Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[C:15]2[C:16]3[N:17]([N:20]=[C:21]([CH3:28])[C:22]=3[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(NCCC#N)CC1C=CC=CC=1.Cl.CCCCCC>CCCCCC.C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@H:11]1[C:15]2[C:16]3[N:17]([N:20]=[C:21]([CH3:28])[C:22]=3[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)c1c(C)nn2ccc3c(c12)C(CCNC(=O)OC(C)(C)C)CC3
Agent: CC(Cc1ccccc1)NCCC#N
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)c1c(C)nn2ccc3c(c12)[C@H](CCNC(=O)OC(C)(C)C)CC3
Yield: 48.7 %

Procedure:
Ethyl 9-{2-[(tert-butoxycarbonyl)amino]ethyl}-2-methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (300 mg) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRALPAK AD (50 mm ID×500 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: A) hexane 100%, B) hexane/ethanol=70/30, mixing ratio: A/B=80/20, flow rate: 60 mL/min, column temperature: 30° C., sample concentration: 10 mg/mL (hexane/ethanol=95/5), injection amount: 300 mg). A fraction solution containing an optically active compound having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give the title compound (146 mg, 99.7% ee). The enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm ID×250 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=95/5, flow rate: 0.5 mL/min, column temperature: 30° C., sample concentration: 0.25 mg/mL (hexane/ethanol=95/5), injection volume: 10 μL).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][O:16][C:15]3=[O:24])[CH2:10][CH2:9]2)=[C:4]([Cl:25])[CH:3]=1.[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH:31]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(O)(=O)C>[Cl:25][C:4]1[CH:3]=[C:2]([NH:1][CH2:31][C:27]2[NH:26][CH:30]=[CH:29][N:28]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:12][CH2:13]1
Reactant: Nc1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Reactant: O=Cc1ncc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: O=C1OCc2ccccc2N1C1CCN(c2ccc(NCc3ncc[nH]3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The product of example 120 step (ii) (0.25 g) was dissolved in 1-methyl-2-pyrrolidinone (6 ml) and this solution was treated with 2-imidazolecarboxaldehyde (0.1 g) followed by acetic acid (0.13 g) and then sodium triacetoxyborohydride (0.37 g). the reaction mixture was stirred at room temperature for three days. At the end of this time the mixture was poured in to excess aqueous dilute hydrochloric acid, this solution was allowed to stand for 10 minutes before being basified by addition of excess aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, the organic layer was washed with water, dried and evaporated under reduced pressure. Purification was by chromatography eluting with methanol/chloroform (7/93). Yield 0.05 g as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:32][NH:33]C(OC(C)(C)C)=O)=[O:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].C(OC(=O)C)C.[ClH:47]>>[ClH:47].[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH:32][NH2:33])=[O:31])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To 6-bromo-2-[4-(N′-tert-butoxycarbonylhydrazinocarbonyl)benzyl]-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (158 mg) was added a solution (5 ml) of 4N hydrochloric acid ethyl acetate at room temperature and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from diisopropyl ether to give the title compound (112 mg, 79%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1.[CH2:32](OC[C@@H]1[C@@H](C=O)[C@@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1)C>>[CH2:1]([O:2][CH2:3][C@@H:4]1[C@@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1)[CH3:32]
Reactant: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOC[C@@H]1[C@@H](C=O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC[C@@H]1[C@@H](/C=C/C(C)=C/C(=O)OCC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 73 %

Procedure:
Following a procedure similar to that for the preparation of Compound 16a but using Intermediate 15b as the starting material afforded the title compound (35 mg, 73% yield) as a white solid:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+].C>CC(C)=O.CC(O)C>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8](=[O:12])[O:9][C:10]=2[CH:11]=1
Reactant: ClCCCBr
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: O=c1ccc2ccc(OCCCCl)cc2o1

