Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])=[C:23]([CH3:34])[NH:22][C:21]=1[CH:35]=O>C(O)C.N1CCCCC1>[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)=[O:26])=[C:23]([CH3:34])[NH:22][C:21]=1[CH:35]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:13][C:12]1=[O:18]
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)N4CCN(C)CC4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.7 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro indol-2-one (59.8 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide 3-[3,5-dimethyl 4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (62 mg, 53%)
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[C:17]([O:19][CH3:20])=[O:18])=O)C1C=CC=CC=1.C(O)(=O)C.[H][H]>C(O)C.[C].[Pd]>[C:17]([OH:19])(=[O:18])[CH3:12].[CH3:20][O:19][C:17]([C@@H:12]1[CH2:13][C@@H:14]([OH:16])[CH2:15][NH:11]1)=[O:18]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1C[C@@H](O)CN1

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-methoxycarbonyl-4-hydroxypyrrolidine (4.34 g) in 95% ethanol (44 ml), 10% palladium-carbon (419 mg) and acetic acid (0.89 ml) were added. The mixture was vigorously stirred at room temperature for 1.5 hours under an atmospheric pressure of hydrogen. Removal of the catalyst gave (2S,4R)-2-methoxycarbonyl-4-hydroxypyrrolidine acetate.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][C:15]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[Cl:3][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[F:5])=[C:15]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:16]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2CN2CCCCC2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Thionyl chloride (0.066 g, 0.56 mmol) was added to a solution of 66.64B (0.023 g, 0.070 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 2 hours. After removing solvent, 66.64C was obtained in 100% yield.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:19]([O-])=[O:20].[Na+].O>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: O=NN(CCCl)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 98.3 %

Procedure:
A solution of 0.60 g of 1-(2-chloroethyl)-3-(β-D-glucopyranosyl)urea in 15 ml of 99% formic acid was admixed with 282 mg of sodium nitrite under ice-cooling and stirring. The mixture was stirred for 1 hour under ice-cooling to effect the nitrosation. The reaction mixture, after addition of 15 ml of cold water thereto, was ice-cooled for 30 minutes and then treated with 5 ml of Amberlite IR-120 (H+ form) for the removal of sodium cation. The reaction mixture so treated was concentrated to dryness below 30° C. by distilling off the solvent under a reduced pressure. The residue was taken up into a small volume of n-propanol and the solution was admixed with a volume of petroleum ether to give a precipitate. The precipitate which deposited was collected by filtration and then dried in a desiccator under vacuum, affording 0.65 g of the titled compound as an amorphous solid of pale yellow color. Yield 92%. mp. 85° C. (decomposition). [α]D16 -14° (c 0.5, methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[F:19])=[N:6][CH:7]=1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>CO>[F:19][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:9]=1[O:8][C:5]1[CH:4]=[CH:3][C:2]([N:1]=[CH:26][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=2)=[CH:7][N:6]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(Oc2ccc(N)cn2)c(F)c1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: COC(=O)c1ccc(Oc2ccc(N=Cc3ccc(C(F)(F)F)cc3)cn2)c(F)c1
Temperature: 25 °C

