Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]([OH:23])=[C:17]([CH2:24][CH3:25])[CH:16]=4)[C:4]=2[C:3]=1[CH3:26])[CH:12]=[CH:11][CH:10]=[CH:9]3.[OH-].[Na+].Cl[S:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=1)(=[O:32])=[O:31]>C1COCC1>[CH3:1][C:2]1[O:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]([O:23][S:30]([C:33]5[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=5)(=[O:32])=[O:31])=[C:17]([CH2:24][CH3:25])[CH:16]=4)[C:4]=2[C:3]=1[CH3:26])[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: CCc1cc(-c2c3ccccc3cc3oc(C)c(C)c23)cc(CC)c1O
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cc(-c2c3ccccc3cc3oc(C)c(C)c23)cc(CC)c1OS(=O)(=O)c1ccc(C(=O)O)c(O)c1
Reaction time: 48 h
Yield: 19 %

Procedure:
At ambient temperature, to a stirred suspension containing 4-(2, 3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenol (0.317 g, 0.919 mmol) and 0.O1M aq. Borax (6 mL) in THF (9 mL) was added 2.5N NaOH (0.397 mL). To the reaction was added dropwise a solution of 4-chlorosulphonyl-2-hydroxybenzoic acid (0.653 g, 2.76 mmol) in THF (12 mL) while maintaining the pH at 10 with the simultaneous addition of 2.5N NaOH. After 48 h, additional 4-chlorosulphonyl-2-hydroxybenzoic acid (0.440 g, 1.86 mmol) in THF (12 mL) was added dropwise while maintaining the pH at 10 with the simultaneous addition of 2.5N NaOH and the reaction was stirred for an additional 48 h. The reaction was quenched with 1N HCl and extracted with ether. The combined ethereal extracts were washed with brine (1×), dried (Na2SO4) and concentrated. Purification on 2% H3PO4 /MeOH treated silica gel eluting with 2% EtOAc/hexane followed by recrystallization (EtOAc/hexane) gave 95 mg (19%) of the title compound as an off white solid, mp 222-227° C. 1H NMR (DMSO-d6) δ 1.09 (t, 6 H), 1.55 (s, 3 H), 2.40 (s, 3 H), 2.55-2.60 (m, 4 H), 7.21 (s, 2 H), 7.37-7.39 (m, 1 H), 7.43-7.49 (m, 3 H), 7.53 (d of d, 1 H), 7.99 (s, 1 H), 8.01-8.04 (m, 1 H), 8.08 (d, 1 H). mass spectrum (-ESI) m/z 543 (M-H). Anal. Calcd. for C31H28O7S.0.5H2O: C, 67.25; H, 5.28; N, 0.00. Found: C, 67.14; H, 5.21; N, 0.08.
