Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH2:34][CH3:35])=[C:16]([CH:22]4[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]4)[C:17]([F:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[ClH:36].O1CCOCC1>ClCCl>[ClH:20].[ClH:36].[NH:24]1[CH2:23][CH:22]([C:16]2[C:15]([O:33][CH2:34][CH3:35])=[C:14]([CH:12]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([CH3:11])=[N:9]3)[CH3:13])[CH:19]=[C:18]([Cl:20])[C:17]=2[F:21])[CH2:25]1
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
To a solution of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate (275 mg, 0.544 mmol) in dichloromethane (2.4 mL) was added 4.0 M hydrogen chloride in dioxane (1.1 mL, 4.4 mmol). The reaction solution was stirred at room temperature for 6 h. The solvent was removed under reduced pressure to give the desired product as a white solid (250 mg, 96%). LCMS calculated for C19H23ClFN6O (M+H)+: m/z=405.2; Found: 405.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@H:15]([C:19](O)=[O:20])[CH2:14]2)=[CH:9][CH:8]=1.C[N:26]1CCOCC1.ClC(OCC)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@H:15]([C:19]([NH2:26])=[O:20])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.8 %

Procedure:
To (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (2.0 g, 6.07 mmol; enantiomeric purity (S):(R)>99.9:0.1) in tetrahydrofuran (40 mL), N-methylmorpholine (676 mg, 6.68 mmol) was added at 0° C. After stirring for 20 min, a solution of ethyl chloroformate (725 mg, 6.68 mmol) was added dropwise over 10 min, and stirring at 0° C. was continued for another 20 min. Ammonia (excess) was then bubbled for 15 min through the resulting suspension. The reaction mixture was warmed up to room temperature and stirred for 15 min. Water (50 mL) was added, and the tetrahydrofuran was evaporated in vacuo. The product, which precipitated, was collected by filtration, washed with water and tert-butyl methyl ether and dried at 45° C. in vacuo to afford (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid amide (1.75 g, 88%). The purity of the product by HPLC was 98.9% (area) and the enantiomeric ratio (S):(R) was determined as 99.8:0.2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH2:8][OH:9])=[CH:2]1>[Pt](=O)=O.C(O)(=O)C>[NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][OH:9])[CH2:2]1
Reactant: OCCCc1cc[nH]c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: OCCCC1CCNC1
Yield: 84.7 %

Procedure:
A solution of 3-(1H-pyrrol-3-yl)-1-propanol (400 mg, 3.20 mmol) in 5 mL of freshly distilled glacial acetic acid containing 40 mg of platinum(IV) oxide was hydrogenated with a H2 balloon for 2 h at 35° C. The catalyst was removed by filtration, and the solvent was evaporated. The residue was heated under reflux for 0.5 h with 4 mL of 30% aqueous NaOH solution to saponify any acetate ester that may have formed. The mixture was extracted with CH2Cl2, and the organic phase was concentrated to obtain the crude pyrrolidine (0.35 g, 85%) as a light-yellow oil, which could be used without purification in the following step. 1H NMR (CDCl3, 300 MHz) δ 3.66 (t, 2H, J=6.3 Hz), 2.62 (dd, 1H, J=7.2, 10.5 Hz), 2.91-2.99 (m, 2H), 2.51 (dd, 1H, J=7.2, 10.8 Hz), 1.93-2.15 (m, 2H), 1.56-1.65 (m, 2H), 1.46 (t, 2H, J=7.2 Hz), 1.37-1.41 (m, 2H). LC-MS (ESI) m/z 130 (M+H+).
Reaction SMILES: Cl.[Cl:2][CH:3]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH2:4]Cl.[CH2:12]([OH:14])[CH3:13]>>[ClH:2].[Cl:2][CH:3]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH2:4][O:14][CH2:12][CH3:13]
Reactant: CCO
Reactant: ClCC(Cl)c1ccncc1
Agent: Cl
Product: CCOCC(Cl)c1ccncc1

