Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])=[C:4]([O:15][CH3:16])[CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26]([C:29](O)=[O:30])[NH:27][CH:28]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26]([C:29]([NH:1][C:2]3[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][C:9]([OH:11])([CH3:12])[CH3:10])=[C:4]([O:15][CH3:16])[CH:3]=3)=[O:30])[NH:27][CH:28]=2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Reactant: COc1cc(N)ccc1OCCC(C)(C)O
Product: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCCC(C)(C)O

Procedure:
Acylation of 4-(4-amino-2-methoxyphenoxy)-2-methylbutan-2-ol from step A with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid to generate the title compound was achieved via the procedure described in step C of Example 1. The crude product was used for next step without further purification.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:42]=[CH:41][C:13]([O:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][C@H:30]([NH:34]C(C(C)(C)C)=O)[C:31]([OH:33])=[O:32])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C@@H:30]([CH2:29][CH2:28][O:27][C:21]1[CH:20]=[C:19]2[C:24]([C:15]([O:14][C:13]3[CH:41]=[CH:42][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:11][CH:12]=3)=[CH:16][CH:17]=[N:18]2)=[CH:23][C:22]=1[O:25][CH3:26])[C:31]([OH:33])=[O:32]
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](NC(=O)C(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](N)C(=O)O
Reaction time: 6 h
Yield: 111.9 %

Procedure:
To a solution of (S)-4-[4-(4-benzoylamino-phenoxy)-6-methoxy-quinolin-7-yloxy]-2-tert-butylcarbonylamino-butyric acid (6.5 mg, 0.011 mmol) in DCM (1 ml) was added TFA (1 ml). The reaction was allowed to stir for 6 hours and then evaporated under reduced pressure to afford the title compound as an off-white solid (6.0 mg, 90% yield).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1N.C=O.[BH3-][C:13]#[N:14].[Na+].[C:16](O)(=O)C>C(#N)C>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[N:14]([CH3:13])[CH3:16]
Reactant: Cc1cccc(Br)c1N
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: Cc1cccc(Br)c1N(C)C
Reaction time: 4 h

