Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=1.[I:24]I.Cl>C1COCC1>[Cl:13][C:14]1[N:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[C:17]([I:24])=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: II
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: FC(F)(F)c1nc(Cl)ccc1I
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 7.1 ml of n-BuLi (1.6M in hexane, 11.3 mmol) in 7 ml THF under argon at −73° C. were added 1.6 ml of diisopropylamine (11.3 mmol) in 3 ml THF within 8 min. After 10 min stirring at the same temperature a solution of 1 g of 2-chloro-6-(trifluoromethyl)-pyridine (5.51 mmol) in 5 ml THF was added within 15 min (temperature between −76 and −75° C.). The dark brown solution was stirred at −75° C. for 1 h 15 min. Finally a solution of 1.4 g of iodine (5.51 mmol) in 10 ml THF was added at −75° C. over 25 min. After additional 45 min stirring at the same temperature 12 ml 2M aqueous HCl were added within 2 min (temperature raised from −78 to −50° C. The cooling device was then removed, the reaction mixture diluted with diethylether. After separation of the organic phase, the aqueous phase was reextracted with diethylether. The combined organic phases were successively washed with 10 ml 1M sodium thiosulfate, saturated NaHCO3 and brine, dried over magnesium sulfate, filtered off and concentrated in vacuo to yield 1.54 (69%) of 6-chloro-3-iodo-2-trifluoromethyl-pyridine as a brown semisolid residue. MS: 307.0
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[C:12](=[CH:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]2=[O:22])=[C:4]([CH3:23])[CH:3]=1.[H][H]>CO.[C].[Pt]>[Br:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]([CH:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]2=[O:22])=[C:6]([CH3:8])[CH:7]=1
Reactant: [H][H]
Reactant: Cc1cc(Br)cc(C)c1C1C(=O)CC(=CC2CCOCC2)C1=O
Agent: [Pt]
Solvent: CO
Product: Cc1cc(Br)cc(C)c1C1C(=O)CC(CC2CCOCC2)C1=O

Procedure:
A solution of 2-(4-bromo-2,6-dimethylphenyl)-4-[1-(tetrahydropyran-4-yl)methylidene]cyclopentane-1,3-dione (0.10 g, 0.26 mmol) in methanol (100 ml) is passed over a cartridge of 10% platinum carbon under a 20 bar hydrogen atmosphere. The reaction mixture is then concentrated in vacuo, and the crude product is purified by flash column chromatography (hexane/ethyl acetate as eluant) to afford rac-2-(4-bromo-2,6-dimethylphenyl)-4-(tetrahydropyran-4-ylmethyl)cyclopentane-1,3-dione.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH:9](OCC)=[O:10]>>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH:9]=[O:10]
Reactant: CCOC=O
Reactant: CN(C)CCCCN
Product: CN(C)CCCCNC=O

Procedure:
A solution of 4-dimethylaminobutylamine (3.0 g) in ethyl formate (30 mL) was stirred and heated at reflux under an atmosphere of nitrogen for 3 hours. After cooling, the mixture was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM (20%) to give N-(4-dimethylaminobutyl)formamide (2.7 g) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][C:24]=2[C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)(=[O:10])=[O:9])[CH:7]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=3)=[CH:23][C:24]=2[C:25]2[CH:29]=[N:28][NH:27][CH:26]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(Cl)cc2-c2cn[nH]c2)cc1F
Reactant: OB(O)c1cccc(F)c1
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: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(-c3cccc(F)c3)cc2-c2cn[nH]c2)cc1F
Reaction time: 0.33 h
Yield: 19.5 %

