Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([NH:12]C=O)([C:6]([OH:8])=[O:7])[CH:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.Cl>O>[NH2:12][C:5]1([C:9]([CH3:11])=[CH:10][C:2]([Br:1])=[CH:3][CH:4]1[N+:15]([O-:17])=[O:16])[C:6]([OH:8])=[O:7]
Reactant: CC1=CC(Br)=CC([N+](=O)[O-])C1(NC=O)C(=O)O
Agent: Cl
Solvent: O
Product: CC1=CC(Br)=CC([N+](=O)[O-])C1(N)C(=O)O
Temperature: 50 °C
Yield: 88.1 %

Procedure:
A mixture of 4-bromo-1-(formyl-amino)-6-methyl-2-nitrobenzoic acid (20 g) (prepared according to US 2004/0167194 A1), concentrated hydrochloric acid (50 ml), and water (150 ml) was heated at 50° C. for 16 h. The reaction mixture was cooled to room temperature, treated ice cold water, and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over sodium sulfate and concentrated to give 1-amino-4-bromo-6-methyl-2-nitrobenzoic acid (16 g). 1H-NMR (400 MHz, CDCl3): 13.53 (bs, 1H), 7.56 (s, 1H), 7.07 (bs, 2H), 2.20 (s, 3H). LCMS: m/z=272.89 (M−H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Br:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][C:18]=1[OH:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:20](OC=C)(=O)[CH3:21]>C1(C)C=CC=CC=1>[Br:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][C:18]=1[O:19][CH:20]=[CH2:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1ccc(O)c(Br)c1
Reactant: C=COC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=COc1ccc(C(=O)OCC)cc1Br
Temperature: 100 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a toluene (8 mL) solution of [IrCl(cod)]2 (54 mg, 0.08 mmol) and sodium carbonate (506 mg, 4.8 mmol) was added ethyl 3-bromo-4-hydroxybenzoate (CAS 37470-58-9) (1.95 g, 7.96 mmol) followed by vinyl acetate (1.5 mL, 15.9 mmol) under argon. The mixture was stirred at 100° C. for 2 hours. The mixture was cooled to room temperature, quenched with wet ether. Solid was filtered off and washed with ether. Column chromatography (3% ethyl acetate/hexane) gave ethyl 3-bromo-4-(vinyloxy)benzoate (1.77 g, 79%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].S(=O)(=O)(O)[OH:28]>ClCCl.C1(C)C=CC=CC=1>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[CH:4]=[O:28]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(C(F)(F)F)ccc(F)c1F
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1c(C(F)(F)F)ccc(F)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2.0 g of 2,3-difluoro-6-trifluoromethylbenzonitrile was dissolved in 20 ml of anhydrous dichloromethane and the resultant solution was cooled down to -78° C. under a nitrogen atmosphere. To the solution was then gradually added dropwise with 7.1 ml of 1.5 M toluene solution of diisobutyl aluminium hydride (DIBAL) over 30 minutes. After stirring the solution at -78° C. for 1 hour, the solution was allowed to room temperature. The solution was then added with 7 ml of saturated aqueous solution of ammonium chloride, stirred for 30 minutes and subsequently added with 33 ml of 5% sulfuric acid. The mixture was then extracted with ether, and the organic layer obtained was washed with saturated saline solution and was then dried over anhydrous magnesium sulfate. After a process for the concentration, the organic solution was purified by using silica gel column chromatography to obtain 1.36 g of the title compound (nD 20.6-1.4357).
Reaction SMILES: O=[O+][O-].[CH3:4]SC.[Cl:7][C:8]([Cl:45])([Cl:44])[CH2:9][O:10][C:11](=[O:43])/[C:12](/[N:16]1[CH:19]([S:20][S:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH:18]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:17]1=[O:42])=[C:13](\O)/[CH3:14]>>[Cl:44][C:8]([Cl:7])([Cl:45])[CH2:9][O:10][C:11](=[O:43])[CH:12]([N:16]1[CH:19]([S:20][S:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH:18]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:17]1=[O:42])[C:13](=[CH2:4])[CH3:14]
Reactant: CSC
Reactant: C/C(O)=C(/C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Agent: O=[O+][O-]
Product: C=C(C)C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1

