Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[NH2:27][CH2:28][CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1>CS(C)=O>[NH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30]([CH2:29][CH2:28][NH:27][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)=[CH:31]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2OC(CNCCc2c[nH]c4ccccc24)CO3)N1
Temperature: 75 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.2 g, 3.2 mmole) and tryptamine (1.5 g, 9.6 mmole) in DMSO (50 ml) were placed in a three-neck flask equipped with a condenser, a thermometer and a nitrogen bubbler immersed into the solution. The reaction mixture was heated at 75° C. for 5 hours, cooled to room temperature and partitioned between water and ethyl acetate. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuum and column chromatographed on silica gel using first ethyl acetate and subsequently 2.5%, 5%, 10% methanol in ethyl acetate as eluants. The free base of the desired product was obtained (0.85 g, 2.3 mmole) as an oil which was dissolved in 50 ml of ethanoldiethyl ether (1/1) solution and treated with 10.3 ml of 0.25 M of fumaric acid in ethanol. Addition of hexane gave 0.30 g of the (S) enantiomer of the title compound as an off-white solid hemi-fumarate, three quarter hydrate, m.p. 175-176° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][C:8](=S)[NH:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1.[NH2:21][CH2:22][C:23]1([CH3:28])OCCO1.O>COCCO>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][C:8]3[N:9]([C:23]([CH3:28])=[CH:22][N:21]=3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1
Reactant: CC1(CN)OCCO1
Reactant: COc1ccc2c(c1)C(c1ccccc1)=NNC(=S)C2
Solvent: O
Solvent: COCCO
Product: COc1ccc2c(c1)C(c1ccccc1)=Nn1c(C)cnc1C2

Procedure:
500 mg of 8-methoxy-1-(phenyl)-4,5-dihydro-3H-2,3-benzodiazepine-4-thione is stirred in 1.5 ml of ethylene glycol monomethyl ether (Cellosolve®) and 548 mg of 2-aminomethyl-2-methyl-1,3-dioxolane while argon is passing through it for 10 hours at 60° C. After filtration and washing with cold ethanol and diisopropyl ether, 550 mg of imino compound, which is dissolved in 10 ml of ethanol, mixed with 10 ml of concentrated hydrochloric acid and refluxed for 3 hours, is obtained. It is added to water, set at pH 11 and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried, filtered and concentrated by evaporation. After recrystallization from ethyl acetate/diisopropyl ether, 240 mg of 8-methoxy-3-methyl-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine with a melting point of 140° C. is obtained.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[C:23]1([Si:29]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>C1C=CC=CC=1>[C:37]1([Si:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:1][CH2:2][C@@:3]23[C@@H:20]4[C@H:11]([C@H:12]5[C@@:16]([CH2:18][CH2:19]4)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]5)[CH2:10][CH2:9][C:8]2=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]3)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO[Si](c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H]1CCC2=O

Procedure:
A solution of 19-hydroxy-4-androstene-3,17-dione, triphenylchlorosilane and pyridine contained in 100 ml of benzene is refluxed for a period of 18 hours. The resulting suspension is filtered and concentrated in vacuo to a yellow oil. The oil is placed on a silica gel chromatographic column packed in chloroform which is further eluted with chloroform. The chloroform eluant is evaporated to dryness in vacuo and the residue is recrystallized from methanol to yield 19-triphenylsiloxy-4-androstene-3,17-dione.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:21]([C:22]([OH:24])=[O:23])=[C:12]2[N:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][N:11]2[N:10]=1.CN(C(O[N:33]1[N:41]=[N:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:21]([C:22]([O:24][N:40]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[N:41]2)=[O:23])=[C:12]2[N:13]=[C:14]([C:17]([F:20])([F:18])[F:19])[CH:15]=[CH:16][N:11]2[N:10]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Nc1nn2ccc(C(F)(F)F)nc2c1C(=O)O
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Nc1nn2ccc(C(F)(F)F)nc2c1C(=O)On1nnc2ccccc21
Temperature: 50 °C

