Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+:2].[OH-].[K+].[CH3:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1.Cl.[S:17](=[O:19])=[O:18]>O>[CH3:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:17]([O-:1])(=[O:19])=[O:18])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1.[Na+:2]
Reactant: O=S=O
Reactant: CN1CCCc2ccccc21
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CN1CCCc2ccc(S(=O)(=O)[O-])cc21
Reaction time: 6 h

Procedure:
The bath temperature was brought to 260° and a mixture of sodium hydroxide 60 g. and potassium hydroxide 40 g. was allowed to fuse. The anhydrous sodium sulfonate 20 g. was added in portions and each was well stirred and wetted by the liquid alkali before the next addition. The light brown sludge slowly darkened, generally producing a spongy cap to the reaction mixture which had to be broken and pushed into the stirred melt. After six hours, all solid had disappeared to produce a dark liquid and brown liquid drops were present on the undersurface of the clock-glass. This was poured directly into water 500 ml. in a conical flask and the the crucible was washed with another 100 ml. of water. The solution was cooled and extracted with benzene 50 ml., and the benzene extract after drying and evaporation gave 0.4 g. of brown oil consisting mainly of kairoline. The alkali solution was made acid pH 1 to 2 with 190 ml. of concentrated hydrochloric acid, sulfur dioxide could be smelt, and the cooled liquid was filtered. Powdered sodium carbonate (about 10 g.) was added to the stirred solution until the pH reached 8 when a light brown gummy precipitate appeared. This was extracted into benzene 150 ml. plus 100 ml., the benzene extract washed with water, dried (Na2SO4) and evaporated to give a clear brown gum which crystallized on standing 52 g. (40%). If chloroform was used for the extraction process emulsions developed which had to be separated by centrifuging.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7]Br)=[CH:4][CH:3]=1.[CH3:11][O:12][CH:13](O)[CH3:14].[Cl-].[Na+].[OH2:18]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][O:18][CH2:14][CH2:13][O:12][CH3:11])=[CH:4][CH:3]=1
Reactant: BrCCc1ccc(Br)cc1
Reactant: COC(C)O
Reactant: O
Agent: [Cl-]
Agent: [Na+]
Product: COCCOCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-bromophenethyl bromide (4.0 g) was added in a dropwise manner to a cooled solution of methoxyethanol (50 ml) and mercury II perchlorate (prepared from 3.39 g of mercury II oxide and 4.71 g of 60% perchloric acid). The mixture was stirred overnight at ambient temperature. Saturated brine (80 ml) was added, the mercury salts removed by filtration and washed with ether. The filtrate was extracted with ether (3×100 ml). The ether extracts were combined, washed with water (20 ml), saturated brine (20 ml), dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel using 10% ethyl acetate in toluene as eluent to give 1-(-4-bromophenethyloxy)-2-methoxyethane (2.2 g) as a colourless oil; NMR(CDCl3): 2.8-2.9(2H,t), 3.4(3H,s), 3.5-3.6(4H,m), 3.6-3.75(2H,t 7.05-7.15(2H,d) and 7.35-7.45(2H,d).
Reaction SMILES: [N+](=[C:3]([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5])=[N-].[CH3:12][C:13](=[C:15]([CH3:17])[CH3:16])[CH3:14]>[Hg]>[CH3:12][C:13]1([CH3:14])[C:15]([CH3:17])([CH3:16])[C:3]1([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Reactant: CC(C)=C(C)C
Agent: [Hg]
Product: COC(=O)C1(C(=O)OC)C(C)(C)C1(C)C
Yield: 30.8 %