Procedure:
Analogously to Example 6a), 647 mg (1 mM) of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid 2,2,2-trichloroethyl ester and 1.2 equivalents of ozone, with subsequent splitting of the ozonide with dimethyl sulphide, give 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1 -yl]-3-hydroxy-crotonic acid 2,2,2-trichloroethyl ester; melting point 129-130° C. (ether/petroleum ether).
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:25])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(=O)(O)[O-].[Na+]>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[O:25])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(O)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1c(OCc2ccc(C(=O)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Yield: 96.2 %

Procedure:
Stir a solution of 3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile (110 mg, 0.264 mmol) in dichloromethane (5 mL) at 0° C. Add Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (H)-one) (120 mg, 0.29 mmol) and stir the reaction for 1.5 hr at room temperature. Dilute the reaction mixture with aqueous saturated sodium bicarbonate (50 mL) and extract with ethyl acetate (3×50 mL). Dry the combined extracts over sodium sulfate, filter and concentrate. Purify the residue via silica gel chromatography, eluting with 7:3 hexanes:ethyl acetate to afford the title compound as a white solid (105 mg, 95%). Mass spectrum (M+H) 414.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([OH:20])=O)=[CH:10][CH:9]=1)(=[O:7])[CH3:6]>C1(C)C=CC=CC=1>[C:5]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([Cl:3])=[O:20])=[CH:10][CH:9]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)c1ccc(C(=O)O)c2ccccc12
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(C(=O)Cl)c2ccccc12
Temperature: 90 °C
Yield: 98.7 %

Procedure:
Thionyl chloride (35.00 g, 0.29 mol) was added to a solution of 4-acetyl-1-naphthalenecarboxylic acid (51.70 g, 0.24 mol) in toluene (350 mL). The mixture was warmed to 90° C. for 8.5 h. After cooling to 25° C., the solvent was removed under reduced pressure to give the title product as an off-white solid (55.1 g, 98.7% yield).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[C:23]([O:25]C2CCCCO2)[CH:22]=[CH:21][C:3]=1[C:4](=[O:20])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C2CCCCO2)=[CH:9][CH:8]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>O>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]=[CH:5][C:4]([C:3]2[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:2]=2[OH:1])=[O:20])=[CH:8][CH:9]=1
Reactant: O=C(C=Cc1ccc(OC2CCCCO2)cc1)c1ccc(OC2CCCCO2)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=C(C=Cc1ccc(O)cc1)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A mixture of 4,000 g of crude 2'-hydroxy-4,4'-bis(tetrahydropyranyloxy)chalcone (purity: 79.4%), 64 mg of p-toluenesulfonic acid and 12 ml of methanol was agitated at room temperature for 2 hours. The mixture was poured into 120 ml of water, and crystals which formed were filtered and washed with 250 ml of water. The crystals obtained were dried to obtain 1.836 g of 4,2',4'-trihydroxychalcone having purity of 79.4% and yield of 77.4%.
Reaction SMILES: C[S-].[Na+].C[O:5][C:6]1[CH:7]=[C:8]([C:12]2([CH2:18][N:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1.Br.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:21][N:19]([CH2:18][C:12]1([C:8]2[CH:7]=[C:6]([OH:5])[CH:11]=[CH:10][CH:9]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH3:20]
Reactant: COc1cccc(C2(CN(C)C)CCOCC2)c1
Agent: Br
Agent: C[S-]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC1(c2cccc(O)c2)CCOCC1
Temperature: 65 °C
Yield: 35.4 %

