Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:35])[C:2]([NH:7][C:8]2[O:9][C:10]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[C:11]([C:13](O)=[O:14])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.O.OC1C2N=N[NH:43]C=2C=CC=1.Cl.CN(C)CCCN=C=NCC.N.O1CCOCC1>C(Cl)Cl.CN(C=O)C>[C:1]1([CH3:35])[C:2]([NH:7][C:8]2[O:9][C:10]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:26][CH2:27]4)=[CH:20][CH:21]=3)=[C:11]([C:13](=[O:14])[NH2:43])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1Nc1nc(C(=O)O)c(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)o1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1Nc1nc(C(N)=O)c(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)o1
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To a solution of 2-(o-toluidino)-5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)oxazole-4-carboxylic acid (0.038, 0.08 mmol) in DCM (0.8 ml) and DMF (0.6 ml) was added hydroxybenzotriazole monohydrate (0.016 g, 0.10 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.024 g, 0.13 mmol) and 0.5M ammonia in dioxane (0.8 ml, 0.4 mmol) and the resultant mixture stirred overnight at room temperature. A further portion each of hydroxybenzotriazole monohydrate (0.016 g, 0.10 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.024 g, 0.13 mmol) and 0.5M ammonia in dioxane (0.8 ml, 0.4 mmol) was added and the resultant mixture stirred for 5 hours at room temperature, followed by the addition of hydroxybenzotriazole monohydrate (0.008 g, 0.05 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.012 g, 0.065 mmol) and 0.5M ammonia in dioxane (0.4 ml, 0.2 mmol) and the reaction mixture was stirred overnight. The solvent was then removed in vacuo and the residue purified by preparative HPLC to afford tert-butyl 4-(4-(2-(o-toluidino)-4-carbamoyloxazol-5-yl)phenyl)piperazine-1-carboxylate (0.012 g, 0.025 mmol, 32%). LCMS (2) Rt: 3.41 min; m/z (ES+) 478.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH:23]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:8][CH:7]=1.Cl>O1CCOCC1.C1COCC1.CO>[ClH:20].[CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH2:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:20])=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reaction time: 0.08 h
Yield: 232.9 %

Procedure:
The solid (S)-2-tert-butoxycarbonylamino-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester (43.45 g, 92.97 mmol) in dioxane (90 mL) was treated with 166 mL of 4.0N hydrochloric acid in dioxane at room temperature. After 5 minutes, the solids went into solution and the mixture was stirred for 2 h. Then, some of the dioxane was removed under vacuum to afford a yellow syrup and 250 mL of ethyl ether was added. A gum was formed which was dissolved in THF (100 mL) and methanol (100 mL). The solvent was removed under vacuum to obtain 43.7 g (100% yield) of (S)-2-amino-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester hydrochloride salt as a white solid: mp 180-195° C. This was stored in the refrigerator under argon atmosphere. ES(+)-HRMS m/e calcd. for C17H16Cl2N2O3 (M+H)+ 367.0616, obsd. 367.0611.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:18]=1[NH2:19].Br.N>C(OCC)C>[C:9]1(=[O:10])[N:5]([CH2:4][CH2:3][CH2:2][NH:19][C:18]2[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:17]=2[CH3:16])[C:6](=[O:15])[C:7]2=[CH:14][CH:13]=[CH:12][CH:11]=[C:8]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Cc1cccc(C)c1N
Agent: Br
Agent: N
Solvent: CCOCC
Product: Cc1cccc(C)c1NCCCN1C(=O)c2ccccc2C1=O

Procedure:
50 g. N-(3-Bromopropyl)-phthalimide and 50 g. 2,6-dimethylaniline are stirred for 5 hours at 100° C. After adding diethyl ether to the reaction mixture, it is filtered off with suction to give 69 g. of the hydrobromide (m.p. 226°-228° C.). The base is liberated from aqueous solution by adding a concentrated aqueous solution of ammonia. There are obtained 48 g. (83% of theory) of the desired product in the form of colorless crystals; m.p. 97°-98° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:9]2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=2)[CH2:30][CH2:29]1
Reactant: CCCCc1cc(CCC=O)n(-c2ccc(C)cc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(C)cc2)n1

