Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.F[B-](F)(F)F.[CH3:21][O+](C)C.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([O:12][CH3:21])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(Cl)cc2C2CCCC12
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=Nc2ccc(Cl)cc2C2CCCC12

Procedure:
A solution of 8-chloro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (200 mg, 0.9 mmol) in dichloromethane (20 ml) is stirred with trimethyloxonium tetrafluoroborate (134 mg, 0.9 mmol) for 24 hours at room temperature. After triethylamine (0.13 ml, 0.9 mmol) is added, the batch is concentrated by evaporation and purified by column chromatography (SiO2, 40% moist) with ethyl acetate-hexane: 180 mg (85%) of product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([S:15]([N:18]2[CH2:21][CH:20]([OH:22])[CH2:19]2)(=[O:17])=[O:16])[CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1([S:15]([N:18]2[CH2:19][C:20](=[O:22])[CH2:21]2)(=[O:17])=[O:16])[CH2:14][CH2:13]1
Reactant: CC1(S(=O)(=O)N2CC(O)C2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1(S(=O)(=O)N2CC(=O)C2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of oxalyl chloride (59 μL, 0.69 mmol) in methylene chloride (1.5 mL) at −78° C. was added dimethyl sulfoxide (0.10 mL, 1.5 mmol) slowly dropwise. The reaction was stirred for 15 minutes following complete addition. A solution of 1-[(1-methylcyclopropyl)-sulfonyl]azetidin-3-ol (64 mg, 0.33 mmol) in methylene chloride (1.0 mL) was added dropwise and the reaction mixture was stirred for 45 min at −60° C. Triethylamine (0.28 mL, 2.0 mmol) was added dropwise and the reaction was stirred for 15 minutes and the bath was removed and the solution allowed to warm to ambient temperature. The solvent was removed in vacuo and ethyl acetate was added. The solution was washed sequentially with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate, decanted and concentrated. The crude product was used without further purification in Step 6.
Reaction SMILES: [CH2:1]([Zn]CC)C.[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14](/[CH:15]=[CH:16]\[CH2:17][OH:18])[C:9]=2[CH2:8][CH2:7]1>C(Cl)Cl>[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([C@H:15]3[CH2:1][C@H:16]3[CH2:17][OH:18])[C:9]=2[CH2:8][CH2:7]1
Reactant: OC/C=C\c1cccc2c1CCO2
Reactant: CC[Zn]CC
Solvent: ClCCl
Product: OC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Temperature: -15 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
Diethylzinc (63 mmol, 1.0 M in hexanes) was added dropwise to a mixture of (cis)-3-(2,3-dihydrobenzofuran-4-yl)prop-2-en-1-ol (12.6 mmol) in 10 mL of CH2Cl2 at −15° C. The resulting mixture was stirred at −15° C. for 1 h followed by the dropwise addition of CH2CI2 (63 mmol). The resulting mixture was warmed to RT and stirred overnight. The crude reaction mixture was then quenched with saturated aqueous NH4Cl solution at 0° and extracted with ether (2×100 mL). The combined organic extracts were washed with saturated aqueous NH4Cl solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography (Hexanes:EtOAc, 4:1) provided 2.06 g (86%) of the desired product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:14]([O:16][C:17]([C:19]1[S:20][C:21]([Cl:25])=[CH:22][C:23]=1[OH:24])=[O:18])[CH3:15]>C(C(C)=O)C>[CH2:14]([O:16][C:17]([C:19]1[S:20][C:21]([Cl:25])=[CH:22][C:23]=1[O:24][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:18])[CH3:15]
Reactant: CCOC(=O)c1sc(Cl)cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc(Cl)sc1C(=O)OCC
Temperature: 30 °C
Yield: 101.5 %

