Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1.[I:14]N1C(=O)CCC1=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[C:6]([O:11][CH3:12])[C:7]([OH:10])=[C:8]([I:14])[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc(O)c(OC)c1
Solvent: C1CCOC1
Product: COC(=O)c1cc(I)c(O)c(OC)c1
Reaction time: 1 h
Yield: 113.6 %

Procedure:
To a solution of 4-hydroxy-3-methoxybenzoic acid methyl ester (5.0 g) in tetrahydrofuran (20 mL) was added N-iodosuccinimide (6.17 g) at 0° C., and the mixture was stirred for 1 hour. The precipitated solid was filtered, washed with water, and dried to give the title compound (9.60 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10](=[O:11])[NH:9][N:8]=2)[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNc1ccc(Br)cn1
Solvent: CC#N
Product: O=c1[nH]nc2ccc(Br)cn12
Temperature: 25 °C

Procedure:
A suspension of 40 g 5-bromo-2-hydrazinylpyridine (212 mmol) and 38 g 1,1′-Carbonyldiimidazole (234 mmol) in 500 mL acetonitrile was refluxed for 2 h. The reaction was then cooled to room temperature overnight. The precipitate was collect by filtration. 6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one as a light brown solid was collected. m/z (ESI)=213.9 [M+H]+. 1H NMR (δ, d6-DMSO, 400 MHz) 12.59 (s, 1H), 8.04 (dd, 1H), 7.21 (m, 2H).
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].[CH3:16][NH:17][CH2:18][C@@H:19]([C@H:21]([C@@H:23]([C@@H:25]([CH2:27][OH:28])[OH:26])[OH:24])[OH:22])[OH:20].O>C1(C)C=CC=CC=1>[CH3:16][NH:17][CH2:18][C@@H:19]([C@H:21]([C@@H:23]([C@@H:25]([CH2:27][OH:28])[OH:26])[OH:24])[OH:22])[OH:20].[OH:3][C:2]([C@H:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:14][CH:15]=1)[CH3:5])=[O:1]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc([C@H](C)C(=O)O)cc1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
Racemic ibuprofen (18.03 g, 87.4 mmol), N-methyl-D-glucamine (8.2 g, 42 mmol), water (0.5 mL), and toluene (150 mL) were heated to 50° C., forming a clear solution. The solution was cooled to 20° C., then in an ice bath, and allowed to stand for 48 hours. The resulting crystalline precipitate was recovered by filtration at 20° C., washed with toluene (30 mL), and dried to give (S)-ibuprofen N-methyl-D-glucamine salt (11.9 g, 68% yield, 92% ee).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])=[CH:26][CH:25]=1)[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([CH2:33][CH3:34])(=[O:31])=[O:32])=[CH:28][CH:29]=1)=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(S(=O)(=O)CC)cc1)C(=O)OC
Solvent: O
Solvent: C1COCCO1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(S(=O)(=O)CC)cc1
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.90 g), 2-(4-ethanesulfonylbenzyl)-3-oxopentanoic acid methyl ester (1.4 g), polyphosphoric acid (10 g) and dioxane (10 mL) was heated at 120° C. for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and the solvent removed under reduced pressure to afford title compound, 1.9 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]([OH:13])[C:6]([Cl:12])([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C.CCCCCC>C(OCC)C>[CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]([O:13][S:21]([CH3:20])(=[O:23])=[O:22])[C:6]([Cl:11])([Cl:12])[C:7]([F:8])([F:9])[F:10])[CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1C(C(O)C(Cl)(Cl)C(F)(F)F)C1(C)C
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)C1C(C(OS(C)(=O)=O)C(Cl)(Cl)C(F)(F)F)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
To a solution of 135 mg (0.794 mmol) of ethyl 2,2-dimethyl-3-(1-hydroxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate obtained in Example 2, in 2 ml of diethyl ether, 0.073 ml (0.94 mmol) of methanesulfonyl chloride and 0.133 ml (0.95 mmol) of triethylamine, were added, and the mixture was stirred at room temperature for 2 hours. After an addition of 5 ml of hexane to the mixture, the precipitated inorganic salt was filtered off, and the filtrate was concentrated under reduced pressure. The product was purified by thin layer chromatography (silica gel, dichloromethane/hexane=1/1) to obtain 157 mg of ethyl 2,2-dimethyl-3-(1-methanesulfonyloxy-2,2-dichloro-3,3,3trifluoropropyl)cyclopropanecarboxylate as a colorless oily substance.
Reaction SMILES: [Br-].[F:2][C:3]([F:8])([F:7])[C:4]([Zn+])=[CH2:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18].CCCCCC>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:4]([C:3]([F:8])([F:7])[F:2])=[CH2:5])=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18]
Reactant: C=C([Zn+])C(F)(F)F
Reactant: FC(F)(F)c1cc(I)ccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(Cl)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
To 1M solution of 1-(trifluoromethyl)ethenyl zinc bromide in tetrahydrofuran (see J. Org. Chem. 1991, 56, 7336 for preparation) (53 mL) under nitrogen atmosphere was added 2-chloro-5-iodobenzotrifluoride (7.1 g), followed by the addition of dichlorobis(triphenylphosphine)palladium(II) (0.65 g). The mixture was stirred under reflux for 2.5 hours and then cooled to room temperature. To the resulting mixture was added hexane (100 mL) and filtered, and the filtrate was washed with water (50 mL) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel eluted with hexane to afford the title compound as colorless oil (4.8 g).
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].C=O.Cl>O>[C:1]([CH:9]1[CH2:14][O:12][C:11](=[O:13])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C1CC(C(=O)c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 120 h
Yield: 84.1 %

