Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2(O)[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:24][CH2:23][C:18]4([O:22][CH2:21][CH2:20][O:19]4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)CO.C[Si](O[Si](C)(C)C)(C)C.[O-2].[Al+3].[O-2].[O-2].[Al+3]>C(Cl)CCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:24][CH2:23][C:18]4([O:19][CH2:20][CH2:21][O:22]4)[CH2:17][CH2:16]3)[CH2:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OC1(c2ccc(F)c(F)c2)CCC(C2CCC3(CC2)OCCO3)CC1
Agent: [Al+3]
Agent: [O-2]
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: OCCO
Solvent: ClCCCl
Product: Fc1ccc(C2=CCC(C3CCC4(CC3)OCCO4)CC2)cc1F
Temperature: 25 °C
Yield: 66.2 %

Procedure:
A mixture of 7.8 g of crude 1-(3,4-difluorophenyl)-4-(1,4-dioxa-8-spiro[4.5]decyl) cyclohexanol, 1.05 ml of ethylene glycol, 1.05 g of Amberlyst® 15 (strongly acid ion exchange resin, Fluka AG) and 80 ml of ethylene chloride was refluxed through neutral aluminum oxide for 3 hours. Subsequently, the mixture was cooled to room temperature and washed twice with water. The aqueous phases were extracted twice with methylene chloride. The organic phases where dried over sodium sulfate, filtered and concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 96:4) gave 4,9 g of 8-[4-(3,4-difluorophenyl)-3-cyclohexenyl]-1,4-dioxaspiro [4.5]decane as colorless crystals.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:11][O:12][C:13](=[O:28])[C@H:14]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>>[CH3:11][O:12][C:13](=[O:28])[C@H:14]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:8](=[O:10])[CH2:7][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Reactant: O=C(O)CC1=CCCCC1
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CC1=CCCCC1

Procedure:
Following General Procedure U and using cyclohex-1-enylacetic acid (Alfa) and N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl ester hydrochloride (Bachem) using General Procedure U, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp=139-142° C.). The reaction was monitored by tlc (Rf=0.27 in 1:1 EtOAc/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([Cl:28])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH:19]=1)[O:10][C:11]([N+:16]([O-:18])=[O:17])([CH3:15])[C:12](Cl)=[O:13].[OH:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:28][C:20]1[CH:21]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:23]=[C:2]([Cl:1])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH:19]=1)[O:10][C:11]([N+:16]([O-:18])=[O:17])([CH3:15])[C:12]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:13]
Reactant: CC(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)(C(=O)Cl)[N+](=O)[O-]
Reactant: CCOC(=O)CO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)C(C)(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
A solution of 15 g of 5-(2,6-dichloro-4-trifluoromethyl- phenoxy)-2-nitro-α-phenoxypropionyl chloride in 30 ml of toluene was added dropwise to a solution of 3.7 g of ethyl hydroxyacetate and 4 g of triethylamine in 70 ml of toluene cooled to 0° to 5° C. The reaction mixture was stirred at room temperature overnight, diluted with 300 ml of toluene, washed to neutrality, dried, filtered and evaporated. 13.5 g ethoxycarbonylmethyl 5-(2,6-dicloro-4-trifluoromethyl-phenoxy)-2nitro-α- phenoxy-propionate were initially obtained in the form of a yellowish oil which then crystallised. Melting point: 75° to 76° C. The yield of pure substance was calculated to be 70.5% of theory.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:20])[CH2:15]1>>[OH:1][C:2]1([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][CH:5]([N:14]2[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)=[O:20])[CH2:15]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(O)(c2nccs2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3nccs3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-thiazol-2-yl-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:15]1[N:20]=[N:19][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=4)[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>>[F:36][C:33]1[CH:34]=[C:35]2[C:30]([CH2:29][CH2:28][N:27]2[CH:24]2[CH2:25][CH2:26][N:21]([C:18]3[N:19]=[N:20][C:15]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=4)=[CH:16][CH:17]=3)[CH2:22][CH2:23]2)=[CH:31][CH:32]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Product: Fc1ccc2c(c1)N(C1CCN(c3ccc(-c4ccc(C(F)(F)F)cc4)nn3)CC1)CC2