Procedure:
1.07 g of potassium carbonate and 1.3 g of ethyl bromoacetate were added to a solution of 1.6 g of the product of Step A in 50 ml of methyl ethyl ketone and the mixture was refluxed for an hour and was cooled to 30° C. The mixture was filtered and the filtrate was evaporated to dryness. The residue was taken up in ethyl acetate and the solution was washed with water, dried and evaporated to dryness to obtain 2.3 g of ethyl (2-ethoxycarbonyl-5-chloro-3-thienyl)-oxyacetate.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33]Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([Cl:11])[N:3]=1
Reactant: O=C(OCCOCCOCCl)c1ccccc1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(Cl)c2ncn(COCCOCCOC(=O)c3ccccc3)c2n1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
A mixture of 2-amino-6-chloropurine (3.0 g) and anhydrous potassium carbonate (2.44 g) in dry dimethylformamide (50 ml) was stirred at room temperature for several hours. To this mixture was added 5 g of 2-(2-benzoyloxyethoxy)ethoxymethyl chloride. The reaction mixture was stirred at room temperature for 4 days and then poured into ice and water. The resulting mixture was extracted with chloroform (3X) and the chloroform extract washed with 10% aqueous acetic acid, with water and then dried over anhydrous sodium sulfate. The solution was filtered and the chloroform evaporated at room temperature and reduced pressure (initially about 20 mm and finally about 1 mm Hg). The residual yellow oil was applied to a column containing silica gel (200 g) in 1:1 ether:chloroform. The column was eluted with 1:1 ether:chloroform followed by chloroform followed by methanol (5%):chloroform (95%). The desired product, 2-amino-6-chloro-9-[2-(2-benzoyloxyethoxy)ethoxymethyl]purine, was eluted in the methanol: chloroform eluate. The fraction exhibiting a single spot on silica gel thin layer chromatography [mobile phase methanol (2%): chloroform (98%)] were combined and evaporated to give a pale yellow oil which gradually solidified. This was recrystallized from benzene to give 2-amino-6-chloro-9-[2-(2-benzoyloxyethoxy)ethoxymethyl]purine 1.5 g), m.p. 111°-112° C.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].O=[C:15]1[CH2:18][CH:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16]1.O>O1CCCC1.C(OCC)C>[C:3]([CH:5]=[C:15]1[CH2:18][CH:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16]1)#[N:4]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCOC(=O)C1CC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C1CC(=CC#N)C1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.730 g, 18.3 mmol) in tetrahydrofuran (100 mL) at 0° C. was added diethyl cyanomethylphosphonate (3.22 mL, 19.9 mmol), dropwise. The cooling bath was removed and the reaction was allowed to reach room temperature and was stirred at this temperature for 45 minutes. The solution was re-cooled to 0° C. and a solution of ethyl 3-oxocyclobutanecarboxylate (2.36 g, 16.6 mmol) in tetrahydrofuran (50 mL) was introduced dropwise. After stirring for 2 hours, water and ethyl ether were added into the reaction. The layers were separated and the aqueous portion extracted with two further portions of ether. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated. The residue was azeotroped once with toluene to afford product, used without further purification in Step 5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[I-].[Na+].Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28]>CN(C)C=O.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCCCCCl
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: OCCCCCCOc1ccc(OCc2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
A mixture of 106.0 g (0.53 mole) of p-benzyloxyphenol (Eastman), 28.6 g (0.53 mole) sodium methoxide (MCB) and about 2 g of sodium iodide in 600 ml of dimethylformamide is stirred for 5 minutes, after which 73 g (0.53 mole) of 6-chlorohexan-1ol (MCB) is added, and the mixture is refluxed with stirring. The methanol formed in the reaction is allowed to distill off. After 2 hours reflux, the mixture is diluted with ice and water, 500 ml of 10% potassium hydroxide is added, and the resultant precipitate collected and dried. The solid is combined with 1 liter of butanone, refluxed and filtered. The residue is cooled, whereupon the desired product crystallizes out. The solid product is stirred with 1 liter of acetone at room temperature, the mixture is filtered to separate additional insoluble byproduct, the acetone boiled off and replaced with methanol, and the methanolic solution cooled to crystallize out the desired product, m.p. 94-97° C.
Reaction SMILES: C(O[CH2:9][C@@H:10]1[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C:11]1=O)C1C=CC=CC=1.P(O)(O)O.O.[CH:29](O)(C)C>[Ir](Cl)(Cl)(Cl)Cl>[CH2:16]([O:15][CH2:14][C:13]1[CH:10]=[CH:9][CH:29]=[CH:11][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1C[C@H](COCc2ccccc2)[C@H]1COCc1ccccc1
Reactant: CC(C)O
Agent: Cl[Ir](Cl)(Cl)Cl
Agent: OP(O)O
Solvent: O
Product: c1ccc(COCc2ccccc2)cc1