Procedure:
To a suspension of Sodium thiomethoxide (0.42 g, 6 mmol) in DMF (1.2 mL) was added N-{[4-(3-methoxyphenyl)tetrahydro-pyran-4-yl]methyl}-N,N-dimethylamine (0.3 g, 1.2 mmol) and the resulting mixture was heated to 65° C. for 7 h, allowed to cool to ambient temperature and quenched with saturated aqueous NH4Cl (6 mL). The mixture was extracted with DCM, dried over Na2SO4, filtered and concentrated in vacuo to provide 0.25 g of crude product. A mixture of the crude and HBr (3 mL) was heated to reflux for 1 h. After cooling, water was added to quench the reaction and the mixture was basified with NaHCO3 and extracted with DCM. The organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (DCM/MeOH (10% NH3)) to provide 3-{4-[(dimethylamino)methyl]tetrahydro-pyran-4-yl}phenol (0.100 g, 35.5%).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:33]1[CH2:38][CH2:37][CH:36]([OH:39])[CH2:35][CH2:34]1.CCN(C(C)C)C(C)C.Cl.C([O-])(O)=O.[Na+]>CO.CC(O)C>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:33]3[CH2:38][CH2:37][CH:36]([OH:39])[CH2:35][CH2:34]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: OC1CCNCC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCC(O)CC2)c(-c2ccn[nH]2)c1
Temperature: 25 °C

Procedure:
A mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2, 80 mg, 0.166 mmol), piperidin-4-ol (33.5 mg, 0.331 mmol), DIPEA (0.116 mL, 0.662 mmol) and iPrOH (0.331 mL) was added to a vial, which was sealed and subjected to MW irradiation at 140° C. for 1 h. Aq. 37% HCl (202 μL, 2.46 mmol) and MeOH (1 mL) was added and the mixture was stirred at RT. The RM was treated with sat. aq. NaHCO3 and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative SFC (Column DEAP, from 21% to 26% in 10 min.) to afford the title product as a white solid. UPLC-MS (Condition 3) tR=0.95 min, m/z=464.1 [M+H]+, m/z=508.0 [M+formic acid-H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.49 (m, 2H) 1.73 (d, J=10.27 Hz, 2H) 2.87 (t, J=10.51 Hz, 2H) 3.50 (d, J=13.08 Hz, 2H) 3.62 (dd, J=8.19, 4.16 Hz, 1H) 4.67 (d, J=4.03 Hz, 1H) 6.54-6.70 (m, 1H) 7.34 (d, J=8.80 Hz, 2H) 7.77 (m, J=1.22 Hz, 2H) 7.88 (d, J=9.05 Hz, 2H) 8.27 (m, J=2.08 Hz, 1H) 8.69-8.78 (m, 1H) 10.31-10.44 (m, 1H) 12.96-13.21 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[C:14]([C:19]#[N:20])=[N:15][CH:16]=[CH:17][CH:18]=1.Cl>[Pd].CO>[NH2:20][CH2:19][C:14]1[C:13]([CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: N#Cc1ncccc1CN1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ncccc1CN1C(=O)c2ccccc2C1=O

Procedure:
To a mixture of 3-((1,3-dioxoisoindolin-2-yl)methyl)picolinonitrile (10 g, 38 mmol) and methanol (80 mL) was added conc. HCl (6.5 mL, 76 mmol) and 10% Pd/C (1 g). The mixture was stirred vigorously under 50 Psi H2 for 6 hrs. The mixture was filtered through the Celite pad and washed with methanol. The combined filtrate was concentrated to give the 2-((2-(aminomethyl)pyridin-3-yl)methyl)isoindoline-1,3-dione as a white solid in quantitative yield. LRMS (M+H+) m/z 268.1.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C(O)(=O)C.[O:13]1[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl>[O:13]1[CH2:18][CH2:17][CH:16]([CH2:19][N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])[CH2:15][CH2:14]1
Reactant: O=CC1CCOCC1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(O)[C@@H]1CCCN1CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of L-proline (1 g; 8.686 mmol) in 1,2-dichloroethane (10 mL)/acetic acid (1.98 mL; 33.007 mmol)) is added tetrahydro-pyran-4-carbaldehyde (0.991 g; 8.686 mmol) and sodium sulfate (˜10 equivalents). After 45 minutes of agitation on an orbital shaker, MP-triacetoxyborohydride resin (4.272 g; 10.423 mmol) is added. The mixture is agitated at room temperature overnight and filtered, washing resin with methylene chloride. The combined filtrate is washed with aqueous saturated sodium bicarbonate solution and brine, dried (Na2SO4), filtered and concentrated in vacuo. Excess acetic acid is removed by successive azeotropic distillation with toluene on the rotary evaporator. Title compound is afforded by this method. ESI m/z 214 [M+H]+
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[C:11]([C:13](O)=[O:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1csc(Cc2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1csc(Cc2ccccc2)n1

