Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:8]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[N:5]=[CH:6][N:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(N)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
A 100-mL single-neck round-bottomed flask was purged with nitrogen and charged with 243b (2.3 g, 7.8 mmol), 10% palladium on carbon (10% wet, 230 mg), and ethanol (40 mL). The mixture was evacuated, charged with hydrogen gas, and stirred at room temperature for 3 h. The hydrogen was then evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 243c (2.0 g, 95%). MS-ESI: [M+H]+ 267.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Cl)=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:18][N:19](C)C(=O)C>[Zn].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.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[C-]#N.[Zn+2]>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:18]#[N:19])=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[CH:6]=1
Reactant: COC(=O)Cc1ccc(Cl)c(OC(F)(F)F)c1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC(=O)Cc1ccc(C#N)c(OC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
A suspension of methyl(4-chloro-3-trifluoromethoxyphenyl)acetate (4.8 g, 17.8 mmol) in N,N-dimethylacetamide (50 mL) in a 250 mL round bottomed flask was degassed by bubbling nitrogen for 15 minutes. To this suspension was then added zinc dust (0.23 g, 3.55 mmol), DPPF (0.79 g, 1.42 mmol), Pd2(dba)3 (0.65 g, 0.71 mmol), and Zn(CN)2 (2.50 g, 21.3 mmol) at room temperature. The nitrogen purge was continued for another 15 minutes before the mixture was heated in a 120° C. oil bath for 12 hours. LC-MS indicated that the starting material was consumed to give the product. LC-MS (IE, m/z): 260 [M+1]+. The mixture was partitioned twice between water and ethyl acetate. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on a silica gel column (5-20% ethyl acetate/hexanes) to yield the title product as a yellowish solid. 1H-NMR (500 MHz, CDCl3) δ ppm 3.77 (s, 2H), 3.78 (s, 3H), 7.39 (d, J=7.5 Hz, 1H), 7.40 (s, 1H), 7.72 (d, J=7.5 Hz, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][O:23][CH2:24]/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:17][CH2:16]1)(=O)C1C=CC=CC=1>C1COCC1>[C:27]1(/[CH:26]=[CH:25]/[CH2:24][O:23][CH2:22][CH2:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(c1ccccc1)N1CCC(CCOC/C=C/c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C(=C/c1ccccc1)\COCCC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.9 %

Procedure:
Lithium aluminum hydride (1.0 M in tetrahydrofuran, 2.1 mL, 2.1 mmol) was added dropwise over 4 minutes to a -78° C. solution of the above amide (0.72 g, 2.1 mmol) in dry THF with stirring under nitrogen. After 3 hours, the reaction was allowed to slowly warm to room temperature. After 21 hours, Celite® was slurried into the reaction mixture, followed by careful quenching with water (20 mL). The mixture was filtered through a Celite® pad and rinsed with ethyl acetate (100 mL). After phase separation, the organic solution was extracted with water (20 mL), brine (20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with ethyl acetate, and concentrated under vacuum to yield (E)-4-[(3-phenyl-2-propenyloxy)ethyl]piperidine (0.18 g, 26%) as a colorless oil. 1H NMR(300 MHz/CDCl3 /TMS, δ): 7.40-7.16(m,10H), 6.60(d,1H,J= 16 Hz), 6.29(dt,1H,J=16,6 Hz), 4.12(dd,2H,J=6,1 Hz), 3.51(t,2H,J=7 Hz), 3.48(s,2H), 2.88-2.85(m,2H), 2.00-1.21 (m,9H). HRMS: Calculated for C23H29NO:335.2249; found: 335.2251.
Reaction SMILES: [Cl:1][C:2]1[C:14]([OH:15])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:14]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][S:23][C:20]2[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][CH:21]=2)=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc(SCCCCCl)cc1
Reactant: CC1(C)OC(=O)Nc2cc(Cl)c(O)cc21
Product: Cc1ccc(SCCCCOc2cc3c(cc2Cl)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 4 from 7-chloro-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(4-methylphenylmercapto)-butylchloride.
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[CH:30][C:29]=2[CH3:38])[C:6]2[CH:39]=[CH:40][CH:41]=[CH:42][C:5]1=2)(=[O:3])[CH3:2].[ClH:43]>O1CCOCC1.CCOCC>[ClH:43].[ClH:43].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[CH:30][C:29]=2[CH3:38])[C:6]2[CH:39]=[CH:40][CH:41]=[CH:42][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2N(Cc2c(C)cnc3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C)cnc3ccccc23)c2ccccc2N(C(C)=O)[C@H]1C
Yield: 79 %