Procedure:
A mixture of 3-benzoylpropionic acid (18 g, 101 mmol), potassium carbonate (10 g, 75 mmol), water (45 mL) and formaldehyde (36% in water, 7.8 mL, 101 mmol) is stirred at room temperature for 5 days, warmed to 30° C. and stirred for 3 additional days. To this mixture is added concentrated hydrochloric acid (10 mL) to pH 5.0, heated at 50° C. for 30 min. and cooled to room temperature. The mixture is extracted with chloroform (4×200 mL) and the combined organic extracts washed with sodium carbonate (10% in water, 3×100 mL). The solution is dried with anhydrous sodium sulfate and filtered. The filtrate is concentrated in vacuo to yield 4-benzoyl-dihydro-furan-2-one (12 g) as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:5])[CH3:4].Br[CH2:13][C:14]1[N:15]([CH3:30])[C:16]2[C:21]([N:22]=1)=[C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[N:19]=[C:18]([Cl:29])[N:17]=2>>[Cl:29][C:18]1[N:17]=[C:16]2[C:21]([N:22]=[C:14]([CH2:13][N:9]3[CH2:10][CH2:11][CH:6]([C:3]([O:2][CH3:1])([CH3:5])[CH3:4])[CH2:7][CH2:8]3)[N:15]2[CH3:30])=[C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:19]=1
Reactant: COC(C)(C)C1CCNCC1
Reactant: Cn1c(CBr)nc2c(N3CCOCC3)nc(Cl)nc21
Product: COC(C)(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1
Yield: 98.3 %

Procedure:
4-(2-methoxypropan-2-yl)piperidine (0.12 g) was reacted with 4-(8-(bromomethyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (0.25 g) via General Procedure E to give 300 mg of crude 4-(2-chloro-8-((4-(2-methoxypropan-2-yl)piperidin-1-yl)methyl)-9-methyl-9H-purin-6-yl)morpholine, of which 0.78 g was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-amine via General Procedure A to yield 12 mg of 155 as a white solid following reverse phase purification. MS (Q1) 531.3 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].S(Cl)([Cl:27])(=O)=O>ClCCCl.CCOC(C)=O>[Cl:27][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:20]([F:21])([F:22])[F:23])[CH:4]=2)=[O:19])[CH:17]=[CH:16][C:15]=1[OH:18]
Reactant: O=C(CCc1ccc(O)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(CCc1ccc(O)c(Cl)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 84 °C
Yield: 44.9 %