Procedure:
2-Benzyl-4-thiazolecarboxylic acid is converted to the methyl ester and the ester is reduced with lithium aluminum hydride in tetrahydrofuran to give 2-benzyl-4-hydroxymethylthiazole. Using this compound as the starting material in the procedure of Example 1 gives N-methyl-N'-[2-((2-benzyl-4-thiazolyl)methylthio)ethyl]thiourea.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[O:5][C:6]1[CH:19]=[CH:18][C:9]([O:10][CH:11]([CH3:17])[C:12](OCC)=[O:13])=[CH:8][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C(OCC)C>[CH3:17][CH:11]([O:10][C:9]1[CH:18]=[CH:19][C:6]([O:5][C:4]2[CH:20]=[C:21]([F:23])[CH:22]=[C:2]([F:1])[CH:3]=2)=[CH:7][CH:8]=1)[CH2:12][OH:13]
Reactant: CCOC(=O)C(C)Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(CO)Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Reaction time: 1 h
Yield: 92.9 %

Procedure:
The thus obtained ethyl 2-[4-(3,5-difluorophenoxy)phenoxy]propionate (15.6 g) was dissolved in diethyl ether (10 ml). The resulting solution was dropwise added to a suspension of lithium aluminum hydride (1.38 g, 36.3 mmol) in diethyl ether (70 ml) with stirring at an inner temperature of -20° to -10° C. After completion of the addition, stirring was continued for 1 hour while keeping the inner temperature at 0° to 5° C. The reaction mixture was poured into a mixture of ice and hydrochloric acid and extracted with ether. The ether layer was dried over anhydrous magnesium sulfate, and the solvent was removed to give 2-methyl-2-[4-(3,5-difluorophenoxy)phenoxy]ethanol (12.6 g).
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])=[CH:17][CH:16]=2)[C:5]=1[C:6]([NH2:8])=[O:7].Cl.[CH2:30]([OH:33])[CH2:31][CH3:32]>O>[Cl:13][C:11]1[CH:10]=[C:9]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:22])=[CH:19][CH:20]=2)[C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:33][CH2:30][CH2:31][CH3:32])[N:12]=1
Reactant: NC(=O)c1c(Nc2ccc(C(=O)N3CCOCC3)cc2)cc(Cl)nc1Cl
Reactant: CCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCOc1nc(Cl)cc(Nc2ccc(C(=O)N3CCOCC3)cc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of powdered solid sodium hydroxide (121 mg, 3.04 mmol) in 1-propanol (10 mL) was stirred at rt until the solid material dissolved. Then 2,6-dichloro-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (600 mg, 1.518 mmol) was added and the mixture was stirred. The resulting suspension was placed in a heating block at 60° C. for 2 hrs. Next, the reaction mixture was cooled to rt and acidified with HCl (4 ml, 1N) and diluted with water. The cloudy precipitate was extracted into CH2Cl2 and concentrated to give 600 mg of light yellow solid. LCMS: (M+H)+=419.20, 421.19 (Cl pattern).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12]Cl)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[F:14][C:15]([F:41])([F:40])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)([OH:29])[CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.C(Cl)Cl.CC(C)=O.CCCCCCC>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:26]3[CH2:27][CH2:28][CH:23]([C:22]([C:30]4[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][CH:35]=4)([C:19]4[CH:20]=[CH:21][C:16]([C:15]([F:14])([F:40])[F:41])=[CH:17][CH:18]=4)[OH:29])[CH2:24][CH2:25]3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCNCC1
Reactant: ClCc1ccc(OCC2CC2)cc1
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CC(C)=O
Product: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccc(OCC3CC3)cc2)CC1
Yield: 71 %