Procedure:
297 mg (70.6%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-methylphenyl)-3-butyl-1H-pyrazol-5-yl)propanal (248 mg, 0.968 mmol), 1-(2-fluorophenyl)piperazine (229 mL, 1.451 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2>[Ni].C(O)C>[C:25]1([CH2:24][CH2:23][O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:14][CH2:13][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH2:13][C:6]3[CH:7]=[CH:11][CH:3]=[CH:4][CH:5]=3)=[C:11]3[C:7]=2[CH2:8][C:9](=[O:12])[NH:10]3)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1Cc2c(CCNCCCCCCOCCc3ccccc3)ccc(O)c2N1
Agent: [Ni]
Agent: Cl
Solvent: CCO
Product: O=C1Cc2c(CCN(CCCCCCOCCc3ccccc3)Cc3ccccc3)ccc(OCc3ccccc3)c2N1

Procedure:
Raney nickel (1.5 g) was added to a solution of the compound from step d) (2.1 g) in dry ethanol (60 ml). The mixture was heated to reflux for 1 hour, the catalyst was removed by filtration and the filtrate evaporated under reduced pressure. Trituration with ether gave an off-white solid which was purified by reverse phase HPLC (SiO2) using methanol:chloroform as eluant. Recrystallisation from isopropyl alcohol gave the subtitled compound as a buff coloured solid.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9]2.CS(O)(=O)=O.[OH-].[Na+]>ClCCl>[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:1][CH2:10][CH2:9]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2cc(Br)ccc21
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1NCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
NaN3 (6.2 g, 94.78 mmol) was added to a solution of 5-bromo-1-indanone (10 g, 47.39 mmol) in 40 mL mixture of methane sulphonic acid and dichloromethane (1:1) in portion wise at 0° C.-5° C. The resulting mixture was stirred for 8 h at room temperature. The reaction mixture was cooled to 0° C. in ice bath, neutralized with 5% aq. NaOH solution, and the aqueous layer with extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with water and brine solution, dried over sodium sulphate, filtered and concentrated under vacuum. The residue was purified by silica gel flash column chromatography by eluting with 30% ethyl acetate in hexane to afford title compound (6.4 g, 60%) as solid. 1H NMR (400 MHz, CDCl3): δ 7.95 (d, J=8.4 Hz, 1H), 7.5 (d, J=8.4 Hz, 1H), 7.4 (s, 1H), 6.1 (bs, 1H), 3.6 (t, J=6.8 Hz, 2H), 3.0 (t, J=6.4 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C(N(CC)CC)C.[Cl:29][CH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>O1CCCC1>[Cl:29][CH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([NH:8][C:9]3[N:14]=[C:13]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:12]=[CH:11][N:10]=3)[CH:7]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (2.83 g, 8.29 mmol) was dissolved in tetrahydrofuran (20 ml), triethylamine (1.4 ml, 9.95 mmol) was added thereto, and the mixture was stirred for 30 minutes. 4-Chloromethyl benzoyl chloride (2.03 g, 10.78 mmol) was added and the whole mixture was reacted under reflux for 4 hours. The mixture was filtered, and the filtrate was concentrated and crystallized from water to give N-(5-(4-chloromethylbenzoylamino)-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (3.12 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].O[CH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[N:28]1[CH3:37]>C1(C)C=CC=CC=1>[CH3:37][N:28]1[C:29](=[O:36])[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]1[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CN1C(=O)c2ccccc2C1O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1c2ccccc2C(=O)N1C
