Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[CH:12]=[O:13].CC1(C)COB([C:22]2[CH:27]=[CH:26][C:25]([C:28]3([CH2:31][OH:32])[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)OC1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.O.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]>[F:14][C:3]1[C:2]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3([CH2:31][OH:32])[CH2:29][CH2:30]3)=[CH:24][CH:23]=2)=[C:10]([F:11])[CH:9]=[C:8]2[C:4]=1[C:5]([CH:12]=[O:13])=[CH:6][NH:7]2
Reactant: O=Cc1c[nH]c2cc(F)c(Br)c(F)c12
Reactant: CC1(C)COB(c2ccc(C3(CO)CC3)cc2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1c[nH]c2cc(F)c(-c3ccc(C4(CO)CC4)cc3)c(F)c12
Temperature: 25 °C
Yield: 27.8 %

Procedure:
A solution of 5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde (200 mg, 0.77 mmol) and {1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclopropyl}methanol (200 mg, 0.77 mmol) in toluene (6 mL) and EtOH (2 mL) was added a solution of potassium carbonate (318 mg, 2.31 mmol) in water (1.0 mL) and Pd(dppf)Cl2 (31 mg, 0.04 mmol) at room temperature under N2. The reaction was cooled to room temperature, and extracted with ethyl acetate (20 mL×3). The organic layers were washed with brine (20 mL), dried over sodium sulfate, concentrated, and purified by column chromatography to give the title compound (70 mg, 28%) as a yellow solid.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:12]5[CH:13]=[CH:14][N:15]=[CH:10][N:11]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H](Nc1nccc(-n2cnc3cc(Nc4ccncn4)ccc32)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 63.6 %

Procedure:
2-[(S)-1-phenylethylamino]-4-[5-aminobenzimidazol-1-yl]pyrimidine (14.0 mg) was dissolved in 2 mL MeOH, 10%Pd/C (20.3 mg) added, the system fitted with a balloon of hydrogen, purging the system twice and leaving the reaction stirring at room temperature for 23 h. The mixture was then filtered through Celite®, washing thoroughly with methanol, and the solvent removed in vacuo. The residue was purified on silica gel (2-5%(2M NH3 in MeOH)/CH2Cl2) to yield 5.5 mg of the title compound. Mass spectrum (ESI) 409.4 (M+1).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([O:37]C)=[O:36])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([C:22](=[O:29])[CH2:23][N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)[CH2:18][C:17]4[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>O1CCOCC1.O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([OH:37])=[O:36])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([C:22](=[O:29])[CH2:23][N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)[CH2:18][C:17]4[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C(=O)Cn1ccnc1)Cc1cc(F)ccc1-3
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C(=O)Cn1ccnc1)Cc1cc(F)ccc1-3
Temperature: 60 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
Methyl 14-cyclohexyl-3-fluoro-6-(1H-imidazol-1-ylacetyl)-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate was dissolved in a solution of dioxane: H2O (1:1) (0.1 M) and to that solution aqueous KOH (3 eq, 5 N) were added. The solution was stirred at 60° C. for 3 h. The solvent was evaporated in vacuo. The crude was then purified by automated RP-MS-HPLC (stationary phase: column Waters SYMMETRY prep. C18, 7 μm, 19×300 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (41%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: CCOC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OCC)C3)cc1

Procedure:
Method as example 34 using (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2 yl)phenyl)urea (example 13) and ethyl chloroformate as starting materials.
Reaction SMILES: [CH2:1]([O:3][P:4]([O:15][CH2:16][CH3:17])([CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2]>CO.O=[Pt]=O>[CH2:16]([O:15][P:4]([O:3][CH2:1][CH3:2])([CH2:6][CH:7]([OH:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:17]
Reactant: CCOC(=O)CC(=O)CP(=O)(OCC)OCC
Agent: O=[Pt]=O
Solvent: CO
Product: CCOC(=O)CC(O)CP(=O)(OCC)OCC
Reaction time: 36 h
Yield: 101.1 %

