Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.O.[NH2:20][NH2:21]>C(O)C>[NH:20]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1)[NH2:21]
Reactant: Fc1cccc(Oc2ccc(C(F)(F)F)cc2)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1cccc(Oc2ccc(C(F)(F)F)cc2)n1
Temperature: 40 °C
Yield: 47.8 %

Procedure:
Next, a reaction flask was loaded with 2-fluoro-6-(4-trifluoromethylphenoxy)pyridine (8.0 g) and ethanol (60 ml), and heated up to 40° C. with stirring. To this mixture, hydrazine monohydrate (7.6 g) was dropwise added in 30 minutes. The temperature of the mixture was raised to the reflux temperature, followed by stirring for 20 hours. Thereafter, the heating was stopped, and the reaction mixture was cooled, followed by filtration to remove insoluble components. The filtrate was condensed by an evaporator to give 2-hydrazino-6-(4-trifluoromethylphenoxy)pyridine (4.0 g).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[CH3:7][C:8]1[N:9]=[C:10]([NH:21][C:22]2[CH:27]=[N:26][CH:25]=[CH:24][N:23]=2)[S:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](SC)=[CH:15][CH:14]=1.[CH3:28]C(C)=O.O>>[CH3:28][S:3]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[S:11][C:10]([NH:21][C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)=[N:9][C:8]=2[CH3:7])=[CH:14][CH:15]=1)(=[O:5])=[O:2]
Reactant: O=S([O-])OO
Reactant: CSc1ccc(-c2sc(Nc3cnccn3)nc2C)cc1
Reactant: CC(C)=O
Agent: [K+]
Solvent: O
Product: Cc1nc(Nc2cnccn2)sc1-c1ccc(S(C)(=O)=O)cc1

Procedure:
Oxone (Potassium peroxymonosulfate) (0.417 g, 0.77 mmol) is added to a stirred solution of [4-methyl-5-(4-methylsulfanyl-phenyl)-thiazol-2-yl]-pyrazin-2-yl-amine (27c) (0.05 g, 0.16 mmol) in acetone-water (9:1). After 2 hours at room temperature the solid precipitate is removed by filtration. The solid is dissolved in methanol, filtered to remove oxone and the solvent is removed from the filtrate to afford the title compound as a yellow solid (0.022 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:12][C:13]([CH:16]=O)([CH3:15])[CH3:14].[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:18]1([CH:16]([NH:7][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:10]=[C:9]([Cl:11])[CH:8]=2)[C:13]([CH3:14])([CH3:15])[CH3:12])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: NC(=O)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(NC(=O)c1cc(Cl)cc(Cl)c1)n1nnc2ccccc21

Procedure:
A suspension of 3,5-dichlorobenzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1C to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:5]([NH2:13])[NH:4][N:3]=1.CO[CH:16](OC)[CH:17]([CH:21](OC)OC)[CH2:18][C:19]#[N:20].ClC1C=CC2N=NN(OC(=[N+](C)C)N(C)C)C=2C=1.C([O-])(O)=O.[Na+]>CS(C)=O.O.CCOC(C)=O>[NH2:13][C:5]1[C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:2]2[N:1]=[CH:16][C:17]([CH2:18][C:19]#[N:20])=[CH:21][N:3]2[N:4]=1
Reactant: COC(OC)C(CC#N)C(OC)OC
Reactant: C=CCOC(=O)c1c(N)n[nH]c1N
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: C=CCOC(=O)c1c(N)nn2cc(CC#N)cnc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a suspension of allyl 3,5-diamino-1H-pyrazole-4-carboxylate 3 (63.49 g, 348.5 mmol) in a mixture of DMSO (340 mL) and water (340 mL), was added 3-(dimethoxymethyl)-4,4-dimethoxy-butanenitrile (85 g, 418.2 mmol), followed by para-toluene Sulfonic acid hydrate (1) (11.27 g, 59.24 mmol). The reaction mixture was heated to 85° C. and stirred overnight. The reaction mixture was cooled with an ice bath. The mixture was diluted with EtOAc (680 mL) and a saturated aqueous solution of NaHCO3 (1.36 L). The precipitate was filtered and rinsed with water, then with a mixture of water and EtOAc. The brown solid was dried under vacuum to give allyl 2-amino-6-(cyanomethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylate 4c as a brown solid (55.94 g, 62% yield).
