Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][O:12][CH2:13][CH:14]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:24]([O:31][C:32]([NH:34][C:35]1[C:36]([C:46]([NH:48][C:49]2[CH:50]=[N:51][CH:52]=[CH:53][C:54]=2[N:55]2[CH2:60][C@H:59]([CH3:61])[C@H:58]([NH:62][C:63](=[O:66])[O:64][CH3:65])[C@H:57]([NH:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71])[CH2:56]2)=[O:47])=[N:37][C:38]2[C:43]([CH:44]=1)=[CH:42][CH:41]=[C:40](Br)[CH:39]=2)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>O1CCOCC1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:24]([O:31][C:32]([NH:34][C:35]1[C:36]([C:46]([NH:48][C:49]2[CH:50]=[N:51][CH:52]=[CH:53][C:54]=2[N:55]2[CH2:60][C@H:59]([CH3:61])[C@H:58]([NH:62][C:63](=[O:66])[O:64][CH3:65])[C@H:57]([NH:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71])[CH2:56]2)=[O:47])=[N:37][C:38]2[C:43]([CH:44]=1)=[CH:42][CH:41]=[C:40]([C:9]1[CH2:10][CH2:11][O:12][CH2:13][CH:14]=1)[CH:39]=2)=[O:33])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2NC(=O)c2nc3cc(C4=CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 31.4 %

Procedure:
A vial was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (104 mg, 0.493 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (35 mg, 0.045 mmol), and K3PO4 (180 mg, 0.849 mmol). The vial was sealed with a septum and purged with nitrogen three times). A solution of tert-butyl methyl [(3R,4S,5S)-1-(3-{[(3-{[(benzyloxy)carbonyl]amino}-7-bromoquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-5-methylpiperidine-3,4-diyl]biscarbamate (200 mg, 0.262 mmol) in 1,4-dioxane (2.0 mL) was added, followed by deoxygenated water (0.50 mL, 28 mmol). The reaction was heated at 60° C. for 2 h. The mixture was purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a yellow solid (63.0 mg, 31%). LCMS calc. for C41H48N7O8 (M+H)+: m/z=766.4. Found: 766.4.
Reaction SMILES: [C:1]1(=[O:25])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][P:12](=[O:19])([O:16]CC)[O:13]CC)[C:4](=[O:20])[C:3]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:2]12.C[Si](Br)(C)C.C1(=O)N(CCCCCCP(=O)O)C(=O)C2=CC=CC=C12.[NH4+].[OH-].O>ClCCl.C(O)(C)C>[C:4]1(=[O:20])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][P:12](=[O:13])([OH:16])[OH:19])[C:1](=[O:25])[C:2]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:3]12
Reactant: CCOP(=O)(CCCCCCN1C(=O)c2ccccc2C1=O)OCC
Agent: C[Si](C)(C)Br
Agent: O=C1c2ccccc2C(=O)N1CCCCCC[PH](=O)O
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C1c2ccccc2C(=O)N1CCCCCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of the diethyl ester product from part (b) (4.0 g., 10.9 mmole) in dry dichloromethane (8.0 ml.) is treated with trimethylsilylbromide (3.6 ml., 27.3 mmole) and stirred at room temperature under argon for 22 hours. The mixture is evaporated to dryness (0.5 mm. of Hg) and the residue taken up in dichloromethane (30 ml.)-water (5 ml.) and stirred vigorously for 15 minutes. The organic phase is separated, dried (Na2SO4), and evaporated. The crystalline residue is triturated with ethyl ether to give 3.20 g. of (6-phthalimidohexyl)phosphinic acid as a white solid; m.p., 159°-160°. Tlc (isopropanol-conc. NH4OH-water; 7:2:1) shows a single spot at Rf =0.20.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[C:10]1([C:16]2[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:16]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=[CH:18][C:19]([CH2:20][O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])=[CH:22][CH:23]=1
Reactant: OCc1ccccc1O
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCc1ccccc1OCc1ccc(-c2ccccc2)cc1