Procedure:
Methyl 4-(5-aminopyridin-2-yloxy)-3-fluorobenzoate (2.0 g, 7.63 mmol) was dissolved in methanol (50 mL). To the resulting solution was added 4-trifluoromethylbenzaldehyde (1.04 mL, 7.63 mmol), and refluxed for 6 hours. The reaction solution was cooled to room temperature, and the resulting precipitated crystals were collected by suction filtration. The collected crystals were washed with methanol, to thereby yield 2.81 g of the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[N:20]O)[C:16]([F:19])([F:18])[F:17])=[CH:10][CH:9]=1.Cl[CH:23]=[CH:24][C:25]#[N:26]>O1CCCC1.C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:24]([C:25]#[N:26])=[CH:23][NH:20][C:15]=2[C:16]([F:19])([F:18])[F:17])=[CH:10][CH:9]=1
Reactant: ON=C(Cc1ccc(Cl)cc1)C(F)(F)F
Reactant: N#CC=CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(F)(F)F)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Potassium-t-butoxide (2.46 g, 0.022 mol) is added in portions to a solution of 3-(p-chlorophenyl)-1,1,1-trifluoro-2-propanone oxime, (E)-, or (Z)-(4.75 g, 0.02 mol) in tetrahydrofuran (20 mL) at such a rate that the temperature if maintained at 25°-30° C. (ice-water bath). The resulting solution is stirred for 15 minutes and then added dropwise to a solution of β-chloroacrylonitrile (1.75 g, 0.02 mol) in tetrahydrofuran (15 mL) at 15°-10° C. over 1/2 hour. The ice bath is removed and the reaction mixture is stirred for 1 hour, diluted with water, made acidic with a small amount of dilute HCl and extracted with ether. The combined ether extracts are washed with water and brine and dried (Na2SO4). Concentration in vacuo gives an oil which is dissolved in methylene chloride and filtered through a bed of flash column silica gel (30 mL size) and washed with an ethyl acetate/methylene chloride mixture (1:1). The filtrate is evaporated and the residual semi-solid is crystallized from methylene chloride/hexanes to give the title product as a yellow solid (2.10 g): mp 162.5°-164.0° C. IR (Nujol) 3200, 2250 cm-1, 1H NMR (DMSO-d6) δ7.42, 7.56 (AB, JAB =8.3 Hz, ArH), 8.03 (s, 1H, 2H); 19F NMR δ-51.2; 13C NMR δ94.2 (C-3), 115.0 (CN), 116.6 (q, 2JCF =38.3 Hz, C-5), 120.6 (q, 1JCF =268.7 Hz, CF3), 127.0 (q, 3JCF =3.5 Hz, C-4), 128.6 (C-2') 129.1 (C-1'), 129.7 (C-2), 130.8 (C-3'), 133.4 (C-4').
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:30][C:31]1[CH:36]=[C:35](Cl)[N:34]=[C:33]([S:38][CH3:39])[N:32]=1.CO>O1CCOCC1>[CH3:39][S:38][C:33]1[N:32]=[C:31]([NH2:30])[CH:36]=[C:35]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[NH:11][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=4)=[N:14][N:13]=3)=[CH:16][CH:17]=2)[N:34]=1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Reactant: CSc1nc(N)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CO
Product: CSc1nc(N)cc(Oc2ccc(-c3nnc(Nc4cccc(C(F)(F)F)c4)[nH]3)cc2)n1
Yield: 27.7 %

Procedure:
4-(5-{[3-(trifluoromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (101.7 mg, 0.31 mmol) was added, followed by 4-amino-6-chloro-2-(methylthio)-pyrimidine (60.3 mg, 0.34 mmol). The vial was capped and microwaved at 200° C. for 10 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension. The resulting reddish-brown solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water system with 0.01% of TFA. The fractions, containing the product, were collected and partitioned between EtOAc and saturated aqueous NaHCO3. Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a white solid (39.5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[S:13](Cl)(=[O:15])=[O:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([CH2:28][NH2:29])=[CH:25][CH:26]=2)[CH:21]=[N:20]1)[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[S:13](=[O:15])(=[O:14])[NH:29][CH2:28][C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][CH:25]=1)[N:19]([CH2:17][CH3:18])[N:20]=[CH:21]2)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCn1ncc2cc(CN)ccc21
Reactant: CCOC(=O)c1ccc(S(=O)(=O)Cl)c(Cl)c1
Product: CCOC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3CC)c2)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from ethyl 3-chloro-4-(chlorosulfonyl)benzoate and (1-ethyl-1H-indazol-5-yl)methanamine (step-3 of Example 14).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH2:21][CH2:20][CH:19]([C:23]([O:25][CH3:26])=[O:24])[C:18]=2[CH:27]=1.C1C[O:31][CH2:30]C1>CCCCCC>[F:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH2:21][CH2:20][C:19]([CH2:30][OH:31])([C:23]([O:25][CH3:26])=[O:24])[C:18]=2[CH:27]=1
Reactant: COC(=O)C1CCOc2ccc(F)cc21
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(CO)CCOc2ccc(F)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5 mL (0.035 mole) of diisopropylamine in 100 mL of THF was cooled to 0° C. and 22.1 mL (0.35 mole) of 1.6M butyllithium in hexane was added dropwise. After stirring for 30 minutes at 0° C. the resulting solution was cooled to -78° C. A solution of 6.2 g (0.0295 mole) of Methyl 6-fluoro-2,3-dihydro-4H-benzopyran-4-carboxylate in 20 mL of THF was then added dropwise while maintaining the temperature below -66° C. The resulting solution was stirred at -78° C. for 3 hours. Gaseous formaldehyde was then bubbled into the solution for 5 minutes. The reaction was allowed to warm to room temperature, then diluted with water and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered and evaporated to give 7.6 g of crude product as an oil. NMR (CDCl3) ppm (delta): 2.20-2.60 (m, 2H), 3.8 (s, 3H), 4.26 (t, 2H, J=5 Hz), 4.90 (m, 2H), 6.80-7.20 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([OH:14])=O)[C:7]1=[O:15].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(Cl)Cl.C(N(CC)C(C)C)(C)C.[NH2:56][C@@H:57]([C:62]1[S:63][CH:64]=[CH:65][CH:66]=1)[CH2:58][C:59]([OH:61])=[O:60]>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:56][C@@H:57]([C:62]2[S:63][CH:64]=[CH:65][CH:66]=2)[CH2:58][C:59]([OH:61])=[O:60])=[O:14])[C:7]1=[O:15]
Reactant: O=C(O)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Reactant: N[C@H](CC(=O)O)c1cccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1cccs1