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]2[N:22]=[C:21]([NH2:23])[C:20]([NH2:24])=[C:19]([NH2:25])[N:18]=2)=[N:9]1.N1C=CC=CC=1.Cl[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38]>ClCCl.CO>[NH2:25][C:19]1[C:20]([NH:24][C:37](=[O:38])[O:39][CH:40]([CH3:42])[CH3:41])=[C:21]([NH2:23])[N:22]=[C:17]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:8]([CH2:7][C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[F:4])[N:9]=2)[N:18]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1N
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)OC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N

Procedure:
Prepared in analogy to Example 2 with 150 mg (0.43 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine trihydrochloride from Example 8A, 7.5 ml of pyridine and 52.47 mg (0.43 mmol) of isopropyl chloroformate. The residue is taken up in a dichloromethane/methanol mixture, filtered and dried.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([OH:13])=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=1.C(OP([C:22](Br)([F:24])[F:23])(=O)OCC)C.CC[O:28]C(C)=O>O.C(#N)C>[F:23][CH:22]([F:24])[O:28][O:13][C:7]1[CH:6]=[CH:5][C:4]([F:3])=[CH:9][C:8]=1[C:10](=[O:12])[CH3:11]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1cc(F)ccc1OOC(F)F
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
Potassium hydroxide (40 g, 714 mmol) was dissolved in water (100 mL) and acetonitrile (100 mL). The reaction mixture was cooled to −78° C. 1-(5-Fluoro-2-hydroxyphenyl)ethan-1-one (5 g, 32.44 mmol) was added to the reaction mixture and stirred for 5 minutes at −78° C. Diethyl[bromo(difluoro)methyl]phosphonate (11.5 mL, 64.88 mmol) was added dropwise to the mixture. The reaction mixture was stirred at −78° C. for 30 minutes, then warmed to room temperature over 1.5 h. The reaction mixture was diluted using EtOAc (2×100 mL). The mixture was washed with brine (50 mL). The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude orange oil was purified by chromatography on silica (Biotage, 100 g cartridge), eluting with 0 to 40% ethyl acetate in heptanes, to afford the title compound (4.86 g, 74%) as a clear oil. δH (500 MHz, CDCl3) 7.47 (ddd, J 0.5, 3.0, 8.5 Hz, 1H), 7.24-7.14 (m, 2H), 6.55 (t, J 73.3 Hz, 1H), 2.62 (s, 3H). Method B HPLC-MS: RT 1.84 minutes, no mass ion observed.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].C(#[N:14])C>>[ClH:11].[NH2:14][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CC#N
Product: Cl
Product: NCC(=O)c1ccc(Cl)cc1
Temperature: 105 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
A mixture of 2-bromo-1-(4-chlorophenyl)ethanone (1.0 eq.) and NaN(CHO)2 (1.1 eq.) in acetonitrile (1.5 mL per mmol) was heated to reflux for 4 h at 105° C. ext. temperature. The formed sodium bromide was removed by filtration and the filtrate concentrated in vacuo. The residue was dissolved in ethanol (2.5 mL per mmol) and conc. aq. hydrochloric acid (0.9 mL per mmol) added at ambient temperature. After stirring for 72 h at room temperature the solids were filtered off and washed with ethanol (1×0.5 mL per mmol). Drying of the solids afforded 2-amino-1-(4-chlorophenyl)ethanone hydrochloride in ca. 50% yield that was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[N+:10]([O-])([OH:12])=[O:11]>>[Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([F:8])=[CH:6][C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(Cl)cc1F
Product: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a 1-chloro-3,4-difluorobenzene (25 g, 0.17 mol) cooled to 0° C. was added fuming nitric acid (50 mL) dropwise over 30 min. The orange solution was warmed to room temperature and stirred for 2 h. The solution was poured slowly over ice and the resultant mixture extracted with diethyl ether. The diethyl ether layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give 26 g (80%) of 1-chloro-4,5-difluoro-2-nitro-benzene: Crude 1H NMR (400 MHz, CDCl3): δ 7.88 (dd, J=9.3, 7.6 Hz, 1H), 7.43 (dd, J=9.3, 7.1 Hz, 1H). The crude material was pure enough to carry on to the next step.