Procedure:
A mixture of 2.92 g (23.49 mmol) of 2-hydroxybenzyl alcohol, 5.00 g (24.67 mmol) of 4-phenylbenzyl chloride and 3.41 g (24.67 mmol) of potassium carbonate in 60 ml of acetone was heated at reflux overnight. The precipitate formed was filtered off. The residue was taken up in 1N NaOH, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and the solvent was removed. The product was purified chromatographically (silica gel, cyclohexane/ethyl acetate 10:1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30](=[O:39])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38])([CH3:28])([CH3:27])[CH3:26].[OH:40][CH2:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[C:25]([O:29][C:30]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][C:41](=[O:40])[C:42]1[CH:50]=[CH:49][C:45]([CH2:46][OH:47])=[CH:44][CH:43]=1)=[O:39])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CO)cc1

Procedure:
HATU (17 g, 45 mmol) was added to a solution of 2-aminophenylcarbamic acid t-butyl ester (Reference Compound No. 1-1, 8.3 g, 40 mmol), 4-hydroxymethylbenzoic acid (6.2 g, 41 mmol) and N,N-diisopropylethylamine (21 mL, 120 mmol) in anhydrous DMF (200 mL), and then the mixture was stirred at room temperature for 16 hours. Water (500 mL) was added thereto, the whole was extracted with ethyl acetate (500 mL) twice, and then the organic layer was washed with brine (500 mL) twice. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 1.7 g of the title reference compound as a pale yellow solid. (Yield 42%)
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10](#[N:16])[CH:11]([CH2:13][C:14]#[N:15])[OH:12]>C(O)C.N1CCCCC1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:13]([C:14]#[N:15])[CH:11]([OH:12])[C:10]#[N:16]
Reactant: N#CCC(O)C#N
Reactant: O=Cc1ccccc1F
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(=Cc1ccccc1F)C(O)C#N

Procedure:
2-Fluorobenzaldehyde (15.8 ml) was dissolved in ethanol (100 ml) and to the stirred solution was added malonitrile (9.9 g). The solution was heated to reflux, the heating discontinued and piperidine (4 drops) was added. Once the vigorous reaction had diminished, the solution was heated for 15 minutes and then chilled. Crystals of product were filtered off and washed with ethanol, m.p. 122° C.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:21][C:22]=1[N+:27]([O-:29])=[O:28]
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(O)c([N+](=O)[O-])c4)c3c2s1
Yield: 60 %

Procedure:
Prepared from VII and 4-amino-2-nitrophenol. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 60%; brown solid; mp>260° C.; IR (KBr) νmax/cm−1 3334, 3081, 2926, 2225, 1627, 1591, 1569, 1525, 1465, 1419, 1395, 1305, 1237, 1171, 1132, 1070, 966, 930, 834, 819; 1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, 1H, J=8.7 Hz), 8.28 (m, 1H), 8.03 (m, 1H), 7.75 (d, 1H, J=8.7 Hz), 7.61 (m, 1H), 7.15 (d, 1H, J=9.0 Hz); HRMS calcd for C16H9N6O3S (M+H+): 365.0457, found 365.0441.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.[Cl-].[Li+].[CH:31]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[N:44][CH:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[N:41]=2)[CH2:36][CH2:35]1)([CH3:33])[CH3:32]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([C:42]3[CH:43]=[N:44][CH:45]=[C:40]([N:37]4[CH2:38][CH2:39][N:34]([CH:31]([CH3:33])[CH3:32])[CH2:35][CH2:36]4)[N:41]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(N2CCN(C(C)C)CC2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cncc(N4CCN(C(C)C)CC4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 4.5 h