Procedure:
A mixture of 20.0 grams (0.13 mole) of dimethyl diazomalonate and 164.35 grams (1.95 moles) of 2,3-dimethyl-2-butene was photolyzed at room temperature for a period of approximately 47 hours in the presence of a 100-watt Hanovia mercury lamp. Most of the unreacted 2,3-dimethyl-2-butene was removed by distillation, at atmospheric pressure, to a head temperature of 73° C. and the still residue was subjected to flash chromatography on a silica gel column to give 9.00 grams (0.04 mole) of dimethyl 2,2,3,3-tetramethylcyclopropanedicarboxylate. NMR analysis of the product indicated the following:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=O)[C:5]([OH:7])=[O:6].[CH3:14][N:15]([CH3:26])[C:16]1[CH:25]=[CH:24][C:19]([CH:20]=[CH:21][CH:22]=O)=[CH:18][CH:17]=1>>[CH3:26][N:15]([CH3:14])[C:16]1[CH:25]=[CH:24][C:19]([CH:20]=[CH:21][CH:22]=[N+:11]([C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[CH3:1])[O-:13])=[CH:18][CH:17]=1
Reactant: CN(C)c1ccc(C=CC=O)cc1
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Product: Cc1cc(C(=O)O)ccc1[N+]([O-])=CC=Cc1ccc(N(C)C)cc1
Yield: 97.4 %

Procedure:
The general procedure of Example 1 was repeated except that 132.4 g (731 mmols) of 3 -methyl-4-nitrobenzoic acid was used instead of p-nitrobenzoic acid and 118.6 g (677 mmols) of 4-dimethylaminocinnamaldehyde was used instead of 4-diethylaminobenzaldehyde, thereby obtaining 213.8 g (yield 97.4%) of α-[p-(dimethylamino)styryl]-N-(2-methyl-4-carboxyphenyl)nitrone with a purity of 96%. The results of the analyses of the thus obtained compound are shown below.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:28][CH2:29][CH2:30][F:31])(=O)=O)=CC=1.Cl>CN(C)C=O.O.C(OCC)(=O)C>[F:31][CH2:30][CH2:29][CH2:28][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCF)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(OCCCF)c(O)c1
Temperature: 0 °C
Reaction time: 37 h
Yield: 50 %

Procedure:
Commercially available 3,4-dihydroxybenzaldehyde (6.5 g, 47.1 mmol) and potassium carbonate (6.83 g, 49.4 mmol) were suspended in N,N-dimethylformamide (30 mL), then 3-fluoropropyl 4-methylbenzenesulfonate described in Production Example 5-1 (11.3 g, 48.4 mmol) was added under nitrogen atmosphere at loom temperature, and the mixture was stirred for 37 hours. The mixture was cooled to 0° C. and then 2 M hydrochloric acid, ethyl acetate, and water were added for partition. The organic layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered. The solvent was evaporated and the resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=4:1-2:1-1:1). The target fraction was concentrated under vacuum to obtain the title compound (4.62 g, 50%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6]([Br:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[Br-:13].[CH2:6]([N+:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCc1ccccc1
Reactant: c1cocn1
Product: [Br-]
Product: c1ccc(C[n+]2ccoc2)cc1
Temperature: 25 °C

Procedure:
2 g oxazole was reacted with 4.95 g benzyl bromide at room temperature for 2 hours and then overnight at 50° C. On cooling to room temperature, solids were filtered and dried. The yield was 3.1 g. The material was dissolved in ethanol and recrystalized with MTBE. The recrystallized compound had a melting point of 177–180° C. and proton NMR spectra consistent with the structure 3-benzyl-oxazol-3-ium bromide. On analysis the compound contained 50.00% C, 4.04% H, 36.36% Br, and 5.08% N.
Reaction SMILES: Cl.[CH:2]1([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[NH:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].[C:16]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)(=[O:20])/[CH:17]=[CH:18]/[CH3:19]>O.CC(C)=O>[C:16]([NH:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:10]2[CH2:11][CH2:12][N:8]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)[C:9]2=[NH:13])(=[O:32])=[O:31])=[CH:28][CH:29]=1)(=[O:20])/[CH:17]=[CH:18]/[CH3:19]
Reactant: N=C1NCCN1C1CCCCC1
Reactant: C/C=C/C(=O)NCCc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C/C=C/C(=O)NCCc1ccc(S(=O)(=O)N2CCN(C3CCCCC3)C2=N)cc1