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, STEP 4, reacting 4-trifluoromethylphenylboronic acid and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[NH:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>O1CCOCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:13]=[C:12]3[C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=N)Nc2ccc3c(c2)OCCO3)cc1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)OCCO3)c(-c2ccc(C)cc2)n1
Temperature: 25 °C

Procedure:
To a mixture of the compound from Step A and 0.80 g (9.5 mmol) of sodium bicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL (4.8 mmol) of ethyl bromopyruvate. The reaction mixture was refluxed overnight. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. Flash chromatography on a Biotage Horizon® system (silica gel, 0 to 50% ethyl acetate in hexanes gradient) gave the title compound as a yellow foam. LC/MS 365.3 (M+1).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:10]2[NH:11][C:12](=[O:14])[O:13][C@H:9]2[CH2:8]1)(=O)=O.[F-:33].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[CH2:26]([O:25][C@@H:15]1[C@H:10]2[NH:11][C:12](=[O:14])[O:13][C@H:9]2[CH2:8][C@H:7]([CH2:6][F:33])[C@H:16]1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CS(=O)(=O)OC[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: O=C1N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CF)C[C@@H]2O1
Yield: 43.2 %

Procedure:
To a solution of ((3aS,4R,5R,6R,7aS)-4,5-bis(benzyloxy)-2-oxooctahydrobenzo[d]oxazol-6-yl)methyl methanesulfonate (2.24 g, 4.86 mmol) in dry acetonitrile (12 mL) at room temperature was added a solution of tetrabutylammonium fluoride (4.933 g, 24.3 mmol) in dry acetonitrile (16 mL). The mixture was heated at reflux under N2 for 4 h. Solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (150 mL), washed with water (2×) and brine, and dried with MgSO4. The solvent was evaporated to give the crude product. This was purified by SiO2 column, eluted with 30-50% EtOAc in hexanes to give (3aS,4R,5R,6S,7aS)-4,5-bis(benzyloxy)-6-(fluoromethyl)hexahydrobenzo[d]oxazol-2(3H)-one (810 mg, 43%). MS m/z 408.1 (M+23, 100%); 1H NMR (400 MHz, CDCl3) δ 7.31-7.42 (m, 10H), 4.99 (s, 1H), 4.93 (d, J=11.7 Hz, 1H), 4.84 (d, J=11.0 Hz, 1H), 4.79 (dd, J=9.2 Hz, 3.2 Hz, 0.5H), 4.65-4.71 (m, 1.5H), 4.65 (d, J=11.1 Hz, 1H), 4.59 (d, J=11.7 Hz, 1H), 4.37 (ddd, J=47.4 Hz, 9.2 Hz, 2.3 Hz, 1H), 3.58 (t, J=6.8 Hz, 1H), 3.51 (t, J=7.8 Hz, 1H), 3.44 (t, J=8.9 Hz, 1H), 2.22 (dt, J=14.9 Hz, 2.9 Hz, 1H), 1.94-2.10 (m, 1H), 1.85-1.93 (m, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:24]=[CH:23][C:10]3[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH2:14][O:15][C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:31]>>[ClH:31].[N:1]1([C:7]2[CH:24]=[CH:23][C:10]3[CH2:11][NH:12][CH2:13][CH2:14][O:15][C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(N3CCOCC3)ccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(cc1N1CCOCC1)OCCNC2
Yield: 54.5 %

Procedure:
A solution of tert-butyl 8-(morpholin-4-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (50.0 mg, 0.150 mmol) in 4N hydrogen chloride-ethyl acetate (1 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (25.0 mg, 54.5%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][C:8]=1[OH:9].Cl[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COC(=O)Cc1ccc(O)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(OC)c1

