Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25]Br)=[C:15]1[CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:36][C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][CH:38]=1.O>CN(C=O)C>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:36][C:37]2[CH:38]=[CH:39][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:45][CH:46]=2)=[C:15]1[CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1c(CCBr)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCCc2c(CO[Si](C)(C)C(C)(C)C)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
1-benzhydryl-3-(2-bromoethyl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-chloro-1H-indole (1 eq) was mixed with Methyl 4-mercaptobenzoate (2 eq) and KC2CO3 (1.9 eq) in DMF (0.09M). The resulting mixture was stirred at rt under N2 overnight. Water was then added, followed by regular work-up (eg. EtOAc extration, brine wash, etc) and column purification (1:6 EtOAc/Hexane as eluent) to give methyl 4-({2-[1-benzhydryl-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)benzoate (yellow oil) in 81% yield.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[NH2:7][S:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[N:12]([CH3:20])[C:11]=1[C:21]([O:23]CC)=O)=[O:9]>O.CC(C)=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]2[N:12]([CH3:20])[C:11]3[C:21](=[O:23])[NH:7][S:8](=[O:9])(=[O:2])[C:10]=3[C:18]=2[CH:17]=1
Reactant: CCOC(=O)c1c(S(N)=O)c2cc(Cl)ccc2n1C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cn1c2c(c3cc(Cl)ccc31)S(=O)(=O)NC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 15.8 gm (0.1 mols) of potassium permanganate in 300 ml of water was added dropwise over a period of 2.5 hours to a solution of 37.6 gm (0.125 mols) of ethyl 3-aminosulfinyl-5-chloro-1-methyl-indole-2-carboxylate in 2500 ml of acetone at 20° C. After stirring overnight at room temperature, the precipitate which had formed was filtered off and washed with warm water and acetone. The filtrate then was evaporated in vacuo at 25°-30° C. to a volume of about 350 ml. The crystallized product, ethyl 5-chloro-1-methyl-3-sulfamoyl-indole-2-carboxylate, was filtered off, washed with water and dried. Yield: 30.5 gm (77% of theory); M.p.: 207°-208° C. After acidification of the filtrate to pH 3, another product, 7-chloro-4-methyl-2H-isothiazolo[4,5-b]indole-3-(4H)-one-1,1-dioxide, was obtained, which was filtered off, washed with water and dried. Yield: 3.9 gm (12% of theory); M.p.: 288° C. (decomposition).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>O1CCCC1>[Cl:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Cl)c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-chlorophenyl isocyanate (0.148 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 100 mg (30.9%) of the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:8][CH3:9])[C:4]([O:6]C)=[O:5].O.[OH-].[Li+:12]>CO.O>[CH3:1][O:2][CH:3]([CH2:8][CH3:9])[C:4]([O-:6])=[O:5].[Li+:12]
Reactant: CCC(OC)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(OC)C(=O)[O-]
Reaction time: 8 h

Procedure:
In a 15-mL RBF was dissolved methyl 2-methoxybutanoate (0.027 g, 0.20 mmol) in methanol (0.75 mL). A solution of lithium hydroxide monohydrate (0.0086 g, 0.20 mmol) in water (0.75 mL) was added, and the mixture was stirred overnight. The mixture was concentrated to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]#[CH:25])[CH:21]=[CH:22][CH:23]=1>CCOCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:25]#[C:24][C:20]2[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=2)[NH2:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C#Cc1cccc(N)c1
Reactant: Fc1ccc(Br)cc1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Nc1cccc(C#Cc2ccc(F)c(F)c2)c1
Temperature: 65 °C
Yield: 38.5 %