Procedure:
To a solution of N-[4-chloro-3-(trifluoromethyl)phenyl]-3-(4-hydroxyphenyl)propanamide (1.33 g, 3.89 mmol) in DCE was added sulfuryl chloride (4.28 mL, 4.28 mmol) slowly over 45 min. The reaction mixture was heated at 84° C. overnight and then additional sulfuryl chloride was added. After heating for 2 h, the reaction mixture was cooled to rt and diluted with EtOAc. The combined organic solutions were washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give the title compound (0.66 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:11][C:12]=2[N+:13]([O-:15])=[O:14])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:26]Br.O>C(O)(=O)C>[Br:26][C:11]1[C:12]([N+:13]([O-:15])=[O:14])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[S:16][C:17]([F:18])([F:20])[F:19]
Reactant: O=[N+]([O-])c1cc(SC(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(-c2ccc(Cl)cc2)[nH]c(SC(F)(F)F)c1Br
Reaction time: 1 h
Yield: 56.6 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-nitro-5[(trifluoromethyl)thio]pyrrole (0.35 g, 0.0011 mol) and sodium acetate (0.11 g, 0.0013 mol) in acetic acid is treated with a solution of bromine (0.21 g, 0.0013 mol) in acetic acid, stirred for one hour, poured into water and extracted with ethyl acetate. The combined organic extracts are washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. Flash chromatography of the residue using silica gel and a 1:9 ethyl acetate/hexanes solution gives the title product as a yellow solid (0.25 g, mp 160°-165° C.) which is identified by 1HNMR, 19FNMR and 13CNMR spectral analyses.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][C:16]=2[C:33](=[O:35])[NH2:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37].N1C=CC=CC=1.CO>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=3)[S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[CH:17][C:16]=2[C:33](=[O:35])[NH2:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2C(N)=O)CC1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: CCS(=O)(=O)N(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(C(N)=O)c1
Yield: 90 %

Procedure:
To a suspension of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-carbamoylphenyl]amino]-1-(E)-propenyl]benzonitrile (0.92 g) obtained in reference example 130 in dichloromethane (15 ml) were successively added dropwise ethanesulfonyl chloride (0.22 ml) and pyridine (0.31 ml) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature overnight. At the end of this time, to the reaction mixture were furthermore added dropwise ethanesulfonyl chloride (0.04 ml) and pyridine (0.16 ml) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 5 hours. After stirring, to the reaction mixture was added methanol (3 ml), and the resulting mixture was evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of dichloromethane and methanol (10:0˜9:1) as the eluent to afford the title compound (1.08 g, yield: 90%) as a yellow oil.
Reaction SMILES: [CH3:1][CH2:2][N:3]([C:10]([C:12]1[C:22](=[O:23])[N:21]([CH3:24])[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=2[C:13]=1[OH:25])=[O:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[OH-].[Na+:27].[Na]>C(O)C>[CH3:1][CH2:2][N:3]([C:10]([C:12]1[C:22](=[O:23])[N:21]([CH3:24])[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=2[C:13]=1[O-:25])=[O:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[Na+:27]
Reactant: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: CCN(C(=O)c1c([O-])c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Yield: 92 %

Procedure:
Deuterated laquinimod prepared in Step 2 was suspended in ethanol and treated with 20% aqueous NaOH solution. The precipitated sodium salt was stirred for 3 hours, filtered and washed with ethanol. Drying in vacuum provided deuterated laquinimod sodium salt (92-94% yield). Identity and purity were proven by NMR, MS and HPLC.
Reaction SMILES: [C:1]([C:4]1[C:13]([NH:14][CH3:15])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:16]([O-])=O)[N:5]=1)(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([C:4]1[C:13]([NH:14][CH3:15])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:16])[N:5]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CNc1cc2c([N+](=O)[O-])cccc2nc1C(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNc1cc2c(N)cccc2nc1C(C)=O

Procedure:
650 mg (2.7 mmol) of 2-acetyl(methyl)amino-5-nitroquinoline and 161 mg of 10% Pd—C are stirred in 25 ml of ethyl acetate for 2 hours in a hydrogen atmosphere at room temperature. The batch is filtered and concentrated by evaporation: 490 mg of product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29](O)=[O:30])=[CH:22][CH:21]=1.C(O)(=O)CC(O)=O.FC1C=CC(N)=CC=1.CCN=C=NCCCN(C)C>CCOC(C)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:29](=[O:30])[CH2:28][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: O=C(O)CC(=O)Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccc(F)cc1
Agent: O=C(O)CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 11 %