Temperature: 20 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
11.5 g of ethoxycarbonylmethylenetriphenylphosphorane are added to a suspension of 4.5 g of 3-hydroxy-2-methyl-2,3-dihydroisoindol-1-one in 110 cm3 of toluene. The reaction mixture is refluxed with stirring for 16 hours and then cooled to a temperature in the region of 20° C. The mixture is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residual oil is taken up in 50 cm3 of diethyl ether. The precipitate formed is filtered off and then washed twice with 10 cm3 of diethyl ether. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. to give an orange-colored oil, which is purified by chromatography under argon pressure (60 kPa) on a column of silica gel (particle size 20-45 μm), eluting with successive mixtures of cyclohexane/ethyl acetate (70/30, 65/35, 60/40 by volume). The fractions comprising the expected product are combined and concentrated under reduced pressure (2 kPa) at a temperature in the region of 30° C. 4.1 g of ethyl (2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a yellow oil. (Rf=0.25, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[C:14]4[CH2:15][NH:16][CH2:17][CH2:18][C:13]=4[NH:12][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[CH2:20][CH2:21][CH2:22][C:23]1[C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[O:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[C:14]4[CH2:15][NH:16][CH2:17][CH:18]([CH2:20][CH2:21][CH2:22][C:23]5[C:27]6[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=6[O:25][N:24]=5)[C:13]=4[NH:12][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)ncc1[nH]c3c(c12)CNCC3
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2c(CCCC3CNCc4c3[nH]c3cnc5cc(Cl)ccc5c43)noc2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture prepared from 5.15 g of 3-chloro-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline, 7.0 g of 3-(3-chloropropyl)-6-fluorobenzisoxazole, 4.0 g of potassium carbonate (powdered) and 30 ml of N,N-dimethylformamide was stirred at 100° C. for 2 hours. The mixture was diluted with 150 ml of water and the oily precipitate was purified by high performance liquid chromatography (HPLC) using dichloromethane/methanol mixtures of 95:5 and 10:1 ratios. The clean fractions were combined and concentrated. The residue was stirred in isopropanol and filtered. The yield was 1.2 g, mp=221°-222° C.
Reaction SMILES: [CH3:1]/[C:2](/[C:14]1[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=1)=[CH:3]\[C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[CH3:1]/[C:2](/[C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1)=[CH:3]\[C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)COc1ccc(/C(C)=C/C(=O)NCc2cccnc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C/C(=C\C(=O)NCc1cccnc1)c1ccc(OCC(=O)O)cc1
Yield: 39 %