Procedure:
A rt solution of tert-butyl(S)-1-((2S,3S)-1-acetyl-2-methyl-5-((3-methylquinolin-4-yl)methyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (96 mg, 167 μmol) in 4 M HCl in dioxane (837 μl) was stirred for 1.5 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((2S,3S)-1-acetyl-2-methyl-5-((3-methylquinolin-4-yl)methyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide dihydrochloride (72.2 mg, 79%) as an off-white solid. MS m/z 474 (MH)+.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26](F)=[C:27]([F:30])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][CH2:41][OH:42])[CH2:35][CH2:34]1>C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH2:16][CH:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:42][CH2:41][CH2:40][CH2:39][N:36]4[CH2:35][CH2:34][N:33]([CH3:32])[CH2:38][CH2:37]4)=[C:27]([F:30])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:18][CH2:19]1)=[O:13])([CH3:9])([CH3:8])[CH3:10]
Reactant: CN1CCN(CCCO)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)c(F)cc23)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(CCCOc2cc3ncnc(C4CCN(C(=O)OC(C)(C)C)CC4)c3cc2F)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 61.3 %

Procedure:
A solution of 1.19M KOtBu in THF (128 μL, 152 μmol) was added dropwise with stirring over 2.5 min to a 0° C. homogeneous solution of 4-(6,7-Difluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (38.1 mg, 109 μmol), as prepared in the previous step, and 3-(4-Methyl-piperazin-1-yl)-propan-1-ol (22.4 mg, 142 μmol) in THF (170 μL). The reaction was stirred at 0° C. for 1.5 hr, and was then partitioned with DCM (2 mL) and 1M NaCl (2 mL). The aq layer was back-extracted with DCM (1×2 mL), and the combined cloudy white organic layers were dried (Na2SO4) and concentrated. The residue was purified by silica flash chromatography (1:2 hex/EtOAc/3% DMEA eluent) to yield the title compound as an off-white foam (32.6 mg, 61%). NOe experiments support the assigned regioisomer. Select 1H-NMR resonances and nOes (300 MHz, CDCl3) δ 7.73 (d, J=11.4 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 3.46 (tt, 1H). Irradiation of the diagnostic methine proton at δ 3.46 generates an nOe to the quinazoline C5 proton at δ 7.73, but not to the quinazoline C8 proton at δ 7.43. The C5 proton has a larger coupling constant than the C8 proton, indicating fluorine substitution at C6 of the quinazoline. LC/MS (ESI): calcd mass 487.3, found 488.3 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[C:6]([CH:9]=1)[CH2:7]O.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[C:6]([CH:9]=1)[CH2:7][Br:18]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(Br)ccc1OCc1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cc(Br)ccc1OCc1cccs1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A solution of 5-bromo-2-(2-thienylmethoxy)benzyl alcohol (0.53 g, 1.77 mmoles) in dichloromethane (12 ml) was cooled in an ice bath and treated with carbon tetrabromide (0.73 g, 2.2 mmol) polymer bound triphenylphosphine (0.65 g, 1.95 mmol) and stirred at ambient temperature for 42 hours. The reaction was filtered and evaporated. Chromatography (eluant: ethyl acetate/hexane) gave 5-bromo-2-(2-thienylmethoxy)benzyl bromide as a white solid (0.29, 45%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=O)[CH2:10][CH2:11][CH3:12])=[CH:6][CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[OH-].[Na+]>O1CCCC1.O>[CH2:9]([NH:8][C:7]1[C:2]([CH3:1])=[C:3]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:4]=[CH:5][CH:6]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(=O)Nc1cccc(-c2ccc(C)cc2)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCCNc1cccc(-c2ccc(C)cc2)c1C
Temperature: 25 °C
Yield: 92.5 %