Procedure:
20.4 g of 1-cyclohexyl-2-imino-imidazolidine hydrochloride are added to 8.5 g of sodium hydroxide in 85 ml of water. There is added to the resulting solution 28.8 g of 4-(2-crotonylaminoethyl)-benzenesulphonyl chloride dissolved in 100 ml of acetone, the reaction mixture becoming warm. It is heated at 90° for half an hour and then concentrated by evaporation under reduced pressure. The residue is recrystallised from ethyl acetate, and 1-{4-[2-(crotonylamino)-ethyl]-phenylsulphonyl}-3-cyclohexyl-2-imino-imidazolidine (trans) which melts at 157° to 158° is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:23][C:22](=O)[O:21][C:19](=[O:20])[CH2:18]2)=[CH:13][C:12]=1[C:25]([F:28])([F:27])[F:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:22]([CH2:23][CH:17]([C:14]3[CH:15]=[CH:16][C:11]([Cl:10])=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=3)[CH2:18][C:19]([OH:21])=[O:20])[NH:9][C:4]=2[CH:3]=1.[ClH:1]
Reactant: O=C1CC(c2ccc(Cl)c(C(F)(F)F)c2)CC(=O)O1
Reactant: Nc1ccc(Cl)cc1N
Product: Cl
Product: O=C(O)CC(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
By a procedure similar to that of example 1.4, starting from 4-chloro-1,2-phenylenediamine and 3-(4-chloro-3-trifluoromethylphenyl)glutaric anhydride, 4-(5-chloro-2-benzimidazolyl)-3-(4-chloro-3-trifluoromethylphenyl)butanoic acid•HCl was obtained as light greyish solid.
Reaction SMILES: C(C1C=CC2OC(C)(C)[C@@H](Br)[C@H](O)C=2C=1)#N.[H-].[Na+].[C:19]([C:21]1[CH:33]=[CH:32][C:24]2[O:25][C:26]([CH3:31])([CH3:30])[CH:27]3[O:29][CH:28]3[C:23]=2[CH:22]=1)#[N:20].[NH:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39]>CS(C)=O.O>[C:19]([C:21]1[CH:33]=[CH:32][C:24]2[O:25][C:26]([CH3:31])([CH3:30])[C@@H:27]([OH:29])[C@H:28]([N:34]3[CH2:38][CH2:37][CH2:36][C:35]3=[O:39])[C:23]=2[CH:22]=1)#[N:20]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: O=C1CCCN1
Agent: CC1(C)Oc2ccc(C#N)cc2[C@@H](O)[C@@H]1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A solution of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-3-bromo-4-hydroxy-2H-benzo[b]pyran (4 g, 14.2 mM) in dimethylsulphoxide (20 ml) was stirred and sodium hydride (60% dispersion in oil, 0.6 g, 15 mM) added. The suspension was stirred for 1 hour when a solution of 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran resulted. 2-Pyrrolidone (1.8 g, 21 mM) and further sodium hydride (0.8 g, 21 mM) were introduced and the mixture stirred at room temperature for an additional 16 hours. Water (40 ml) was slowly added to the mixture to induce crystallisation of the product after which it was cooled in ice and filtered under suction. Crystallisation from ethanol (20 ml) gave the title compound as a cream coloured solid in 60% yield. Recrystallisation from ethyl acetate afforded the pure product as needles, m.p. 226.5°-227.5° having an nmr spectrum and t.l.c. characteristics identical to those of the compound of Description 6.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][C@@H:22]([C:24]3[CH:35]=[CH:34][C:27]4[O:28][C:29]([CH3:33])([CH3:32])[O:30][CH2:31][C:26]=4[CH:25]=3)[O:21][C:20]2=[O:36])[CH:5]=[CH:6][CH:7]=1.[CH3:37][NH:38][S:39]([CH:42]=[CH2:43])(=[O:41])=[O:40].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:32][C:29]1([CH3:33])[O:28][C:27]2[CH:34]=[CH:35][C:24]([C@H:22]3[O:21][C:20](=[O:36])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]4[CH:3]=[C:2](/[CH:43]=[CH:42]/[S:39]([NH:38][CH3:37])(=[O:41])=[O:40])[CH:7]=[CH:6][CH:5]=4)[CH2:23]3)=[CH:25][C:26]=2[CH2:31][O:30]1
Reactant: C=CS(=O)(=O)NC
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(Br)c4)C(=O)O3)ccc2O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNS(=O)(=O)/C=C/c1cccc(CCCCOCCCCCCN2C[C@@H](c3ccc4c(c3)COC(C)(C)O4)OC2=O)c1
Yield: 20.5 %