Procedure:
Triethylamine (994.9 mg, 1.370 mL, 9.832 mmol) was added to a suspension of 2-amino-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5d (2.2 g, 8.938 mmol) in chloroform (22 mL). TBTU (2.870 g, 8.938 mmol) was added to the solution and the reaction mixture was heated at 50° C. for 20 min, during which time a yellow precipitate formed. The reaction mixture was cooled to ambient temperature. The precipitate was isolated by filtration and washed with chloroform to leave the product (benzotriazol-1-yl 2-amino-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate) 6d as an off white solid (2.8 g, 86% yield).
Reaction SMILES: Cl.F[C:3]1[C:8]([CH3:9])=[C:7]([I:10])[CH:6]=[CH:5][N:4]=1.[OH2:11]>COCCOC>[I:10][C:7]1[CH:6]=[CH:5][NH:4][C:3](=[O:11])[C:8]=1[CH3:9]
Reactant: O
Reactant: Cc1c(I)ccnc1F
Agent: Cl
Solvent: COCCOC
Product: Cc1c(I)cc[nH]c1=O
Reaction time: 1.5 h

Procedure:
12M Hydrochloric acid (13 mL) was added to a solution of 2-fluoro-4-iodo-3-methylpyridine (12.2 g) in DME (15 mL) at room temperature. The mixture was stirred at 100 C for 1.5 hours with an alkali trap. Water (150 mL) was added to the reaction mixture at room temperature. The mixture was stirred at the same temperature for 2 hours. The precipitate was collected by filtration, washed with water. A suspension of the solid in ethanol (20 mL) was stirred at 80 C for 30 minutes. Diisopropyl ether (150 mL) was added to the mixture. The mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with diisopropyl ether to give the title compound (9.82 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:32]1([CH3:38])[CH2:36][O:35][C:34](=[O:37])[O:33]1>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:32]3([CH3:38])[CH2:36][O:35][C:34](=[O:37])[O:33]3)[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(Cl)COC(=O)O1
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2nn(C3(C)COC(=O)O3)c3ncccc23)cc(C(C)(C)C)c1O
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution 3.2 g of the compound of Example 1 in 20 ml of dimethylformamide are added 2 g of potassium carbonate and 1.6 g of 4-chloro-4-methyl-2-oxo-1,3-dioxolane, and the mixture is stirred at 60° C. for 6 hours. The reaction mixture is poured into ice-cold water and the precipitate is extracted with ethyl acetate. After the extract is washed with water, dried and concentrated, the residue is recrystallized from a mixed solvent of hexane and toluene to give 3 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1-(4-methyl-2-oxo-1,3-dioxolan-4-yl)-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 190°-191° C.
Reaction SMILES: [N+:1]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH:14]=[C:13]2[O:32]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](C1C=CC(COC(C2N3C(=O)[C@@H](NC(=O)COC4C=CC=CC=4)[C@H]3SCC=2OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)=CC=1)([O-])=O>FC(F)(F)C(O)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[OH:32])=[O:11])=[CH:46][CH:47]=1)([O-:3])=[O:2]
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(OC(c3ccccc3)c3ccccc3)=CS[C@H]12
Agent: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OC(c3ccccc3)c3ccccc3)CS[C@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 340 mg of the resulting isomer mixture, consisting of 7β-phenoxyacetamido-3-diphenylmethoxy-ceph-2-em-4α-carboxylic acid p-nitrobenzyl ester and 7β-phenoxyacetamido-3-diphenylmethoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester, in a mixture of 0.5 ml of trifluoroacetic acid and 9.5 ml of methylene chloride is stirred for 40 minutes at room temperature. The mixture is concentrated by evaporation in vacuo, toluene is added to the residue, and the mixture is again concentrated by evaporation. The resulting residue (which still contains trifluoroacetic acid) is chromatographed on 15 g of acid-washed silica gel, using toluene/ethyl acetate (3:1), whereby 7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester is obtained; IR spectrum (methylene chloride): characteristic bands at 2.95, 3,3, 5.6, 5.75 sh, 5.9, 5.95 sh, 6.55, 7.45, 8.15 and 8.3μ; NMR spectrum (deuterochloroform): characteristic bands at 3.4 (2H, AB q, l=17 Hz), 4.57 (2H, s), 5.06 (1H, d,l=5 Hz), 5.35 (2H, AB q, l=14 Hz), 5.7 (1H, dd, l=5, 10 Hz), 6.8-8.4 (10 H, c), 11.4 (1H, br. s.) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>CCO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CC=C(c2ccc(N)nn2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(c2ccc(N)nn2)CC1
Yield: 88.9 %