Reaction SMILES: [C:1](Cl)(=[O:6])[O:2][CH:3]([Cl:5])[CH3:4].[CH:8]([OH:11])([CH3:10])[CH3:9].N1C=CC=CC=1>C(Cl)Cl>[C:1](=[O:6])([O:11][CH:8]([CH3:10])[CH3:9])[O:2][CH:3]([Cl:5])[CH3:4]
Reactant: CC(C)O
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)OC(C)Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a solution of 1-chloroethyl carbonochloridate (10 g, 69.9 mmol) in DCM (200 mL) was added a solution of isopropanol (5.9 mL, 76.9 mmol) and pyridine (6.75 mL, 83.9 mmol) in DCM (50 mL) at −20° C. The reaction was stirred at 0° C. for 2 h, then at rt for another 2 h. The mixture was washed with 1N HCl solution (250 mL×2), followed by brine (250 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as colorless oil (9.6 g, 82.4%). The product was used in the next step without further purification. The title compound was characterized by 1H NMR as shown below:
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.C(OCC)C.[NH4+:12].[Cl-].C1COCC1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[NH2:12][C:20]1[CH:21]=[CH:22][C:23]([C:5]#[CH:6])=[CH:24][N:19]=1
Reactant: [NH4+]
Reactant: C#C[Si](C)(C)C
Reactant: C1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#Cc1ccc(N)nc1
Reaction time: 8 h
Yield: 61 %

Procedure:
2-Amino-5-bromopyridine (8.65 g, 50.0 mmole) and bis-trimethyl-silylacetamide (36.76 mL, 150.0 mmole) was stirred at 100° C. overnight. The mixture was purified by distillation to give 10.41 g (85%) of the protected amine. 2-Trimethylsilylamlno-5-bromopyridine (4.90 g, 20.0 mmole), bis(triphenylphosphine)palladium-(II) chloride (0.70 g, 1.00 mmole) and trimethylsilylacetylene (5.65 mL, 40.0 mmole) in piperidine (2 mL) was stirred under nitrogen at 80° C. overnight. Diethyl ether and NH4Cl (aq) was added to the mixture and the organic phase was separated, dried over Na2SO4 and evaporated. Tetrabutylammonium chloride (50.0 mL, 100.0 mmole) and THF (250 mL) was added to remove the protection groups and the mixture was stirred overnight. THF was evaporated. The residue was purified by silica gel column chromatography (EtOAc/Hexane, 40:60) to give 2.36 g, (61%) of the titled compound. 1H NMR (250 MHz, CDCl3) δ 3.05 (s, 1H), 4.65 (br s, 2H), 6.45 (d, 1H), 7.50 (dd, 1H), 8.25 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3](/[CH:9]=[CH:10]/[C:11]([O:13]CCCC)=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C>CO.C(O)=O.[C].[Pd]>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([CH2:9][CH2:10][C:11](=[O:13])[NH:1]2)=[N:4][CH:5]=1
Reactant: CCCCOC(=O)/C=C/c1ncc(F)cc1N
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O=C1CCc2ncc(F)cc2N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a suspension of 9.1 g of butyl (2E)-3-(3-amino-5-fluoropyridin-2-yl)acrylate and 0.9 g of 10% palladium carbon in 30 mL of methanol, 4 mL of formic acid was added, and 15 mL of triethylamine was added dropwise thereto under ice cooling. The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, insoluble matter was filtered out, and the filter residue was washed using 30 mL of toluene. The filtrate and the wash liquid were combined and the solvent was evaporated under reduced pressure. To the obtained residue, 30 mL of toluene was added, the mixture was stirred at 100° C. for 2 hours and 30 minutes. To the reaction mixture, 30 mL of water was added dropwise at 45° C. and the mixture was cooled to 5° C. The solid product was obtained by filtration and washed in the order of water and toluene to give 5.7 g of 7-fluoro-3,4-dihydro-1,5-naphthyridin-2(1H)-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[C:16](=S)=[S:17].II>C(O)C.O1CCOCC1>[N:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[C:16]=[S:17]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: S=C=S