Procedure:
About 2 g of 4-(1,2-dichloroethyl)pyridine hydrochloride were refluxed in absolute ethanol overnight. Excess ethanol was then evaporated, and the remaining traces were removed on a vacuum pump. The process resulted in the production of 2.5 g of 4-(1-chloro-2-ethoxyethyl)pyridine hydrochloride.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[CH:28]1([C:34](O)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])(=[O:17])=[O:16])[CH2:12][N:11]2[C:34]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:35])=[O:9])[CH2:5][CH2:6]1)#[N:3]
Reactant: O=C(O)C1CCCCC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2C(=O)C2CCCCC2)CC1

Procedure:
L52. (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K5 was coupled with cyclohexane carboxylic acid in analogy to experiment A1 to give (2S,4R)-1-cyclohexanecarbonyl-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as an amorphous pale yellow solid. MS: 498.3 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[O:15]1[C:19]2([CH2:24][CH2:23][CH:22]([CH:25]3[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]3)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH2:3]([C:4]1[CH:9]=[CH:8][C:7]([C@H:28]2[CH2:27][CH2:26][C@H:25]([CH:22]3[CH2:21][CH2:20][C:19]4([O:18][CH2:17][CH2:16][O:15]4)[CH2:24][CH2:23]3)[CH2:30][CH2:29]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: BrCCc1ccccc1
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1ccc([C@H]2CC[C@H](C3CCC4(CC3)OCCO4)CC2)cc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
4-Bromoethylbenzene (s4) (30.0 g) and THF (1,000 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. n-Butyllithium (1.57M in n-hexane; 124 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. 4-(1,4-Dioxaspiro[4.5]decan-8-yl)-cyclohexanone (s5) (38.6 g) in THF (200 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The resulting reaction mixture was poured into a vessel containing an aqueous solution of ammonium chloride (500 ml) and ethyl acetate (500 ml), and mixed with them. The mixture was allowed to stand and separate into organic and aqueous layers, and the latter was extracted. The separated organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure. p-Toluenesulfonic acid (1.6 g) and toluene (300 ml) were added to the residue, and the mixture was heated to reflux for 2 hours, while distilled water was removed. After the reaction mixture had been cooled to 30° C., water (500 ml) and toluene (900 ml) were added and mixed with it. The mixture was allowed to stand and separate into two layers of organic and aqueous layers, and the latter was extracted. The organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The resulting solution was purified by fractionation using column chromatography with toluene as an eluent and silica gel as a stationary phase powder. The product was dissolved in a mixed solvent of toluene (250 ml) and Solmix A-11 (250 ml), to which Pd/C (0.3 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The resulting residue was purified by fractionation using column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and by recrystallization from heptane, and then dried to give 8-(trans-4-(4-ethylphenyl)cyclohexyl)-1,4-dioxaspiro[4.5]decane (s6) (33.2 g). The yield based on the compound (s1) was 62.3%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([OH:12])=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH3:13][C:14]1[C:15](B(O)O)=[CH:16][C:17]2[C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[C:22]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[CH3:13][C:14]1[C:15]([C:2]2[CH:3]=[C:4]([C:7]([OH:12])=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])=[CH:16][C:17]2[C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[C:22]=2[CH:23]=1
Reactant: COc1cc(O)c(C=O)cc1Br
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
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: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(O)c(C=O)cc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 72.1 %