Procedure:
To a stirred mixture of 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 1-B; 26 mg, 0.10 mmol), 3-(4-fluorophenylamino)-3-oxopropanoic acid (22 mg, 0.11 mmol; prepared from malonic acid and 4-fluoroaniline according to the methods described in WO 2005/030140 and by Shih and Rankin, Synth. Comm. 1996, 26(4), 833-836), and CH2Cl2 (1 mL) was added EDCI (38 mg, 0.20 mmol). The reaction was stirred at room temperature for 2 days. The mixture was diluted with EtOAc (10 mL) and washed with water (3×5 mL), brine (5 mL), dried (Na2SO4), filtered, and concentrated. The crude was purified on a pre-packed Isoelute silica gel column (10 g silica), eluting with a gradient of 20% EtOAc/hexanes, 1:1 EtOAc/hexanes, 2:1 EtOAc/hexanes, and then neat EtOAc. The product was obtained as a waxy solid (5 mg, 11%). 1H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 9.10 (s, 1H), 8.52 (m, 1H), 7.80 (m, 2H), 7.57 (m, 3H), 7.27 (m, 2H), 7.04 (m, 2H), 6.53 (d, J=4 Hz, 1H), 3.52 (s, 2H). LRMS (ESI pos) m/e 440 (M+1). HPLC: 97% purity (220 nm).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH:7]=1.[NH4+].[Cl-]>CCO.[Fe]>[NH2:21][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)ccc2[N+](=O)[O-])C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)ccc2N)C1
Reaction time: 4 h
Yield: 76 %

Procedure:
To a solution of tert-butyl 3-((5-bromo-2-nitrophenyl)amino)pyrrolidine-1-carboxylate (crude) (550 mg, 1.5 mmol) in EtOH (10 mL) was added Fe powder (1.27 mg, 22.7 mmol) and NH4Cl (1.20 g, 0.227 mmol, in 10 ml water). After stirring for 4 h at refluxing temperature, the reaction mixture was filtered over a Celite pad and the filtrate concentrated. The residue used for next step without further purification (410 mg, Yield 76%). LCMS (m/z): 356.1 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:7])=[O:6].[CH3:14][N:15]1[C:19]([SH:20])=[N:18][N:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:5]([CH2:4][CH2:3][CH2:2][S:20][C:19]1[N:15]([CH3:14])[N:16]=[N:17][N:18]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(CCCCl)c1ccccn1
Reactant: Cn1nnnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCS(=O)(=O)c1ccccn1
Yield: 33.4 %

Procedure:
2-Pyridyl 3-chloropropyl sulfone (2.2 g) and 1-methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g) are dissolved in acetone (50 ml). Potassium carbonate (1.4 g) is added to the solution and the mixture is refluxed for 5 hours. Acetone is distilled off and water is added to the residue. The mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Kieselgel 60). The column is eluted with chloroform-methanol and the product is recrystallized from ethanol to obtain 3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiopropyl 2-pyridyl sulfone (1 g) as colorless prisms, m.p. 98.5°-101° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[Br:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([F:36])[CH:30]=1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:33][C:32]1[CH:34]=[CH:35][C:29]([Br:28])=[CH:30][C:31]=1[F:36])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: Nc1ccc(Br)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (3.8 g, 18 mmol) was dissolved in 150 mL dry diethyl ether under Ar, cooled in an ice water bath, added dry pyridine (8.6 mL, 106 mmol) followed by the dropwise addition of oxalyl chloride (4.6 mL, 53 mmol). A precipitate formed immediately. The reaction was stirred vigorously at 0° C. for one hour, then at ambient temperature for one hour. 100 mL diethyl ether was then added. The solides were filtered off and washed with diethyl ether. The filtrates were concwentrated to an off-white oil. The solid was redissolved oil in 50 mL dry DCM under Ar, cooled to 0° C., and 6 mL pyridine was added, followed by 4-bromo-2-fluoroaniline (3.4 g, 17.7 mmol). The reaction was allowed to warm to ambient temperature, stirred for 3 hours then concentrated. The concentrate was redissolved in 250 mL EtOAc, washed with 10% HCl (3×100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated. The residue was purified on a silica gel column eluted with 20% moving to 40% EtOAc in hexanes to yield title compound as a white solid. (3.2 g, 47%) APCI (AP−): 385.1, 387.1 (M−H)−.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]2[CH2:26][CH2:27][CH:28]([C:31]([NH:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:9]=[CH:10]4)=[O:32])[CH2:29][CH2:30]2)=[CH:23][CH:24]=1
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Reactant: O=C(O)C1CCC(c2ccc(Cl)cc2)CC1
Product: O=C(Nc1ccc2c(cnn2CCN2CCCC2)c1)C1CCC(c2ccc(Cl)cc2)CC1