Procedure:
A stirred mixture (5R)-3-{6-[4-(3-bromophenyl)butoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (1.0 g), N-methylethenesulphonamide (WO 95/09166), (462 mg), tri-o-tolylphosphine (200 mg), palladium acetate (165 mg) and triethylamine (5 ml) in dry DMF (15 ml) was heated at 90° C. for 18 h. The mixture was cooled and filtered. The filtrate was poured into water (200 ml) and extracted into ethyl acetate (3×50 ml). The combined extracts were washed with water (100 ml) and (Na2SO4) and evaporated in vacuo. The residual oil was purified by chromatography on Biotage (40 g) eluting with diethyl ether-ethyl acetate (9:1) to give the title compound (220 mg). LCMS RT=3.70 min.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH2:22][C:23]([O-:25])=O)[C:19]([CH3:21])([CH3:20])[C:12]2=[N:11][C:10]=1[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=[O:27])C1C=CC=CC=1.[Li+].C(Cl)CCl.C1C=[CH:44][C:45]2N(O)N=[N:48][C:46]=2C=1>C(Cl)(Cl)Cl.C(N)C#C.[Hg](OC(C)=O)OC(C)=O>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH:28][C:26]([C:10]2[N:11]=[C:12]3[C:19]([CH3:21])([CH3:20])[N:18]([CH2:22][C:23]4[O:25][C:45]([CH3:44])=[CH:46][N:48]=4)[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[OH:8])=[O:27])=[CH:31][CH:32]=1
Reactant: On1nnc2ccccc21
Reactant: CC1(C)c2nc(C(=O)NCc3ccc(F)cc3)c(OCc3ccccc3)c(=O)n2CCN1CC(=O)[O-]
Agent: C#CCN
Agent: CC(=O)O[Hg]OC(C)=O
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: Cc1cnc(CN2CCn3c(nc(C(=O)NCc4ccc(F)cc4)c(O)c3=O)C2(C)C)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of lithium (3-(benzyloxy)-2-{[(4-fluorobenzyl)amino]carbonyl}-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydro-8H-pyrazino[1,2-a]pyrimidin-8-yl)acetate (1 eq.) in CHCl3, propargylamine (1.1), EDC (2 eq.) and HOBt (2 eq.) were added and the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was taken up in EtOAc, washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The resulting crude was directly dissolved in acetic acid and Hg(OAc)2 (0.1 eq.) was added. The mixture was heated at 100° C. overnight and was then concentrated under reduced pressure. The residue was directly purified by RP-HPLC and after lyophilisation of the desired fractions, the O-benzyl protected material was dissolved in MeOH and stirred 1 hour under an H2 atmosphere in the presence of 10% Pd/C. The catalyst was then filtered off through celite, the filtrate was concentrated under reduced pressure and then the residue was dissolved in MeCN and H2O and lyophilized to afford the titled oxazole. 1H-NMR (400 MHz, d6-DMSO) δ 12.17 (br. s, 1H), 9.43 (t, J=6.2 Hz, 1H), 7.37 (dd, J=8.1 Hz, J=5.7 Hz, 2H), 7.17 (t, J=8.9 Hz, 2H), 6.77 (s, 1H), 4.47 (d, J=6.2 Hz, 2H), 3.80 (s, 2H), 3.71 (t, J=5.0 Hz, 2H), 3.00 (t, J=5.1 Hz, 2H), 2.27 (s, 3H), 1.53 (s, 6H); MS (ES) C22H24FN5O4 requires 441. Found: 442 (M+H+).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].[NH2:25][CH:26]1[C:37](=[O:38])[N:28]2[C:29]([C:34]([OH:36])=[O:35])=[C:30]([CH3:33])[CH2:31][S:32][C@H:27]12>>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([NH:25][CH:26]2[C:37](=[O:38])[N:28]3[C:29]([C:34]([OH:36])=[O:35])=[C:30]([CH3:33])[CH2:31][S:32][C@H:27]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCNC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Yield: 67.8 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2 g.) and 7-amino-3-methyl-3-cephem-4-carboxylic acid (1.6 g.) were treated in a similar manner to that of Example 21-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer, 2.1 g.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:29][C@H:30]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:31]1>C(Cl)Cl.O>[CH2:35]([N:32]1[CH2:33][CH2:34][C@H:30]([NH:29][C:11](=[O:13])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:10])[CH2:31]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CCN(Cc2ccccc2)C1
Temperature: -5 °C
Reaction time: 2 h
Yield: 108.1 %