Reaction SMILES: [C:1]1([NH:7][CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(NN)(C1C=CC(C)=CC=1)(=O)=O.C(Cl)(Cl)Cl>C(O)C>[C:1]1([NH:7][CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2CCC1Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: c1ccc(NC2CCc3ccccc3C2)cc1
Temperature: -10 °C
Yield: 80 %

Procedure:
2.37 grams (0.01 mol.) of 2-phenylaminotetralone (formula I: R = phenyl) are refluxed during 6 hours in 50 ml of ethanol, in the presence of one equivalent of tosylhydrazine. After the removal of the alcohol, 100 ml of alcohol-free chloroform are added to the residue (crude tosylhydrazone). After cooling to -10°C, 0.011 mol. of catecholborane are added and the reaction is allowed to take place during 30 minutes. 0.03 mol. of trihydrated sodium acetate are then added so as to initiate the decompositon of the intermediate addition product and the mixture is refluxed during 1 hour. After cooling, 100 ml of water are added and the pH is adjusted at 13. The obtained 2-phenylaminotetraline (yield: 80%) is extracted by means of chloroform and converted into hydrochloride. Melting point: 193° - 196°C.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH:5]1([CH2:10][C:11](Cl)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1.O.[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH:5]1([CH2:10][C:11]([C:18]2[CH:19]=[CH:20][C:15]([CH3:21])=[CH:16][CH:17]=2)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Cc1ccccc1
Reactant: O=C(Cl)CC1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(C(=O)CC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Add aluminum trichloride (2.719 g, 20.4 mmol) in three portions to a solution of cyclopentylacetyl chloride (2 g, 13.6 mmol) in anhydrous toluene (30 mL) at 0° C. Stir the solution at room temperature overnight. Cool to 0° C., add water and extract the aqueous phase with EtOAc. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to give the desired intermediate as an oil (2.5 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl.O.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]([C:4]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[CH:25][CH:26]=2)=[O:6])=[CH:7][C:8]([F:11])=[CH:9][N:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CN)cc1
Reactant: O=C(O)c1cc(F)cnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Cl)cc1
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a stirred solution of 2-chloro-5-fluoronicotinic acid (2.0 g, 10 mmol) and tert-butyl 4-(aminomethyl)benzoate (1.65 g, 8 mmol) in dichloromethane (25 mL) were successively added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (2.88 g, 15 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (1.53 g, 10 mmol), and triethylamine (5 mL). After being stirred overnight, the reaction mixture was poured into water (100 mL). The organic layer_was separated and the aqueous layer was extracted with dichloromethane (50 mL×2). The combined organic layers were washed with brine (100 mL), dried (sodium sulfate), and evaporated. The residue was purified by flush column chromatography on silica gel (200 g) eluting with dichloromethane/ethyl acetate (20/1) to afford 2.39 g (82%) of the title compounds as white solids: 1H-NMR (CDCl3) δ 8.33 (1H, d, J=3.1 Hz), 7.97 (2H, d, J=8.4 Hz), 7.91 (1H, dd, J=7.9, 3.1 Hz), 7.40 (2H, d, J=8.4 Hz), 7.04 (1H, br.s), 4.70 (2H, d, J=5.9 Hz), 1.58 (9H, s).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:23][C:19]4[N:18]=[C:17]([CH3:16])[CH:22]=[CH:21][N:20]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Cc1ccnc(N)n1
Solvent: c1ccncc1
Product: Cc1ccnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)n1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 4-methylpyrimidin-2-amine (22 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 297.3, found 298.3 (M+1)+. Retention time 2.14 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][CH:22]=[CH:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O.CN(C)C=O.Cl.[OH-].[Na+]>O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][CH:22]=[CH:23][C:24]3[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=3)=[CH:16][CH:15]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(C=CC=Cc2ccc(C=CC=Cc3ccc([N+](=O)[O-])cc3)cc2)cc1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(C=CC=Cc2ccc(C=CC=Cc3ccc(N)cc3)cc2)cc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
21.22 g of 1,4-bis[4-(4-nitrophenyl)-1,3-butadienyl]benzene was put into 800 ml of dimethylformamide (DMF). To this mixture, 33.51 g of iron powder and an aqueous solution of hydrochloric acid prepared by diluting 8.5 ml of concentrated hydrochloric acid with 28 ml of water were successively added with stirring, and the obtained mixture was further stirred at 95 to 102° C. for 4 hours. The resultant mixture was cooled to 90° C., and adjusted to pH 9 by the addition of a 40% aqueous solution of sodium hydroxide. Thereafter, the insoluble matter was removed from the mixture by filtration using Celite™. The filtrate was concentrated to about 400 ml under reduced pressure. With the addition of 20 ml of water, the concentrated filtrate was cooled to room temperature. The separating crystals were collected by filtration, and successively washed with water and methanol, and heated with the application of heat under reduced pressure, whereby 13.40 g of mud yellow crystals was obtained in a 73.5% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=1)=[O:4].[CH2:18](I)[CH3:19].[H-].[Na+].Cl>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH3:19])[C:13]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=1)=[O:4]
Reactant: COC(=O)c1ccc2[nH]c3c(c2c1)CCCC3
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c2c(c3cc(C(=O)OC)ccc31)CCCC2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1,2,3,4-Tetrahydrocarbazole-6-carboxylic acid methyl ester (460 mg) prepared by the method described in Journal of Chemical Society, p.809 (1926) was dissolved in 2.5 mL of DMF, and the solution was added with 0.3 mL of ethyl iodide and 120 mg of sodium hydride and stirred at room temperature at 50° C. for 2 hours under a nitrogen flow. Then, the reaction mixture was added with water, neutralized with 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane) to obtain 490 mg of N-ethyl-1,2,3,4-tetrahydrocarbazole-6-carboxylic acid methyl ester.
