Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:33])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([CH:28](OC)[O:29]C)[CH:20]=2)[CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1.O>[CH2:2]([O:9][C:10](=[O:33])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([CH:28]=[O:29])[CH:20]=2)[CH:13]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(OC)c1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
12N HCl (33 mL) and water (66 mL) were added to a mixture of [3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenyl]-carbamic acid benzyl ester (0.14 mol) in THF (400 mL) and the reaction mixture was stirred for 48 hours at room temperature. The mixture was diluted with H2O (500 mL) and extracted 2 times with diisopropyl ether. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The resulting product was removed with a spatula and dried under vacuum to yield the title compound as a residue.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([CH2:10][OH:11])=[N:6][CH:7]=[CH:8][CH:9]=1.Cl[C:13]1[C:14]([CH:28]2[CH2:31][CH2:30][CH2:29]2)=[CH:15][C:16]2[N:17]([C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:20][N:21]=2)[N:18]=1>CN(C=O)C.O>[CH:28]1([C:14]2[C:13]([O:11][CH2:10][C:5]3[C:4]([CH3:3])=[CH:9][CH:8]=[CH:7][N:6]=3)=[N:18][N:17]3[C:19]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[N:20][N:21]=[C:16]3[CH:15]=2)[CH2:29][CH2:30][CH2:31]1
Reactant: Clc1nn2c(-c3cccnc3)nnc2cc1C1CCC1
Reactant: Cc1cccnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccnc1COc1nn2c(-c3cccnc3)nnc2cc1C1CCC1
Reaction time: 18 h
Yield: 14.5 %

Procedure:
Sodium hydride (60% dispersion in oil, 13.4 mg, 0.34 mmol) was added to a solution of (3-methylpyridin-2-yl)methanol (38 mg, 0.31 mmol) in dry DMF (1 ml) at room temperature. After 1 h at room temperature a solution of 6-chloro-7-cyclobutyl-3-(pyridin-3-yl)-1,2,4-triazolo[4,3-b]pyridazine (80 mg, 0.28 mmol) was added and the reaction stirred for 18 h. The reaction mixture was diluted with water (10 ml) and stirred for 10 minutes after which time the mixture was filtered and the residue washed, first with water, then with diethyl ether. The residue was purified by chromatography on silica gel, eluting with 0-5% dichloromethane-methanol to afford the title pyridazine (15.1 mg, 14%). 1NMR (250 MHz, CDCl3) δ1.83-1.89 (1H, m), 1.96-2.23 (3H, m), 2.28-2.40 (2H, m), 2.43 (3H, s), 3.57-3.67 (1H, m), 5.59 (2H, s), 7.23 (1H, m), 7.45-7.50 (1H, m), 7.58-7.61 (1H, d, J=7.6 Hz), 7.85 (1H, d, J=1.5 Hz), 8.49 (1H, m), 8.66 (2H, m), 9.71 (1H, br s). MS (ES+) m/e 373 [MH]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[C:7]([OH:12])[CH:8]=2)[O:3]1.C1N2CN3CN(C2)CN1C3.[C:26](O)(C(F)(F)F)=[O:27]>C(O)(=O)C>[OH:12][C:7]1[C:6]([CH3:13])=[C:5]([CH3:14])[C:4]2[O:3][C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][C:9]=2[C:8]=1[CH:26]=[O:27]
Reactant: Cc1c(O)cc2c(c1C)OC(C)(C)CC2
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C=O)c1O)CCC(C)(C)O2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2,2,7,8-Tetramethylchroman-6-ol (2.0 g, 9.7 mmol) and hexamethylene tetramine (680 mg, 4.05 mmol) were weighed into a 20-mL scintillation vial, after which TFA (640 μL) and acetic acid (6.4 mL) were added. The vial was sealed, and the resulting mixture heated to 100° C. for 90 min, during which time a deep red color developed. The mixture was then concentrated to a red oil at 55° C. in vacuo. The darkly-colored residue was stirred in a biphasic mixture of 50 mL ethylacetate (EtOAc) and 50 mL 1 M aqueous sodium bicarbonate for 1 hr. At this time, the organic layer was removed, and successively washed with 1 M aqueous sodium bicarbonate (2×50 mL), 1 M aqueous citric acid (2×50 mL), and brine (50 mL). The residual organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to 2.1 g yellow oil. Crude purification was accomplished by silica gel chromatography (gradient elution 0→10% EtOAc/Heptane) to obtain 1.0 g 6-hydroxy-2,2,7,8-tetramethylchroman-5-carbaldehyde product, which was immediately dissolved in DMF (88 mL) and treated with MOMCl (670 μL, 8.8 mmol) and Di-isopropyl ethyl amine (DiPEA) (2.2 mL, 13.2 mmol). The reaction mixture was heated to 50° C. for 2 hr and then subsequently diluted in EtOAc (75 mL). The organics were washed successively with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (25 mL each), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (gradient elution 0→15% EtOAc/Heptane) afforded the 6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-carbaldehyde (920 mg) as a colorless oil. 1H NMR (CDCl3, 400 MHz) 10.4 (s, 1H), 4.93 (s, 2H), 3.56 (s, 3H), 3.06 (t, 2H), 2.18 (s, 3H), 2.13 (s, 3H), 1.72 (t, 2H), 1.28 (s, 6H) ppm.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=2)[N:26]=[CH:25][N:24]=1>>[CH3:34][O:33][C:29]1[CH:28]=[C:27]2[C:32]([C:23]([N:18]3[CH2:19][CH2:20][CH:15]([N:5]4[C:6](=[O:14])[C:7]5[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=5)[N:3]([CH3:2])[C:4]4=[O:21])[CH2:16][CH2:17]3)=[N:24][CH:25]=[N:26]2)=[CH:31][CH:30]=1
Reactant: COc1ccc2c(Cl)ncnc2c1
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Product: COc1ccc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)ncnc2c1
Yield: 22 %

