Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19][C@H:20]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.[CH3:32][O:33][CH2:34]/[CH:35]=[CH:36]/B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[OH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:8]1[N:7]=[C:6]([NH:19][C@H:20]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:21]2)[C:5]2[C:10](=[CH:11][C:2](/[CH:36]=[CH:35]/[CH2:34][O:33][CH3:32])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3cc(Br)ccc23)C1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC/C=C/c1ccc2c(N[C@H]3CCN(C(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: 110 °C
Yield: 74.5 %

Procedure:
(S)-tert-Butyl 3-(7-bromo-2-(2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate (0.099 g, 0.20 mmol), trans-3-methoxy-1-propenylboronic acid pinacol ester (0.051 g, 0.23 mmol), Na2CO3 (0.066 g, 0.62 mmol), palladium tetrakistriphenyl phosphine (0.012 g, 0.011 mmol) was dissolved in a toluene (1 mL) and water (0.3 mL) and the mixture was degassed in a sealed tube. The reaction mixture was heated at 110° C. for 16 h. The reaction mixture was cooled and diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Further purification by silica column chromatography eluting with a gradient from 1% to 10% methanol in dichloromethane, gave the title compound as a yellow solid (0.071 g, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:20]=[C:19]3[N:10]([C:11](=[O:21])[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=43)[N:9]=2)=[CH:4][CH:3]=1.[CH3:22][O-].[Na+].CI>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:20]=[C:19]3[N:10]([C:11](=[O:21])[N:12]([CH3:22])[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=43)[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: O=c1[nH]c2ccccc2c2nc(-c3ccc(Cl)cc3)nn12
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Product: Cn1c(=O)n2nc(-c3ccc(Cl)cc3)nc2c2ccccc21
Temperature: 0 °C

Procedure:
To a mixture of 2-(4-chlorophenyl)-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)one (6 g) in dry dimethylsulphoxide (150 ml) is added sodium methoxide (1.3 g). The mixture is heated under nitrogen for one hour at 85° and methyl iodide (1.3 ml) in dimethyl sulphoxide (10 ml) added. A white solid forms rapidly. The reaction mixture is heated three hours longer, cooled and poured into ice water (800 ml). The precipitated white solid is washed with water, air dried (7.2 g) and recrystallized from dimethylacetamide twice to afford pure 2-(4-chlorophenyl)6-methyl-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)one, mp 323°-325°.
Reaction SMILES: [CH2:1]([SH:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[H-].[Na+].Br[CH:25]1[CH2:28][CH2:27][CH:26]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C=O)C>[CH2:1]([S:21][C:26]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:28][CH2:25]1)[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CCOC(=O)C1CCC1Br
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC1(C(=O)OCC)CCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a solution of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaene-1-thiol (305 mg, 1.00 mmol) in dry DMF (10 mL) at 0° C. under inert atmosphere was added NaH (60% in mineral oil, 44 mg, 1.1 mmol). After fifteen minutes ethyl 2-bromo-cyclobutane carboxylate (170 μL, 1.05 mmol) was added and the mixture was stirred for 1.5 hour at 0° C. The reaction was quenched by addition of sat. aq. NH4Cl (20 mL). Heptane (50 mL) was added, and the phases were separated. The water phase was extracted with heptane (2×25 mL). The combined organics were washed with water (25 mL) and brine (25 mL), dried (MgSO4), filtered and evaporated to give 409 mg of the title compound as a crude oil. Purification by flash chromatography on silica gel using isocratic elution (heptane:acetone 98:2) afforded 243 mg (56% yield) of the title compound as oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1)[CH3:2].C([Li])CCC.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1COCC1.CCCCCC>[CH2:1]([O:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCOCn1cnc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOCn1c(C(=O)OCC)nc2ccccc21
Temperature: -60 °C
Yield: 35.9 %