Procedure:
To a solution of 2-bromo-6-methylaniline (0.5 g, 2.69 mmol) in acetonitrile (30.0 mL) at ambient temperature was added a 37% aqueous solution of formaldehyde (4.0 mL, 53.6 mmol), followed by NaBH3CN (1.40 g, 22.1 mmol). The pH of the reaction was adjusted to pH 5-6 with glacial acetic acid, and the reaction was stirred for 4 h, then the solvent was removed. The residue was dissolved in EtOAc, and basified with NaOH 2N, dried over MgSO4, and filtered. The solvent was removed, and the residue was purified by silica gel flash chromatography with EtOAc (15%) and hexanes (85%) as eluent to produce Compound 150 as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH2:27])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35](Cl)(Cl)=[O:36].C(N(CC)CC)C.[NH2:46][C:47]1[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=1>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH:27][C:35]([NH:46][C:47]3[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=3)=[O:36])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2cccs2)c(=O)[nH]c2cc(Cl)c(N)cc12
Reactant: Nc1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2cccs2)c(=O)[nH]c2cc(Cl)c(NC(=O)Nc3ccncc3)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[2-(6-amino-7-chloro-2-oxo-3-thiophen-2-yl-1,2-dihydroquinolin-4-yloxy)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester in dry methylene chloride at 0° C. is added phosgene followed by an excess of triethylamine and the mixture stirred for 1 hour at 0° C. At this time, 4-aminopyridine is added and the mixture allowed to warm to room temperature. Upon completion of the reaction, the mixture is diluted with ethyl acetate and the mixture quenched by the addition of 10% citric acid. The organic portion is concentrated in vacuo to provide the crude title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1.[H-].[Na+].Cl[C:19]1[N:20]=[N:21][C:22]([Cl:34])=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][CH:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]1>CN(C=O)C.O>[Cl:34][C:22]1[N:21]=[N:20][C:19]([O:15][CH:13]2[CH2:12][N:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH2:14]2)=[C:24]([N:25]2[CH2:30][CH2:29][CH:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)[CH:23]=1
Reactant: CC(=O)C1CCN(c2cc(Cl)nnc2Cl)CC1
Reactant: OC1CN(c2ccc3ccccc3n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)C1CCN(c2cc(Cl)nnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
To a solution of 1-(quinolin-2-yl)azetidin-3-ol (see PREPARATION P1.2, step 1; 0.78 g, 3.8 mmol) in DMF (20 mL) at room temperature was added sodium hydride (60% wt in mineral oil) (0.18 g, 7.6 mmol). The mixture was stirred at room temperature for 10 min and then 1-(1-(3,6-dichloropyridazin-4-yl)piperidin-4-yl)ethanone (1.0 g, 3.8 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes) to give the title product (1.1 g, 2.6 mmol, 70% yield) as white solid. ESI-MS (M+1): 438 calc. for C24H25ClN4O2 437.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]#[N:18])=[N:4][C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[C:6](Cl)[N:7]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.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>[NH2:1][C:2]1[C:3]([C:17]#[N:18])=[N:4][C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(-c2nc(C#N)c(N)nc2Cl)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2nc(C#N)c(N)nc2-c2ccccc2)cn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
3-Amino-5-chloro-6-(6-methoxy-3-pyridyl)-2-pyrazinecarbonitrile (1.35 g) was dissolved in dioxane (135 ml). To the solution were added phenylboronic acid (1.89 g) and Pd(PPh3)4 (179 mg) and Na2CO3 (2.19 g) in water (27 ml) at 25° C. The reaction mixture was heated at 80° C. for 2 hours, then at ambient temperature for 3 hours. The above mixture was portioned to EtOAc and water. The organic layer was separated and washed with aq. Na2CO3 and brine, and dried over MgSO4. Evaporation of solvent in vacuo gave oily residue, which was purified by chromatography on silica gel (EtOAc:n-Hexane=1:1, v/v) to give 3-amino-6-(6-methoxy-3-pyridyl)-5-phenyl-2-pyrazinecarbonitrile as yellow crystal which was crystallized from EtOAc (1.15 g).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][CH3:17])[C:11]=2[F:18])(O)[CH2:5][CH2:4]1)[CH3:2].S(=O)(=O)(O)O.C1(C)C=CC=CC=1>O>[CH2:1]([N:3]1[CH2:4][CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][CH3:17])[C:11]=2[F:18])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCC(O)(c2cccc(SC)c2F)CC1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCN1CC=C(c2cccc(SC)c2F)CC1
Temperature: 70 °C
Yield: 57.6 %

Procedure:
A mixture of 1-ethyl-4-[2-fluoro-3-(methylthio)phenyl]piperidin-4-ol (42 g, 156 mmol), sulphuric acid (conc, 8.5 ml) and toluene (200 ml) was heated in a Dean-Stark trap for 20 h. The mixture was cooled to 70° C., water (200 ml) was added and the phases were separated. The aqueous phase was basified with aqueous sodium hydroxide (5 M) and extracted with ethyl acetate (2×50 ml). The combined organic phases was dried (MgSO4) and evaporated to dryness to give the title compound (22.6 g). MS m/z (rel. intensity, 70 eV) 251 (M+, bp), 236 (85), 147 (65), 146 (45), 110 (44).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([C:17]([CH3:19])=[CH2:18])[CH2:15][C:14](=O)[CH2:13][CH:12]3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH-:28].[NH4+:29].Cl>CCO.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@H:16]([C:17]([CH3:19])=[CH2:18])[CH2:15]/[C:14](=[N:29]/[OH:28])/[CH2:13][C@H:12]3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: [NH4+]
Reactant: C=C(C)C1CC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Agent: Cl
Solvent: O
Solvent: CCO
Product: C=C(C)[C@@H]1C/C(=N/O)C[C@@H](c2cccc(Cl)c2)[C@@]12C(=O)Nc1cc(Br)ccc12
Temperature: 25 °C
Yield: 75.3 %