Procedure:
13.9 mg (0.03 mmol) of 5-chloro-4-((6-chloro-4-(1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide was dissolved in 1 mL of 1,4-dioxane, and 6.3 mg (0.05 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 3.5 mg (10 mol %) of Pd(PPh3)4, 12.4 mg (0.09 mmol) of Na2CO3, and 0.2 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 20 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, dimethylchloride:ethanol=15:1) to obtain 3.2 mg (19.7% yield) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:41])=[C:5]([C@@H:9]2[C@:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])([C:14]#[N:15])[C@H:12]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[NH:11][C@H:10]2[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([OH:40])=O)[CH2:33][CH2:32]2)=[O:30])[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:75][CH2:76][CH2:77][NH:78][CH3:79]>C(Cl)Cl>[Cl:2][C:3]1[C:4]([F:41])=[C:5]([C@@H:9]2[C@:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])([C:14]#[N:15])[C@H:12]([CH2:24][C:25]([CH3:27])([CH3:28])[CH3:26])[NH:11][C@H:10]2[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([N:78]([CH2:77][CH2:76][OH:75])[CH3:79])=[O:40])[CH2:33][CH2:32]2)=[O:30])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N2CCC(CC(=O)O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CNCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCO)C(=O)CC1CCN(C(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac {1-[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-acetic acid hydrochloride salt (80 mg, 0.127 mmol) in methylene chloride (5 mL), HATU (77 mg, 0.28 mmol) and DIPEA (94 uL, 0.54 mmol) were added followed by 2-hydroxy-ethyl-methyl amine (Oakwood, 20 mg, 0.27 mmol) and the mixture was stirred at rt overnight. The reaction was quenched with water and the mixture was extracted with methylene chloride (3×10 mL) and the extracts were combined and dried over sodium sulfate. The solvent was removed and the residue was chromatographed on a reverse phase HPLC (acetonitrile/water, 25-85%) to give a white solid. 46 mg.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:18][C:19]1[CH:38]=[CH:37][C:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1.ClC1C=CC=C(C(OO)=[O:47])C=1>O1CCCC1>[CH3:1][S:2]([CH2:3][CH2:4][CH2:5][N:6]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:30]=2)=[CH:37][CH:38]=1)[C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:11]=1)=[O:47]
Reactant: COC(=O)CCc1ccc(OCc2ccc(CN(CCCSC)c3nc(-c4ccccc4)cs3)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2ccc(CN(CCCS(C)=O)c3nc(-c4ccccc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
A mixture of methyl 3-{4-[(4-{[[3-(methylthio)propyl](4-phenyl-1,3-thiazol-2-yl)amino]methyl}benzyl)oxy]phenyl}-propanoate (280 mg), m-chloroperbenzoic acid (122 mg) and tetrahydrofuran (10 mL) was stirred at room temperature for 3 hr. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:0 in volume ratio) to give the title compound (180 mg, yield 62%) as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[CH3:5][O:6][C:7]1[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=1[C:9](Cl)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>N1C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=1[C:9]([O:4][CH2:3][CH2:2][Cl:1])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Reactant: OCCCl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccccc1C(OCCCl)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
2-Chloroethanol (4.02 ml, 60 mmol) and monomethoxytrityl chloride (9.2643 g, 30 mmol) were stirred in pyridine (150 ml) at room temperature for 3 hours. Cold water (15 ml) was added to the reaction solution and the mixture was stirred for 30 minutes, and the reaction mixture was extracted with chloroform (500 ml) and washed with water (200 ml ×3 times). The organic layer was dried with anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was distilled under a reduced pressure. n-Hexane (100 ml) was added to the residue to effect crystallization, and thus 9.6307 g (yield=91%) of 2-chloroethyl monomethoxytrityl ether <1> was obtained.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[C:12]3=[O:19])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:20](O)[CH2:21][CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[N:1]1([S:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[C:12]23[O:23][CH2:22][CH2:21][CH2:20][O:19]2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCCC3)cc2C1=O
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C1Nc2ccc(S(=O)(=O)N3CCCC3)cc2C12OCCCO2
Temperature: 25 °C
Yield: 168.9 %

Procedure:
A stirred mixture of 5-(pyrrolidin-1-ylsulfonyl)-1H-indole-2,3-dione (0.88 g, 3.14 mmol), 1,3-propanediol (0.92 mL, 1.26 mmol, 4 eq) and p-toluenesulfonic acid (1.19 g, 6.28 mmol, 0.2 mole % ) in benzene (100 mL) was refluxed with a Dean Stark Trap for 6 hours. The reaction was cooled to room temperature, washed with sat. aq. NaHCO3 (1×), water (2×), and brine (1×), dried over NaHCO3 (1×,), filtered and concentrated. The crude product was purified on Biotage KP silica gel eluting with 90/10 CH2Cl2/EtOAc to give the title compound as a white solid (0.72 g, 68% ). NMR (300 Mz, DMSO-d6): consistent. MS: (API-ES+) 338 [M+H] consistent.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc2ncccc2c1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3ncccc3c2)cc1

Procedure:
prepared by reaction of quinolin-6-ylamine with 4-tert-butyl-benzenesulfonyl chloride
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO.C(Cl)Cl.Cl>[OH-].[K+]>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCCCN1CCN(c2ccc(C(C)=O)cc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1ccc(N2CCN(CCCCC(=O)O)CC2)cc1
Temperature: 100 °C
Yield: 47.9 %

