33][S:42]([C:39]2[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][CH:38]=2)(=[O:44])=[O:43])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)Nc2cc3nc(-c4ccccc4)n(-c4ccccc4)c3cc2OCCCCCC(=O)OC(C)C)cc1

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester was reacted according to general operating instructions 13 with 4-methylbenzenesulfonic acid chloride.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[C:9]([C:11]#[N:12])=[CH:10][C:5]2=[N:4][N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:8]1[C:9]([C:11]#[N:12])=[CH:10][C:5]2[N:6]([C:2]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: C1COCCN1
Reactant: N#Cc1cc2nnc(Cl)n2cc1-c1ccc(Cl)cc1Cl
Product: N#Cc1cc2nnc(N3CCOCC3)n2cc1-c1ccc(Cl)cc1Cl
Reaction time: 5 h

Procedure:
A solution of the crude [3-chloro-6-(2,4-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile (50 mg, 0.148 mmol) in morpholine (1.2 mL) was heated at 110° C. and stirred for 5 h. The reaction mixture was concentrated in vacuum, the remaining residue was suspended in water (10 mL) and extracted with AcOEt (3×5 mL). The combined organic fractions were dried over Na2SO4, filtered, and evaporated to give the crude 6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-[1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile, which was used without further purification. MS: 374 [M+1+]; HPLC: AtRet=1.94.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:13][CH:12]([CH3:14])[CH2:11][C@H:3]([NH:2][S:23]([CH3:22])(=[O:25])=[O:24])[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NS(C)(=O)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-tert-Butyl 2-amino-4-methylpentanoate hydrochloride (1.53 g, 6.84 mmol) was dissolved in dichloromethane and triethylamine (3.15 mL, 22.57 mmol). Methanesulfonyl chloride (0.638 mL, 8.21 mmol) was added dropwise, and the reaction stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NaHCO3 and extracted with dichloromethane (3×50 mL). The solvent was removed in vacuo to give (S)-tert-butyl 4-methyl-2-(methylsulfonamido)pentanoate: 1H NMR (300 MHz, CDCl3) δ ppm 4.71 (d, J=9.7, 1H), 3.98 (td, J=9.5, 5.5, 1H), 2.92 (s, 3H), 1.84 (dt, J=13.1, 6.6, 1H), 1.54 (s, 9H), 1.44-1.48 br s, 1H), 0.96 (dd, J=6.6, 2.4, 6H); MS (ESI−) m/z 264 (M−H)−. (S)-tert-Butyl 4-methyl-2-(methylsulfonamido)pentanoate was dissolved in 10 mL of 4 N HCl in dioxane and stirred at room temperature overnight. The solvent was removed under a stream of nitrogen and under high vacuum to give (S)-4-methyl-2-(methylsulfonamido)pentanoic acid: 1H NMR (300 MHz, CDCl3) δ ppm 4.86 (d, J=9.6, 1H), 4.17 (td, J=9.6, 4.8, 1H), 3.18-3.07 (m, 1H), 2.99 (s, 3H), 1.96-1.80 (m, 1H), 1.64 (dddd, J=23.4, 13.9, 9.1, 5.0, 2H), 1.40 (t, J=7.3, 1H), 0.98 (dd, J=6.6, 3.3, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Sc1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccncc2)CC1

Procedure:
By a similar manner to Reference Example 35, 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) was reacted with 4-mercaptopyridine (0.67 g, 6.0 mmol) to give the titled compound as pale yellow oily substance (1.33 g, 90%)