Procedure:
The suspension of rac-(1S,2S,6R)-6′-bromo-2-(3-chlorophenyl)-6-isopropenyl spiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (0.23 g, 0.52 mmol) and NH4OH—HCl (0.1 g, 0.52 mmol) in EtOH-water (3/2, 20 mL) was allowed to reflux for 1 h. TLC analysis indicated the formation of desired product and complete consumption of starting material. The reaction was cooled to room temperature, and water was added. The mixture was extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:2, then 1:1) to give the title compound as a white solid (0.18 g, 75%): HRMS (ES+) m/z Calcd for C22H20BrClN2O2+H [(M+H)+]: 459.0470, Found: 459.0470.
Reaction SMILES: [CH2:1]([C:3]1[CH:24]=[C:23]([CH3:25])[C:22]([CH:26]=[O:27])=[CH:21][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:2].[O-:28][Mn](=O)(=O)=O.[K+]>O1CCCC1.O>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([CH:10]2[CH2:9][CH2:8][N:7]([C:5]([C:4]3[C:3]([CH2:1][CH3:2])=[CH:24][C:23]([CH3:25])=[C:22]([CH:21]=3)[C:26]([OH:28])=[O:27])=[O:6])[CH2:12][CH2:11]2)=[CH:14][CH:15]=1)#[N:18]
Reactant: CCc1cc(C)c(C=O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C)c(C(=O)O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a round-bottom flask was added a solution of 4-(1-(2-ethyl-5-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 211.5, 720 mg, 2.00 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). A solution of KMnO4 (640 mg, 4.05 mmol, 2.00 equiv) in water (20 mL) was added dropwise. The resulting solution was stirred for 15 h at 60° C. then cooled to rt with a water bath. The solids were removed with filtration. The filtrate was extracted with 3×30 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 600 mg (80%) of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoic acid as a light yellow solid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([O:12][P:13]([O:27][CH2:28][CH3:29])([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]([OH:26])=O)=[CH:18][CH:17]=1)=[O:14])[CH3:11].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:54][CH2:55][C@@H:56]1[O:60][C:59](=[O:61])[N:58]([C:62]2[CH:67]=[CH:66][C:65]([C:68]3[S:69][CH2:70][C:71](=[O:74])[NH:72][N:73]=3)=[C:64]([F:75])[CH:63]=2)[CH2:57]1>CN(C=O)C>[F:75][C:64]1[CH:63]=[C:62]([N:58]2[CH2:57][CH:56]([CH2:55][NH:54][C:24]([CH:23]=[CH:22][C:19]3[CH:18]=[CH:17][C:16]([O:15][P:13](=[O:14])([O:12][CH2:10][CH3:11])[O:27][CH2:28][CH3:29])=[CH:21][CH:20]=3)=[O:26])[O:60][C:59]2=[O:61])[CH:67]=[CH:66][C:65]=1[C:68]1[S:69][CH2:70][C:71](=[O:74])[NH:72][N:73]=1
Reactant: NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Reactant: CCOP(=O)(OCC)Oc1ccc(C=CC(=O)O)cc1
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: CN(C)C=O
Product: CCOP(=O)(OCC)Oc1ccc(C=CC(=O)NCC2CN(c3ccc(C4=NNC(=O)CS4)c(F)c3)C(=O)O2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 539.4 %