Procedure:
N-(tert-Butoxycarbonyl)-L-alanine (12.8 g) was dissolved in methylene chloride (50 mL) and the solution cooled to -5° C., and treated with N-methylmorpholine (6.7 g). The resulting mixture was stirred and cooled to -5° to -10° C. and a cold (-5° C.) solution of isobutyl chloroformate (8.5 g) in methylene chloride (100 mL) added slowly while keeping the temperature at or below -5° C. The mixture was stirred for another 30 minutes at -5° to -10° C. To this mixture was then added a cold (0° C.) solution of (S)-3-amino-1-benzylpyrrolidine (10.0 g) in methylene chloride (100 mL) while keeping the temperature between 0° and -10° C. The reaction mixture was stirred at 0° to -5° C. for 1 hour and then at 15° to 25° C. for 2 hours. The mixture was treated with 300 mL of demineralized water and the layers separated. The organic phase was extracted with a solution of sodium bicarbonate (18.5 g) in demineralized water (200 mL) followed by demineralized water (300 mL). The organic phase was dried over sodium sulfate (50 g) and the product solution concentrated under vacuum to give 1-benzyl-3-(S)-[2-(S) (tert-butoxycarbonylamino)-propionylamino]pyrrolidine (21.3 g) as an off white solid (mp: 102°-105° C.) which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[C:8]([S:9][CH3:10])=[C:7]([NH2:11])[N:6]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[N:5]=1)(=[O:3])[CH3:2].[CH:24](OC)(OC)[O:25]C.O.[C:32]1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO>[NH2:11][C:7]1[N:6]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:20])([F:21])[F:22])=[CH:14][C:13]=2[Cl:23])[N:5]=[C:4]([C:1]([O:25][CH3:24])([O:3][CH3:32])[CH3:2])[C:8]=1[S:9][CH3:10]
Reactant: CSc1c(C(C)=O)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(C)(OC)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC
Temperature: 40 °C
Reaction time: 64 h

Procedure:
A mixture of 2.0 g (0.0052 mole) of 3-acetyl-5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylthio-1H-pyrazole, 1.7 ml (0.0156 mole) of trimethyl orthoformate, 0.060 g (0.0003 mole) of para-toluenesulfonic acid monohydrate and 10 ml of methanol was heated at 40° C. for about 8 hours, then left 64 h at 20° C. The mixture was mixed with a saturated solution of NaHCO3, extracted with dichloromethane, and successively dried, filtered, evaporated, chromatographed on silica gel. 0.59 g of the title compound having a melting point of about 149° C. was obtained.
Reaction SMILES: C1N=C[N:3](C(N2C=NC=C2)=O)C=1.[CH2:13]1[C:21]2[C:16](=[CH:17][C:18](O)=[CH:19][CH:20]=2)C[CH2:14]1>CN(C=O)C>[NH:3]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Oc1ccc2c(c1)CCC2
Solvent: CN(C)C=O
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25 %