Procedure:
The title compound of Example 7 (17 g, 63.8 mmol) was dissolved in 200 mL of methanol. To this solution was added PtO2 (1.7 g, 10% w/w). The mixture was degassed by evacuation of air, then refilling with hydrogen. This degassing procedure was repeated three times. The pressure in the Parr-shaker was set to 50 psi, and the mixture was shaken for 36 hours. The catalyst was filtered through a Celite pad and the filtrate was concentrated on a rotavap to give 17.3 g (~100%) of the title compound as a white solid, m.p. 33° C. to 35° C.
Reaction SMILES: [CH2:1]([P:3]([C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[Cl:31])[CH:17]=[CH:16][C:15]=1[NH:32][OH:33])([O:5][N:6]=[C:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:4])[CH3:2]>C(O)C>[CH2:1]([P:3]([C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=2[Cl:31])[CH:17]=[CH:16][C:15]=1[N:32]=[O:33])([O:5][N:6]=[C:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:4])[CH3:2]
Reactant: CCOC(=O)C(C)=NOP(=O)(CC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1NO
Solvent: CCO
Product: CCOC(=O)C(C)=NOP(=O)(CC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1N=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of ethyl 2-[P-ethyl-2-hydroxyamino-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxyimino]propionate (400 mmol) and ferric chloride (600 mmol) in aqueous ethanol (1:3 water:ethanol; 10 ml) is stirred at RT for 10 min. The reaction is filtered and the filtrate is diluted with methylene chloride, washed, dried and evaporated to dryness to give ethyl 2-[P-ethyl-2-nitroso-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxyimino]propionate.
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][C:7]([NH:11][C:12]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[O:13])([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH:2]([C:3]12[CH2:10][C:7]([NH:11][C:12]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[O:13])([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2)=[O:1]
Reactant: O=C(NC12CCCC(CO)(CC1)C2)c1cnccn1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CC12CCCC(NC(=O)c3cnccn3)(CC1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a solution of N-(5-(hydroxymethyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide (540 mg, 2.1 mmol) in DCM (20 mL) was added PCC (670 mg, 3.1 mmol) in portions and the reaction mixture was stirred at room temperature for two hours. The mixture was filtered through a pad of silica gel and the filtrate was concentrated. The resulting residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2/1) to yield 350 mg (65%) of the title compound, N-(5-formylbicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide, as a white solid. ESI-MS m/z: 260 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:28])[CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([OH:27])=[CH:24][CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:13]=[N:12]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:40][C@@H:41]1[CH2:45][CH2:44][CH2:43][N:42]1[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])(=O)=O.O>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:28])[CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH2:40][C@@H:41]5[CH2:45][CH2:44][CH2:43][N:42]5[C:46]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:47])=[CH:24][CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:13]=[N:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cn1cc(Nc2ncnc3cc(O)ccc23)cn1)Nc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc2c(Nc3cnn(CC(=O)Nc4cccc(F)c4)c3)ncnc2c1
Yield: 60.9 %

Procedure:
A solution of N-(3-fluorophenyl)-2-{4-[(7-hydroxyquinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamide (0.590 g, 0.97 mmol), cesium carbonate (1.95 g, 5.98 mmol) and tert-butyl (2S)-2-{[(methylsulphonyl)oxy]methyl}pyrrolidine-1-carboxylate (0.325 g, 1.16 mmol) in dimethylacetamide (10 ml) was heated at 80° C. for 18 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulphate and evaporated in vacuo to leave a brown oil which was purified by silica gel chromatography. Elution with 5 to 7% methanol in dichloromethane gave tert-butyl (2S)-2-[({4-[(1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]quinazolin-7-yl}oxy)methyl]pyrrolidine-1-carboxylate (0.332 g, 61% yield) as a light brown solid.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]2=[N:8][CH:7]=1)CCC.Br[C:28]1[CH:29]=[CH:30][C:31]([F:34])=[N:32][CH:33]=1>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>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:6]2[N:10]3[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[N:14][C:9]3=[N:8][CH:7]=2)=[CH:33][N:32]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Fc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cn1