Procedure:
4-(4-Acetylphenyl)-1-piperazinevaleric acid, methyl ester (15.3 mg) is suspended in 0.1 mL of potassium hydroxide solution (33.2 mg/mL). After heating at 100° C. for 150 min, the starting material is completely dissolved and absent by TLC (10% MeOH/CH2Cl2). After acidifying the reaction solution to pH 4 by adding 0.2N HCl, the aqueous solution is extracted with methylene chloride. After evaporation of the organic layer to dryness, the residue is dissolved in methylene chloride and filtered. Evaporation of the organic layer gives 7 mg of 4-(4-acetylphenyl)-1-piperazinevaleric acid as a white solid. 1H-NMR (CDCl3) spectrum is consistant with the assigned structure. MS (FAB) m/e 305 (M+ +H), 327 (M+ +Na), 348 (M+ +2Na--H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[CH:21]([S:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27])([CH3:23])[CH3:22].C(OCC)(=O)C>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[S:24][CH:21]([CH3:23])[CH3:22])[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: CC(C)Sc1ccccc1N
Reactant: COc1ccc(Cn2nnc3c(Cl)nc(Cl)nc32)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(Cn2nnc3c(Nc4ccccc4SC(C)C)nc(Cl)nc32)cc1
Temperature: 25 °C

Procedure:
A solution of 5,7-dichloro-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (0.03 g) and 2-(isopropylthio)aniline (0.1 g) in dioxane (10 mL) was heated at 100° C. for 10 h. It was then cooled down to room temperature and ethyl acetate (20 mL) was added. The mixture was washed with saturated sodium bicarbonate (10 mL), and dried over sodium sulfate. Solvent was removed under reduced pressure and the remaining residue was purified on a silica gel column (ethyl acetate:hexane=1:10) to give desired product. ESMS calculated for C21H21ClN6OS (m/z): 440.1; found (M+H+): 441.1.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[Cl:16][C:17]1[CH:30]=[CH:29][C:28]2[C:19](=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=1>ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:30]=[CH:29][C:28]2[C:19](=[C:20]([CH:9]=[O:10])[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=1
Reactant: Clc1ccc2cc3ccccc3cc2c1
Reactant: CN(C=O)c1ccccc1
Solvent: Clc1ccccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c2ccccc2cc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
N-methylformanilide (2.45 kg, 18.12 mol) was treated with phosphorus oxychloride (2.66 kg, 17.35 mol) over a 40 min period at ambient temperature. The intermediate Vilsmeier complex was stirred for 2 h at room temperature, then treated with 2-chloroanthracene (described in example 1a) (963 g, 4.53 mol), and o-dichlorobenzene (1.0 L). The resulting bright yellow mixture was heated gradually over 1.5 h to 9° C. at which point an exotherm ensued raising the reaction temperature to 115° C. The heat was removed until the exotherm subsided (45 min), after which time the mixture was heated for 9 h at 90° C., then cooled. TLC analysis (silica gel; ethyl acetate:hexane 1:4) showed a small amount of unreacted anthracene (Rf 0.90), a small amount of the 3-chloro isomer (Rf 0.65), and the 2-chloro isomer (Rf 0.58) as the major component. The cooled reaction mixture was poured into ice/water (27 L) precipitating a dark brown tar. The aqueous layer was decanted away from the tar and extracted with methylene chloride (5×2 L). The combined extracts were used to redissolve the tar. The methylene chloride solution was washed with 3N hydrochloric acid (4×1.5 L), followed by water (2 L), then dried over magnesium sulfate. The extracts were filtered, then pressure-filtered through a bed of silica gel, eluting with methylene chloride until all of the desired compound had been recovered. The eluent was concentrated on the rotary evaporator to give a slurry of bright yellow crystals (in o-dichlorobenzene). The crystals were collected by filtration, washed with diethyl ether (2×500 ml), then vacuum dried to afford 619.7 g (56.9%) of the desired 2-chloro-9-formylanthracene (mp 148°-150° C.). 1H NMR (CDCl3) 11.35 (s, 1H), 9.02 (d, J=0.9 Hz, 1H), 8.81 (d, J=8.9 Hz, 1H), 8.56 (s, 1H), 7.98 (m, 1H), 7.90 (d, J=8.9 Hz, 1H), 7.66 (m, 1H), 7.53 (m, 1H), 7.42 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:17][CH3:18]>CN(C=O)C.CC(=O)OCC>[Cl:1][C:2]1[N:7]([CH2:17][CH3:18])[C:6](=[O:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Oc1cc(Cl)nc(Cl)n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(Cl)nc(Cl)cc1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A solution of 2,6-dichloro-pyrimidin-4-ol (1.0 g, 6.1 mmol) and K2CO3 (1.1 g, 7.9 mmol) in DMF (10 mL) was stirred at RT for 15 min. The reaction mixture was cooled to 0° C., and iodoethane (1.1 mL, 6.7 mmol) was added dropwise. After stirring overnight at RT, the reaction mixture was diluted with EA, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica chromatography (20:1, EA:PE) to give 330 mg (28%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.37 (t, J=7.6 Hz, 3H), 4.76 (q, J=6.8 Hz, 2H), 6.67 (s, 1H). [M+H] Calc'd for C6H6Cl2N2O, 193, 195, 197. Found, 193, 195, 197.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(=O)(O)[O-].[Na+].[I:15]I>CO.O>[F:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:6])=[C:7]([I:15])[CH:8]=1
Reactant: II
Reactant: Cc1cc(N)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(N)c(I)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
Into a solution of 4-fluoro-3-methylaniline (8.75 g, 70 mmol) in methanol (65 mL) and water (65 mL) was added sodium bicarbonate (5.88 g, 70 mmol) followed by portionwise addition of powdered I2 (17.78 g, 70 mmol). The mixture was stirred at room temperature overnight then treated with water (300 mL). The aqueous mixture was extracted with CH2Cl2 (3×200 mL). The organics were combined and washed with sat. aq. sodium thiosulfate, water, and brine. The mixture was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography with 30-100% CH2Cl2/hexane to give 4-fluoro-2-iodo-5-methylaniline (12.1 g, 69%), which contained ˜10% of the undesired isomer (4-fluoro-2-iodo-3-methylaniline).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.Cl[CH2:34][CH2:35][N:36]1[CH:40]=[N:39][CH:38]=[N:37]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:32][C:2]([F:31])([F:1])[C:3]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[N:18]([CH2:34][CH2:35][N:36]4[CH:40]=[N:39][CH:38]=[N:37]4)[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: ClCCn1cncn1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1CCn1cncn1
Temperature: 140 °C