Reaction SMILES: O[CH:2]([CH2:23]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]N1C(=O)C2N(C)C=NC=2N(C)C1=O.C(O)CCCCCCC=C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(N(CC)CC)C>ClCCl.O>[CH3:35][S:36]([CH2:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9])(=[O:38])=[O:37]
Reactant: Cn1cnc2c1c(=O)n(CCCCCCCC(O)CO)c(=O)n2C
Reactant: CS(=O)(=O)Cl
Agent: C=CCCCCCCCO
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCCCCCCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
This example illustrates a synthesis procedure for 1-(8,9-dihydroxynonyl)-3,7-dimethylxanthine (CT1561). The synthesis began by adding a solution of 8-nonene-1-ol (1.50 g, 10.5 mmol) in dichloromethane (100 ml) at 0° C. to methanesulfonyl chloride (1.20 g, 813 μl, 10.5 mmol), followed by triethylamine (1.59 g, 15.8 mmol). After stirring for 1 hr at 0° C., the reaction mixture was allowed to warm to room temperature. The reaction mixture was poured into 100 ml of water and extracted with dichloromethane (3×50 ml). The organic portions were combined, dried with sodium sulfate, and evaporated to give 9-methanesulfonyl-1-nonene as a yellow oil (2.25 g, 97% yield, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([OH:12])[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([O:12][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][O:25]1)[CH3:11]
Reactant: C1=COCCC1
Reactant: CC(O)C(=O)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(OC1CCCCO1)C(=O)c1ccc(F)cc1F
Yield: 97.7 %

Procedure:
2',4'-Difluoro-2-hydroxypropiophenone (61 g) was dissolved in methylene chloride (500 ml), to which was added, under ice-cooling, p-toluene sulfonic acid.hydrate (1.0 g). To the mixture was added, under ice-cooling while stirring, 3,4-dihydro-2H-pyran (41.4 g) during 10 minutes. The mixture was stirred, under ice-cooling, for one hour, to which was added a 5% aqueous solution of sodium hydrogen carbonate (240 ml). The mixture was stirred for 10 minutes under ice-cooling. The methylene chloride layer was separated and dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residual oily product was purified by means of a silica gel column chromatography (hexane: ethyl acetate=5:1) to afford 2',4'-difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (86.5 g) as a pale yellow oily product.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:22]([C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[O:19][C:18]([F:17])([F:29])[F:30])=[N:16][N:15]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1ccccc1OC(F)(F)F
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccccc2OC(F)(F)F)o1
Yield: 38 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2-(trifluoromethoxy)-benzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 134 mg, 38%) which was obtained as a white solid. MS: m/e=388.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]O)[C:3]=1[OH:10].[C-:11]#[N:12].[Na+]>CN(C)C=O.O>[F:1][C:2]1[C:3]([OH:10])=[C:4]([CH2:8][C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccc(F)c1O
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cccc(F)c1O

Procedure:
A solution of 4.89 g of 2-fluoro-6-hydroxymethylphenol and 2.08 g of sodium cyanide in 120 ml of N,N-dimethylformamide is stirred at 120° C. over 24 hours. The reaction mixture is cooled, diluted with water and concentrated by evaporation. The residue is diluted with water and neutralized with conc. acetic acid (caution! hydrocyanic acid). The mixture is extracted with dichloromethane (3×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a violet solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.32 (1:2 EtOAc-heptane); Rt=3.12.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].CC(O)(C)C.CC(O)C.O.[H][H]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Reactant: [H][H]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(Nc2nc([C@@H](O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 50 °C