Procedure:
N,N-Diisopropylethylamine (0.507 ml, 2.91 mmol) was added to 3-[4-(diethoxy-phosphoryloxy)phenyl]acrylic acid (0.065 g, 0.217 mmol) [prepared according to the procedure described in Tetrahedron Lett 1996, 37, 3635] and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.124 g 0.326 mmol) in DMF (3 ml) and stirred for 20 minutes at room temperature. 2-[4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-4H-[1,3,4]thiadiazin-5-one (0.084 g, 0.259 mmol) was added and stirring continued at room temperature overnight. The reaction mixture was partially evaporated under vacuum, diluted with water (5 ml), and extracted with ethyl acetate (50 ml). The extract was washed with brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% MeOH/DCM) to give pure product as a white solid (0.71 g, 54%); MS (m/z): [M+H]+=607.
Reaction SMILES: C1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)C=CC=CC=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1B(O)O>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:7]1[NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=1[C:14]=23
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1ccc(F)cc1F
Product: O=C1NCCc2c(-c3ccc(F)cc3F)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (200 mg, 0.75 mmol) and 2,4-difluorophenylboronic acid (131 mg, 0.83 mmol) were coupled to yield 2-(2,4-difluoro-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 156 mg (69%), as a pale-yellow solid. mp 196-197° C.; 1H NMR (300 MHz, d6-DMSO) δ2.84 (m, 2H), 3.37 (m, 2H), 7.25 (app t, 1H, J=7.7 Hz), 7.27 (m, 1H), 7.47 (m, 1H), 7.57 (dd, 1H, J=8.1, 0.9 Hz), 7.64 (m, 1H), 7.70 (dd, 1H, J=7.5, 0.9 Hz) 8.08 (br t, 1H), 11.58 (br s, 1H); MS (FAB, MH+) 299; Anal. (C17H12N2OF2.0.3 H2O.0.37 CHCl3) C, H, N.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([CH2:9]O)[S:8][C:4]=2[CH:3]=[N:2]1.[ClH:11].S1C2C=C[N:17]=CC=2C=C1CN>>[Cl-:11].[NH:1]1[C:5]2[CH:6]=[C:7]([CH2:9][NH3+:17])[S:8][C:4]=2[CH:3]=[N:2]1
Reactant: OCc1cc2[nH]ncc2s1
Reactant: Cl
Reactant: NCc1cc2cnccc2s1
Product: [Cl-]
Product: [NH3+]Cc1cc2[nH]ncc2s1

Procedure:
Intermediate F was prepared from (1H-thieno[3,2-c]pyrazol-5-yl)methanol (F-6) following similar procedures for synthesizing intermediate D from D-3, as described above.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:21]>>[CH:1]1([CH2:7][CH:8]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([Cl:21])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(CC1CCCCC1)CC1CCCCC1
Product: O=C(Cl)C(CC1CCCCC1)CC1CCCCC1
Yield: 92.4 %

Procedure:
A solution of 2.97 g (11.8 mmol) of bis-(cyclohexylmethyl)acetic acid in 20 mL SOCl2 was stirred at room temperature overnight. The SOCl2 was removed under reduced pressure, the residue taken up in Et2O, and the solvent removed under reduced pressure. The residue was taken up in hexane and the solvent removed under reduced pressure leaving 2.94 g (92.4% yield) of the product as an oil. The structure was confirmed by mass spectroscopy.
Reaction SMILES: [O-]CC.[Na+].[NH2:5][C:6]1[S:10][C:9]2[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[C:7]=1[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)=O.[C:24](OCC)(=[O:32])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl>C(O)C.O>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][C:25]1[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[S:10][C:6]2=[N:5][C:24]=1[OH:32])[CH3:31]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: Cc1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1c(O)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 100 °C
Yield: 23.5 %

Procedure:
To a solution of sodium ethoxide 21% in ethanol (1.8 mL; 4.8 mmol) in dry ethanol (30 mL) under a nitrogen atmosphere was added (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(p-tolyl)methanone (1.09 g; 4 mmol) and diethyl succinate (0.929 mL; 5.6 mmol). The mixture was heated to 100° C. for 24 h. The reaction mixture was dissolved with water (8 ml) and acidified with a solution of hydrochloric acid 1N to pH 1 and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over sodium sulphate and concentrated under reduced pressure. The crude was suspended in dry ethanol (30 mL) and a catalytic amount of concentrated sulfuric acid (10 drops) was carefully added. The reaction mixture was heated to reflux for 21 h. The volatiles were removed under reduced pressure and the remaining residue was purified by flash-chromatography on silica gel using a gradient of methanol (1-20%) in ethyl acetate as eluent to furnish 0.358 g (19.6%) of ethyl[2-hydroxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate as an ochre solid. ESI/APCI(+): 382 (M+H).
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([OH:5])=O.[CH:22]([NH:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([N:25]([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CC(C)NC(C)C
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(C(C)C)C(C)C