Procedure:
The procedure similar to that described in Example 57 was repeated, except that 354.0 g (1.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 4-chloro-7-methoxyquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. As a result, 96.2 mg (yield: 22%) of Compound 85 was obtained as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:11]1([C:17]#[C:18][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[CH:9][CH:10]=3)[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cnc2ccnn2c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C(#Cc1cnc2ccnn2c1)c1ccccc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Bis-(triphenylphosphine)-palladium (II) dichloride (27 mg, 0.04 mmol) was dissolved in 1 ml of THF. 6-Bromo-pyrazolo[1,5-a]pyrimidine (150 mg, 0.76 mmol) and phenylacetylene (130 μl, 1.21 mmol) were added at room temperature. Triethylamine (310 μl, 2.3 mmol), triphenylphosphine (6 mg, 0.023 mmol) and copper (I) iodide (4 mg, 0.023 mmol) were added and the mixture was stirred for 2 hours at 65° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with heptane:ethyl acetate 100:0->50:50. The desired compound was obtained as a yellow solid (150 mg, 90% yield), MS: m/e=220.3 (M+H+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(Cl)([Cl:17])=O>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([Cl:17])=[O:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CCC(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: CC(=O)N1CCC(CCC(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(1-Acetyl-4-piperidinyl)propionic acid (10.0 g) was added by portions to thionyl chloride (30 ml) at room temperature. After stirring at room temperature for 30 minutes, thionyl chloride was evaporated under reduced pressure to give the crude product of 3-(1-acetyl-4-piperidinyl)propionyl chloride. Aluminum chloride (20 g) was added by portions to a suspension of the crude product and 2,2,2-trifluoro-N-(2-methoxyphenyl)acetamide (10.0 g) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was poured into ice (200 g), extracted with ethyl acetate, and washed with brine. The organic layer was, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel chromatography (eluting solvent; ethyl acetate), and the solvent was evaporated to give the title compound as colorless crystals (8.83 g) having a melting point of 77 to 79° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:13]=2[N:14]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:13]=2[N:14]=1
Reactant: COc1ccc2sc(C)nc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2sc(CBr)nc2c1

Procedure:
2.58 g (14.5 mmol; 1.3 eq.) of N-bromosuccinimide and a spatula tip's worth of aza-bis-isobutyronitrile are added to 2 g (11.16 mmol) of 2-methyl-5-methoxy-1,3-benzothiazole in solution in 25 ml of anhydrous carbon tetrachloride. The reaction mixture is heated under reflux and under irradiation for 6 hours, with a spatula tip's worth of aza-bis-isobutyronitrile added every 2 hours. After returning to ambient temperature, the insoluble part formed is filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a silica column (eluent: ethyl acetate/heptane 1/4). The expected product is obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]([CH:13]1[CH2:17][CH2:16][O:15][CH2:14]1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:9][C:4]1[C:3]2[NH:10][C:11]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)=[N:1][C:2]=2[CH:7]=[C:6]([OH:8])[CH:5]=1
Reactant: Nc1cc(O)cc(Cl)c1NC(=O)C1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Oc1cc(Cl)c2[nH]c(C3CCOC3)nc2c1
Reaction time: 2 h