Procedure:
A multinecked flask as described in Example 1 was charged with 5.0 g (0.026 mol) of 3,4-difluorobromobenzene, 50 ml of dried, degassed triethylamine, 3.0 g (0.026 mol) of 3-aminophenylacetylene, 0.07 g (0.1 mmol) of bis(triphenylphosphine) palladium II chloride, 0.1 g (0.38 mmol) of triphenylphosphine, and 0.02 g (0.1 mmol) of cuprous iodide. The reaction mixture was heated at 65° C. for 36 hours at which point gas chromatography showed the reaction to be complete. The product mixture was cooled to room temperature and diluted with 50 ml of ether. Filtration of the insoluble triethylamine hydrobromide salt by-product followed by concentration of the filtrate gave the crude product (4.2 g, 78% yield) as a off-white solid. Short path distillation of the crude product under reduced pressure gave 2.38 g (0.01 mol, 38% yield) of the purified product as a colorless liquid which crystallized on standing.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([C:22]([O:24][CH3:25])=[O:23])[CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]O)=[C:29]([N+:35]([O-:37])=[O:36])[CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][CH2:14][CH:13]([N:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:10])=[O:11])[CH2:31][C:30]1[CH:33]=[CH:34][C:27]([Cl:26])=[CH:28][C:29]=1[N+:35]([O-:37])=[O:36])[C:22]([O:24][CH3:25])=[O:23]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CO
Reactant: COC(=O)[C@H](COC1CCCCO1)NS(=O)(=O)c1ccc(OC)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(COC1CCCCO1)N(Cc1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1.67 g (4.4 mmol) of (D,L) N-(4-methoxybenzenesulfonyl)-O-(2-tetrahydropyranyl) serine, methyl ester, 0.825 g (4.4 mol) of 4-chloro-2-nitrobenzyl alcohol and 1.16 g (4.4 mmol) of triphenylphosphine in 4.5 ml of tetrahydrofuran was added dropwise a solution of 0.766 g (4.4 mmol) of diethyl azodicarboxylate in 1 ml of tetrahydrofuran. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. The residue was triturated with diethyl ether, filtered and the filtrate passed through a thin pad of hydrous magnesium silicate. The pad was washed with ethyl acetate and the total filtrate concentrated to dryness under vacuum to give 4.54 g of solid. The solid was chromatographed on silica gel with hexane-ethyl acetate (55:45) as solvent. The fractions containing product were combined and the solvent removed to give 0.55 g of oily solid; Mass spectrum (ES) 543.1 (M+H).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][N:23]([CH2:2][CH:3]2[CH2:5][CH2:4]2)[C:22](=[O:26])[CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1cc(OCc2ccccc2)ccn1CC1CC1
Yield: 99.7 %

Procedure:
(Bromomethyl)cyclopropane (3.68 g, 27.33 mmol) and potassium carbonate (10.3 g, 74.52 mmol) were added to a solution of 4-benzyloxy-1H-pyridin-2-one (5.0 g, 24.84 mmol) in acetonitrile (200 ml) and the mixture was heated at reflux temperature for 16 hours. Subsequently, the reaction mixture was filtered through diatomaceous earth and concentrated in vacuo. The crude residue was then triturated with diethyl ether to yield pure D1 (6.32 g, 98%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](I)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:24][CH:25]([OH:28])[C:26]#[CH:27].CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:27]#[C:26][CH:25]([OH:28])[CH3:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cc2c1O
Reactant: C#CC(C)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)C#Cc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C
Yield: 20 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example No. 40 (800 mg), 3-butyn-2-ol (0.20 mL), PdCl2 (PPh3)2 (32.3 mg), and 1.16 mL Et3N in 4.64 mL anhydrous DMF is heated at 90° C. for 1 hr. The reaction mixture is cooled to room temperature and partitioned between EtOAc and H2O. The aqueous layer is washed with EtOAc (3×). The combined organic layers are dried over Na2SO4 and condensed to obtain a red-brown residue. The residue is chromatographed eluting with 3% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 139.2 mg (20%) of the title compound as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[IH:12].C(O)(=O)C>O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([I:12])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: I
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(I)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 2 liter single-neck round bottom flask with a mechanical stirrer was charged 2-amino-6-chloropurine (41.0 g, 242 mmol). The flask was cooled in an ice-water bath. The the reaction flask was charged HI (47% solution, pre-cooled in a refrigerator, 250 mL) in one portion. The resulting suspension was stirred for 16 hours at ice-water bath temperature. Water (500 mL) was charged to the reaction flask. The suspension was stirred at 0° C. for 1 hour. The precipitate was filtered and washed with water (3×250 mL). The filter cake was transferred to a 250 mL filtration flask. 6 M NaOH solution (85 mL) was added to the solid through the filter to rinse out residual solid and wash into the filter flask. The solution obtained was added slowly to a boiling solution of acetic acid (25 mL) and water (250 mL). The resulting suspension was cooled to room temperature and stirred at room temperature for 2 hours. The solid was collected by centrifugation, washed with water (2×250 mL), followed by heptane (250 mL). The solid was first spin-dried on the centrifuge for 30 minutes and then dried in a vacuum oven overnight to provide the desired product (61.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]([OH:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(O)C1(c2ccc(Cl)cc2)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)CC(=O)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.8 %