Procedure:
A mixture of 3-bromo-6-hydroxy-4-methoxy-benzaldehyde (2 g, 8.66 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid (3.18 g, 12.99 mmol), potassium carbonate (4.79 g, 34.63 mmol) and water (4 mL) in anhydrous 1,2-dimethoxyethane (140 mL) was degassed with argon for 15 minutes prior to the addition of tetrakis(triphenylphosphine)palladium(0) (2.0 g, 1.73 mmol). The reaction mixture was heated under reflux for 15 hours, allowed to cool to room temperature and extracted with ethyl acetate (2×100 mL). The organic extracts were successively washed with water (100 mL), a saturated aqueous solution of NH4Cl (100 mL), a saturated aqueous solution of NaCl (100 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography, using a Biotage 40M cartridge, eluting with 5% ethyl acetate/95% hexane, to give 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzaldehyde as a white solid (2.2 g, 73%).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[C@@H:37]([OH:39])[CH3:38])[N:16]=3)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[C@@H:37]([OH:39])[CH3:38])[N:16]=3)[CH2:9]1
Reactant: C[C@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-{2-[2-((S)-1-hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl}azetidine-1-carboxylic acid tert-butyl ester (109 mg, 0.20 mmol) in DCM (5 mL) was added TFA (2 mL) and the resulting mixture stirred at r.t. for 45 min. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound (70 mg, 80%). LCMS (method A): RT 1.87 min [M+H]+ 449.4
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[N:21][CH:22]=[C:23]([CH:28]=2)[C:24]([O:26][CH3:27])=[O:25])O1>>[OH:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH:20]=[N:21][CH:22]=[C:23]([CH:28]=2)[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:4]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: COC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)c1cncc(-c2ccc(CCO)cc2)c1

Procedure:
According to General Method 3A, 6.00 g (29.8 mmol) of 2-(4-bromophenyl)ethanol and 19.6 g (74.6 mmol) of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate were reacted. Yield: 6.12 g (74% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[C:14]1[N:19]=[C:18]([C:20]#[N:21])[C:17]2[N:22]=[CH:23][N:24](C3CCCCO3)[C:16]=2[CH:15]=1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:11])[F:12])=[CH:6][C:5]=1[C:14]1[N:19]=[C:18]([C:20]#[N:21])[C:17]2[N:22]=[CH:23][NH:24][C:16]=2[CH:15]=1)[CH3:2]
Reactant: CCOc1ccc(C(F)(F)F)cc1-c1cc2c(ncn2C2CCCCO2)c(C#N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCOc1ccc(C(F)(F)F)cc1-c1cc2[nH]cnc2c(C#N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(2-Ethoxy-5-trifluoromethyl-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-imidazo-[4,5-c]pyridine-4-carbonitrile (67 mg) and para-toluenesulfonic acid hydrate (10 mg) were added in methanol (5 ml) and DCM (5 ml). The mixture was stirred at room temperature overnight before concentration and purification on preparative HPLC to afford 6-(2-Ethoxy-5-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile. 1H NMR (MeOH) δ 8.55 (s, 1H) 8.48 (s, 1H) 8.15 (s, 1H) 7.70 (d, 1H) 7.29 (d, 1H) 4.26 (q, 2H) 1.46 (t, 3H) MS m/z 333.1 (m+1)
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:17]=[CH:16][C:15]([S:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CSc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(SC[C@@H]2CCCN2)cc1
Reaction time: 3.5 h
Yield: 30.2 %