Procedure:
0.5 g of ethyl [4-[(E)-1-methyl-2-[N-(3-pyridylmethyl)carbamoyl]ethenyl]-phenoxy]acetate from Example 85 was mixed with 0.39 g of anhydrous potassium carbonate and 20 ml of 50% aqueous methanol, and then refluxed for 2 hours. The reaction mixture was adjusted to pH 6 with 3 mol/l HCl while cooling on ice, and the precipitate was filtered and dried to give [4-[(E)-1-methyl-2-[N-(3-pyridylmethyl)carbamoyl]ethenyl]phenoxy]acetic acid (179.6 mg, 39%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH2:34][CH2:35]CC(F)(F)C(F)(F)F)[C:31]([OH:33])=[O:32])[C:7]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)([CH2:12][CH2:13][CH3:14])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[F:44][C:45]([F:67])([C:63]([F:66])([F:65])[F:64])[CH2:46][CH2:47]CCC(CCCCCC=C)C(OCC)=O>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH2:34][CH2:35][CH2:47][CH2:46][C:45]([F:67])([F:44])[C:63]([F:66])([F:65])[F:64])[C:31]([OH:33])=[O:32])[C:7]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)([CH2:12][CH2:13][CH3:14])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: C=CCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O
Product: CCCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 29 and ethyl 2-(5,5,6,6,6-pentafluorohexyl)-8-nonenoate prepared separately, the same procedure as shown in Example 13 was repeated to give 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoic acid.
Reaction SMILES: [CH2:1]([O:6][C:7](=[O:18])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][C:15]#[C:16][CH3:17])=[O:11])CC#CC>C1(C)C=CC=CC=1>[O:6]1[CH2:1][CH2:17][C:16]#[C:15][CH2:14][CH2:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][C:7]1=[O:18]
Reactant: CC#CCCOC(=O)CCC(=O)OCCC#CC
Solvent: Cc1ccccc1
Product: O=C1CCC(=O)OCCC#CCCO1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
In a dry 500 mL Schlenk-tube, which has been flooded with argon, succinic acid dipent-3-inyl ester (5.00 mmol, 1.251 g), [Mo(≡N)(OSiPh3)3(phen)].0.5 toluene (0.500 mmol, 581.2 mg), MnCl2 (0.500 mmol, 62.9 mg) and molecular sieve (10.0 g, 5 Å, powder) were suspended in 250 mL of toluene. The reaction solution was stirred for 24 h at 80° C. and was filtered after cooling over a short silica gel column. The filtrate was concentrated and the residue was purified by means of column chromatography (hexane/EtOAc 4:1). 1,6-dioxacyclododec-9-in-2,5-dione was isolated as colorless oil (yield 60%). 1H NMR (400 MHz, CD2Cl2): δ=4.21-4.14 (m, 4H), 2.61 (s, 4H), 2.44-2.37 (m, 4H); 13C NMR (100 MHz, CD2Cl2): δ=171.9 (2×C), 79.0 (2×C), 61.6 (2×CH2), 30.2 (2×CH2), 19.7 (2×CH2); IR (film): v=2965, 2915, 2840, 1729, 1458, 1421, 1383, 1353, 1336, 1267, 1251, 1158, 1053, 1030, 1000, 952, 837 cm−1; MS (EI) m/z (%): 166 (1), 101 (14), 78 (100), 66 (59), 65 (16), 55 (7), 40 (12), 28 (7); HRMS (ESI): m/z: calculated for C10H12O4+Na: 219.0628; found: 219.0627.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].I[CH2:11][CH2:12][C@H:13]([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH3:18])=[O:15].[H-].[Na+]>C1COCC1>[CH2:23]([Si:20]([CH2:21][CH3:22])([CH2:25][CH3:26])[O:19][C@H:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[CH3:24]
Reactant: COC(=O)CC(=O)OC
Reactant: CCOC(=O)[C@H](CCI)O[Si](CC)(CC)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CCC(C(=O)OC)C(=O)OC)O[Si](CC)(CC)CC
Temperature: -78 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
A solution of dimethyl malonate (6.155 ml, 53.72 mmol), (S)-ethyl 4-iodo-2-(triethylsilyloxy)butanoate (10.00 g, 26.86 mmol) and THF (100 mL), dimethyl malonate, (S)-ethyl 4-iodo-2-(triethylsilyloxy)butanoate (10.00 g, 26.86 mmol) was cooled to −78° C. and maintained under N2. To the solution was added sodium hydride (2.149 g, 53.72 mmol, 60% dispersion in mineral oil) portion wise over 5 min and the resulting mixture stirred at −78° C. for 3 h. The reaction was warmed to RT and stirred for 48 h. The reaction was quenched by adding H2O and extracted with EtOAc. The organic extract was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with EtOAc/hexane (4:1) to afford 4.2 g, (41%) of (S)-4-ethyl 1,1-dimethyl 4-(triethylsilyloxy)butane-1,1,4-tricarboxylate (398).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20](OC)(OC)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1.[CH3:31][C@@H:32]([OH:36])[C@H:33]([OH:35])[CH3:34].CC1C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CC1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH2:21][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[O:36][C@H:32]([CH3:31])[C@@H:33]([CH3:34])[O:35]1
Reactant: C[C@@H](O)[C@@H](C)O
Reactant: COC(Cn1cncn1)(OC)c1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C[C@H]1OC(Cn2cncn2)(c2ccc(Cl)cc2Cl)O[C@@H]1C
Yield: 50 %