Procedure:
(S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (60.0 mg, 0.124 mmol), tetrakis(triphenylphosphine)palladium(0) (21.5 mg, 0.019 mmol), lithium chloride (15.8 mg, 0.373 mmol), and copper(I) iodide (7.1 mg, 0.037 mmol) were taken in a microwave vial and the vial vacuum pumped and flushed with argon three times. To this mixture was added 2-(4-isopropylpiperazin-1-yl)-6-(tributylstannyl)pyrazine (73.9 mg, 0.149 mmol) in dioxane (1.5 mL), and the resulting mixture was stirred at 100° C. for 4.5 h. The reaction mixture was cooled, filtered through Celite (ethyl acetate eluent), and concentrated. Purification by flash column chromatography on silica gel using 79:20:1 DCM/MeOH/NH3 (0 to 100%) in DCM provided the product. LCMS-ESI+ calc'd for C32H39ClN5O3S (M+H+): 608.2; Found: 608.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>ClCCl>[CH:19]1([C:22]([O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:23])[CH2:21][CH2:20]1
Reactant: COCCOCCOCCO
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCCOCCOC(=O)C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylene glycol monomethyl ether (1.1 eq, 5.26 mmol, 0.84 ml), triethylamine (1.1 eq, 5.26 mmol, 0.73 ml) was taken in a 10 ml round bottom flask and dichloromethane (3 ml) was added. This mixture was cooled to 0° C. and then cyclopropanecarbonyl chloride (4.78 mmol, 0.5 g, 0.43 ml) was added in a dropwise fashion maintaining the temperature at 0° C. with constant stirring. A yellowish-orange solid was observed after some time. Stirring was continued for 1 hr at 0° C. The reaction was monitored by thin layer chromatography, and then quenched with saturated ammonium chloride solution. It was then transferred to a separatory funnel, washed with 5% sodium bicarbonate (2×5 ml), 1:1 hydrochloric acid (2×5 ml) and then with brine (5 ml). The dichloromethane layer was separated from the aqueous layer, dried over anhydrous sodium sulphate, filtered, and evaporated in vacuo to give the title product as a pale yellow liquid. Purification was attempted by flash chromatography and vacuum distillation (b.p.=144° C., 3.0 mm of Hg) which afforded the pure product as a colorless liquid (527.0 mg, 48%).
Reaction SMILES: [F:1][C:2]([F:22])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][NH:14][C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[F:23][C:24]([F:30])([F:29])S([O-])(=O)=O.[Yb+3].[F:32][C:33]([F:39])([F:38])S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.O.C(OCC)C>[F:1][C:2]([F:22])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:13][C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:33]([F:39])([F:38])[F:32])[CH:8]=3)[CH:16]=2)[CH2:3][C@@H:2]([OH:6])[C:24]([F:30])([F:29])[F:23])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: Oc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Agent: [Yb+3]
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: O[C@H](CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(OCc2cccc(C(F)(F)F)c2)c1)C(F)(F)F
Temperature: 25 °C
Yield: 597.5 %

Procedure:
EX-20B) A solution of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]phenol (5.1 g, 16.2 mmol) from EX-20A, R-(+)-1,1,1-trifluoro-2,3-epoxypropane (1.5 mL, 17.4 mmol), and ytterbium trifluoromethanesulfonate (1.0 g, 10 mol %) in 10 mL of acetonitrile was heated at 50° C. in a sealed glass tube for 4 h. The reaction mixture was cooled to room temperature, then diluted with water and diethyl ether and extracted. The ether layer was washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO4, and concentrated in vacuo to give 5.64 g (81%) of the desired (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy]phenyl]methyl][3,3,3-trifluoro-2-hydroxy-propyl)amino]-phenol product as a yellow oil. 1H NMR (acetone-d6) δ 7.41 (t, 1H), 7.23 (d, 1H), 7.16-7.20 (m, 2H), 6.97 (t, 1H), 6.42 (tt, 1H), 6.18-6.24 (m, 3H), 4.77 (s, 2H), 4.43-4.48 (m, 1H), 3.58 (dd, 1H), 3.39 (dd, 1H).
Reaction SMILES: C([P:4]([CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:31])[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[O:18]2)=[C:13]([O:32][CH3:33])[CH:12]=1)([CH:6]([CH3:8])[CH3:7])=[O:5])(C)C.[N-]=[N+]=[N-].[Na+].CN(C)C=[O:41].C(OCC)(=O)C>O>[OH:5][P:4]([CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:31])[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[O:18]2)=[C:13]([O:32][CH3:33])[CH:12]=1)([CH:6]([CH3:7])[CH3:8])=[O:41]
Reactant: COc1ccc(-c2cc(=O)c3c(OC)cc(OCP(=O)(C(C)C)C(C)C)cc3o2)cc1OC
Reactant: CN(C)C=O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2cc(=O)c3c(OC)cc(OCP(=O)(O)C(C)C)cc3o2)cc1OC
Temperature: 100 °C
Yield: 33 %