Procedure:
0.10 g (0.39 mmol) N-(2-amino-6-chloro-4-hydroxyphenyl)tetrahydrofuran-3-carboxamide were placed in 20 mL methanol, a spatula tip of p-toluenesulphonic acid monohydrate was added and the mixture was boiled for 2 h. The reaction mixture was evaporated down i.vac. and purified by chromatography. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:22])[NH:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 0° C. solution of piperazine-1-carboxylic acid tert-butyl ester (114 g) in DCM (500 mL) was treated with phenyl isocyanate (65 mL). After 1 hour (h), the mixture was allowed to warm to room temperature (rt). After 15 h, the resulting mixture was filtered and the solid was washed with DCM (2×100 mL), giving the title compound as a white amorphous solid (95 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](O)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[C:23]1([C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:14][OH:15])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
To a suspension of LAH (3.9 g, 0.104 mol) in dry THF (200 mL) was stirred at 0° C. for 20 min. A solution of 2,2,2-triphenylacetic acid (10 g, 0.034 mol) in dry THF (50 mL) was added in a drop-wise manner. The reaction mixture was stirred at RT overnight. Excess LAH was quenched with 1.5 N HCl and the reaction mixture was further stirred for 2 h at RT. The reaction mixture was filtered through celite, washed with ethyl acetate and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography on silica gel (4% ethyl acetate in pet. ether) to give the title compound (4.6 g, 48%). TLC: Pet. ether/EtOAc, 7:3, Rf=0.2
Reaction SMILES: C(O)CC.Cl.[CH2:6]([O:8][NH2:9])[CH3:7].[CH3:10][N:11]1[C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][O:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[CH3:33])=O)=[CH:14][CH:13]=[N:12]1>O>[CH2:6]([O:8][N:9]=[C:16]([C:15]1[N:11]([CH3:10])[N:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][O:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[CH3:33])[CH3:7]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=O)c2ccnn2C)c1
Reactant: CCON
Agent: Cl
Solvent: O
Solvent: CCCO
Product: CCON=C(c1ccccc1COc1cc(C)ccc1C)c1ccnn1C
Yield: 45.9 %

Procedure:
n-Propanol (2 ml) and ethoxyamine hydrochloride (0.18 g, 1.8 mmol) were added to 2-(2,5-dimethylphenoxy-methyl)phenyl 1-methylpyrazol-5-yl ketone (0.20 g, 0.6 mmol), and the mixture was stirred under reflux for 3 days. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give isomer A (0.11 g, 50.4%, as colorless crystals) and isomer B (0.10 g, 45.9%, as colorless crystals) of 2-(2,5-dimethylphenoxymethyl)phenyl 1-methylpyrazol-5-yl ketone O-ethyloxime.
Reaction SMILES: [S:1]([C:6]([C:9]([C:12]([O:14][K])=[O:13])([F:11])[F:10])([F:8])[F:7])([O:4][K])(=[O:3])=[O:2].Cl>O>[S:1]([C:6]([F:7])([F:8])[C:9]([F:10])([F:11])[C:12]([OH:14])=[O:13])([OH:4])(=[O:3])=[O:2].[S:1]([C:6]([C:9]([C:12]([OH:14])=[O:13])([F:10])[F:11])([F:7])[F:8])([OH:4])(=[O:3])=[O:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2]
Reactant: O=C(O[K])C(F)(F)C(F)(F)S(=O)(=O)O[K]
Agent: Cl
Solvent: O
Product: O=C(O)C(F)(F)C(F)(F)S(=O)(=O)O

Procedure:
Ten grams of KO3SCF2CF2COOK were dissolved in 30 ml warm water and placed in a 50 cm×2.5 cm glass column containing a 20 cm bed of "Amberlite IR-120" ion-exchange resin in the acid (H+) form, which had been previously prepared by treating the column with 6 N hydrochloric acid and rinsing with distilled water. The column was eluted with distilled water. The first 150 ml of eluate was concentrated under reduced pressure to yield the hydrate of 3-sulfoperfluoropropionic acid, HO3SCF2CF2COOH.8H2O.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1)=[CH2:2].[C:12]([NH:18][C:19]1[N:20]=[C:21]([OH:30])[C:22]2[CH:28]=[C:27](Br)[CH:26]=[N:25][C:23]=2[N:24]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([NH:18][C:19]1[N:20]=[C:21]([OH:30])[C:22]2[CH:28]=[C:27]([CH:2]=[CH:1][C:3]3[NH:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=3)[CH:26]=[N:25][C:23]=2[N:24]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(Br)cnc2n1
Reactant: C=Cc1ccc(C(=O)OC)[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C=Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)[nH]1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A mixture of methyl 5-vinylpyrrole-2-carboxylate (298 mg, 2.0 mmol), 2-pivaloylamino4-hydroxy-6-bromopyrido[2,3-d]pyrimidine (683 mg, 2.1 mmol), palladium acetate (22.5 mg, 0.1 mmol), tri-o-tolylphosphine (60.9 mg, 0.2 mmol), and triethylamine (7.0 mL) in acetonitrile (20 mL) was heated overnight at reflux. The reaction mixture was cooled to room temperature, and the solid which formed collected by filtration, washed with cold acetonitrile, and dried to give methyl 5-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethenyl]pyrrole-2-carboxylate as a yellow solid (706 mg, 89%). The product can be used in the next step without further purification. An analytical sample, mp >260° C., was obtained by recrystallization from methanol: 1H NMR (DMSO-d6) δ 12.28 (s, 1H), 12.08 (s, 1H), 11.40 (s, 1H), 8.93 (s, 1H), 8.40 (s, 1H), 7.36 (d, 1H, J=16.6 Hz), 7.27 (d, 1H, J=16.6 Hz), 6.81 (m, 1H), 6.48 (m, 1H), 3.76 (s, 3H), 1.23 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.C(N(CC)CC)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:41]([NH:40][CH2:38][CH3:39])=[O:42])[CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@H]4CCCNC4)ncnc32)cc1
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCC[C@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 87.1 %