Procedure:
6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-amine (300 mg, 1.58 mmol, Eq: 1.00) was dissolved in EtOH (30 ml). The reaction solution was hydrogenated in an H-Cube apparatus (60 psi) at room temperature with Pd/C by running mixture through the cycle twice until reaction was complete as determined by tlc. The solvent was removed in vacuo to afford 270 mg (89%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=3)[C:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1.[CH3:22][C:23]([OH:27])([C:25]#[CH:26])[CH3:24]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[NH2:21][C:18]1[O:19][CH2:20][C:5]2([N:17]=1)[C:4]1[CH:3]=[C:2]([Br:1])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:26]#[C:25][C:23]([CH3:24])([OH:27])[CH3:22])=[CH:9][CH:10]=1
Reactant: NC1=NC2(CO1)c1cc(Br)ccc1Oc1ccc(I)cc12
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(C)(O)C#Cc1ccc2c(c1)C1(COC(N)=N1)c1cc(Br)ccc1O2
Temperature: 60 °C
Yield: 63.9 %

Procedure:
To a 25 mL flask was added 2′-bromo-7′-iodo-5H-spiro[oxazole-4,9′-xanthen]-2-amine (536 mg, 1.173 mmol), bis(triphenylphosphine)palladium(II) chloride (82 mg, 0.117 mmol), copper(I) iodide (22.33 mg, 0.117 mmol). THF (10 ml), 2-methylbut-3-yn-2-ol (0.459 ml, 4.69 mmol) and DIPA (1.657 ml, 11.73 mmol) were added and the mixture was heated at 60° C. for 16 hrs. The mixture was filtered through Celite and concentrated. Separation on 12 g Redi-Sep column using 15-80% DCM/MeOH/NH4OH 90:10:1 in DCM gave 4-(2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)-2-methylbut-3-yn-2-ol (310 mg, 0.750 mmol, 64% yield) and ˜200 mg of symmetric product containing impurities, which was purified again using stacker of two 12 g Redi-Sep column, eluent 45-75% DCM/MeOH/NH4OH in DCM to afford 4,4′-(2-amino-5H-spiro[oxazole-4,9′-xanthene]-2′,7′-diyl)bis(2-methylbut-3-yn-2-ol).
Reaction SMILES: ClC1C(CSCCN)=[N:4]C=CC=1.[S:13]([OH:17])([OH:16])(=[O:15])=[O:14].CS[C:20](=[NH:22])[NH2:21]>O>[S:13]([OH:17])([OH:16])(=[O:15])=[O:14].[NH2:21][C:20]([NH2:22])=[NH:4]
Reactant: CSC(=N)N
Reactant: NCCSCc1ncccc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: N=C(N)N

Procedure:
A solution of 3-chloro-2-((2-aminoethyl)thiomethyl)pyridine (22.4 g) and S-methylisothiourea sulphate (15.1 ) in water (100 ml) was heated under reflux for 3 hours. Concentration, acidification with sulphuric acid and dilution with ethanol afforded 2-[3-chloro-2-pyridyl)methylthio)ethyl]guanidine sulphate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:11][CH2:12][CH2:13][OH:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:11][CH2:12][CH2:13][OH:14])=[O:9]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(NCCO)c1cncc(Br)c1
Reaction time: 72 h

Procedure:
5-Bromonicotinic acid (0.020 g, 0.10 mmol), 2-aminoethanol (9.16 mg, 0.15 mmol), HATU (0.046 g, 0.12 mmol), DIPEA (0.052 g, 0.40 mmol), and dioxane (2 mL) were added to a 20 mL vial. The vial was sealed and placed on a heater/shaker for 3 days at 40° C. The reaction mixture, containing the title compound, was used without purification.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]([OH:24])[CH2:22][N:23]=2)=[CH:14][CH:13]=1>ClCCCl>[CH3:10][S:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:19][CH:20]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:21]([O:24][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:22][N:23]=2)=[CH:16][CH:17]=1
Reactant: O=C=Nc1ccccc1
Reactant: CSc1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Solvent: ClCCCl
Product: CSc1ccc(C2=NCC(OC(=O)Nc3ccccc3)C(c3ccccc3)O2)cc1
Temperature: 80 °C
Yield: 39.7 %