Reaction time: 18 h
Yield: 1066.7 %

Procedure:
A stirred mixture of compound 1 (418 mg, 1.2 mmol) and (R)—P-Phos RuCl2(R)-DAIPEN (5.4 mg, 0.0048 mmol) at room temperature was subjected to five cycles pressurizing with nitrogen to 40 psi and then depressurizing. Then KOtBu/tBuOH (1 M, 14.4 μL, 0.0144 mmol) in 9:1 i-PrOH/H2O (4 mL) was added and the mixture was subjected to five cycles of pressurizing with nitrogen to 40 psi and then depressurizing. The stirred mixture was then subjected to ten cycles of pressurizing with hydrogen to 435 psi and then depressurizing. The mixture was then stirred at 900 rpm under hydrogen (435 psi) at 50° C. for 18 hrs. The mixture was allowed to cool to room temperature and vented carefully. MeOH (8 mL) was added, and a sample (0.2 mL) was analyzed by chiral HPLC and LCMS (Phenomenex Luna C18) eluted with a gradient of CH3CN in 0.1% aq. HOAc. The above procedure was carried out in analogous fashion in an additional 12 runs. Samples of the required specification (>98%, >95% enantiomeric excess) were combined and filtered through celite, washing with MeOH. The filtrate was concentrated to dryness and further dried under high vacuum overnight to afford compound I as an off-white solid (4.48 g, 12.8 mmol). 1H NMR (300 MHz, DMSO-d6) δ 12.13 (br s, 1H), 10.38 (br s, 1H), 8.59 (d, J=7.7 Hz, 1H), 7.70-7.98 (m, 2H), 7.45-7.64 (m, 3H), 7.06-7.24 (m, 2H), 6.45 (s, 1H), 5.80 (s, 1H), 5.67 (s, 1H), 2.26 (s, 3H); LC-MS (ESI) m/z: 350 (M+H)+. Analysis by chiral HPLC showed a 96.7% enantiomeric excess of the earlier eluting enantiomer.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:14])=[CH:10][C:11]([OH:13])=O.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH3:40][C:41]1([CH2:47][CH2:48][C:49]2[C:54]([CH3:56])([CH3:55])[CH2:53][CH2:52][CH2:51][C:50]=2[CH3:57])[NH:46][CH2:45][CH2:44][CH2:43][O:42]1>C1COCC1.CN(C1C=CN=CC=1)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:14])=[CH:10][C:11]([N:46]1[CH2:45][CH2:44][CH2:43][O:42][C:41]1([CH3:40])[CH2:47][CH2:48][C:49]1[C:54]([CH3:56])([CH3:55])[CH2:53][CH2:52][CH2:51][C:50]=1[CH3:57])=[O:13]
Reactant: CC1=C(CCC2(C)NCCCO2)C(C)(C)CCC1
Reactant: CC(=CC(=O)O)c1ccc(O)cc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=CC(=O)N1CCCOC1(C)CCC1=C(C)CCCC1(C)C)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 11.1 g (0.050 mol) of 3-(2,4-dihydroxy-phenyl)-3-methyl-acrylic acid in 500 mL of anhydrous THF is added 10.3 g (0.050 mol) of DCC. After stirring for 10 min, 6.8 g (0.050 mol) of HOBt, 11.3 g (0.045 mol) of 2-methyl-2-[2-(2,6,6-trimethyl-cyclohex-1-enyl)-ethyl]-[1,3]oxazinane (8) and 1.1 g (0.009 mol) of DMAP are added and stirred at 0° C. for 1 h, warmed to room temperature and stirred for an additional 24 h. The mixture is cooled to 0° C., filtered and the solvent is removed in vacuo. The residue is diluted with ethyl acetate and washed three times with saturated sodium bicarbonate, followed by 10% citric acid and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product 9 is further purified by flash chromatography on basic alumina with 20:1 chloroform/methanol.