Procedure:
To solution of N-(2,4′-dimethyl-1,1′-biphenyl-3-yl)butanamide (15 g, 0.056 mol) in anhydrous tetrahydrofuran (500 ml) was added dropwise lithiumaluminium hydride (1 M solution in ether; 112 ml) under nitrogen. The resultant mixture was heated at 75° C. for 5.5 h then allowed to cool to room temperature for 16 h. To the reaction mixture was added dropwise wet ether (50 ml), then 2M NaOH (50 ml) and water (50 ml). The mixture was filtered, the solid residues washed with ether and the filtrate dried (Na2SO4), and the solvents removed in vacuo. The residue was partitioned between CH2Cl2 (400 ml) and water (20 ml). The CH2Cl2 layer was dried (Na2SO4) and the solvent removed in vacuo to afford the title compound as a yellow oil (13.12 g).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([O:11][C@@H:12]3[CH2:16][CH2:15][NH:14][CH2:13]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:21][O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:21][O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][N:14]1[CH2:15][CH2:16][C@@H:12]([O:11][C:10]2[CH:17]=[CH:18][C:7]([O:6][C:5]3[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:8][CH:9]=2)[CH2:13]1
Reactant: COC(=O)CCCBr
Reactant: Clc1ccc(Oc2ccc(O[C@@H]3CCNC3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCN1CC[C@@H](Oc2ccc(Oc3ccc(Cl)cc3)cc2)C1
Temperature: 60 °C
Yield: 21.2 %

Procedure:
(R)-3-[4-(4-Chloro-phenoxy)-phenoxy]-pyrrolidine (344 mg, 1.05 mmol) was taken into anhydrous dimethylformamide (5 mL), and methyl-4-bromobutyrate (209 mg, 1.16 mmol), potassium carbonate (290 mg, 2.1 mmol) was added. The reaction was sealed and heated to 60° C. and left to react for 24 h. The mixture was then partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate 3×. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash column chromatography (50:1 packing ration, eluted with 5% methanol in dichloromethane) to obtain the title product (86.8 mg, 21%); LCMS; m/z 390 (M) 71% pure; 1H NMR (400 MHz, DMSO); δ 1.66-1.80 (m, 3H), 2.22-2.26 (m, 1H), 2.31-2.35 (m, 2H), 2.37-2.41 (m, 3H), 2.58-2.67 (m, 2H), 2.81-2.84 (m, 1H), 3.58 (s, 3H), 4.80-4.83 (m, 1H), 6.91-6.95 (m, 4H), 6.98-7.00 (m, 2H), 7.37-7.39 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:21])=[O:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 26.5 %

Procedure:
In a similar fashion using route 18 general procedure 27, 8-aminoquinoline (420 mg, 2.91 mmol), 4-chloro-2-nitro-benzenesulfonyl chloride (Intermediate 454) (1.1 g, 4.37 mmol), pyridine (1.5 ml), DMAP (cat.) and DCM (10 ml) gave the title compound (280 mg, 16%) after purification by column chromatography with n-hexane/EtOAc (90:10) elution.
Reaction SMILES: [CH2:1]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[CH2:3][CH2:2]1.[C:13](=O)([O:16]C)[O:14][CH3:15].[H-].[Na+].Cl>CO>[O:5]=[C:4]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:12][CH2:1][CH2:2][CH:3]1[C:13]([O:14][CH3:15])=[O:16]
Reactant: COC(=O)OC
Reactant: O=C1CCCCc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCCc2ccccc2C1=O
Temperature: 80 °C

Procedure:
A mixture of benzosuberone (8 g, 50 mmol) and neat dimethyl carbonate (45 mL) at ambient temperature under nitrogen was treated with sodium hydride (60% in mineral oil, 4 g, 100 mmol) in 0.1 mL of dry methanol, heated at 80° C. for 3 hours, cooled to ambient temperature, treated with 2 N hydrochloric acid (55 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate) and concentrated to provide the title compound as an oil, as a 3:1 mixture of enol and keto forms of product determined by NMR spectroscopy. The NMR of the main enol form was: 1H NMR (CDCl3) δ 2.03-2.16 (m, 4H), 2.64 (m, 2H), 3.82 (s, 3H), 7.23 (m, 1H), 7.33 (m, 2H), 7.62 (m, 1H), 12.6 (br s, 1H); MS (ESI+) m/z 219 (M+H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].[OH-].[K+].S(OC)(O[CH3:20])(=O)=O>CO>[CH3:20][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C)c(NC=O)c(C)c1C