Procedure:
Phenyl isocyanate (0.79 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2[-4-(methylthio)phenyl]-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.8 g) in 1,2-dichloroethane (25 cc). The solution obtained is heated to 80° C. for 4 hours and then concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization in acetonitrile, (5RS, 6SR)-2-[4-(methylthio)phenyl]-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (1 g), m.p. 170° C., is obtained.
Reaction SMILES: [CH:1]1[CH:20]=[CH:19][C:17](=[O:18])/[C:3](=[CH:4]/[NH:5][CH2:6][CH2:7][NH:8]/[CH:9]=[C:10]2/[CH:11]=[CH:12][CH:13]=[CH:14][C:15]/2=[O:16])/[CH:2]=1.O.O.O.O.C([O-])(=O)C.[Co+2:29].C([O-])(=O)C.C(O)(=O)C.[N+](C1C=C(C=C([N+]([O-])=O)C=1)C(O)=O)([O-])=O>C(Cl)Cl.C1(C)C=CC=CC=1>[Co+3:29].[CH:12]1[CH:13]=[CH:14][C:15](=[O:16])/[C:10](=[CH:9]/[NH:8][CH2:7][CH2:6][NH:5]/[CH:4]=[C:3]2/[CH:2]=[CH:1][CH:20]=[CH:19][C:17]/2=[O:18])/[CH:11]=1
Reactant: [Co+2]
Agent: CC(=O)[O-]
Agent: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=C1C=CC=C/C1=C/NCCN/C=C1\C=CC=CC1=O
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: [Co+3]

Procedure:
To a stirred solution of ‘salen’ ligand (7e) (43 mg, 0.045 mmol, 1 equiv.) in 5 mL CH2Cl2, a methanolic (2 mL) solution of cobalt (II) acetate tetrahydrate (11.4 mg, 45 μmol, 1.0 equiv.), was added via cannula, under Ar. The Co(II)-salen complex precipitated out as a red solid. After filtration, the Co(II) complex was taken up in CH2Cl2 or toluene (2 mL) and stirred with acetic acid (>10 equiv.) or 3,5-dinitrobenzoic acid (1 equiv.) open to the air. The oxidation was followed by TLC, formation of a greenish-brown spot of lower Rf {Co-(III) complex} from the visibly red, higher Rf spot characteristic of the Co-(II) salen. When TLC indicated the completion of the reaction (2-12 h), the solvent was evaporated, and the Co(III)-salen complex further dried in vacuo. The Co(III) carboxylate complexes so prepared were used for HKR experiments, under ISES (bilayer) conditions or under neat ‘Jacobsen’ (conventional) conditions.
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].C(OC(Cl)=O)C(C)C.[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH3:29])[CH:23]=[CH:22][C:21]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([OH:38])=O)[CH2:31]1.C(N)C>O1CCCC1>[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH3:29])[CH:23]=[CH:22][C:21]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([NH:3][CH2:1][CH3:2])=[O:38])[CH2:31]1
Reactant: COCOc1ccc(C2CCCC(C(=O)O)C2)c(OCOC)c1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: CCN
Solvent: C1CCOC1
Product: CCNC(=O)C1CCCC(c2ccc(OCOC)cc2OCOC)C1
Reaction time: 0.5 h

Procedure:
Triethylamine (11 μl) and isobutylchloroformate (10 μl) were added to a stirred solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanecarboxylic acid in anhydrous tetrahydrofuran (2 ml) under argon at 0° C. After 30 min, ethylamine (0.5 ml, 2M solution in tetrahydrofuran) was added. The reaction mixture was partitioned between water (20 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound as a solid (24 mg, quant.) and a mixture of diastereoisomers; m/z (ES+) 352 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:17][CH:18]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]2)[C:10]([NH:12][C:13]([NH:15][CH3:16])=[O:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:17][CH:18]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]2)[C:10]([NH:12][C:13]([NH:15][CH3:16])=[O:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC(=O)NC(=O)C(CC1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CNC(=O)NC(=O)C(CC1CCC(=O)C1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
A solution of 1-[2-(3,4-dichloro-phenyl)-3-(3-hydroxy-cyclopentyl)-propionyl]-3-methyl-urea (prepared as in Example 35, 60.5 mg, 0.17 mmol) in methylene chloride (1.68 mL) was treated with pyridinium chlorochromate (20 wt. % on basic alumina, 218 mg, 0.20 mmol). The reaction mixture was stirred at 25° C. for 4 h. At this time, the reaction was filtered through a plug of celite (ethyl acetate as eluent). The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 methylene chloride/methanol) afforded 1-[2-(3,4-dichloro-phenyl)-3-(3-oxo-cyclopentyl)-propionyl]-3-methyl-urea (45.8 mg, 76.1%) as a white solid: mp 70-74° C.; FAB-HRMS m/e calcd for C16H18Cl2N2O3 (M+H)+ 357.0773. found 357.0768.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:5][N:4]=1>[Pd].C(O)C>[CH3:1][NH:2][C:3]1[N:4]=[CH:5][C:6]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:7][C:8]=1[NH2:9]
Reactant: CNc1ncc(-c2ccncc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNc1ncc(-c2ccncc2)cc1N