Procedure:
Starting materials: 2,6,10-trimethyl-14-oxo-2,6,10-pentadecatrienoic acid and diisopropylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[CH3:13][C:14]1[CH:15]=[C:16]([NH:23][C:24]([C:26]2([CH3:29])[CH2:28][O:27]2)=[O:25])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:29][C:26]([OH:27])([CH3:28])[C:24]([NH:23][C:16]2[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:14]([CH3:13])[CH:15]=2)=[O:25])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Product: Cc1cc(NC(=O)C(C)(O)COc2ccc(F)c(C(F)(F)F)c2)ccc1[N+](=O)[O-]

Procedure:
3-(4-Fluoro-3-trifluoromethylphenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 starting from 4-fluoro-3-(trifluoromethyl)phenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1% methanol). 1H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.53 (3H, s), 4.06 (1H, d, J=9.9 Hz), 4.32 (1H, d, J=9.9 Hz), 6.23 (1H, s), 7.24-7.31 (2H, m), 7.38-7.43 (1H, m), 7.87 (1H, dd, J=9.0 Hz, J=2.1 Hz), 7.91 (1H, d, J=2.0 Hz), 8.03 (1H, d, J=9.0 Hz), 10.14 (1H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.O.O.O.O.O.O.[S-2:28].[Na+].[Na+].CCOCC.Cl>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[SH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [S-2]
Reactant: O=[N+]([O-])c1cccc(OCc2ccccc2)c1Cl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])c1cccc(OCc2ccccc2)c1S
Temperature: 22 °C
Reaction time: 30 h

Procedure:
To a solution of 8.56 g (32.5 mmol) of 1-(benzyloxy)-2-chloro-3-nitrobenzene in 120 mL of DMF was added 15.6 g (64.9 mmol) of pulverized sodium sulfide nonahydrate. The mixture was stirred vigorously at 22° C. for 30 hours and then poured into a vigorously stirred mixture of ether and 1 N HCl. The organic layer was washed with water then brine, dried (Na2SO4), and evaporated. The residue was crystallized from dichloromethane (DCM) and hexane to give 2-(benzyloxy)-6-nitrobenzenethiol.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([C:6]1[S:18][C:17]([NH2:19])=[N:16][N:15]=1)[CH3:9]
Reactant: NNC(N)=S
Reactant: CC(Oc1ccc(Cl)cc1Cl)C(=O)O
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(Oc1ccc(Cl)cc1Cl)c1nnc(N)s1
Temperature: 90 °C

Procedure:
A 250 milliliter, 3-neck flask adapted with a Claisen adaptor, paddle stirrer, thermometer, an addition funnel and condenser, was charged with 28.2 grams (0.120 mole) of 2-(2,4-dichlorophenoxy)propanoic acid, (10.9 grams, 0.120 mole) of thiosemicarbazide and 90 milliliters of dioxane. The slurry was heated to 90° C. and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 (20.2 grams, 0.13 mole) was slowly added (for 38 minutes) while maintaining the temperature within 90°-95° C. The resulting mixture was refluxed for 115 minutes, and then evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane). One hundred (100) milliliters of water was added and 50 percent NaOH solution was also added until the pH of the solution was 10. An oil formed, which was extracted with a mixture of CH2Cl2, CHCl3 and diethyl ether, and the organic phase was dried over anhydrous MgSO 4, filtered and topped on a roto-vac at 70° C. to a grey sludge. Upon addition of diethylether, a first crop of crystals formed which were removed by filtration and then dried in a vacuum oven at 80° C. to crystals containing 5-[1-(2,4-dichlorophenoxy)ethyl-2-amino-1,3,4-thiadiazole (9.7 grams). Addition of hexane to the filtrate produced a second crop of crystals which were filtered off, dried in a vacuum oven at 80° C. to 10.1 grams of crystals. The first and second crop of crystals were combined, and recrystallized from the minimum amount of an ethanol water mixture, suction filtered, and dried in a vacuum oven at 80° C. to 17.1 grams of a grey powder of 5-[1-(2,4-dichlorophenoxy)ethyl]-2-amino-1,3,4-thiadiazole. (Melting point 119°-123° C.).