Procedure:
A mixture of 16.8 g (0.104 mole) of 7-hydroxycoumarin, 31.6 g (0.2 mole) of 1-bromo-3-chloropropane and 41.5 g (0.3 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 24 hr. The mixture was filtered with difficulty to give a milky filtrate. The filtrate was treated with charcoal and filtered through Celite® to give a clear filtrate. The filtrate was concentrated under reduced pressure to give a solid residue. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration; and dried to yield 19.1 g (77%) of fluffy, white solid. An analytical sample, m.p. 100°-102° C., was obtained on recrystallization from 2-propanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=1[CH3:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(B(O)O)c1C
Reactant: CC(C)(C)OC(=O)N(N)Cc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cccc(NN(Cc2ccccc2)C(=O)OC(C)(C)C)c1C
Temperature: 50 °C
Yield: 39.6 %

Procedure:
A mixture of N-benzyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 27; 790 mg, 3.55 mmol), 2,3-dimethylphenylboronic acid (Aldrich; 522 mg, 3.48 mmol), copper(II) acetate (646 mg, 3.55 mmol) and triethylamine (500 μL, 3.55 mmol) in 1,2-dichloroethane (5.5 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N-benzyl-N′-(2,3-dimethyl-phenyl)-hydrazinecarboxylic acid tert-butyl ester (450 mg, 39%) as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7](I)=[N:8][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.[CH3:17][N:18]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:37].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19](=[O:37])[N:18]([CH3:17])[CH:27]=3)=[N:8][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(I)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2nc(S(C)(=O)=O)ccc2OCC2CC2)c2ccccc2c1=O
Temperature: 70 °C
Reaction time: 18 h
Yield: 52.7 %

Procedure:
A mixture of 3-(cyclopropylmethoxy)-2-iodo-6-methylsulfonylpyridine (140.0 mg, 0.40 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (136.5 mg, 0.48 mmol), K3PO4 (252.7 mg, 1.19 mmol) and Pd(dppf)Cl2 (29.2 mg, 0.04 mmol) in dioxane (5 mL) and H2O (1 mL) was stirred at 70° C. for 18 hrs under N2. The mixture was filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (81.0 mg, 53.1%). 1H NMR (CDCl3, 400 MHz) δ 8.33 (dd, J1=8.4 Hz, J2=1.2 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.74 (s, 1H), 7.67 (t, J=8.4 Hz, 1H), 7.55 (t, J=8.4 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 4.01 (d, J=6.8 Hz, 2H), 3.60 (s, 3H), 3.25 (s, 3H), 1.10-0.98 (m, 1H), 0.45-0.37 (m, 2H), 0.23-0.17 (m, 2H). LCMS: 385.1 (M+1)+
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])/[CH:3]=[CH:4]/[CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[CH:6]1[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[BH4-].[Na+].C(O)(=O)C>CO>[OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])/[CH:3]=[CH:4]/[CH:5]1[CH2:9][CH2:8][CH:7]([OH:10])[CH:6]1[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCCCCC(O)/C=C/C1CCC(=O)C1C/C=C\CCCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCC(O)/C=C/C1CCC(O)C1C/C=C\CCCC(=O)O

Procedure:
50 mg of 7-[2-(3-hydroxy-3-pentyl-trans-1-propenyl)-5-oxo-cyclo-pentyl]-cis-5-heptenoic acid were dissolved in 20 ml of methanol and in the course of 1.5 hours three 50 mg portions of NaBH4 were added. The reaction solution was adjusted to pH 7 with glacial acetic acid, the solvent was distilled off under reduced pressure, the residue was acidified in 1 ml of H2O with 2 N hydrochloric acid to pH 1 and extracted three times with 150 ml portions of ether. The combined ether extracts were washed with water, dried and condensed.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([CH:12]2OCC[O:13]2)[CH:3]=1.FC(F)(F)C(O)=O>CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([CH:12]=[O:13])[CH:3]=1
Reactant: N#CCOc1ccc(Cl)cc1C1OCCO1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: N#CCOc1ccc(Cl)cc1C=O
Reaction time: 8 h
Yield: 93.7 %