Procedure:
To a degassed solution of 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine was added 5-bromo-2-fluoropyridine (0.128 ml, 1.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (173 mg, 0.15 mmol) and the mixture heated at reflux for 5 h. The crude reaction was washed with water and extracted with ethyl acetate. After adding isohexane a dark solid was collected by suction filtration. The solid was adsorbed onto silica and purified by chromatography on silica gel, eluting with isohexane on a gradient of ethyl acetate (20-60%), to give 3-(2-fluoropyridin-5-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (150 mg) as a dark solid: δH (500 MHz, CDCl3) 7.12 (1H, m), 7.30 (1H, d, J 7), 7.99-8.02 (1H, m), 8.10 (1H, s), 8.46 (1H, s), 8.72 (1H, d, J 7); m/z (ES+) 282, 283 (M++H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=O)[CH3:16])=[CH:10][CH:9]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][CH3:16])=[CH:10][CH:9]=1
Reactant: CC(=O)Nc1ccc(Br)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCNc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a suspension of lithium aluminum hydride (1.1 g, 29 mmol) in anhydrous tetrahydrofuran (70 ml) was added dropwise at 0° C. a solution of N-(4-bromophenyl)acetamide (2.5 g, 12 mmol) in anhydrous tetrahydrofuran (30 ml). The reaction mixture was warmed to room temperature, and stirred for 15 mins. After further stirring at 60° C. for 2 hrs, the mixture was cooled to 0° C. Water (1.8 ml) was added dropwise by small portions, and 2M aqueous sodium hydroxide solution (1.55 ml) was added dropwise. After stirring for 15 mins, sodium sulfate was added, and the mixture was further stirred for 15 mins. The mixture was filtered through a Celite pad, and the insoluble material was washed with dichloromethane. The filtrate and washing solution were combined and concentrated under reduced pressure to give 4-bromo-N-ethylaniline (2.28 g, yield 95%) as a yellow oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([F:11])=[CH:8][CH:9]=2)[N:4]([CH2:12][CH3:13])[CH:3]=1.[O:14]=[C:15]1[NH:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.O1CCOCC1>[CH2:12]([N:4]1[C:5]2=[N:6][C:7]([F:11])=[CH:8][CH:9]=[C:10]2[C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:16][C:15]2=[O:14])=[CH:3]1)[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CCn1cc(Br)c2ccc(F)nc21
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCn1cc(N2CCN(C(=O)OC(C)(C)C)CC2=O)c2ccc(F)nc21
Yield: 103.4 %

Procedure:
3-Bromo-1-ethyl-6-fluoro-1H-pyrrolo[2,3-b]pyridine (13.00 g, 53.48 mmol), tert-butyl 3-oxopiperazine-1-carboxylate (11.78 g, 58.83 mmol), N,N′-dimethylethane-1,2-diamine (2.36 mL, 21.93 mmol), copper(I) iodide (2.24 g, 11.77 mmol), potassium phosphate (tribasic, n-hydrate) (12.49 g, 58.83 mmol), and 1,4-dioxane (250 mL) are combined under a nitrogen atmosphere with stirring and heated to reflux overnight. The reaction is cooled, poured onto brine (ca. 500 mL) and the product extracted with CHCl3 (ca. 2×300 mL). The combined organic extracts are dried over magnesium sulphate, filtered, and concentrated in vacuo to give a yellow oil. This is purified by column chromatography on silica, eluting with 0 to 90% EtOAc in hexane, to give the title compound as an orange oil (20.039 g, 55.29 mmol). MS (m/z): 363 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([C:18](=[O:24])[CH2:19]S(C)(=O)=O)=[C:12]([O:25][CH3:26])[CH:11]=2)=[CH:4][N:3]=1.[Al]>O1CCCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:25][CH3:26])[C:13]([C:18](=[O:24])[CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1C(=O)CS(C)(=O)=O
Agent: [Al]
Solvent: C1CCOC1
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1C(C)=O