Procedure:
A mixture of (2S-trans)-2,3-bis[(benzyloxy)methyl]cyclobutanone (0.25 g., 0.806 mmole), iridium tetrachloride (0.016 g., 0.0483 mmole), phosphorous acid (0.397 g., 4.84 mmole) and water (0.3 ml.) in isopropanol (3 ml.) was refluxed overnight. The solvent was evaporated on a rotary evaporator. The residue was taken up in ethyl acetate and washed successively with 10% hydrochloric acid, brine, and 5% sodium bicarbonate. The organic layer was dried (magnesium sulfate) and the solvent was evaporated to give [1S-(1α,2β,3β)]-3-hydroxy-1,2-cyclobutanedimethanol, dibenzyl ether; TLC (40% ethyl acetate/hexane) Rf =0.51.
Reaction SMILES: [N:1]1([CH:5]2[CH2:10][CH2:9][N:8](CC3C=CC=CC=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[N:1]1([CH:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc(CN2CCC(N3CCC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C1CN(C2CCNCC2)C1

Procedure:
3.2 g (13.9 mmol) 4-azetidin-1-yl-1-benzyl-piperidine dissolved in 50 mL MeOH were hydrogenated in the autoclave in the presence of 0.5 g Pd/C (10%) at 50° C. and 3 bar hydrogen pressure until the calculated volume of hydrogen had been taken up. The catalyst was filtered off and the solvent was eliminated under reduced pressure.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.[I-].[CH2:9]([NH:27][C:28]1[C:29]([NH2:34])=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)C.O.C(OCC)(=O)C>[CH2:9]([N:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]=[C:2]1[C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)C=O
Reactant: CCCCCCCCCCCCCCCCCCNc1ccccc1N
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCn1c(C(=O)OCC)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
Ethyl glyoxylate (7.861 g) and iodide (4.886 g) were added to a solution containing N-octadecyl-1,2-benzenediamine (6.940 g) in ethanol (100 ml) and the mixture was stirred for 2 hours at room temperature. A solution containing sodium thiosulfate pentahydrate (4.813 g) in water (60 ml) was added dropwise to the reaction mixture while being stirred. The reaction mixture, with ethyl acetate added thereto, was washed with saturated brine, dried over sodium sulfate anhydride, and concentrated. The residue (10.06 g) was purified by silica gel column chromatography (silica gel 255 g, chloroform), thereby yielding the entitled compound (6.442 g) as pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:11][CH2:12][N:13]([CH:16]2[CH2:19][O:18][CH2:17]2)[CH2:14][CH:15]=1)([O-])=O.CCO>CCOC(C)=O.[Pd]>[O:18]1[CH2:19][CH:16]([N:13]2[CH2:14][CH2:15][CH:10]([C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[NH2:1])[CH2:11][CH2:12]2)[CH2:17]1
Reactant: O=[N+]([O-])c1cnccc1C1=CCN(C2COC2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cnccc1C1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.5 %

Procedure:
Pd on C, wet, Degussa (240 mg, 0.2255 mmol) was added to a stirred solution of 3-nitro-4-[1-(oxetan-3-yl)-3,6-dihydro-2H-pyridin-4-yl]pyridine (614 mg, 2.350 mmol) in EtOAc (20 mL)/EtOH (20 mL). The reaction was placed under an atmosphere of hydrogen and stirred at ambient temperature for 15 hours. The catalyst was removed by filtration through a pad of celite and the filtrate concentrated in vacuo to give the 4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-3-amine as a pale yellow solid (518 mg, 95% Yield). MS (ES+) 234.2.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([SH:12])[CH:9]=[C:8]([CH3:13])[C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23]>C1(C)C=CC=CC=1>[NH2:7][C:6]1[C:8]([CH3:13])=[CH:9][C:10]([S:12][CH2:23][CH2:22][C:21]([O:25][CH3:26])=[O:24])=[CH:11][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(S)cc(C(C)(C)C)c1N
Reactant: C=CC(=O)OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCSc1cc(C)c(N)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.2 %