Procedure:
At room temperature, a mixture of (4-chloro-2-[1,3]dioxolan-2-yl-phenoxy)-acetonitrile (28.68 g, 0.12 mol) and trifluoroacetic acid (41.04 g, 0.36 mol) in EtOAc (500 mL) was stirred overnight. Then the solution was washed with water, saturated NaHCO3 solution twice, dried over anhydrous Na2SO4, and concentrated to give crude product (22 g). The crude product was directly used for next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22](=[O:23])[C:21]3=[CH:24][S:25][CH:26]=[C:20]3[NH:19][C:18]2=[O:27])[CH2:11][CH2:10]1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([N:19]1[C:20]2=[CH:26][S:25][CH:24]=[C:21]2[C:22](=[O:23])[N:17]([CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]2)[C:18]1=[O:27])(=[O:37])[CH3:36]
Reactant: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3cscc3c2=O)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CCn2c(=O)c3cscc3n(C(C)=O)c2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of 3-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[3,4-d]pyrimidine-2,4-dione (1.0 g, 2.6 mmol) in methylene chloride (50 ml) was cooled by an external ice bath and triethylamine (0.393 g, 3.88 mmol) and acetyl chloride (0.305 g, 3.88 mmol) were added. After stirring for 1 hour, the mixture was warmed to room temperature and quenched with water (10 ml). The separated organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solution was concentrated in vacuo, treated with toluene (10 ml) and reconcentrated to give the product (0.93 g, 83.5% yield) which was recrystallized from methylene chloride-hexanes to give the analytical sample as light brown crystals, mp 128°-129° C.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].S(OOS([O-])(=O)=O)([O-])(=O)=[O:13].[K+].[K+].S(=O)(=O)(O)O>>[O:5]=[C:4]1[C:2](=[O:3])[NH:1][C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:13]1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2ccccc2oc1=O
Reaction time: 0.25 h

Procedure:
103 parts of isatin are introduced slowly into a solution of 190 parts of potassium peroxydisulfate in 1,300 parts of 90% strength sulfuric acid at from 0° C. to 10° C. The mixture is then stirred for 10-20 minutes, after which it is poured onto ice. The product is filtered off and dried, giving 110 parts of 2,3-dioxo-1,4-benzoxazine, of melting point 285° C. (with decomposition).
Reaction SMILES: [NH:1]([CH3:9])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[CH3:10][N:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]=[N:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[CH3:12].N[C@H](C(O)=O)C(C)C.CC1OC(C)CN(C(CN2C(=O)SC3C2=CC=CC=3)=O)C1.N(C)[C@H](C(O)=O)C(C)C>O1CCOCC1.O>[CH3:10][N:11]([CH3:12])[C:13]1[CH:14]=[CH:15][C:16]([N:19]=[N:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[C:6](=[O:8])[CH:2]([CH:3]([CH3:4])[CH3:5])[N:1]([CH3:9])[C:28]3=[S:29])=[CH:23][CH:22]=2)=[CH:17][CH:18]=1
Reactant: CN[C@H](C(=O)O)C(C)C
Reactant: CN(C)c1ccc(N=Nc2ccc(N=C=S)cc2)cc1
Agent: CC(C)[C@H](N)C(=O)O
Agent: CC1CN(C(=O)Cn2c(=O)sc3ccccc32)CC(C)O1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C1C(=O)N(c2ccc(N=Nc3ccc(N(C)C)cc3)cc2)C(=S)N1C
Yield: 95.6 %