Procedure:
In analogy to the procedure of Example XIV, the title compound is prepared from 16 g (0.082 mol) of methyl 3-methoxy-4-hydroxyphenylacetate, 14.5 g (0.082 mol) of 2-chloromethylquinoline and 3.28 g (0.082 mol) of sodium hydroxide.
Reaction SMILES: C1(C(=O)C(=NO)C)C=CC=CC=1.[CH2:13]([C:15]1[N:16]=[C:17]([C:27]2[C:28]([O:34][CH3:35])=[N:29][CH:30]=[CH:31][C:32]=2[I:33])[N:18]([OH:26])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C>>[I:33][C:32]1[CH:31]=[CH:30][N:29]=[C:28]([O:34][CH3:35])[C:27]=1[C:17]1[N:18]([OH:26])[C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:15]([CH3:13])[N:16]=1
Reactant: CCc1nc(-c2c(I)ccnc2OC)n(O)c1-c1ccccc1
Agent: CC(=NO)C(=O)c1ccccc1
Product: COc1nccc(I)c1-c1nc(C)c(-c2ccccc2)n1O
Yield: 36 %

Procedure:
1-Phenyl-propane-1,2-dione 2-oxime (0.103 g, 0.631 mmol) was reacted as described for the synthesis of 4-ethyl-2-(4-iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol and afforded the title material (0.093 g, 36%). LCMS (+ESI, M+H+) m/z 407.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][O:8][C:9]2=[O:14])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][O:8][C:9]2=[O:14]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2c1CCOC2=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.9 %

Procedure:
A 250 mL round-bottom flask was charged with a solution of 5-nitro-1H-isochromen-1-one (3.0 g, 15.7 mmol) in absolute ethanol (60 mL) and 10% Pd/C (600 mg). The reaction vessel was evacuated and filled with hydrogen via balloon. The reaction suspension was stirred at room temperature in hydrogen atmosphere (via balloon) for 17 h. The resulting mixture was filtered and the solvent was removed on a rotary evaporator. After drying under reduced pressure, 2.40 g, (14.9 mmol, 95%) of 5-aminoisochroman-1-one were isolated as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][N:14]=[C:15]=[S:16]>C(#N)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:15]([NH:14][CH3:13])=[S:16])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN=C=S
Reactant: CC(C)(C)c1ccc(CN)cc1
Solvent: CC#N
Product: CNC(=S)NCc1ccc(C(C)(C)C)cc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
At 20 to 30° c., a solution of 163 g (1 mol) of 4-tert.-butylbenzylamine in 100 ml of anhydrous acetonitrile was dripped, while cooling, into a mixture of 73 g (1 mol) of methyl isothiocyanate in 80 ml of anhydrous acetonitrile. The mixture was stirred for 3 hours at 20° C. and then for a further hour at 80 to 90° C. before being evaporated down. The crude product was precipitated with hexane from ethyl acetate, washed with hexane and dried under reduced pressure at 60° c.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:19]([OH:24])[C:20]([F:23])([F:22])[F:21])=[C:6]([NH:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(C)(C)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:19](=[O:24])[C:20]([F:22])([F:23])[F:21])=[C:6]([NH:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: O=C(CCc1ccccc1)Nc1cc(F)ccc1C(O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: O=C(CCc1ccccc1)Nc1cc(F)ccc1C(=O)C(F)(F)F
Reaction time: 18 h