Procedure:
1-Ethoxymethylbenzimidazole (1.76 g) was dissolved in dry THF (40 ml) in a dry argon atmosphere, cooled to -60° C., and a solution of n-butyl lithium (1.58M) in hexane (9 ml) was added dropwise with stirring and allowed to react for 1 hr. After ethyl chloroformate (1.62 g) was added dropwise, the mixture was slowly returned to room temperature and allowed to react overnight. THF was distilled off, the residue was dissolved in ethyl acetate, washed with water, dried over anhydrous Na2SO4, and the solvent was distilled off. Purification of the residue by column chromatography on silica gel gave the title compound (0.89 g) as an oily product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:11][N:12](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:11]#[N:12])=[CH:3][C:4]=1[O:9][CH3:10]
Reactant: COc1cc(Br)cnc1N
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc(C#N)cnc1N
Temperature: 100 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
To a solution of 5-bromo-3-methoxy-pyridin-2-amine (3.00 g, 14.8 mmol) in N,N-dimethylformamide (55 mL) under a nitrogen atmosphere was added zinc (II) cyanide (2.78 g, 23.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.06 g, 1.77 mmol). The reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was diluted with ethyl acetate and washed successively with a saturated solution of ammonium hydroxide and brine. The phases were separated. The organic phases was dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:5) to give 6-amino-5-methoxy-pyridine-3-carbonitrile (1.2 g, 54% yield). 1H NMR (400 MHz, CDCl3): 7.99 (s, 1H), 6.99 (s, 1H), 3.88 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): 152.83, 144.58, 141.27, 118.32, 115.52, 97.66, 55.65. LC-MS (Method B): RT 0.69, 150 (M+H+)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S([O:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])(=O)=O.[F:20][C:21]([N+:27]([O-:29])=[O:28])([N+:24]([O-:26])=[O:25])[CH2:22]O.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[F:20][C:21]([N+:27]([O-:29])=[O:28])([N+:24]([O-:26])=[O:25])[CH2:22][O:12][CH2:13][Si:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: O=[N+]([O-])C(F)(CO)[N+](=O)[O-]
Reactant: C[Si](C)(C)COS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)COCC(F)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h
Yield: 43.9 %