Procedure:
From a stock solution of 0.500 M N-(Me)-D,L-valine (20 mmol in 40 mL 0.25 M KOH), a 5.0-mL aliquot (2.5 mmol MeVal) was heated to 60° C. and mixed with 0.100M DABITC (5.0 mL, 0.5 mmol) in dioxane. In order to obtain a homogeneous solution another 3.5 mL dioxane and 2.5 mL water were added. This reaction mixture became inhomogeneous in contrast to the mixture containing Val, indicating that the DABTH-MeVal formed precipitated. The reaction was monitored by TLC (SiO2 Tol/EtOAc, 2:1; spots developed with both UV and long wavelength light) and after 30 min all the DABITC had been consumed. The subsequent extraction was performed as described above. The product crystallized from DCM:hexane (1:4, v/v) to yield 189.0 mg (99.5%) of the desired product. Analysis: m.p. 164.5-169° C., Rf-TLC 0.73 (SiO2; EtOAc:MeOH, 4:1). UV (acetonitrile:water 1:1) λmax=265 nm, ε265=26000 (see also FIG. 12). Fluorescence measurements: see FIGS. 9 and 10. 1H NMR(CDCl3, 25° C.) δ1.05, 1.25[d+d, 3+3H, J=6.9, 7.1 Hz, CH3(γ,γ′)], 2.47 [m, 1H, J=3.3, 6.9, 7.1 Hz, CH(β)], 3.09 [s, 6H, N(CH3)2] 3.4[s, 3H, N—CH3], 4.4 [d, 1H, J=3.3 Hz, CH(α)], 6.74, 6.77 [d+d, 2H, azobenzene C6—H, C7—H] 7.37, 7.40 [d+d, 2H, azobenzene C5—H, C8—H] 7.87, 7.90, 7.92, 7.95 [4d, 4H, azobenzene C1—H—C4—H].
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17][C:4]21[C:8](=[O:9])[N:7]([C:10]1[CH2:11][O:12][C:13](=[O:16])[C:14]=1[CH3:15])[CH2:6][CH2:5]2.[OH:28][CH:29]1[CH2:46][N:45]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:44][CH2:43][C:30]21[C:34](=[O:35])[N:33]([C:36]1[CH2:37][O:38][C:39](=[O:42])[C:40]=1[CH3:41])[CH2:32][CH2:31]2>C(Cl)Cl>[CH3:1][O:2][CH:3]1[CH2:20][NH:19][CH2:18][CH2:17][C:4]21[C:8](=[O:9])[N:7]([C:10]1[CH2:11][O:12][C:13](=[O:16])[C:14]=1[CH3:15])[CH2:6][CH2:5]2.[OH:28][CH:29]1[CH2:46][N:45]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:44][CH2:43][C:30]21[C:34](=[O:35])[N:33]([C:36]1[CH2:37][O:38][C:39](=[O:42])[C:40]=1[CH3:41])[CH2:32][CH2:31]2
Reactant: COC1CN(C(=O)OC(C)(C)C)CCC12CCN(C1=C(C)C(=O)OC1)C2=O
Agent: CC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3O)C2=O)COC1=O
Solvent: ClCCl
Product: COC1CNCCC12CCN(C1=C(C)C(=O)OC1)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 6-methoxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (CIS, faster) (2.17 g, 5.70 mmol) in methylene chloride (7 mL) was added trifluoroacetic (7 mL, 91 mmol) and the resulting solution was stirred at rt for 2 h. After concentration the residue was basified on ion exchange column washing with methanol first, then eluted with 1 N ammonia in methanol to give 6-methoxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (CIS, faster). LC/MS: (M+1)+: 281.11.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:21]Br>ClCCl>[Br:21][C:18]1[CH:19]=[C:14]([CH2:13][CH2:12][C@H:9]2[CH2:8][CH2:7][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)[CH:15]=[CH:16][C:17]=1[OH:20]
Reactant: BrBr
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(O)cc2)CC1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(O)c(Br)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A solution of 2.7 g of 4-[2-(trans-4-pentylcyclohexyl)ethyl]phenol in absolute dichloromethane was treated dropwise at 0° C. with a solution of 1.6 g of bromine in 20 ml of absolute dichloromethane. The mixture was stirred for 1 hour and then poured into ice-water. The organic phase was separated and the aqueous phase was back-extracted three times with 50 ml of dichloromethane each time. The combined organic phases were washed with 50 ml of 2N sodium carbonate solution and several times with water, dried over magnesium sulphate and concentrated. Recrystallization of the resulting crude product from hexane at 0° C. gave 3.4 g of 2-bromo-4-[2-(trans-4-pentylcyclohexyl)ethyl]phenol.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:8][C:9]#[N:10].[Na].O=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[C:9]([CH2:8][C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[NH:1][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)#[N:10]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: N#CC[C@H]1CCCC[C@@H]1N
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N[C@H]2CCCC[C@@H]2CC#N)CC1
Reaction time: 0.25 h
Yield: 43.7 %