Procedure:
A mixture of [(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 6; 0.064 mmol), 1-(2-chloroethyl)-1H-[1,2,4]triazole (0.096 mmol), K2CO3 (0.128 mmol) in DMF (1 mL) was heated in a microwave reactor at 140° C. for 10 min, then cooled to rt and concentrated in vacuo. The resultant residue was purified by silica gel chromatography (DCM/MeOH) to afford (5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[2-(1H-1,2,4-triazol-1-yl)ethyl]-1,3-thiazolidine-2,4-dione as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[CH:16][C:15]=1[C:27]([F:30])([F:29])[F:28].Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([C:27]([F:30])([F:28])[F:29])[CH:16]=2)=[N:22]1)=[O:12])[CH3:9]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)n[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
Triethylamine (0.17 g, 1.7 mmol) and ethyl isocyanate (0.12 g, 1.7 mmol) were added to a solution of 3-(4-chloro-3-trifluoromethylphenyloxy)-5-methylpyrazole (0.42 g, 1.5 mmol) in ethyl acetate (5 ml) at 0° C., and the mixture was allowed to have room temperature gradually and stirred for 5 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a yellow viscous substance of N-ethyl-3-(4-chloro-3-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.42 g, yield: 80.1%). 1H-NMR (CDCl3, TMS, ppm): δ 1.22 (t, J=7.2 Hz, 3H), 2.59 (d, J=0.8 Hz, 3H), 3.38 (dq, J=5.9 and 7.2 Hz, 2H), 5.73 (q, J=0.8 Hz, 1H), 6.91 (br s, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.49 (dd, J=2.4 and 8.8 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H).
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:15]Br>>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:15][C:14]2[CH:17]=[CH:18][C:19]([F:20])=[C:12]([F:11])[CH:13]=2)[N:6]=[C:7]([OH:9])[CH:8]=1
Reactant: Fc1ccc(CBr)cc1F
Reactant: Nc1cc(O)nc(S)n1
Solvent: O
Product: Nc1cc(O)nc(SCc2ccc(F)c(F)c2)n1

Procedure:
The subtitle compound was prepared according to the procedure of Example 1 step i) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (2.0 g) with 3,4-difluorobenzyl bromide (2.66 g) to afford the subtitle compound as a white solid. Yield: 3.35 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1.[N:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[C:26]=[O:27]>C(O)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:26]([NH:25][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:27])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(N)cc2)c1C
Reactant: O=C=Nc1ccccc1
Solvent: CCO
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NC(=O)Nc3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
To a mixture of [4-(4-amino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (115 mg, 0.34 mmol) and isocyanato-benzene (36 mg, 0.29 mmol) was added ethanol (5 mL) under nitrogen. The resulting suspension was stirred at room temperature for 4 hours and the precipitated solids were collected by filtration, washed with cold ethanol, and air-dried to give {6-chloro-3-methyl-4-[4-(3-phenyl-ureido)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (44 mg, 28%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.86 (s, 1 H), 8.77 (s, 1 H), 7.95 (d, J=8.8 Hz, 1 H), 7.86 (s, 1 H), 7.64 (d, J=8.5 Hz, 2 H), 7.42-7.53 (m, 3 H), 7.30 (t, J=7.8 Hz, 2 H), 7.20 (d, J=1.8 Hz, 1 H), 7.15 (d, J=8.5 Hz, 2 H), 6.94-7.03 (m, 1 H), 3.96 (s, 2 H), 3.66 (s, 3 H), 2.10 (s, 3 H). HRMS calcd. for C27H24ClN2O3 [(M+H)+] 459.1470, obsd. 459.1470.