Procedure:
A solution of 2.55 g of N-tert-butyloxycarbonyl-(2S)-2-(4-trifluoromethylphenylthiomethyl)-pyrrolidine in 5.64 ml of trifluoroacetic acid is stirred for 1 hour at 0° C. and then for 3.5 hours at room temperature. The reaction mixture is poured onto 10% sodium bicarbonate solution, extracted with ethyl acetate, washed twice with 2M hydrochloric acid, the water phase is extracted with ether, made basic with sodium bicarbonate, extracted three times with ethyl acetate, washed with common salt solution, dried on sodium sulfate and concentrated by evaporation. 557 mg of (2S)-2-(4-trifluoromethylphenylthio-methyl)-pyrrolidine is obtained.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:10]1[C:11]([NH2:19])=[N:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=12>COCCOC>[CH2:7]([O:6][C:4]([C:3]1[N:19]=[C:11]2[N:10]=[C:14]3[N:13]([CH2:18][CH2:17][CH2:16][CH2:15]3)[N:12]2[CH:2]=1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1nc2n(n1)CCCC2
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(n1)nc1n2CCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl bromopyruvate (10.23 g) was added to the mixture of 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (5.8 g) in 1,2-dimethoxyethane (320 mL). The reaction mixture was stirred for 5 hours at room temperature and concentrated to 100 mL under reduced pressure. The precipitate was obtained by an addition of diethyl ether (200 mL), followed by filtration. The precipitate was dissolved in ethanol (175 mL) and stirred for 20 hours at 110° C. in shield tube. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with saturated potassium carbonate solution and extracted with chloroform. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then eluted with ethyl acetate—methanol (1/1). The title compound was obtained as a pale yellow solid (7.56 g, 77%). 1H-NMR (400 MHz, CDCl3) δ 1.42 (t, 3H, J=7.1 Hz), 2.14–2.25 (m, 4H), 3.11 (t, 2H, J=6.1 Hz), 4.37 (t, 2H, J=5.7 Hz), 4.41 (q, 2H, J=7.1 Hz), 7.57 (s, 1H).
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH3:9])[C:6](Cl)=[O:7])(=[O:3])[CH3:2].[NH2:10][C:11]1[C:12]([I:25])=[C:13]([C:22]([OH:24])=[O:23])[C:14]([I:21])=[C:15]([C:19]=1[I:20])[C:16]([OH:18])=[O:17].O>CC(N(C)C)=O>[C:1]([O:4][C@@H:5]([CH3:9])[C:6]([NH:10][C:11]1[C:19]([I:20])=[C:15]([C:16]([OH:18])=[O:17])[C:14]([I:21])=[C:13]([C:12]=1[I:25])[C:22]([OH:24])=[O:23])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)O[C@@H](C)C(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 57.5 %

Procedure:
(S)-1-chloro-1-oxopropan-2-yl acetate (0.75 ml, 5.91 mmol) was added drop-wise to a solution of 5-amino-2,4,6-triiodoisophthalic acid (1.0 g, 1.79 mmol) in DMA (5 ml). The resulting mixture was stirred at about 50° C. for 5 hours and 20 minutes. 80 ml of water was added to the reaction mixture at room temperature after which the suspension formed was cooled to a temperature between 0° C. and 5° C. and stirred for 25 minutes at this temperature. The suspension was filtered and the solid washed with water. The product was dried in a vacuum oven at 40° C. to yield (S)-5-(2-acetoxypropanamido)-2,4,6-triiodoisophthalic acid (0.695 g, 1.03 mmol). The MS, 1H-NMR and 13C-NMR data are consistent with the structure for (S)-5-(2-acetoxypropanamido)-2,4,6-triiodoisophthalic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([NH2:15])[CH2:13][CH:12]=[CH:11][CH2:10]1>CO.Cl.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N[C@@H]1CC=CC[C@H]1c1ccc(Cl)cc1Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N[C@@H]1CCCC[C@H]1c1ccc(Cl)cc1Cl

Procedure:
To a solution of Example 2B (100 mg, 0.041 mmol) in 1:1 in methanol (2 mL), two drops of concentrated HCl and 10% palladium on carbon (10 mg) were added. The solution was purged with nitrogen and subjected to an atmosphere of H2 over a twelve hour period. The solution was filtered through Celite and concentrated to give the title compound. 1H NMR (300 MHz, C5D5N) δ ppm 7.26 (s, 1H), 7.17-7.19 (m, 2H), 3.96-3.99 (m, 1H), 3.65-3.69 (m, 1H), 2.94-2.96 (m, 1H), 2.06-2.08 (m, 1H), 1.80-1.83 (m, 1H), 1.58-1.67 (m, 2H), 1.25-1.39 (m, 3H). MS (ESI+) m/z 245 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[O:11]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:11]1[CH:15]=[CH:14][C:13]([C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=2)=[CH:12]1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: OB(O)c1ccoc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2ccoc2)cc(C)c1O
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 68.7 %