Procedure:
7-{(diisopropylphosphoryl)-methyloxy}-3′,4′,5-trimethoxyflavone (0.5 g, 0.99 mmol, produced in Step 1 of Example 6) and sodium azide (0.5 g, 7.69 mmol) were added dropwise to N,N-dimethylformamide (20 mL) and warmed at 100° C. for 8 hours. The reaction solution was cooled to room temperature, and 50 mL of ethyl acetate and 50 mL of water were added dropwise, followed by separation of the organic layer from the aqueous layer. 10 mL of conc. hydrochloric acid was added dropwise to the aqueous layer which was then extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and then evaporated to afford 0.15 g (yield: 33%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=2)=[N:10][C:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[C:9]([O:20][C:21]2[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=2)[C:27]#[N:28])=[N:10][C:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(-c2cccnc2)nc1Oc1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(Oc2nc(-c3cccnc3)ncc2N)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Compound 14g (0.78 g; 2.0 mmol) in CH2Cl2 (20 mL) was added TFA (4 mL). The mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure to afford Compound 14h. The crude product was used in the next reaction without further purification. MS: m/z 290.3 (M+H)+.
Reaction SMILES: P(=O)(O)(O)O.[Cl-].[Na+].[CH2:8]([OH:30])[C@H:9]1[O:14][C@H:13]([O:15][C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H:12]([OH:27])[C@@H:11]([OH:28])[C@@H:10]1[OH:29]>O>[O:15]=[CH:13][C@@H:12]([C@H:11]([C@@H:10]([C@@H:9]([CH2:8][OH:30])[OH:14])[OH:29])[OH:28])[OH:27]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
To 1 ml of a buffer solution containing 20 mM phosphoric acid and 6.7 mM sodium chloride, 300 mg of maltose (Wako Pure Chemical Industries Ltd. product) were dissolved, and then, 10 mg of α-amylase (saccharification type, Seikakagaku Corporation product by using Bacillus subtilis) and 1 mg of ε-poly-L-lysine hydrochlorate were added and dissolved. The resulting solution was allowed to react at 60° C. for 24 hrs. After the reaction was completed, the reaction solution was heated in a boiled water to stop the enzyme reaction, and filtered through a 0.45 μm membrane filter. The quantity of glucose in the filtrate was measured by a high speed liquid chromatographic method. The quantity of glucose thus obtained was 265 MG.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[SH:12][CH2:13][C:14]([OH:16])=[O:15].C(OCC)(=O)C>O1CCCC1.N1CCCC1>[N+:1]([CH2:4][CH:5]([S:12][CH2:13][C:14]([OH:16])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])C=Cc1ccccc1
Reactant: O=C(O)CS
Solvent: C1CCNC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CSC(C[N+](=O)[O-])c1ccccc1
Reaction time: 2 h
Yield: 81.3 %