Procedure:
To a solution of CDI in 25 mL anhydrous DMF was added 1 (0.76 g, 1.72 mmol), see Example 4, in one portion. The mixture was allowed to stir at room temperature for 15 minutes, then at 80° C. for 2 hours. The solution was then cooled to room temperature, the 5-indanol added, and stirring continued for 16 hours. The reaction was quenched by pouring into 200 mL H2O, and the resulting yellow precipitate filtered and air dried. Column chromatography (30% EtOAc/Hex→50% EtOAc/Hex) yielded 0.24 g (25%) of 2, mp 258°-260° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].[Br-].[CH:14]1([Zn+])[CH2:17][CH2:16][CH2:15]1.C1(C2C(C(O)=O)=CC=CC=2)CCCC1>>[CH:14]1([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([OH:7])=[O:6])[CH2:17][CH2:16][CH2:15]1
Reactant: [Zn+]C1CCC1
Reactant: CCOC(=O)c1cccc(Br)c1
Agent: O=C(O)c1ccccc1C1CCCC1
Agent: [Br-]
Product: O=C(O)c1cccc(C2CCC2)c1

Procedure:
This intermediate was prepared from ethyl 3-bromobenzoate and cyclobutylzinc bromide in two steps according to the preparation of 6-cyclopentyl-benzoic acid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH3:15][C:16]1([N:29]2[CH2:34][CH2:33][NH:32][CH:31]([CH3:35])[CH2:30]2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>C(Cl)(Cl)(Cl)Cl>[CH3:15][C:16]1([N:29]2[CH2:34][CH2:33][N:32]([CH:7]3[C:6]4[C:10](=[CH:11][C:3]([C:2]([F:13])([F:14])[F:1])=[CH:4][CH:5]=4)[C:9](=[O:12])[CH2:8]3)[CH:31]([CH3:35])[CH2:30]2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]1
Reactant: CC1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1
Reactant: O=C1C=Cc2ccc(C(F)(F)F)cc21
Solvent: ClC(Cl)(Cl)Cl
Product: CC1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CC(=O)c2cc(C(F)(F)F)ccc21

Procedure:
A solution of 6-(trifluoromethyl)-1H-inden-1-one (100 mg, 0.505 mmol) and tert-butyl 4-methyl-4-(3-methylpiperazin-1-yl)piperidine-1-carboxylate (420 mg, 1.412 mmol) in carbon tetrachloride (8.00 mL) was heated at 60° C. for 18 h with stirring. After evaporation of solvent, the residue was purified on silica gel to give two diastereomers (3/1 ratio). Yield 180 mg (72%). LC-MS [M+1]=496.4.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[O:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[CH2:13][CH2:12]1>[Ru]>[O:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:14]([OH:21])[CH2:13][CH2:12]1
Reactant: O=C1CCOc2ccccc21
Agent: [Ru]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O[C@@H]1CCOc2ccccc21
Temperature: 30 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
Argon was introduced into a 20 mL Schlenk-type reaction tube and bathed in an ice bath, then triethyl amine (3.6 mL, 26 mmol), formic acid (1.2 mL, 31 mmol), 4-chromanone (1.48 g, 10 mmol, substrate/catalyst ratio=500) and ruthenium complex RuCl[(R,R)-Tsdpen] (p-cymene) (12.7 mg, 0.02 mmol) were set therein, stirred at 30° C. for 24 hours. On its course, samples were collected after 3 hours for 1HNMR and HPLC analyses of the product. The conversion rate after 3 hours was 66%, and the optical purity was 99% ee. The reaction was allowed to further continue, and after 24 hours, (R)-4-chromanol was produced at 100% yield of and 99% ee optical purity.