Procedure:
A mixture containing 21 g. of 2-methylamino-3-nitro-5-(4-pyridinyl)pyridine, 200 ml. of ethanol and 2 g. of 10% palladium-on-charcoal was shaken under catalytic hydrogenation conditions in a Parr apparatus at room temperature for three hours. The reaction mixture was filtered and the solvent distilled off in vacuo. The remaining solid was recrystallized from acetonitrile, washed with ether and dried in vacuo at 70° C. to yield 3-amino-2-methylamino-5-(4-pyridinyl)pyridine (alternatively named N6 -methyl-[3,4'-bipyridine]-5,6-diamine), m.p. 184°-187° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][C:12]1([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[CH2:16][C:15](=O)[NH:14][CH2:13]1)C.O.[OH-].[Na+]>O1CCCC1>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([C:12]2([CH2:11][CH2:10][OH:9])[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: CCOC(=O)CC1(c2ccc(OC)c(OC)c2)CNC(=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2(CCO)CCNC2)cc1OC
Temperature: 10 °C
Reaction time: 18 h

Procedure:
Combine lithium aluminum hydride (0.99 g, 26.0 mmol) and anhydrous tetrahydrofuran (20 mL). Slowly, add (3-(3,4-dimethoxyphenyl)-5-oxopyrrolidin-3-yl)acetic acid ethyl ester (2.0 g, 6.5 mmol) as a solution in anhydrous tetrahydrofuran (40 mL). After the addition is complete. heat to reflux. After 18 hours, cool in an ice-bath. Add water (1 mL) dropwise at such a rate that the temperature of the reaction mixture does not rise above 20° C. Cool to 10° C., add 15% sodium hydroxide solution (1.0 mL). Add water (3 mL). After 15 minutes, filter the reaction mixture and concentrate the filtrate invacuo to give the title compound: Rf= 0.68 (silica gel, 5/1 ethyl acetate/methanol).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:13])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.[OH-].[K+].Cl>C(O)C>[OH:13][C:5]1[C:4]([C:1](=[O:3])/[CH:2]=[CH:19]/[C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([C:15]([F:14])([F:24])[F:25])[CH:17]=2)=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(=O)c1cccc(C(=O)O)c1O
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(C(=O)/C=C/c2cccc(C(F)(F)F)c2)c1O
Temperature: 0 °C
Reaction time: 24 h
Yield: 47.6 %

Procedure:
3-acetyl-2-hydroxybenzoic acid 32 (0.9 g, 5 mmol) and 3-(trifluoromethyl)benzaldehyde 33 (0.96 g, 5.5 mmol) were dissolved in 100 mL ethanol. After addition of the same volume of 25% aq KOH, the reaction mixture was stirred for 24 h. The mixture was poured into ice-water and the PH was adjusted to 2 with conc. HCl. The precipitate was filtered, washed with H2O and dried to give 34 (0.8 g, 47% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH2:12][CH3:13])[C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[O:15]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:15]([C:22]1[CH:23]=[C:24]([CH2:25][CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([CH3:14])[CH2:12][CH3:13])[CH:27]=[CH:28][CH:29]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CCC(C)(C(C)=O)c1ccc(Cl)cc1
Product: CCC(C)(CCCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1

Procedure:
In the same manner as described in Synthesis Example 2, 3-(4-chlorophenyl)-3-methyl-2-pentanone and 3-phenoxybenzaldehyde were treated to give 1-(3-phenoxyphenyl)-4-(4-chlorophenyl)-4-methyl-hexane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([SH:12])[N:7]=1)[CH3:2].Cl[CH2:15][C:16](=[O:18])[CH3:17]>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:15][C:16](=[O:18])[CH3:17])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(S)n1
Reactant: CC(=O)CCl
Product: CCOC(=O)Cc1cccc(SCC(C)=O)n1

Procedure:
Prepared according to the procedure described in Example 1, Step 3, using the following starting materials: (6-mercapto-pyridin-2-yl)-acetic acid ethyl ester and chloroacetone.