Procedure:
A solution of ethyl 1-(p-chlorophenyl)-β-hydroxy-cyclopropanepropionate (7.9 g, 29.4 mmol) and 4-methyl-morpholine N-oxide (14.0 g, 120 mmol) in acetonitrile containing 30 4 Å molecular sieves is stirred at room temperature for 20 minutes, treated with tetrapropyl-ammonium perruthenate (0.8 g, 2.3 mmol), stirred for two hours while maintaining the reaction mixture temperature at room temperature with an ice-water bath, diluted with diethyl ether, filtered through diatomaceous earth, and concentrated in vacuo to obtain a residue. A solution of the residue in diethyl ether is washed sequentially with water, 5% sulfuric acid, water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a dark oil. Chromatography of the oil using silica gel and a 1:19 to 3:17 ethyl acetate/hexanes gradient gives the title product as a pale yellow oil (4.3 g, 55%) which is identified by NMR spectral analyses.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9](O)=[O:10])([O-:3])=[O:2].C(OCC)(=O)C.S(Cl)([Cl:23])=O.Cl>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([Cl:23])=[O:10])([O-:3])=[O:2]
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cl)C=Cc1cccc([N+](=O)[O-])c1
Yield: 96.9 %

Procedure:
193.2 g (1 mole) of 3-nitrocinnamic acid and 650 g of ethyl acetate were placed in a reaction vessel. While 200 g of thionyl chloride with some drops of DMF was dropped into the reaction mixtures, the reaction mixtures were refluxed with stirring until the generation of hydrogen chloride gas stopped. The reacted solution was concentrated until a solid could be precipitated and poured into hexane. The precipitate was separated by filtration and dried. 205 g of 3-nitrocinnamoyl chloride was yielded.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[NH:5][S:4]1(=[O:13])=[O:12].[P:14]([O-:22])([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[CH2:17]([O:16][P:14]([O:19][CH2:20][CH3:21])([O:22][CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[NH:5][S:4]1(=[O:13])=[O:12])=[O:15])[CH3:18]
Reactant: CCOP(=O)([O-])OCC
Reactant: CCCC1NS(=O)(=O)N(CCl)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC1NS(=O)(=O)N(COP(=O)(OCC)OCC)C1=O
Yield: 35 %

Procedure:
2-Chloromethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1 g; 4.42 mmol) was added to a solution of diethyl phosphate (Formula III: A=B=Et) (1.02 g; 6.62 mmol) in methylene chloride (5 ml) containing triethylamine (0.67 g; 6.63 mmol), and the mixture was allowed to reflux for 24 hours and then cooled. The mixture was concentrated in vacuo and the residue purified by silica gel flash chromatography (50% ethyl acetate/hexane) to afford 0.54 g (35%) of 2-(diethoxyphosphinyloxymethyl)-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: R1 =H; R2=propyl; R3 =H; A=B=Et) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:12])[CH:10]=[O:11])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[C:9]([CH3:12])[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CC(C=O)=Cc1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=Cc1ccc(F)cc1)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution of 113 g (0.69 mole) of 3-(4-fluorophenyl)-2-methyl-2-propen-1-al in 800 ml ethanol at 10° C. was added in portions 13.1 g (0.345 mole) of sodium borohydride. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The mixture was cooled in an ice bath while 350 ml of 1 N hydrochloric acid was added dropwise to give a final pH of ~7. The mixture was diluted with 500 ml water and extracted three times with methylene chloride. The organic extracts were dried and concentrated and the residue distilled to give 56.1 g (49%) of colorless liquid, b.p. 68°-70° C. (0.15 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1I.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:11])[C:17]=1[Cl:18]
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: Nc1cc(Cl)c(I)cc1N
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: Nc1cc(Cl)c(-c2cccc(Cl)c2Cl)cc1N
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-5-iodobenzene-1,2-diamine (100 mg, 0.37 mmol) in dioxane (15 ml) and water (5 ml) was added (2,3-dichlorophenyl)boronic acid (141.3 mg, 0.74 mmol), sodium carbonate (118.2 mg, 1.10 mmol) and Pd(PPh3)4 (42.9 mg, 0.04 mmol). The resulting solution was stirred overnight at 100° C. within an inert atmosphere of nitrogen. The resulting solution was concentrated under vacuum and dissolved in water (100 ml) and extracted with ethyl acetate (4×30 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with between 5% to 25% ethyl acetate in petroleum ether to afford 4-chloro-5-(2,3-dichlorophenyl)benzene-1,2-diamine as a brown solid (92 mg, crude). Finally, the solution of 4-chloro-5-(2,3-dichlorophenyl)benzene-1,2-diamine (100 mg, 0.35 mmol) in pentafluoropropionic acid (35 ml) and hydrochloric acid (conc, 7 ml) was stirred overnight at 100° C. and then concentrated under vacuum. The residue was dissolved in water (100 ml) and extracted with ethyl acetate (4×30 ml), dried over anhydrous sodium sulfate and concentrated. The crude product (500 mg) was purified by Prep-HPLC to afford 5-chloro-6-(2,3-dichlorophenyl)-2-(pentafluoroethyl)-1H-1,3-benzodiazole. TFA salt as a white solid (42 mg).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[Cl:22]C1C=C(C=CC=1Cl)C=O>>[Cl:22][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(Cl)c2)s1