Procedure:
Into a round bottom was added 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (0.400 g, 0.00151 mol;), N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.573 g, 0.00151 mol;), Methylene chloride (14 mL, 0.23 mol;), and N,N-Diisopropylethylamine (1310 uL, 0.00754 mol;). The reaction was stirred until all contents were dissolved and preactivation was complete. (R)-3-Amino-3-thiophen-2-yl-propionic acid (0.28 g, 0.0016 mol;) was added and the reaction was allowed to stir for 1-2 hours then an LC-MS was taken which showed product at 1.47. The reaction was worked up by washing with citric acid and brine then drying with magnesium sulfate. The crude concentrated reaction was taken on directly to the next step. ES (+) MS m/e=419.08
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[N+:17]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br)([O-:19])=[O:18]>C(#N)C>[N+:17]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cccc(OCc2ccccc2[N+](=O)[O-])c1

Procedure:
To 3-hydroxybenzamide (0.137 g; 1 mmol) was added potassium carbonate (0.138 g; 1 mmol) and 2-nitrobenzyl bromide (0.216 g; 1 mmol) in anhydrous acetonitrile (10 ml). The mixture was heated under reflux for 5 hours.
Reaction SMILES: [OH:1][C:2]1([CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][CH:10]1[O:16][CH3:17])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[H-].[Na+].[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C(Cl)Cl>[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([O:1][C:2]1([CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][CH:10]1[O:16][CH3:17])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)=[O:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC1C=CC(Br)=CC1(O)Cc1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COC1C=CC(Br)=CC1(Cc1cnccn1)OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.6 g of 2-(1-hydroxy-2'methoxy-5'-bromobenzyl)pyrazine were dissolved in 15 ml of methylene chloride. At 0° C., 0.2 g of NaH were added, resulting in the evolution of a gas and formation of a precipitate. 0.4 ml of trimethylacetyl chloride were added in one portion. The reaction mixture was stirred at room temperature overnight. The solvent was then stripped from the reaction mixture, and the residue was extracted with ice water and methylene chloride. The methylene chloride layer was washed with water, dried (MgSO4), filtered and stripped of the solvent to yield 0.9 g of 3-(1-trimethylacetoxy-2'-methoxy-5'-bromobenzyl)-pyrazine.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:13]2[CH3:28])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([NH:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:13]2[CH3:28])=[CH:9][CH:10]=1)(=[O:3])=[O:4])(=[O:31])[CH3:30]
Reactant: COC(=O)CC1=C(C)C(=Cc2ccc(S(N)(=O)=O)cc2)c2ccc(OC)cc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)CC1=C(C)C(=Cc2ccc(S(=O)(=O)NC(C)=O)cc2)c2ccc(OC)cc21
Yield: 50 %