Procedure:
A mixture of 9.5 parts of 1-[2(2,4-dichlorophenyl)-2,2-dimethoxyethyl]-1H-1,2,4-triazole 4-methylbenzenesulfonate, 2 parts of (2R, 3R)(-)-2,3-butanediol, 1 part of 4-methylbenzenesulfonic acid and 90 parts of methylbenzene is stirred and refluxed for 3 days. The reaction mixture is cooled and alkalized with a sodium hydroxide solution 20%. The whole is poured onto water and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using ethyl acetate as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2'oxybispropane and petroleumether (1:1 by volume). The product is filtered off and dried, yielding 3.2 parts (50%) of (-)-(4R,trans)-1-[2-(2,4-dichlorophenyl)-4,5-dimethyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole; mp. 82.5° C.; [α]D =-30.26° (c=0.5% CHCl3)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1.[CH:20]1([CH2:26][N:27]=[C:28]=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([CH2:26][NH:27][C:28](=[O:29])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C=NCC1CCCCC1
Reactant: CC1(C)CN(Cc2ccccn2)c2ccc(O)cc21
Product: CC1(C)CN(Cc2ccccn2)c2ccc(OC(=O)NCC3CCCCC3)cc21

Procedure:
The title compound was synthesized from 1-(2-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with cyclohexylmethylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (16.5 mg, 53%) having the following characteristics.
Reaction SMILES: Br[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:15]1([C:25]([OH:27])=[O:26])[CH2:20][NH:19][CH2:18][CH2:17][N:16]1[C:21]([CH3:24])([CH3:23])[CH3:22])=[N:7]2.[Li]CCCC.[Sn:33](Cl)([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37].O>C1COCC1>[CH2:42]([Sn:33]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:38][CH2:39][CH2:40][CH3:41])[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:15]1([C:25]([OH:27])=[O:26])[CH2:20][NH:19][CH2:18][CH2:17][N:16]1[C:21]([CH3:24])([CH3:23])[CH3:22])=[N:7]2)[CH2:43][CH2:44][CH3:45]
Reactant: CC(C)(C)N1CCNCC1(C(=O)O)c1ccc2c(Br)c([N+](=O)[O-])ccc2n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c([N+](=O)[O-])ccc2nc(C3(C(=O)O)CNCCN3C(C)(C)C)ccc12
Reaction time: 2 h
Yield: 50.4 %

Procedure:
To a -100° C. solution of 15 (200 mg, 0.46 mmol) in dry THF (8 ml) was added nBuLi (1.6M, 0.50 mmol, 0.31 ml) dropwise. The resulting black-green solution was stirred for 10 min. at which time Bu3SnCl (0.15 ml, 0.54 mmol) was added neat. The solution was allowed to reach room temperature and stirred 2 h. Water was added and the mixture was extracted with ether. The combined ether extracts were dried (MgSO4) and concentrated to a brown oil. HPLC purification of the oil (Whatman Partisil 10 column, 90:10 CH2Cl2 :EtOAc) afforded the tributylstannyl derivative 16 (150 mg, 50%). 1H NMR d (ppm): 0.85 t (CH3), 1.15-1.55 m (3 CH2), 1.49 s (3 CH3), 3.58 dd (CH2), 3.83 dd (CH2), 7.00 d (CH arom), 7.63 d (CH arom), 8.18 d (CH arom), 8.30 d (CH arom).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=O)=[O:9])=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:35][C@H:36]([CH2:40][OH:41])[CH:37]([CH3:39])[CH3:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([NH:35][C@H:36]([CH2:40][OH:41])[CH:37]([CH3:39])[CH3:38])=[O:14])=[O:9])=[CH:18][CH:19]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccc(F)cc1
Reactant: CC(C)[C@H](N)CO
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccc(F)cc1
Yield: 78.7 %

Procedure:
N-(4-fluorobenzyloxycarbonyl)-L-prolyl-L-valinol was prepared from 16.1 g (60.2 mmol) p-fluorobenzyloxycarbonyl-L-proline, 8.22 g (60.2 mmol) isobutyl chloroformate, 6.09 g (60.2 mmol) N-methylmorpholine, and 6.21 g (60.2 mmol) L-valinol, substantially according to the mixed anhydride procedure described in Example 1. The resulting crude product (19.46 g) was recrystallized from a mixture of 100 mL ethyl acetate and 200 mL n-hexane to give 16.69 g (47.4 mmol, 78.7%) of N-(4-fluorobenzyloxycarbonyl)-L-prolyl-L-valinol, m.p. 123°-124°. αD25 -60.2° (C=1.02 g/100 mL in acetone). An nmr obtained for this material spectrum verified the assigned structure: 1H NMR (CDCl3 /TMSi), 220 mc, δ0.85, m, 6H (valinol CH3); δ1.9, m, 2H (proline γ-CH2); δ2.2, m, 3H (valinol β-CH and proline β-CH2); δ 3.35, m, 3H (proline δCH2); δ 3.58, m, 2H (CH2OH); δ 4.34, m, H (valinol α-CH); δ 5.0, s, 2H (benzyl CH2); δ 6.30-6.80, m, H (NH); δ 7.03, m, 2H (aromatic); δ 7.35, m, 2H (aromatic).