Procedure:
A solution of 7.0 g. of 4'-[(2,4-diamino-5-pyrimidinyl)-methyl]-2',6'-dimethoxy-2-(methylsulfonyl)-acetophenone in 80 ml. of 20% aqueous tetrahydrofuran is reduced with 1 g. of amalgamated aluminum at 40° over a period of 1 hour. The reaction mixture is filtered and the filtrate is concentrated to 1/3 its original volume and is adjusted to a pH of 9 with 4N sodium hydroxide solution. The precipiated product is taken up in ethyl acetate. The ethyl acetate extracts are dried over magnesium sulfate and evaporated. The residue is recrystallized from methanol and there is obtained 4'-[(2,4-diamino-5-pyrimidinyl)-methyl]-2',6'-dimethoxy-acetophenone, having a m.p. of 282°-285° (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([CH2:57][CH3:58])=[CH:53][CH:52]=2)=[CH:4][C:5]([C@H:11]2[C@H:16]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@@H:15]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:14]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@H:13]([CH2:41][O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[O:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:63]O>>[Cl:1][C:2]1[C:3]([CH2:50][C:51]2[CH:52]=[CH:53][C:54]([CH2:57][CH3:58])=[CH:55][CH:56]=2)=[CH:4][C:5]([C@H:11]2[C@H:16]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:15]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:14]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@H:13]([CH2:41][O:42][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[O:12]2)=[C:6]([CH:10]=1)[C:7]([O:9][CH3:63])=[O:8]
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(C(=O)O)cc2Cl)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(C(=O)OC)cc2Cl)cc1

Procedure:
To a cold (0° C.) stirred solution of 5-chloro-4-(4-ethylbenzyl)-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzoic acid (0.15 g, 0.188 mmol) in methanol (10 mL) was added dropwise sulfurous dichloride (0.034 g, 0.021 mL). The mixture was heated to reflux and kept refluxing overnight. The volatiles were removed under reduced pressure, and the residue was quenched with water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium bicarbonate, then with water and then with brine, and dried over anhydrous sodium sulfate. After removal of the volatiles, 153 mg of crude solid product was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[N:17][C:18]([Cl:21])=[N:19][CH:20]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:21][C:18]1[N:19]=[CH:20][C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])=[CH:16][N:17]=1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Clc1ncc(Br)cn1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2cnc(Cl)nc2)C1=O
Yield: 26.5 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465 mmol) was reacted with 5-bromo-2-chloro-pyrimidine (163.7 mg, 0.8465 mmol), 1,4-dioxane (30 mL), copper iodide (16 mg, 0.08465 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium carbonate (468 mg, 3.3860 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in chloroform), followed by preparative HPLC afforded 65 mg of the product (26.5% yield).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:11]=2)[CH2:6]1.O[Li].O>O1CCOCC1.O>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[NH:19][CH2:18][CH2:17][CH2:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][CH:5]([CH2:4][C:3]([OH:26])=[O:2])[CH2:14][CH2:13]2
Reactant: COC(=O)CC1CCc2cc(OCCCNc3ncccn3)ccc2C1
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC1CCc2cc(OCCCNc3ncccn3)ccc2C1
Temperature: 100 °C
Yield: 16.2 %