Agent: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N=C=S)cc1
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
A mixture comprising 4-aminobenzoic acid (0.20 g, 1.5 mmol), dioxane (5 mL), a saturated sodium hydrogencarbonate aqueous solution (5 mL) and carbon disulfide (0.37 mL, 6.1 mmol) was stirred in a nitrogen atmosphere at room temperature for 19 hours and then concentrated under reduced pressure to dryness. The obtained residue was dissolved in water (8.0 mL), and 1M sodium hydroxide aqueous solution (1.5 mL) was added. With stirring at room temperature, an ethanol (8.0 mL) solution of iodine (0.38 g, 1.5 mmol) was dropwise added thereto over a period of 8 minutes, followed by stirring at room temperature for further 12 minutes. Then, the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to remove ethanol and dioxane as far as possible. Then, 1M hydrochloric acid (4.5 mL) was added, and the precipitated solid was collected by filtration to obtain 4-isothiocyanatobenzoic acid as a ocher solid (0.20 g, yield: 78%). The HPLC purity was 62%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:4]=1.Br[CH2:16][CH2:17][Cl:18].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:18][CH2:17][CH2:16][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[O:7][N:6]=2)=[CH:9][CH:10]=1.[N:19]1([CH2:16][CH2:17][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[C:3]([CH2:2][OH:1])[O:7][N:6]=3)=[CH:9][CH:10]=2)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: OCc1cc(-c2ccc(O)cc2)no1
Reactant: c1c[nH]cn1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1cc(-c2ccc(OCCCl)cc2)no1
Product: OCc1cc(-c2ccc(OCCn3ccnc3)cc2)no1

Procedure:
{3-[4-(2-chloro-ethoxy)-phenyl]-isoxazol-5-yl}-methanol was synthesized using 4-(5-hydroxymethyl-isoxazol-3-yl)-phenol and 2-bromo-1-chloroethane in the same manner as in Example 10, and then 2 equivalents of imidazole and 3 equivalents of potassium carbonate were added to the compound and refluxed with acetonitrile. After 12 hours of the reaction, the solvent was dried under reduced pressure and purified by column chromatography to obtain {3-[4-(2-imidazol-1-yl-ethoxy)-phenyl]-isoxazol-5-yl}-methanol. A carbamoylation of the compound was performed in the same manner as in Example 1-3 to obtain carbamic acid 3-[4-(2-imidazol-1-yl-ethoxy)-phenyl]-isoxazol-5-ylmethyl ester as a desired compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[C:14](=O)([O-])[O-].[K+].[K+].IC.Cl>CN(C=O)C>[CH3:14][O:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(C(C)=O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A slurry of 1-(2-hydroxy-3-nitrophenyl)ethanone (1.00 g, 5.52 mmol) and potassium carbonate (3.05 g, 22.08 mmol) in DMF (20 mL) was stirred at room temperature for 30 minutes, then iodomethane (1.338 mL, 16.56 mmol) was added dropwise and the resulting mixture was allowed to stir at room temperature overnight. LCMS indicated some un-reacted starting material remained, therefore additional iodomethane (1.338 mL, 16.56 mmol) was added and the mixture was warmed to 50° C. over 2 days. Reaction was quenched by the addition of water to give a solution followed by adjusting the pH with 1N HCl to ˜7. The resulting solution was extracted with ethyl acetate (80 mL×3) and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the product, 1-(2-methoxy-3-nitrophenyl)ethanone (1.05 g, 5.38 mmol, 97% yield) as a tan oil. HPLC (Method N) RT=1.86 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH2:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[C:29](=[O:45])[N:30]([CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[C:31]2=[O:36].