Procedure:
1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine and 4-(4-chloro-phenyl)-cyclohexanecarboxylic acid were processed as described in Example 17 to provide the title compound. MS (DCI/NH3) MS m/z 451 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.48 (m, 2 H), 1.64 (m, 2 H), 1.75–2.06 (m, 8 H), 2.42 (m, 1 H), 2.57 (m, 1 H), 3.03 (m, 2 H), 3.52 (m, 2 H), 3.71 (q, J=5.82 Hz, 2 H), 4.74 (t, J=6.24 Hz, 2 H), 7.29 (m, 2 H), 7.35 (m, 2 H), 7.55 (m, 1 H), 7.67 (m, 1 H), 8.13 (s, 1 H), 8.18 (s, 1 H), 9.69 (br s, N H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]([CH3:13])[C:10](=[O:14])[CH:9]=[CH:8]2.[CH2:15]=[O:16].S(=O)(=O)(O)O.C1N2CN3CN(C2)CN1C3>Cl.ClCCl>[CH3:1][O:2][C:3]1[C:12]2[N:11]([CH3:13])[C:10](=[O:14])[CH:9]=[CH:8][C:7]=2[C:6]([CH:15]=[O:16])=[CH:5][CH:4]=1
Reactant: C=O
Reactant: COc1cccc2ccc(=O)n(C)c12
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1ccc(C=O)c2ccc(=O)n(C)c12
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 57.8 %

Procedure:
8-Methoxy-1-methyl-1H-quinolin-2-one (21.14 g, 0.11 mol) and paraformaldehyde (10.6 g) were suspended in concentrated hydrochloric acid (105 ml), and 4 ml of concentrated sulfuric acid was added, followed by stirring at 70 to 80° C. for 2.5 hours. After cooling to room temperature, ice water was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was dissolved in 400 ml of chloroform, and hexamethylenetetramine (4.25 g, 0.03 mol) was added, followed by heating under reflux for 2.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. 50% acetic acid (110 ml) was added to the residue, and stirring was carried out at 100° C. for 2 hours. After cooling to room temperature, water was added, and the insoluble matter was collected by filtration and dried to thereby obtain 13.81 g (yield: 57%) of 8-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-5-carboxaldehyde as a light yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.C(OC(=O)C)(=O)C>C(O)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[CH:10]/[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: O=Cc1cccc(O)c1
Reactant: Cc1nc2ccccc2s1
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: Oc1cccc(/C=C/c2nc3ccccc3s2)c1
Temperature: 120 °C
Yield: 39.7 %

Procedure:
A mixture of 25 g of 3-hydroxybenzaldehyde, 36.6 g of 2-methylbenzothiazole, 38.8 ml of acetic anhydride and 7.7 ml of formic acid was heated at 120° C. for 25 hours. The low boiling materials were evaporated together with toluene under reduced pressure, and the residue was added to 150 ml of methanol and refluxed with addition of 3 g of potassium carbonate for 1 hour. After cooled to room temperature, the mixture was filtered and filtrate was concentrated. The crude product formed was washed with methanol and ethyl ether and dried under reduced pressure to obtain 20.6 g (yield 40%) of the title compound.