Procedure:
A solution of 4a (100 mg) in pyridine (5 ml) was added acetic anhydride (2 ml). The mixture was heated at 110° for 1 hour and concentrated in vacuo. The crude mixture was purified via preparative tlc using 2000 μm silica gel plates developed with 30% ethyl acetate in chloroform. The isolated product was recrystallized from acetone-hexane to give pure Z methyl 1-[4-(N-acetylaminosulfonyl)phenyl]methylene-5-methoxy-2-methyl-1H-3-indenylacetate (55 mg, 50%): m.p. 172.5°-174.5° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[CH:4][C:3]1=[O:27]>C(OCC)(=O)C.CCOCC.[Pd]>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:4][C:3]1=[O:27]
Reactant: O=C(CCCCOC1=CC(=O)C(=O)c2ccccc21)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(O)CCCCOC1=CC(=O)C(=O)c2ccccc21
Reaction time: 10 h
Yield: 37 %

Procedure:
Benzyl ester 2 (1.90 g, 5.22 mmol) was hydrogenated at 30 psi with Pd (400 mg) in ethyl acetate (120 mL) for 6 h. The catalyst was removed by filtration through celite, the solvent was evaporated in vacuo and the residue was oxidized with Ag2O (1.45 g, 6.25 mmol) in Et2O by stirring for 10 h. Following filtration and evaporation of the solvent the product was crystallized from benzene to afford 0.53 g of pure material. The mother liquor was purified by flash chromatography (CH2Cl2/MeOH 15:1), the product dissolved in CH2Cl2, extracted with aqueous NaHCO3 solution, acidified to pH 1 with 3% HCl and extracted back with CH2Cl2 to give additional 0.25 g of pure material (total yield 55%), mp 134-136° C.; 1H NMR (CDCl3) 8.12 (d, J=7.0 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.70 (t, J=7.5 Hz, 1H), 7.59 (t, J=7.4 Hz, 1H), 7.27 (s, 1H), 4.18 (t, J=5.9 Hz, 2H), 2.51 (t, J=7.0 Hz, 2H), 1.75-2.15 (m, 4H).
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13](O)=O)[C@@H:11]([CH3:16])[O:10]C1(C)C)=O)(C)(C)C.[NH2:19][C:20]1[C:21]([Cl:36])=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([F:35])[CH:28]=2)[CH:23]=[CH:24][C:25]=1[NH2:26]>>[NH2:8][C@H:12]([C:13]1[NH:26][C:25]2[CH:24]=[CH:23][C:22]([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([F:35])[CH:28]=3)=[C:21]([Cl:36])[C:20]=2[N:19]=1)[C@H:11]([OH:10])[CH3:16]
Reactant: C[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Reactant: N#Cc1ccc(-c2ccc(N)c(N)c2Cl)cc1F
Product: C[C@@H](O)[C@H](N)c1nc2c(Cl)c(-c3ccc(C#N)c(F)c3)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 using (4S,5R)-3-(tert-butoxycarbonyl)-2,2,5-trimethyl-1,3-oxazolidine-4-carboxylic acid (Preparation 57) and 3′,4′-diamino-2′-chloro-3-fluorobiphenyl-4-carbonitrile (Preparation 80). The final residue was purified using silica gel column chromatography eluting with DCM:MeOH (7N NH3), 97:3 to 93:7 and freeze dried for 18 hours.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3]1.[S:13]([NH2:17])([NH2:16])(=[O:15])=[O:14].[BH4-].[Na+]>C(O)C.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:16][S:13]([NH2:17])(=[O:15])=[O:14])=[CH:3]1
Reactant: NS(N)(=O)=O
Reactant: Cn1cc(C=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1cc(CNS(N)(=O)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Methylindole-3-carboxaldehyde (1.66 g, 10.4 mmol) was dissolved in anhydrous ethanol (50 mL). Sulfamide (4.5 g, 47 mmol) was added and the mixture was heated to reflux for 16 hours. Additional sulfamide (1.0 g, 10.4 mmol) was added and the mixture was heated to reflux for 24 hours. The mixture was cooled to room temperature. Sodium borohydride (0.722 g, 12.5 mmol) was added and the mixture was stirred at room temperature for one hour. The reaction was diluted with water (50 mL) and extracted with DCM (3×75 mL). The extracts were concentrated and about 1 mL of methanol was added to create a slurry which was filtered to yield the title compound as a white powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.C(O)C>[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(S)cc1
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: Nc1ccc(Sc2ccnc3cc(C(F)(F)F)ccc23)cc1
Yield: 74.1 %