Reaction SMILES: [CH:1]([S:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])([CH3:3])[CH3:2].[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15](Cl)=[O:16])[CH2:12][CH3:13].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:4]([CH:1]([CH3:3])[CH3:2])=[O:5])=[N:7]1)=[O:16])[CH2:12][CH3:13]
Reactant: CC(C)S(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)n1cnc(S(=O)C(C)C)n1

Procedure:
A mixture of 6.4 g. 3-isopropylsulphinyl-1,2,4-triazole, 8.0 ml. dipropylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 10 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The cooled reaction mixture was filtered and the filtrate distilled under reduced pressure to give 1-dipropylcarbamoyl-3-isopropylsulphinyl-1,2,4-triazole as an oily residue which subsequently solidified, m.p. 15° - 20°C. Elemental analysis satisfactory.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:11]([C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17](B(O)O)[CH:18]=1)#[N:12].C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:15]1[CH:14]=[C:13]([C:11]#[N:12])[CH:18]=[CH:17][C:16]=1[F:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(F)c(B(O)O)c1
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1cc(C#N)ccc1F)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 43.3 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.00 g, 6.1 mmol), 5-cyano-2-fluorophenylboronic acid (CombiBlocks; 1.00 g, 6.84 mmol), copper(II) acetate (1.1 g, 6.1 mmol) and triethylamine (2.1 mL, 15.1 mmol) in 1,2-dichloroethane (30 mL) was heated in an oil bath at 60° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 120 g column, eluting with 10-50% ethyl acetate/hexanes, to give N′-(5-cyano-2-fluoro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (700 mg, 44%) as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][C:17]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)([C:20](OCC)=[O:21])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)C>[CH2:7]([N:14]1[CH2:19][CH2:18][C:17]([CH2:20][OH:21])([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C1(Nc2cccc(C)c2)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1cccc(NC2(CO)CCN(Cc3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a slurry of lithium aluminum hydride (330 mg, 8.7 mmol) in anhydrous diethyl ether (25 mL) at 0° C., a solution of ethyl 1-benzyl-4-(3-methylphenylamino)piperidine-4-carboxylate (2.8 g, 7.94 mmol) in diethyl ether (10 mL) was added dropwise with the temp. of the reacting mixture maintained below 10° C. The resulting mixture was stirred at 0° C. for 30 min, and quenched with successive addition of water (0.33 mL), 15% aqueous NaOH (0.33 mL), and water (1 mL). The resultant slurry was stirred at room temp. for 30 min., and was filtered through a small plug of Celite. The filtrate was washed brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title alcohol as white solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:21]([OH:23])=[O:22])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[NH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].IC.[CH3:26]COC(C)=O>CN(C=O)C>[CH3:26][O:22][C:21](=[O:23])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[NH:13][CH:12]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of BOC-5-hydroxy-tryptophan (5.9 g, 18.4 mmol) and iodomethane (3.43 mL) in DMF (80 mL) was added powered KHCO3 (3.68 g). The reaction mixture was stirred at rt for 4 hours. EtOAc (500 mL) was added and the mixture was washed with brine (500 mL) and water (500 mL). The organic phase was concentrated and the residual oil was triturated with CH2Cl2 (20 mL). The formed white solid was collected by filtration, washed with CH2Cl2 (20 mL) and dried to give the desired product (4.48 g, 73%). MS (DCI) m/z 335 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCN(C)CC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 1-methylpiperazine. ES-MS m/e (%): 469 (M+H+, 100).