Procedure:
To a solution of N-[5-fluoro-2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]benzenepropanamide from Step 4 (178 mg, 0.521 mmol) and methylene chloride (15 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxyl-3 (1H)-one (885 mg, 2.08 mmol) followed by tert-butanol (15 mL) under an argon atmosphere at 23° C. After 18 h, sat'd NaHCO3 (31 mL) was added followed by solid sodium thiosulfate (5.20 g, 32.9 mmol). After 1 h at 23° C., the organic layer was separated from the aqueous. The aqueous was extracted with ether (2×100 mL), and the combined organics were washed with sat'd NaHCO3: sat'd Na2S2O3 (3×80 mL), brine (1×80 mL), and dried (MgSO4). After concentration in vacuo, the crude residue was purified by flash chromatography (ethyl acetate:hexane 1:3) which afforded N-[5-fluoro-2-(2,2,2-trifluoro-1-oxoethyl)phenyl]benzenepropanamide (80 mg as a yellow gum: 1H NMR (CDCl3) δ 2.78 (t, J=7 Hz), 3.07 (t, J=7 Hz), 6.82-6.91 (m), 7.17-7.33 (m), 7.92-8.03 (m), 8.67-8.73 (m), 11.11 (br s); 13C NMR (CDCl3) δ 31.0, 40.2, 108.2 (d, J=27.8 Hz), 110.45 (d, J=22.5 Hz), 111.6, 116.4 (q, J=290 Hz), 126.4, 128.2, 128.5, 134.5 (d, J=5 Hz), 139.9, 139.9, 146.2 (d, J=14 Hz), 167.9 (d, J=258 Hz), 171.6, 181.9. MS (EI) 339 (M+), 320, 270, 207. IR (neat) 1712, 1677 cm−1. Anal. Calc'd. for C17H13NO2F4: C, 60.18; H, 3.86; N, 4.13. Found: C, 59.82; H, 4.08; N, 3.94.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22]([NH2:29])=[N:23][NH:24]2>O1CCCC1>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22]([NH:29][CH:8]=[C:9]1[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]1=[O:18])=[N:23][NH:24]2
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Nc1n[nH]c2cccc(F)c12
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1n[nH]c2cccc(F)c12

Procedure:
The named compound is prepared by substituting 4-fluoro-1H-indazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2186 gms. of 4-fluoro-1H-indazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [C:1]12([N:11]=[C:12]=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1.CCN(CC)CC>C(Cl)Cl>[C:1]12([NH:11][C:12]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: c1ccc2c(c1)CCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC12CC3CC(CC(C3)C1)C2)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 35.7 mg (0.2 mmol) 1-adamantyl isocyanate, 20 mg (0.168 mmol) indoline and 51 mg (0.5 mmol) NEt3 in 2 mL DCM was shaken at room temperature overnight and evaporated to dryness. The residue was taken up in DMF and subjected to column chromatography on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid to yield after evaporation of the product containing fractions 15.2 mg (30%) of the title compound as white solid. MS(m/e): 297.4 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:13]([CH3:19])([CH2:17][CH3:18])[CH2:14][CH2:15][OH:16])[CH3:12].C(N(CC)CC)C>ClCCl.O>[CH2:11]([C:13]([CH3:19])([CH2:17][CH3:18])[CH2:14][CH:15]=[O:16])[CH3:12]
Reactant: CCC(C)(CC)CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)(CC)CC=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 78 %

Procedure:
Step D To a solution of oxalyl chloride (0.96 mL, 11 mmol) (Aldrich) in dichloromethane (20 mL) at −78° C. was added the solution of dimethyl sulfoxide (1.56 mL, 22 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 3-ethyl-3-methyl-pentan-1-ol (1.3 g, 10 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. Triethylamine (5 mL, 36 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3-ethyl-3-methyl-pentanal as a light yellow oil (Yield: 1 g, 78%).
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:7][C@@H:8]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])SC)#[N:2].[Cl:26][C:27]1[CH:28]=[C:29]([C@@H:33]([C@@H:42]2[CH2:47][CH2:46][CH2:45][NH:44][CH2:43]2)[O:34][CH2:35][CH2:36][NH:37][C:38](=[O:41])[O:39][CH3:40])[CH:30]=[CH:31][CH:32]=1>CN(C=O)C.CCN(CC)CC.C(OCC)(=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([C@@H:33]([C@@H:42]2[CH2:47][CH2:46][CH2:45][N:44]([C:4](=[N:3][C:1]#[N:2])[NH:7][C@H:8]([CH2:9][N:10]([CH3:18])[C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:43]2)[O:34][CH2:35][CH2:36][NH:37][C:38](=[O:41])[O:39][CH3:40])[CH:30]=[CH:31][CH:32]=1
Reactant: CSC(=NC#N)N[C@@H](CC1CCCCC1)CN(C)C(=O)OC(C)(C)C
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=NC#N)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Temperature: 105 °C
Yield: 2.3 %