Procedure:
4-Bromo-2,6-dimethylphenol (350 mg, 1.74 mmol), 3-furanylboronic acid (269 mg, 2.26 mmol), Pd(dppf)Cl2 (71 mg, 0.087 mmol) and sodium carbonate (553 mg, 5.22 mmol) were dissolved in DME:water=4 mL:2 mL, followed by stirring in microwave at 120° C. for 20 minutes. After the completion of the reaction, the reaction mixture was filtered using Celite. The obtained filtrate was extracted with ethyl acetate, dried over magnesium sulfate, and purified by column chromatography (hexane:ethyl acetate=9:1) to obtain 4-(furan-3-yl)-2,6-dimethylphenol (225 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][N:3]=1>CO.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(-c2ccccc2)cnc1N
Yield: 96 %

Procedure:
0.46 g of 2-amino-3-nitro-5-phenylpyridine (starting material C2) dissolved in 50 ml methanol are hydrogenated over 0.05 g of 10% strength Pd/C until no starting material is detectable by TLC. After filtration, the solvent is evaporated and the residue is chromatographed over silica gel (dichloromethane/methanol 20:1+1% triethylamine). Concentration of the pure fractions and drying in vacuo gives 0.38 g of the title compound as a brownish oil. The mass spectrum shows the molecular peak MH+ at 186.2 Da.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH2:10][CH:9]1[C:21]([OH:23])=[O:22])=O)(C)(C)C.CCOCC>Cl.O1CCOCC1>[Cl:20][C:16]1[CH:15]=[C:14]([NH:13][C@@H:11]2[CH2:12][NH:8][C@H:9]([C:21]([OH:23])=[O:22])[CH2:10]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2cccc(Cl)c2)CC1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(O)[C@@H]1C[C@H](Nc2cccc(Cl)c2)CN1
Yield: 82 %

Procedure:
4-(3-Chloro-phenylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (Preparation 41, 155 mg, 0.456 mmol) was stirred in 4 M HCl in dioxan (4 ml) at 0° C. for 2 hours. Ether (4 ml) was added and the resultant white hygroscopic solid filtered off and dried in vacuo at 40° C. to give the title compound (90 mg, 60.3%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1)[C:2]#[C:3][CH3:4].[CH3:15][C:16]1[C:17]([NH2:31])=[N:18][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[C:27]([NH2:30])[CH:28]=3)[O:23][CH2:22][CH2:21]2)[N:20]=1>>[NH2:31][C:17]1[C:16]([CH3:15])=[N:20][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:12]([C:9]4[CH:8]=[N:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][N:10]=4)=[O:14])[CH:28]=3)[O:23][CH2:22][CH2:21]2)[N:18]=1
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Reactant: CC#CCOc1cnc(C(=O)O)cn1
Product: CC#CCOc1cnc(C(=O)Nc2ccc3c(c2)C2(CCO3)N=C(C)C(N)=N2)cn1
Yield: 25.6 %

Procedure:
The title compound (28 mg, 24% yield) was prepared as described for Example 13a starting from 5-(but-2-ynyloxy)pyrazine-2-carboxylic acid (Intermediate 36, 58 mg, 0.30 mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 63 mg, 0.27 mmol). The crude product was purified by flash chromatography (4 g silica, gradient elution of (EtOAc/MeOH/conc. NH3 (80/20/1) in heptane) followed by preparative chromatography. The pure fractions were combined and evaporated. The residual oil was solidified by evaporation with EtOAc and heptanes: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85 (t, 3 H), 1.88-1.96 (m, 2 H), 2.23 (s, 3 H), 4.28-4.48 (m, 2 H), 5.07 (q, 2 H), 6.55 (s, 2 H), 6.79 (d, 1 H), 7.02-7.10 (m, 1 H), 7.55-7.64 (m, 1 H), 8.39 (d, 1 H), 8.84 (d, 1 H), 10.26 (s, 1 H); MS (APCI+) m/z 405 [M+H]+.