Procedure:
To a stirred solution of 1.00 g (5.1 mmol) of 2-tert-butyl-4-mercapto-6-methylaniline and 0.05 g (0.5 mmol) of triethylamine in 5 mL of toluene at -5° C. is added dropwise a solution of 0.44 g (5.1 mmol) of methyl acrylate in 5 mL of toluene. The reaction mixture is stirred for 24 hrs at room temperature. The solvent is removed in vacuo and the crude product is purified by flash column chromatography (silica gel, 95:5, heptane:ethyl acetate eluent) to give 0.95 g (66%) of the title compound as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11](O)=[O:12])=[C:9]([CH3:14])[N:8]([C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:6]=2[N:7]=1.ON1C2C=CC=CC=2N=N1.Cl.C(C(N=C=NCCCN(C)C)C)C.C(N(CC)CC)C.[NH2:54][CH2:55][C:56]1[C:57]([OH:64])=[N:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62]>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:54][CH2:55][C:56]3[C:57]([OH:64])=[N:58][C:59]([CH3:63])=[CH:60][C:61]=3[CH3:62])=[O:12])=[C:9]([CH3:14])[N:8]([C@@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1c(C(=O)O)c2cnc(Cl)nc2n1[C@H](C)c1ccccc1
Agent: CCC(C)N=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(Cl)ncc23)c(O)n1
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To a solution of (R)-2-chloro-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (100 mg, 0.32 mmol) in dichloromethane (10 mL) was added with 1-hydroxybenzotriazole (65 mg, 0.48 mmol), 1-Ethyl-3-(3-dimethylaminopropyl)ethyl-carbodiimide hydrochloride (92 mg, 0.48 mmol) and triethylamine (97 mg, 0.96 mmol). After stirred for 30 minutes, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (49 mg, 0.32 mmol) was added and the reaction mixture was stirred at room temperature for 12 hours. The solution was concentrated, diluted with water (20 mL), extracted with ethyl acetate (20 mL). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to afford (R)-2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (100 mg, 70%). LRMS (M+H+) m/z: calcd 449.16. found 449.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[I:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=3)[N:18]=2)[CH:15]=1>CN(C)C=O>[CH3:6][N:4]([CH3:5])/[CH:3]=[CH:26]/[C:25]([C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:13]3[CH:12]=[CH:11][C:10]([I:9])=[CH:15][N:14]3[CH:16]=2)=[CH:20][CH:21]=1)=[O:27]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(-c2cn3cc(I)ccc3n2)cc1
Solvent: CN(C)C=O
Product: CN(C)/C=C/C(=O)c1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 150 °C

Procedure:
N,N-dimethylformamide dimethyl acetal (363 μL) was added dropwise to a solution (50 mL) of 1-[4-(6-iodoimidazo[1,2-a]pyridin-2-yl)phenyl]-1-ethanone (495 mg) in dimethylformamide, and the mixture was heated at 150° C. for 16 hours. The reaction mixture was concentrated, and the residue was purified through silica gel column chromatography (dichloromethane:methanol=97:3), followed by concentration under reduced pressure, to thereby yield the title compound (274 mg).
Reaction SMILES: CC(C)(C)C([O:5][C:6]1[CH:13]2[CH:9]([CH2:10][CH:11]([CH:14]3[O:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH2:12]2)[C:8](=[O:20])[C:7]=1[C:21]1[C:26]([CH2:27][CH3:28])=[CH:25][C:24]([CH3:29])=[CH:23][C:22]=1[CH2:30][CH3:31])=O>CO.[OH-].[Na+]>[CH2:30]([C:22]1[CH:23]=[C:24]([CH3:29])[CH:25]=[C:26]([CH2:27][CH3:28])[C:21]=1[CH:7]1[C:6](=[O:5])[CH:13]2[CH:9]([CH2:10][CH:11]([CH:14]3[O:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH2:12]2)[C:8]1=[O:20])[CH3:31]
Reactant: CCc1cc(C)cc(CC)c1C1=C(OC(=O)C(C)(C)C)C2CC(C3OCCCO3)CC2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(C3OCCCO3)CC2C1=O
Yield: 85.9 %

Procedure:
0.100 g (0.22 mmol) of 2-(2,6-diethyl-4-methylphenyl)-5-(1,3-dioxan-2-yl)-3-oxo-3,3a,4,5,6,6a-hexahydropentalen-1-yl 2,2-dimethylpropanoate in 10 ml of methanol and 4 ml of 1N aqueous sodium hydroxide solution is stirred at room temperature for 2 h. The mixture is then concentrated, the residue is taken up in water, the mixture is acidified to pH 4 using 2N HCl and extracted with ethyl acetate, the extract is dried (magnesium sulphate) and the solvent is distilled off. Chromatographic purification of the residue on silica gel (mobile phase ethyl acetate/hexane 1:6) gives 70 mg (86%) of the desired compound in the form of colourless needles of m.p. 100-101° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][C:13]1[C:14]([NH2:28])=[N:15][C:16]2([C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH2:27])[CH:25]=3)[O:20][CH2:19][CH2:18]2)[N:17]=1>>[NH2:28][C:14]1[C:13]([CH3:12])=[N:17][C:16]2([C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:9](=[O:11])[C:3]4[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=4)[CH:25]=3)[O:20][CH2:19][CH2:18]2)[N:15]=1
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Product: CC1=NC2(CCOc3ccc(NC(=O)c4ncc(Cl)cc4Cl)cc32)N=C1N
Yield: 63.5 %