Procedure:
To a solution of {6-[3-(pyrimidin-2-ylamino)-propoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-acetic acid methyl ester (0.09 g) in 1,4-dioxane (5 mL) was added a solution of LiOH.H2O (0.04 g) in H2O (2 mL) and the reaction was heated to 100° C. for 1 h. The reaction was cooled to room temperature and concentrated under reduced pressure. Water was added to the residue and the mixture was cooled in an ice bath. The mixture was brought to pH 5 by the addition of 1N HCl. The aqueous suspension was extracted with CH2Cl2 and CHCl3. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified using silica gel chromatography. Elution with 10% MeOH/CH2Cl2 gave the title compound as a white solid (14 mg). NMR (300 MHz, MeOH-d4) δ8.24 (broad s, 2H), 7.32 (broad s, 1H), 6.82 (d, J=8.25 Hz, 1H), 6.68-6.63 (m, 2H), 6.52 (t, J=4.76 Hz, 1H), 4.08 (t, J=6.11 Hz, 2H), 3.63 (d, J=5.59 Hz, 2H), 2.83 (dd, J=15.90, 3.70 Hz, 1H), 2.71 (d, J=3.32 Hz, 2H), 2.42-2.34 (m, 3H), 2.11 (dd, J=11.82, 5.88 Hz, 3H), 1.90 (d, J=11.76 Hz, 1H), 1.46-1.32 (m, 1H); MS (+ESI) m/z 342 (M+H)+; Calculated for C19H23N3O3.0.5 H2O: C, 64.94; H, 6.88; N, 11.96. Found: C, 65.43; H, 6.72; N, 11.48.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]4[C:19](=[O:20])[N:18]([CH2:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:17](=[O:29])[C:15]4=3)[N:10]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:46](Cl)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:10]2[C:11]3=[N:12][CH:13]=[C:14]4[C:19](=[O:20])[N:18]([CH2:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:17](=[O:29])[C:15]4=[C:16]3[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:46](=[O:53])[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH:7]=[CH:6][CH:5]=3)=[N:9]2)=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(Cn2nc(-c3cccc(N)c3)c3c4c(cnc32)C(=O)N(CCc2ccccc2)C4=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nc(-c3cccc(NC(=O)c4ccccc4)c3)c3c4c(cnc32)C(=O)N(CCc2ccccc2)C4=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 9.1 %

Procedure:
To an ice cooled solution of 1-(3-aminophenyl)-3-(4-methoxybenzyl)-7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (200 mg) in dichloromethane (6 ml), triethylamine (0.08 ml, 0.59 mmol) and Benzoyl chloride (0.05 ml, 0.59 mmol) were added. The reaction mixture was warmed to room temperature and stirred for 2-3 hours. After completion of reaction (TLC, LCMS), the reaction mixture was diluted with dichloromethane (15 ml) and was washed with water (10 ml). The dichloromethane layer was dried over sodium sulfate and evaporated under reduced pressure. The crude compound was purified by reverse phase HPLC on a C-18 column to give N-(3-(3-(4-methoxybenzyl)-6,8-dioxo-7-phenethyl-3,6,7,8-tetrahydropyrazolo[3,4-b]pyrrolo[3,4-d]pyridin-1-yl)phenyl)benzamide (22 mg, 11%) as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[C:6]2=[N:5][C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=3.[Cl:26][C:27]1[N:28]=[CH:29][NH:30][C:31]=1[Cl:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:26][C:27]1[N:28]=[CH:29][N:30]([CH2:2][C:3]2[N:7]3[C:8]4[C:13]([NH:14][C:15](=[O:16])[C:6]3=[N:5][C:4]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=4)[C:31]=1[Cl:32]
Reactant: Clc1nc[nH]c1Cl
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cn1cnc(Cl)c1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
A suspension of 1-bromomethyl-2-ethoxycarbonyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 3) (2.1 g, 5.0 mmol), 4,5-dichloroimidazole (1.5 g, 11.0 mmol) and potassium carbonate (1.5 g, 11 mmol) in acetonitril (100 ml) was stirred at 80° C. for 5 h and overnight at room temperature. The solvent was evaporated in vacuo and the residue submitted to flash chromatography on silica gel 60 eluting with dichloromethane/methanole (19:1) to give 540 mg (23%) of the title compound. M.p. 240° C.