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:25][CH2:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[C:29](=[O:45])[N:30]([CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[C:31]2=[O:36])=[O:7]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(Cl)c(Cl)c4)c3C2=O)C(=O)N1
Temperature: 40 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
3,4-Dichlorobenzoic acid (0.30 g, 1.6 mmol) was dissolved in 10 mL DMF and CDI (0.30 g, 1.9 mmol) was added. The mixture was stirred at 40° C. for 1 hour, and then 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.50 g, 1.6 mmol) and triethylamine (0.31 g, 3.1 mmol) were added. After an additional 90 minutes stirring at 40° C., the mixture was cooled. The solvent was evaporated, and the residue was dissolved in 60 mL CH2Cl2, and this solution was washed with water (2×60 mL), dried (MgSO4), and evaporated. The residue was chromatographed using a methylene chloride-methanol gradient, eluting 0.49 g of the product with 98:2 methylene chloride-methanol, in 70% yield: mp 161-163° C.; 1H NMR (DMSO-d6) δ 2.06-2.09 (m, 1H), 2.51-2.58 (m, 2H), 2.84-2.91 (m, 1H), 4.94 (d, J=5.7 Hz, 2H), 5.17 (dd, J=12.6 Hz, d=5.3 Hz, 1H), 7.74-7.95 (m, 5H), 8.17 (d, J=1.9 Hz, 1H), 9.33 (t, J=5.7 Hz, 1H), 11.10 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.5, 48.9, 122.0, 127.2, 127.7, 129.3, 130.8, 131.3, 131.6, 133.3, 134.3, 134.9, 138.8, 164.4, 167.0, 167.5, 169.8, 172.8; Anal. calcd for C21H15Cl2N3O5: C, 54.80; H, 3.28; N, 9.13. Found: C, 54.85; H, 3.36; N, 8.95.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[CH2:6]2.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:24]=O)[CH:22]=2)[CH:17]=[N:16]1>>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](/[CH:24]=[C:6]3/[C:7](=[O:14])[NH:8][C:9]4[C:5]/3=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=4)[CH:22]=2)[CH:17]=[N:16]1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: COc1cc2c(cc1OC)NC(=O)C2
Product: COc1cc2c(cc1OC)/C(=C\c1ccc3cn[nH]c3c1)C(=O)N2
Yield: 66.9 %

Procedure:
The title compound (43 mg, 67%) was synthesized as an orange yellow solid according to the method described for Example A67 (oil temp 75° C., reflux 90 min) using 5,6-dimethoxyindolin-2-one (38.6 mg, 0.2 mmol) and 1H-indazole-6-carbaldehyde (29.2 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.26 (s, 1H), 10.36 (s, 1H), 8.14 (s, 1H), 7.95-7.85 (m, 2H), 7.57 (s, 1H), 7.46-7.37 (m, 1H), 7.24 (s, 1H), 6.52 (s, 1H), 3.78 (s, 3H), 3.53 (s, 3H); MS ESI 322.1 [M+H]+, calcd for [C18H15N3O3+H]+ 322.1.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[OH-:29].[Na+].Cl.[CH2:32]([O:34][CH:35](O)[CH3:36])[CH3:33]>>[CH2:32]([O:34][CH2:35][CH2:36][O:29][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH3:33]
Reactant: COC(=O)c1ccc(-c2ccc(OCCCCCCCCBr)cc2)cc1
Reactant: [OH-]