Procedure:
To a solution of (S)-tert-butyl 2-((cyanoimino)(methylthio)methylamino)-3-cyclohexylpropyl(methyl)carbamate (200 mg, 0.543 mmol) in DMF (8 mL) and Et3N (0.5 mL) was added methyl 2-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate (178 mg, 0.543 mmol). The mixture was heated at 100-110° C. for 48 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (30 mL×4), dried over Na2SO4 and concentrated to give the residue, which was purified by column to give methyl 2-((R)-(3-chlorophenyl)((R)-1-(N′-cyano-N—((S)-1-cyclohexyl-3-(N-methyl-N-(tert-butoxycarbonyl)amino)propan-2-yl)carbamimidoyl)piperidin-3-yl)methoxy)ethylcarbamate (8 mg, 2%).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6](=[O:10])[CH2:7][C:8]#[N:9])[CH2:5][CH2:4]1.[CH3:11][C:12]1[N:20]=[C:19]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:3]1([C:6](=[O:10])[CH:7]([C:14]([C:13]2[C:12]([CH3:11])=[N:20][C:19]([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)=[CH:18][CH:17]=2)=[O:15])[C:8]#[N:9])[CH2:5][CH2:4]1
Reactant: N#CCC(=O)C1CC1
Reactant: Cc1nc(-n2cncn2)ccc1C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-n2cncn2)ccc1C(=O)C(C#N)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
A THF (2 ml) suspension of sodium hydride (0.06 g, 60% oil suspension, 18.78 mmol) was cooled in an ice bath, and a THF (2 ml) solution of 3-cyclopropyl-3-oxopropanenitrile was dripped thereto. To the obtained reaction solution, a THF (3 ml) solution of 2-methyl-6-(1H-1,2,4-triazol-1-yl) nicotinic acid chloride (0.16 g, 0.73 mmol) was dripped. The resultant was stirred at room temperature for 3 hours. The obtained reaction solution was made acidic with a citric acid aqueous solution, and the product was extracted with ethyl acetate. The obtained organic layer was washed with water, dried with magnesium sulfate and concentrated to obtain the desired product (0.14 g, yield 64%).
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12](Cl)[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.[CH3:18][NH2:19]>>[NH2:4][C:5]1[CH:13]=[C:12]([NH:19][CH3:18])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(=O)Nc1cc(Cl)c([N+](=O)[O-])cc1C(=O)O
Reactant: CN
Product: CNc1cc(N)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A mixture of 2-acetylamino-4-chloro-5-nitrobenzoic acid (10.0 g) and 40% aqueous methylamine solution (60 ml) is stirred at 80° C. for 10 hours and then evaporated under reduced pressure. To the residue is added 40% aqueous methylamine solution (100 ml), and the resulting solution is stirred at 80° C. for 20 hours. After cooling, the mixture is diluted with water (50 ml) and then adjusted to the pH of about 4 with acetic acid. The precipitate is collected and recrystallized from acetonitrile to give the title compound (7.6 g), mp 260°-272° C.
Reaction SMILES: [Cl-].[Li+].O.[CH2:4]([C:12]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])(C(OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]>CS(C)=O>[F:32][C:27]([F:33])([C:28]([F:29])([F:30])[F:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH:12]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C=CCCCCCCC(CCCCC(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 180 °C
Reaction time: 16 h
Yield: 78.8 %

Procedure:
Lithium chloride (401 mg, 9.540 mmol) and water (86 mg, 4.770 mmol) were added to a solution of diethyl 2-(7-octenyl)-2-(5,5,6,6,6-pentafluorohexyl)malonate (2.12 g, 4.770 mmol) in dimethyl sulfoxide (8 ml) followed by stirring for 16 hours at 180° C. After cooling, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/50) to give ethyl 2-(5,5,6,6,6-pentafluorohexyl)-9-decenoate (1.40 g, Yield 79%) as a colorless oil.