Procedure:
[(1R,2S)-2-aminocyclohexyl]acetonitrile (1.1 g) was dissolved in MeOH (10 mL) and sodium methoxyde (0.45 mL) was added. The mixture was stirred for 15 minutes then tert-butyl 4-oxopiperidine-1-carboxylate (0.85 g, 4.27 mmol) was added. A solution containing sodium cyanoborohydride (0.36 g, 5.22 mmol) and zinc chloride (0.35 g, 2.60 mmol) in MeOH (2 mL) was then added drop wise and the mixture stirred at room temperature. The solvent was then removed under reduced pressure and the residue was diluted in dichloromethane and was washed with 1N NaOH and brine. The crude was purified by high pH prep LCMS to provide 0.6 g of the title compound. MS (M+1): 322.27
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[I:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[N:11]([CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[I:15])[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Reactant: ClCc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2I)n(C)c1=O
Temperature: 25 °C
Reaction time: 168 h

Procedure:
8-Chlorotheophylline (8.5 g, 39.6 mmol) was dissolved in 400 ml of DMF and 2-iodobenzyl chloride (10.0 g, 39.6 mmol), potassium carbonate (5.47 g, 39.6 mmol), and potassium iodide (10 mg, 0.06 mmol) were added. The mixture was stirred at room temperature for 7 days. Water (2500 ml) and EtOAc (800 ml) were added and the layers were separated. The aqueous layer was extracted with 2×500 ml of EtOAc, and the combined organic layer was washed with 500 ml of water, 500 ml of brine, dried over sodium sulphate, and filtered. The solvent was evaporated and the crude product was crystallized from diethyl ether and petrol, to give compound (5A) as white crystals. The mother liquor was evaporated and resuspended in diethyl ether and petrol, to give a second crop of compound (5A).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH2:8][CH3:9])=[CH:3]\[CH2:4][OH:5].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:1]/[C:2](/[CH2:6][CH2:7][CH2:8][CH3:9])=[CH:3]\[CH:4]=[O:5]
Reactant: CCCC/C(C)=C/CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCCC/C(C)=C/C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a suspension solution of alcohol 13b (739 mg, 5.7 mmol), 4 Å molecular sieves (2.9 g, activated), and NMO (1.33 g, 11.4 mmol) in CH2Cl2 (12 mL) at 0° C., was added TPAP (120 mg,0.34 mmol) in one-portion. The resulting dark reaction mixture was allowed to stir at 0° C. for 30 min, before being diluted with CH2Cl2 (20 mL), and then filtered through a short pad of silica gel. The filtrate was concentrated in vacuo to afford aldehyde 14c (704 mg, 98% yield) as a colorless oil. The aldehyde is sufficiently pure for immediate use without further purification:
Reaction SMILES: [CH3:1][P@@:2]([C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH2:4][CH2:5][P@@:6]([CH3:16])([C:8]([CH3:15])([CH3:14])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])=[O:3]>C(Cl)(Cl)Cl>[CH3:16][P:6]([C:8]([CH3:15])([CH3:14])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])([CH2:5][CH2:4][P:2]([CH3:1])([C:17]([CH3:23])([CH3:24])[CH2:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:3])=[O:7]
Reactant: CC(C)(C)CC(C)(C)[P@@](C)(=O)CC[P@](C)(=O)C(C)(C)CC(C)(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(C)CC(C)(C)P(C)(=O)CCP(C)(=O)C(C)(C)CC(C)(C)C

Procedure:
The resultant product was found to be (−)-(S, S)-1,2-bis-[methyl(1,1,3,3-tetramethylbutyl)phosphinoyl]ethane having an optical rotation of [α] 25D=−2.85 (C 1.05, CHCl3). The results of this compound analyzed by NMR and other means are shown below.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Cl)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>CCOCC>[CH2:24]([N:26]([CH2:27][CH3:28])[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[CH3:25]
Reactant: O=C(c1ccccc1)C(OCCCl)(OCCCl)c1ccccc1
Reactant: CCNCC
Solvent: CCOCC
Product: CCN(CC)CCOC(OCCN(CC)CC)(C(=O)c1ccccc1)c1ccccc1

Procedure:
20 g (0.057 mole) of benzil-di-(2-chloroethyl)ketal are stirred with 150 g (2.05 moles) of diethylamine for 24 hours at 140° C. in a pressure autoclave. After cooling, the reaction mixture is taken up in ether and extracted with water. The ether layer is dried over Na2SO4 and concentrated. The residual oil is dried in a high vacuum.