Procedure:
The title compound is prepared by an analogous procedure to N-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) by replacing 3,4-difluorobenzaldehyde with 3,4-dichlorobenzaldehyde.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([O:9][C@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH:22]([C:24](OCC)=[O:25])[NH2:23]>CN1C(=O)CCC1.CCOC(C)=O>[O:25]=[C:24]1[NH:22][N:23]=[C:1]([C:3]2[N:8]=[C:7]([O:9][C@H:10]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[CH:6]=[CH:5][CH:4]=2)[NH:2]1
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc(C#N)n2)C1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc(-c3n[nH]c(=O)[nH]3)n2)C1
Temperature: 175 °C

Procedure:
To crude (S)-tert-butyl 3-((6-cyanopyridin-2-yl)oxy)pyrrolidine-1-carboxylate (1.044 g) in NMP (1.5 mL) was added ethyl hydrazinecarboxylate (0.752 g, 7.22 mmol). The reaction mixture was heated at 175° C. overnight and was subsequently cooled and diluted with EtOAc. The organic phase was washed with saturated aqueous NH4Cl, dried, and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](F)[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][CH:22]([OH:24])[CH3:23]>>[Cl:1][C:2]1[CH:10]=[C:9]([O:24][CH:22]([CH3:23])[CH3:21])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)O
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)Oc1cc(Cl)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
A mixture of 2-chloro-4-fluoro-5-nitro-benzoic acid (5.0 g, 22.8 mmol) and cesium carbonate (29.7 g, 91.1 mmol) in 2-propanol (100 mL) is heated at 50° C. overnight. The solvent is removed in vacuo and 100 mL of water is added. Concentrated aqueous HCl is added dropwise to this solution at 0° C. until pH=2. The product precipitate which forms is isolated by filtration, washed by water and dried under vacuum to give 2-chloro-4-isopropoxy-5-nitro-benzoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].[C:25]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]([CH3:25])[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc(-c2ccccc2OCc2ccccc2)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (0.25 g, 0.00078 mole) in DMF (5 mL) was added K2CO3 (0.225 g, 0.00163 mole) followed by methyl iodide (0.116 g, 0.00081 mole) and at the resulting mixture was stirred at ambient temperature for 1 hour. The mixture was then quenched with iced water and the resulting precipitate was isolated by filtration. The solid was recrystallized from ethyl acetate to afford 0.251 g (96%) of 5-(2-benzyloxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 337.15 (M+1)+, 90.13%. To a stirred solution of 5-(2-benzyloxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (0.251 g, 0.00075 mole) in methanol (40 mL) was added 10% Pd/C (0.05 g) and the resulting mixture was stirred under an atmosphere of hydrogen for 1 hour. The mixture was then filtered through celite and the celite was washed with methanol. The combined filtrate was concentrated under reduced pressure to afford 0.169 g (92%) of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 247.1 (M+1)+, 99%. To a stirred solution of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (0.169 g, 0.00069 mol) in a mixture of THF (10 mL), methanol (5 mL) and H2O (5 mL), was added LiOH.H2O (0.087 g, 0.00206 mol) at ambient temperature and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and acidified with 10% HCl. The product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 0.13 g (87%) of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid. LCMS: 219.07 (M+1)+, 81.5%
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[CH2:19][CH2:20][C:21]#[N:22]>>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[CH2:19][C:20]1[C:21]([NH2:22])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: COc1cccc(Cl)c1CCC#N
Reactant: Nc1ccccc1C=O
Product: COc1cccc(Cl)c1Cc1cc2ccccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-aminobenzaldehyde and 3-(2-chloro-6-methoxyphenyl)propionitrile.