Procedure:
To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3S)-piperidin-3-yl]-9H-purin-6-amine (16 mg, 0.036 mmol, 1 eq.) in 2 mL of THF was added triethylamine (0.015 mL, 0.109 mmol, 3 eq.) and ethyl isocyanate (0.004 mL, 0.055 mmol, 1.5 eq). The reaction is stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 16 mg (86%) of (3S)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}-N-ethylpiperidine-1-carboxamide. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06-1.34 (m, 3 H) 1.53-1.95 (m, 4 H) 2.12-2.29 (m, 1 H) 3.07 (br. s., 2 H) 3.32 (br. s., 1 H) 3.72-4.41 (m, 3 H) 5.06 (br. s., 1 H) 6.02 (d, J=6.12 Hz, 1 H) 7.08-7.66 (m, 8 H) 8.45 (br. s., 1 H), [M+H]+ 510.3.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]([CH2:18][OH:19])=[CH:16][C:15]([C:20]([OH:22])=O)=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C:31]2=[O:36])=[CH:26][CH:25]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CCN(CC)CC>[O:36]=[C:31]1[CH2:32][O:33][CH2:34][CH2:35][N:30]1[C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:20]([C:15]2[CH:16]=[C:17]([CH2:18][OH:19])[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[N:14]=2)=[O:22])=[CH:29][CH:28]=1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C(O)c1cc(CO)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)c1cc(CO)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Reaction time: 16 h

Procedure:
To 100 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-hydroxymethyl-1H-pyrazole-3-carboxylic acid in 2 ml DCM and 0.1 ml NEt3, 67 mg 4-(4-Amino-phenyl)-morpholin-3-one and 74 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. The mixture was concentrated under reduced pressure and triturated in a mixture of water/DMF. The precipitate was collected by filtration and washed with water containing 0.5% TFA. The product was obtained as a white solid which was dried under reduced pressure.
Reaction SMILES: Cl[O-].[Na+].[OH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].[OH-].[Na+].[I-:16].[Na+]>CO>[OH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[I:16])[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cccc(O)c1
Reactant: [I-]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(I)c(O)c1
Temperature: 0 °C
Reaction time: 72 h
Yield: 39.2 %

Procedure:
1319 g (1.52 mol) of commercial 9.6% sodium hypochlorite solution are added dropwise to a solution of 200 g (1.45 mol) of 3-hydroxybenzoic acid, 61 g (1.52 mol) of sodium hydroxide powder and 228 g (1.52 mol) of sodium iodide in 2 l of methanol cooled beforehand to 0° C. The reaction medium is stirred at room temperature for 72 hours. After evaporating off the methanol, the solution is cooled to 10° C. and acidified with aqueous hydrochloric acid solution to pH 2. The mixture is stirred for 2 hours and the product precipitates. The product is filtered off, washed thoroughly with water and dried under vacuum at 50° C. 150 g (39%) of 3-hydroxy-4-iodobenzoic acid are obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:5].O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=2[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[O:5])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccccc1C(=O)NCCCn1ccnc1
Solvent: O
Product: O=C(NCCCn1ccnc1)c1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
2-Amino-N-(3-imidazol-1-ylpropyl)benzamide (32.9 g) was dissolved in pyradine (165 ml) and 4-chlorobenzenesulphonyl chloride (41.2 g) was added in portions. The temperature of the reaction mixture rose to 52° C. The solution was stirred at room temperature for 4 hours and poured into water (1.5 l) to precipitate an oil which slowly solidified on standing. The solid was collected, washed with water and recrystallised from ethanol to give 2-(4-chlorobenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)-benzamide (24.4 g), in the form of a white solid, m.p. 175°-177° C.