Procedure:
This compound was prepared in a manner analogous to that of Step D of Example 12, with 0.4 gram (0.002 mole) of 4-(cyclopropylmethoxy)phenylmethyl chloride (prepared as in Step A of Example 16), 0.9 gram (0.002 mole) of 4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine, and 1.1 grams (0.008 mole) of N,N-diisopropylethylamine in about 30 mL of dimethyl sulfoxide as reagents. The crude reaction product was subjected to column chromatography on silica gel with 1:1 heptane:methylene chloride, pure methylene chloride, 11:10 heptane:methylene chloride, and 1:10 acetone:methylene chloride used succesively as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.8 gram of N-[4-(cyclopropylmethoxy)phenylmethyl]-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccc(F)cc1F)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccc(F)cc1F)C2
Yield: 78.2 %

Procedure:
A mixture of 7-(2,4-difluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.43 g), aminoguanidine hydrochloride (0.18 g), concentrated hydrochloric acid (0.39 ml), water (0.39 ml) and ethanol (50 ml) was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate, and the mixture was concentrated under reduced pressure. The residue was recrystallized from water-ethanol to give 7-(2,4-difluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 60) (0.45 g) as colorless crystals.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[C:12]4[CH:24]=[CH:23][S:22][C:13]=4[C:14](=[O:21])[NH:15][C:16]=3[CH:17]=[CH:18][C:19]=2[OH:20])=[CH:6][CH:5]=1)[CH3:3].[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(Cl)Cl.C1COCC1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:20][C:19]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:21])[C:13]3[S:22][CH:23]=[CH:24][C:12]=3[C:11]=2[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([C@H:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH3:3])=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](N)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NS(C)(=O)=O)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Reaction time: 1.5 h
Yield: 2.6 %

Procedure:
A solution of (R)-9-[4-(1-aminoethyl)phenyl]-8-hydroxythieno[2,3-c]quinolin-4(5H)-one (28 mg, 0.83 mmol) and methanesulfonyl chloride (82 μL, 1.0 mmol) in 1:1 methylene chloride/THF (6 mL) and DMF (1.5 mL) was stirred at room temperature for 10 min followed by the addition of N,N-diisopropylethylamine (170 μL, 1.0 mmol). The reaction mixture was stirred for 1.5 h, concentrated and purified by preparatory HPLC (C18 silica, water/acetonitrile w/0.05% TFA gradient) to afford the desired product (8.9 mg, 2%) as a light brown solid: 1H NMR (500 MHz, CD3OD) δ 7.59-7.55 (m, 2H), 7.53 (d, J=5.5 Hz, 1H), 7.39 (d, J=8.9 Hz, 1H), 7.31-7.30 (m, 2H), 7.16 (d, J=8.9 Hz, 1H), 6.02 (d, J=5.4 Hz, 1H), 4.71 (q, J=4.6 Hz, 1H), 2.82 (s, 3H), 1.62 (d, J=7.0 Hz, 3H); ESI MS m/z 415 [C20H18N2O4S2+H]+; HPLC 96.4% (AUC), tR=10.14 min.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:7][CH:8]=1)(=[O:3])[CH3:2].C(OC(=O)[CH2:21][Si:22](C)([CH3:24])[CH3:23])C>C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:6]2[O:5][C:4]([C:1]([O:3][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH2:2])=[CH:8][CH:7]=2)=[CH:11][CH:12]=1
Reactant: CC(=O)c1ccc(Cc2ccc(F)cc2)o1
Reactant: CCOC(=O)C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=C(O[Si](C)(C)C)c1ccc(Cc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
A solution of 2-acetyl-5-(4-fluorobenzyl)furan (10 g, 46 mmol) and trimethylsilylacetic acid ethyl ester (10.9 g, 68 mmol) in anhydrous THF (30 ml) was cooled at −20° C. To a solution was added anhydrous tetrabutylammoniumfluoride (0.2 g). The reaction mixture was gradually warmed up to room temperature and stirred for 15 minutes at 50° C. The THF was evaporated under reduced pressure. The residue was distilled under reduced pressure. The fraction showing b.p. 130° C. (0.5 mmHg) was collected to give [1-[5-(4-fluorobenzyl)furan-2-yl]vinyloxy]-trimethylsilane (11.7 g). Yield 88%.