Procedure:
A solution of nitrostyrene (10 g, 0.067 mol) in tetrahydrofuran (250 ml) is treated with mercaptoacetic acid (7.4 g, 5.6 ml, 0.08 mol) followed by pyrollidine (3 drops). After stirring for 2 hours the reaction mixture is concentrated onto silica gel and chromatographed, eluting with 4:1, hexanes:ethyl acetate, to give the title product as a solid (13.14 g, 81% yield).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([N:18]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:6]([OH:17])[CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.O.[OH-].[Li+].P([O-])(O)(O)=O.[K+]>O1CCCC1.O>[CH2:10]([O:9][CH2:8][CH2:7][CH:6]([OH:17])[CH:5]([N:18]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:4]([OH:33])=[O:3])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(C(O)CCOCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(C(O)CCOCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 13.0 g (29 mmol) racemic (2S,3R and 2R,3S)-5-benzyloxy-2-dibenzylamino-3-hydroxy-pentanoic acid ethyl ester in 150 ml tetrahydrofurane were added 4.88 g (116 mmol) lithium hydroxide monohydrate dissolved in 41 ml water. The mixture was stirred at 60° C. for 16 hours. A 1 M aqueous solution of potassium dihydrogenphosphate was added followed by extraction with ethylacetate. Chromatography on silicagel with heptane/etylacetate 4:1 to 1:1 yielded 8.57 g (70%) racemic (2S,3R and 2R,3S)-5-benzyloxy-2-dibenzylamino-3-hydroxy-pentanoic acid, MS m/e (%): 420.1 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[F:27]>ClCCl.N1C=CC=CC=1>[F:20][C:21]1[CH:22]=[C:23]([S:28]([NH:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([N:9]3[CH2:13][CH2:12][C@H:11]([N:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[CH3:19])[CH2:10]3)=[CH:5][CH:6]=2)(=[O:29])=[O:30])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NS(=O)(=O)c1ccc(F)c(F)c1
Yield: 35.8 %

Procedure:
The title compound was synthesized substantially in the same manner as Example 3 by coupling of 2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine (0.025 g, 0.096 mmol) with 3,4-difluorobenzenesulfonyl chloride (0.061 g, 0.288 mmol) in dichloromethane (3 mL) and pyridine (0.5 mL) to obtain 0.015 g (36%) of the title compound.
Reaction SMILES: [C:1]1(=[CH:7][CH:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl.CO>O1CCOCC1>[C:1]1(=[CH:7][CH:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([O:14][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[Cl:22])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClCc1ccccc1Cl
Reactant: CC(C)(C)C(O)C(C=C1CCCCC1)n1cncn1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)C(OCc1ccccc1Cl)C(C=C1CCCCC1)n1cncn1
Temperature: 65 °C
Yield: 61 %

Procedure:
A solution of 13.1 g (0.15 mol) of 1-cyclohexylidene-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pentan-3-ol (Example 2) in 50 ml of dioxane was added dropwise to a suspension of 2.0 g of 80% strength sodium hydride in 50 ml of dioxane and the mixture was then warmed to 65° C. for 45 minutes. After cooling, 10.0 g (0.06 mol) of 2-chlorobenzyl chloride were added dropwise and the mixture was heated under reflux overnight. 5 ml of methanol were then added and the reaction was concentrated. The residue was taken up in methylene chloride and the methylene chloride mixture was washed several times with water. The organic phase was dried over sodium sulphate, concentrated and finally degassed under a high vacuum. 14.2 g (72% of theory) of 1-cyclohexylidene-3-(2-chlorobenzyloxy)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pentane were obtained as a yellowish oil with a refractive index of nD20 =1.5349.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH:20]2[CH2:22][CH:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][C:19]=32)[N:16]=[C:15]([CH3:23])[NH:14]4)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.I[CH2:29][CH2:30][CH3:31].O>[OH-].[Na+].CO.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH2:22][CH:20]([C:19]3[CH:18]=[C:17]4[C:13](=[CH:12][C:11]=32)[N:14]=[C:15]([CH3:23])[N:16]4[CH2:29][CH2:30][CH3:31])[CH2:21]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCI
Reactant: Cc1nc2cc3c(cc2[nH]1)C1CC3CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCCn1c(C)nc2cc3c(cc21)C1CC3CN(C(=O)OC(C)(C)C)C1
Temperature: 40 °C

Procedure:
(For conditions, see; Pilarski, B. Liebigs Ann. Chem. 1983, 1078.) 6-Methyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene-13-carboxylic acid tert-butyl ester (80 mg, 0.267 mmol) was stirred in 50% aqueous NaOH solution (3 mL) and DMSO (1 mL) then treated with 1-iodopropane (0.03 mL, 0.321 mmol). This mixture was warmed to 40° C. for 2 hours then cooled, treated with H2O and extracted with ethyl acetate. The organic layer was washed with H2O (3 times) then dried (Na2SO4), filtered and concentrated to an oil (90 mg, 0.253 mmol). (TLC 5% methanol/CH2Cl2 (NH3) Rf 0.15).