Procedure:
The title compound (59 mg, 62% yield) was prepared as described for Example 13a starting from 3,5-dichloropicolinic acid (45 mg, 0.23 mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 54 mg, 0.23 mmol): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-2.01 (m, 2 H), 2.22 (s, 3 H), 4.29-4.49 (m, 2 H), 6.57 (s, 2 H), 6.75-6.85 (m, 2 H), 7.48-7.57 (m, 1 H), 8.41 (d, 1 H), 8.68 (d, 1 H), 10.39 (s, 1 H); MS (APCI+) m/z 404 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([C:29]1[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=1)[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH:20]=[CH2:21])=[CH:14][CH:13]=2)[N:9]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:8]=1)C.[Li+].[OH-]>C1COCC1.O>[CH2:19]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:9]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[N:8]=[C:7]([CH2:6][CH:5]([C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[C:4]([OH:36])=[O:3])[CH:11]=2)=[CH:17][CH:16]=1)[CH:20]=[CH2:21]
Reactant: C=CCNc1ccc(-c2cc(CC(C(=O)OCC)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCNc1ccc(-c2cc(CC(C(=O)O)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Reaction time: 3 h
Yield: 77.5 %

Procedure:
To a solution of 3-[5-(4-allylamino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester (90 mg, 0.2 mmol) was added LiOH (14 mg, 0.58 mmol, 3 equiv) in 2:1 THF/H2O (1 mL). After 3 h at 45° C., the mixture was purified by preparative reversed-phase HPLC (acetonitrile/water) to afford the desired compound (70 mg, 77 %). MS (ESI): mass calculated for C29H29N3O2, 451.23; m/z found, 452.6 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.21-7.03 (m, 8H), 6.93 (d, J=8.8, 2H), 6.26 (s, 1H), 5.88-5.83 (m, 1H), 5.29-5.24 (m, 2H), 4.06 (dd, J=10.4, 5.1 Hz, 1H), 3.79(d, J=6.3 Hz, 2H), 3.54 (dd, J=15.0, 10.4 Hz, 1H), 3.09 (dd, J=15.0 5.1 Hz, 1H), 2.33 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[O:19])[C:15]([Cl:27])=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[O:19])[C:15]([Cl:27])=[CH:14][C:10]=1[C:11]([NH:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)c2cc(OCc3ccccc3)c(C(=O)O)cc2Cl)CC1
Reactant: Nc1cccnc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2cc(OCc3ccccc3)c(C(=O)Nc3cccnc3)cc2Cl)CC1
Reaction time: 8 h
Yield: 25.5 %

Procedure:
To a solution of 2-(benzyloxy)-5-chloro-4-(4-methylpiperazine-1-carbonyl)benzoic acid (may be prepared as described in D 76) (108 mg, 0.278 mmol) in N,N-dimethylformamide (DMF) (5 mL) was added DIPEA (0.97 ml, 0.555 mmol), 3-aminopyridine (39.2 mg, 0.417 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt) (45 mg, 0333 mmol) and EDC (96 mg, 0.5 mmol). The solution was stirred overnight. The solvent was removed in vacuo and the residue was purified by MDAP (tartan, High pH, 25 minute run) to give a white solid (33 mg, 9% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[C:19]1([S:25]([O-:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+]>>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][S:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:27])=[O:26]
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccccc3)c(C)o2)cc1
Yield: 83.7 %

Procedure:
Method A. Reaction of chloride 2 (267 mg, 1.0 mmol) and sodium benzenesulfinate (173 mg, 1.1 mmol) gave benzoate 16 (311 mg, 84%) as a white powder: mp (EtOAc) 159-161° C.; 1H NMR (CDCl3) δ 8.07 (ddd, J=8.7, 1.9, 1.5 Hz, 2 H, H-2, H-6), 7.91 (ddd, J=8.7, 1.9, 1.5Hz, 2 H, H-3, H-5), 7.82 (ddd, J=8.2, 2.0, 1.2Hz, 2 H, H-2′, H-6′), 7.64 (tt, J=7.5, 1.2Hz, 1 H, H-4′), 7.52 (br dd, J=8.2, 7.5Hz, 2 H, H-3′, H-5′), 4.32 (s, 2 H, CH2SO2), 3.94 (s, 3 H, OCH3), 2.32 (s, 3 H, CH3); MS m/z 372.3 (MH+, 100%). Anal. calcd for C19H17NO5S: C, 61.44; H, 4.61; N, 3.77. Found: C, 61.75; H, 4.62; N, 3.75%.