Procedure:
4-Chloro-7-trifluoromethylquinoline (0.043 moles, 10.0 g), 4-aminothiophenol (0.043 moles, 5.3 g) and 4-dimethylaminopyridine (0.04 moles, 4.9 g) were stirred in 250 ml ethanol for 3 days. The reaction mixture was filtered, concentrated, ethyl acetate added, washed with water and dried over sodium sulfate. The solution was concentrated and the product purified by HPLC over silica gel eluted with 25% ethyl acetate/hexane to yield 4-(4-aminophenylthio)-7-trifluoromethylquinoline 10.2 g, 74%. Mass Spec (FD) 320. Calculated for C16H11F3N2S: C, 59.99; H, 3.46; N, 8.74. Found: C, 60.08; H, 3.49; N, 8.77.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[C:5]2[CH2:19][CH2:20][C:21](O)=[O:22].Cl.[F:25][C:26]([F:41])([F:40])[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[C:5]2[CH2:19][CH2:20][C:21]([N:37]1[CH2:36][CH2:35][N:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[O:27][C:26]([F:40])([F:25])[F:41])[CH2:39][CH2:38]1)=[O:22]
Reactant: FC(F)(F)Oc1ccccc1N1CCNCC1
Reactant: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)O)c2cc(Cl)ccc21
Agent: Cl
Product: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)N2CCN(c3ccccc3OC(F)(F)F)CC2)c2cc(Cl)ccc21

Procedure:
Prepared from 5-chloro-2-(4-chlorophenyl)-1-methyl-1H-indole-3-propanoic acid (Description 12) and 1-[2-(trifluoromethoxy)phenyl]piperazine hydrochloride (Description 19) according to the method of Description 25. 1H NMR (360 MHz, CDCl3) δ7.60 (1H, d, J 1.7 Hz), 7.49 (2H, m), 7.32 (2H, m), 7.24-7.18 (4H, m), 7.04-7.00 (1H, m), 6.93 (1H, dd, J 1.3, 8.0 Hz), 3.71 (2H, t, J 5.0 Hz), 3.54 (3H, s), 3.37 (2H, t, J 5.0 Hz), 3.02 (2H, m), 2.95 (2H, t, J 5.0 Hz), 2.80 (2H, t, J 5.0 Hz), and 2.54 (2H, m). m/z (ES+) 576, 578 (M+1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+:10].[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[S:19])=[CH:13][CH:12]=1.[CH3:21][CH2:22][OH:23]>C1COCC1.C(#N)C>[C:14]([C:13]1[CH:12]=[CH:21][C:22](=[O:23])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:20])=[CH:12][CH:13]=2)[C:18]=1[S-:19])#[N:17].[Na+:10]
Reactant: CCO
Reactant: Cc1ccc(N=C=S)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1ccc(-n2c([S-])c(C#N)ccc2=O)cc1
Temperature: 25 °C
Yield: 39 %

Procedure:
Sodium bis(trimethylsilyl)amide (36.8 mL, 1.0M in THF, 36.8 mmol) was added slowly to a solution of 4-tolyl isothiocyanate (2.5 g, 16.75 mmol) in THF (30 mL) and acetonitrile (5 mL) at −78° C. The mixture was warmed to r.t. over 1 h. N,N-Dimethyluracil (2.35 g, 16.75 mmol) and EtOH (20 mL) were added and the mixture heated at reflux for 4 h. Volatiles were removed in vacuo and the residue was dissolved in EtOH (6 mL). Et2O (˜60 mL) was added slowly to produce a fine, off-white solid. The suspension was cooled to 0° C. and the solid filtered off, washed with Et2O and dried to give the title compound as an off-white solid (1.7 g, 39%). δH (DMSO-d6) 7.15-7.12 (3H, m), 6.80-6.77 (2H, m), 5.60 (1H, d, J 9.1 Hz), 2.30 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH2:6].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1([C:29](Cl)=[O:30])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH:6][C:29]([C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:30]
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: NCc1ccc(F)c(F)c1
Product: O=C(NCc1ccc(F)c(F)c1)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 3,4-difluorobenzylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.