Procedure:
Potassium carbonate (6 g) was added to a solution of 3.5 g (0.0148 mol) of trimethylsilylmethyl trifluoromethanesulfonate and 2.3 g of 2-fluoro-2,2-dinitroethanol in 5 ml of methylene chloride, and the mixture was stirred for 16 hrs. This suspension was added with stirring to a mixture of 30 ml of ice water and 30 ml of carbon tetrachloride. The carbon tetrachloride layer was washed with 10 ml of water, dried over magnesium sulfate, and distilled to give 1.56 g (45%) of trimethylsilylmethyl 2-fluoro-2,2-dinitroethyl ether, bp 52° (0.75 mm).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][N:10]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[O:12][C:11]2=[O:25])=[C:4]([O:26][CH3:27])[CH:3]=1.N1C=CC=CC=1.[Br:34][CH2:35][C:36](Br)=[O:37].[K+].[Br-]>C1COCC1>[Br:34][CH2:35][C:36]([NH:1][C:2]1[CH:3]=[C:4]([O:26][CH3:27])[C:5]([CH2:9][N:10]2[N:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=3)[O:12][C:11]2=[O:25])=[CH:6][C:7]=1[Cl:8])=[O:37]
Reactant: O=C(Br)CBr
Reactant: COc1cc(N)c(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(NC(=O)CBr)c(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
3-[(4-Amino-5-chloro-2-methoxyphenyl)methyl]-5-[4-(trifluoromethyl) phenyl]-1,3,4-oxadiazol-2(3H)-one (3 g, 7.5 mmol) and pyridine (0.68 ml, 8.41 mmol) were dissolved in THF (35 ml) under N2 and cooled to 0° C. Bromoacetyl bromide (0.72 ml, 8.26 mmol) was added dropwise and the reaction mixture stirred for 18 h at 24° C. before being partitioned between ethyl acetate (400 ml) and 0.1N HCl solution (50 ml). The organic phase was washed with saturated NaHCO3 solution and brine, and dried over MgSO4. Active carbon (500 mg) was added and the solution filtered through a plug of Celite. Concentration gave 3.8 g (98%); mp 140-182° C. (dec); IR(KBr, υ=cm-1) 3348, 2972, 1784, 1672, 1594, 1234, 1168, 1066; 1H NMR (300 MHz, DMSO-d6) δ 3.77 (3H, s), 4.15 (2H, s), 4.90 (2H, s), 7.47-7.48 (2H, m), 7.86 (2H, d, J=8.4 Hz), 7.96 (1H, d, J=8.3 Hz), 9.30 (1H, s); MS(ESl)m/z: 520(MH+)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)[CH2:3][CH2:2]1.C1(COC2N=C(C(O)=O)C=CC=2C2CCCO2)CC1.[NH2:39][C@@H:40]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:41]([NH2:43])=[O:42]>>[C:41]([C@@H:40]([NH:39][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:44][CH:45]([CH3:47])[CH3:46])(=[O:42])[NH2:43]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1ccc(C2CCOC2)c(OCC2CC2)n1
Agent: O=C(O)c1ccc(C2CCCO2)c(OCC2CC2)n1
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CCOC2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using the mixture of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (mixture from Example 114 d), and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=376.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.CC([O-])(C)C.[Na+]>CCOCC.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([C:10]#[N:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrCCOCCBr
Reactant: N#CCc1ccc(F)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#CC1(c2ccc(F)c(F)c2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture 2-(3,4-difluorophenyl)acetonitrile (25.00 g, 163 mmol) and 2-bromoethyl ether (22.8 mL, 163 mmol) in ether was added dropwise through an addition funnel to a mixture of sodium 2-methylpropan-2-olate (39.2 g, 408 mmol) in DMF (163 mL) at 0° C. The reaction was then allowed to warm to ambient temperature and stirred for 3 hours. The reaction mixture was quenched with 12N HCl, diluted with 400 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 100 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound which was used without further purification. MS (m/z)=224 (M+H)+.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C(O)(=O)C>[CH3:3][N:4]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]1[CH:6]=[CH:7][C:8]([Br:1])=[CH:9][CH:10]=1
Reactant: CC(C)CCN(C)c1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CCN(C)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
A solution of 58 g of bromine in 60 ml of acetic acid was added dropwise at about 15° C. over one hour to a mixture of 64 g of the product of Step A in 300 ml of acetic acid and the mixture was stirred at 80° C. for 8 hours and was poured into iced water. The mixture was extracted with methylene chloride and the organic phase was washed with aqueous sodium bicarbonate, with water, dried and evaporated to dryness. The residue was distilled to obtain 70 g of N-methyl-N-(3-methylbutyl)-4-bromo-aniline boiling at 119° C. at 0.5 mm Hg.
Reaction SMILES: [CH3:1][C:2]([C:5]([NH2:7])=[NH:6])([CH3:4])[CH3:3].Cl.[Cl:9][C:10](Cl)(Cl)[S:11]Cl.[OH-].[Na+]>ClCCl.O>[C:2]([C:5]1[N:7]=[C:10]([Cl:9])[S:11][N:6]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)C(=N)N
Reactant: ClSC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1nsc(Cl)n1
Temperature: -15 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
6.83 g (50.00 mmol) of tert-butylcarbamidine hydrochloride are dissolved in 60 ml of dichloromethane and treated with 8.37 g (45.00 mmol) of trichloromethanesulphenyl chloride, before the reaction mixture is cooled to −15° C. A solution of 10.00 g (250 mmol) of sodium hydroxide in 20 ml of water is added dropwise and the mixture obtained is stirred at AT for 3 h. After adding 50 ml of dichloromethane, extracting three times with water and drying the combined organic phases over MgSO4, the solvent is evaporated under vacuum. (5.81 g, 90% purity, 60% yield, log P (pH 2.3)=3.44).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH2:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:10])[N:5]=[C:6]([CH:8]2[CH2:9][CH:13]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1
Reactant: C=Cc1cc(Cl)nc(C)n1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1c1cc(Cl)nc(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-chloro-2-methyl-6-vinylpyrimidine (4-1, 15.0 g, 97 mmol 1.0 eq) in Toluene (300 mL) was heated to 100° C. under a nitrogen atmosphere. A solution of ethyl diazoacetate (30.2 mL, 291 mmol, 3.0 eq) was added as a solution in toluene (100 mL) over 1.5 hours. Heating was continued for 2 hours. The reaction mixture was allowed to cool to room temperature and concentrated to dryness. The residue was partitioned between saturated sodium bicarbonate solution (1 L) and ethyl acetate (1 L). The organic layer was separated, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to give ethyl 2-(6-chloro-2-methylpyrimidin-4-yl)cyclopropanecarboxylate (4-2) as a colorless oil.
Reaction SMILES: Cl.[CH3:2][NH:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][Cl:6].[C:10](Cl)(=[O:12])[CH3:11]>C1(C)C=CC=CC=1>[CH3:2][N:3]([C:10](=[O:12])[CH3:11])[C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][Cl:6]
Reactant: CN[C@@H](CCl)C(=O)O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)N(C)[C@@H](CCl)C(=O)O
Yield: 91 %