Reactant: CCOC(C)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOCCOCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% suspension in mineral oil, 108 mg) was added to ethoxyethanol (10 ml), and the solution was stirred at 60° C. for 20 minutes. To the solution was added Methyl 4-[4-(8-bromooctyloxy)phenyl]benzoate (1.26 g), and the reaction mixture was stirred at 70° C. for 2 hours. To the reaction mixture was added 10% sodium hydroxide aqueous solution (2.4 ml), and the solution was stirred at 70° C. for 1 hour. After cooling, the solution was adjusted to pH 2.0 with 1 N hydrochloric acid. The precipitate was collected by filtration, and dried to give 4-[4-[8-(2-Ethoxyethoxy)octyloxy]phenyl]benzoic acid (1.13 g).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH2:8][CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][CH:12]=1)([CH3:4])[CH3:3].C([Cl:23])(=O)C.CCOC(C)=O>CO>[ClH:23].[CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH:8]=1)([CH3:3])[CH3:4]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(C#C[Si](C)(C)C)CC1
Solvent: CO
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#CC1=CCNCC1
Product: Cl
Temperature: 25 °C
Yield: 75.7 %

Procedure:
tert-Butyl 4-[(trimethylsilyl)ethynyl]-3,6-dihydropyridine-1(2H) -carboxylate (2.75 g, 9.8 mmol) was stirred in methanol (10 mL) and acetyl chloride (2.1 mL, 29.2 mmol) was added dropwise. The temperature rose from 18° C. to 30° C. during the addition, and the mixture was kept at 40° C. until there was no more starting material by tic. The mixture was cooled to room temperature, EtOAc (15 mL) was added and the solid filtered off to give an off-white solid (1.6 g).
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:10]1[C:17]([Cl:18])=[N:16][C:14](Cl)=[N:13][C:11]=1[Cl:12].Cl>C1COCC1.C1(C)C=CC=CC=1>[Cl:12][C:11]1[N:10]=[C:17]([Cl:18])[N:16]=[C:14]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: Brc1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: II
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Clc1nc(Cl)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
7.80 g (0.32 mol) of iodine-activated magnesium turnings in 20 ml of anhydrous THF are heated briefly to 60° C. Then 47.1 g (0.30 mol) of bromobenzene and 80 ml of THF are added dropwise over 30 min and the mixture is heated for 1.5 hours to 65° C. After cooling, the Grignard solution is added over 1 hour to a mixture of 51.6 g (0.28 mol) of cyanuric chloride and 140 ml of THF, while keeping the temperature of the mixture in the range from 10° to 20° C. When the addition is complete, the mixture is stirred at for 3 hours at 25° C. The mixture is then diluted with 280 ml of toluene, the resultant suspension is poured into 300 g of 12% aqueous HCl, the organic phase is separated, washed with a total amount of 400 g of water and concentrated. The resultant material (melting point 117°-120° C.) is recrystallised from hexane, giving the title compound in a yield of 61%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]1[CH:8]=[C:9]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.[Br:18]N1C(=O)CCC1=O>C1COCC1.CCCCCC>[Br:18][C:5]1[S:1][C:2]([NH:6][C:7]2[CH:8]=[C:9]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)Nc1cccc(Nc2nccs2)c1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(Br)s2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 85.4 %

Procedure:
To a stirred solution of N-(3-(thiazol-2-ylamino)phenyl)methanesulfonamide 55 (1.17 g, 1.85 mmol) in anhydrous THF (25 mL) was added N-bromosuccinimide (0.363 g, 2.03 mmol) at room temperature. Reaction mixture was stirred for 14 hours at ambient temperature. After completion of the reaction (as judged by TLC), it was concentrated and the crude product was MPLC (Biotage) silica column chromatographed using Acetone:Hexane as an eluent to obtain N-(3-((5-bromothiazol-2-yl)amino)phenyl)methanesulfonamide 56 (0.55 g, 86% yield). MS (ES) m/z 348 (M+H+).