Procedure:
181 g of methyl 3-chloroalanine hydrochloride were heated under reflux with 163.9 g of acetyl chloride in 1.5 l of anhydrous toluene for about 5 hours until a clear solution was obtained. This was evaporated to dryness and the residue was crystallized from ethyl acetate/petroleum ether. 170 g of product of m.p. 104° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1.C(O[C:15]([S-])=[S:16])C.[K+]>C(O)C>[F:9][C:6]1[C:7]2[O:8][C:15]([SH:16])=[N:1][C:2]=2[CH:3]=[CH:4][C:5]=1[O:10][CH3:11]
Reactant: COc1ccc(N)c(O)c1F
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc2nc(S)oc2c1F
Temperature: 80 °C
Reaction time: 64 h
Yield: 52.7 %

Procedure:
To a solution of 6-amino-2-fluoro-3-methoxyphenol (220 mg) in ethanol (10 mL) was added potassium ethylxanthate (450 mg), and the mixture was stirred at 80° C. for 64 hr. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. The obtained residue was dissolved in water, and the solution was acidified with 1 M hydrochloric acid. After stirring for 10 min, the mixture was extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (147 mg).
Reaction SMILES: Cl.[CH2:2]([S:6]([NH:9][C@@H:10]([CH2:15][NH2:16])[C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7])CCC.CS([Cl:21])(=O)=O>>[ClH:21].[CH3:2][S:6]([NH:9][C@@H:10]([CH2:15][NH2:16])[C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7]
Reactant: CCCCS(=O)(=O)N[C@@H](CN)C(=O)OC
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: COC(=O)[C@H](CN)NS(C)(=O)=O

Procedure:
5-7 was prepared as described above for the butylsulfonylamino analog (5-6) using methanesulfonyl chloride at the appropriate stage.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]1[CH2:16][O:15][CH2:14][CH2:13]1>C[C@@H](N(C)C)[C]1[C](P(C2C=CC=CC=2)C2C=CC=CC=2)[CH][CH][CH]1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.[Fe].O>[OH:15][C@@H:16]1[C:12]2[C:2](=[CH:10][CH:9]=[CH:14][CH:13]=2)[CH:3]=[CH:7][C@H:8]1[N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C1CCOC1
Agent: [Fe]
Agent: C[C@H]([C]1[CH][CH][CH][C]1P(c1ccccc1)c1ccccc1)N(C)C
Agent: [CH]1[CH][CH][C](P(c2ccccc2)c2ccccc2)[CH]1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C=Cc2ccccc2[C@H]1O
Temperature: 80 °C
Yield: 52 %

Procedure:
To a flame dried round bottom flask, [Rh(COD)Cl]2 (5.4 mg, 0.011 mmol), (R)-(S)-BPPFA (12.2 mg, 0.022 mmol), phthalimide (510 mg, 3.47 mmol) and 1 (100 mg, 0.69 mmol) were added. THF (4 mL) was then added, followed by heating to 80° C. for 3 days. The reaction mixture was then poured in to water and extracted three times with ethyl acetate. The organic layers were combined, washed with brine dried over Na2SO4, and concentrated in vacuo. The resulting solid was purified by flash chromatography (30% ethyl acetate in hexanes) to give 2 as a white crystalline solid (103.5 mg, 52%). The ee was determined to be 74% using HPLC analysis on a CHIRALCEL OD column, λ=486 nm. Retention times in 10% isopropanol in hexanes were 21.1 min (major) and 29.1 min. Rf=0.36 on silica gel (30% ethyl acetate:hexanes); mp 175-176° (dec); [α]25D=−6.1° (c=12.9, CHCl3); IR (KBr, cm−1) 3536 (br), 3067 (w), 2921 (w), 1772 (m), 1693 (s), 1388 (s), 1084 (m), 955 (m), 719 (s); 1H NMR (400 MHz, CDCl3) δ 7.78-7.75 (2H, m), 7.68-7.64 (2H, m), 7.57-7.55 (1H, m), 7.26-7.22 (2H, m), 7.09-7.07 (1H, m), 6.51 (1H, dd, J=9.7, 2.7 Hz), 5.84 (1H, ddd, J=9.7.2.7, 2.2 Hz), 5.48 (1H, d, J=12.8 Hz), 5.12 (1H, ddd, J=12.8, 2.5, 2.4 Hz), 2.82 (1H, s); 13C NMR (400 MHz, CDCl3) δ 168.6, 137.3, 134.2, 132.6, 132.1, 128.7, 128.2, 128.1, 126.9, 126.5, 124.4, 123.5, 70.9, 55.3. HRMS calcd for C18H11NO2 (M−-H2O): 273.2939. Found: 273.0793.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>CC(C)=O>[CH3:16][S:17]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)(=[O:19])=[O:18]
Reactant: O=C1CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.1 %

Procedure:
To a suspension of 4-piperidone monohydrate hydrochloride (2.0 g, 13 mmol) and K2CO3 (9.0 g, 65.2 mmol) in acetone (40 ml) was added methanesulfonyl chloride (5.96 g, 52.1 mmol) at 0-5° C. The mixture was stirred at 25° C. for 24 h. The solid material was removed by filtration, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 80% ether in hexanes) to afford the desired ketone (1.20 g, 52%) as a colorless solid. mp 102-104° C.; 1H NMR (500 MHz, CDCl3) δ2.58 (t, J=6.4 Hz, 4H), 2.90 (s, 3H), 3.60 (t, J=6.4 Hz, 4H).
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.[CH2:29]([N:31](CC)CC)[CH3:30].BrCC#N>C(#N)C>[CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][N:19]1[CH2:30][C:29]#[N:31])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCCCCC1CNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1
Reactant: CCN(CC)CC
Agent: N#CCBr
Solvent: CC#N
Product: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(CC#N)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 4.9 %

Procedure:
A stirred solution of crude 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (210 mg, 0.50 mmol, 1 equiv) and triethylamine (0.21 mL, 1.51 mmol, 3 equiv), in anhydrous acetonitrile (3 mL) was treated with bromoacetonitrile (42 μl, 0.60 mmol, 1.2 equiv), at rt and under nitrogen. The resulting reaction mixture was stirred at rt for 18 h, evaporated to dryness and purified by chromatography over silica gel, with an eluant of 2.5% methanol in dichloromethane. The desired fractions were pooled, evaporated to dryness, and lyophilized to furnish the title compound (11.2 mg, 10%) as a fluffy white powder: TLC Rf=0.2 (5% methanol in dichloromethane); 1H NMR (300 MHz, CD3OD) δ 5.44 (d, J=5.49, 1), 4.38–4.23 (m, 4), 2.29 (s, 3), 1.52 (m, 11), 1.16–1.09 (m, 12);. MS (ESPOS): 458.5 [M+H]+, MS (ESNEG): 456.5 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=1.[CH2:24]1C[O:27][CH2:26][CH2:25]1.C(N(CC)CC)C.C(Cl)(=O)C=C>CN(C=O)C>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=1)=[CH:3][C:2]([NH:1][C:26](=[O:27])[CH:25]=[CH2:24])=[CH:11][CH:10]=2)#[N:13]
Reactant: C1CCOC1
Reactant: CC(C)c1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(C(C)C)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved 1.00 g (3.31 mmol) 6-amino-4-[(3-isopropylphenyl)amino]-3-quinolinecarbonitrile in 2.0 ml hot DMF, added 12 ml THF, and chilled to 0° C. under N2. Added 507 μl (3.64 mmol) triethylamine and 303 μl (3.64 mmol) acryloyl chloride. Removed ice bath at 15 minutes and at 1 hour stripped solvent. Slurried residue with dilute sodium bicarbonate, collected solids and washed with water. Recrystallized from ethyl acetate and dried in vacuo, giving 366 mg of orange solid: mass spectrum (electrospray m/e): M+H=357.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24]
Reactant: CC(C)=CCBr
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCSc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.30 g (102.0 mmol) of 2-bromothiophenol, 160 ml of DMF and 15.50 g (112.0 mmol) of potassium carbonate are introduced into a three-necked flask. 13 ml (112.0 mmol) of 1-bromo-3-methyl-2-butene are added dropwise and the reaction mixture is stirred at room temperature for two hours. It is poured into water and extracted with ethyl acetate and the organic phase is separated by settling, washed with water, dried over magnesium sulphate and evaporated. 26.00 g (99%) of the expected compound are collected in the form of an orangey oil.