Procedure:
N-(4-Hydroxy-2,3,6-trimethylphenyl)formamide (30.0 g, 167 mmol) was dissolved into a mixed solvent comprising of a 4 N aqueous solution of potassium hydroxide (100 ml) and methanol (300 ml) and then dimethyl sulfate (42.0 g, 334 mmol) was added into the resulting solution. The mixture was refluxed with heating for 14 hours. The reaction mixture was cooled down and the crystals precipitated were collected by filtration to obtain N-(4-methoxy-2,3,6-trimethylphenyl)formamide as a crude product. To a suspension of this compound in methanol (200 ml) was added concentrated hydrochloric acid (50 ml) and the mixture was refluxed with heating for 3 hours. The reaction mixture was cooled down to room temperature and then neutralized with an 8 N aqueous solution of sodium hydroxide. The product was extracted twice with ethyl acetate. The combined extracts were washed with a 10% aqueous solution of sodium hydrosulfite, dried on magnesium sulfate, and then concentrated under reduced pressure. The residue was crystallized from isopropyl ether to obtain 21.0 g (76% yield) of the title compound. Melting point: 70-72° C.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[C:9]([NH2:17])=[C:8]([CH:18]([CH3:20])[CH3:19])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>ClC1C=CC=CC=1Cl>[N:1]1([C:6]2[N:7]=[C:8]([CH:18]([CH3:20])[CH3:19])[C:9]3[NH:17][C:21](=[O:22])[C:13]4=[N:14][CH:15]=[CH:16][N:12]4[C:10]=3[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)c1nc(-n2ccnc2)nc(-n2ccnc2)c1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Clc1ccccc1Cl
Product: CC(C)c1nc(-n2ccnc2)nc2c1[nH]c(=O)c1nccn12
Temperature: 25 °C

Procedure:
Combine 2,4-bis(1H-imidazol-1-yl)-6-(2-propyl)pyrimidin-5-amine (6 g, 22.3 mmol) with 4.5 g (27.8 mmol) of carbonyldiimidazole in 150 mL of 1,2-dichlorobenzene and heat at reflux under N2 for 2 hours. Cool to ambient temperature. Filter the precipitate and wash with CH2Cl2. Dissolve the solids in 500 mL of 10% HCl, treat with charcoal, filter, and make the filtrate basic with NH4OH. Filter the resulting precipitate, wash with water and then with acetone to provide 2-(1H-imidazol-1-yl)-4-(2-propyl)imidazo[2,1-h]pteridin-6(5H)-one; NMR (DMSO+CF3CO2D): δ1.32 (d, 6), 3.84 (m, 1), 7.15 (s, 1), 7.67 (s, 1), 8.04 (s, 1), 8.5 (s, 1) and 8.69 (s, 1 ) ppm.
Reaction SMILES: O[C:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:2](=[CH2:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:18]=[CH:17]2
Reactant: CCOC(=O)C(C)(O)c1ccc2cc(OC)ccc2c1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C=C(C(=O)OCC)c1ccc2cc(OC)ccc2c1
Yield: 64 %

Procedure:
Ethyl 2-hydroxy-2-(6-methoxynaphth-2-yl)propionate (5,0 g, 18,2 mmol), Dowex HCR-W2 strong acid exchange resin (0,50 g) and acetic anhydride (4,09 g, 40,1 mmol) were added to acetic acid (100 g) and refluxed for 7 hours, cooled and the resin was removed by filtration. Ethyl 2-(6-methoxynaphth-2-yl)acrylate was produced in 64,6% yield and could be used without purification.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH3:19])[C:15]=2[C:16]([OH:18])=O)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].FC1C=C(NC2C=NN(C)C=2C(O)=O)C=CC=1>>[CH:1]([C:4]1[C:5]2[C:16](=[O:18])[C:15]3[N:14]([CH3:19])[N:13]=[CH:12][C:11]=3[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cccc(Nc2cnn(C)c2C(=O)O)c1
Agent: Cn1ncc(Nc2cccc(F)c2)c1C(=O)O
Product: CC(C)c1cccc2[nH]c3cnn(C)c3c(=O)c12

Procedure:
The title compounds were prepared as an inseparable mixture with a ratio of 1.2:3 according to the procedure of step 2 in EXAMPLE 3 using 4-[(3-isopropylphenyl)amino]-1-methyl-1H-pyrazole-5-carboxylic acid (EXAMPLE 10, step 1), instead of 4-[(3-fluorophenyl)amino]-1-methyl-1H-pyrazole-5-carboxylic acid.
Reaction SMILES: ClC1C=C(C=CC=1)C(O)=[O:6].O.[N:12]1[C:21]2[C:16](=[C:17]3[CH:29]=[CH:28][CH:27]=[CH:26][C:18]3=[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]3=2)[N:15]=[CH:14][CH:13]=1>ClCCl>[N+:12]1([O-:6])[C:21]2[C:16](=[C:17]3[CH:29]=[CH:28][CH:27]=[CH:26][C:18]3=[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]3=2)[N:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: c1ccc2c(c1)c1ccccc1c1nccnc21
Solvent: O
Solvent: ClCCl
Product: [O-][n+]1ccnc2c3ccccc3c3ccccc3c21
Temperature: 25 °C
Yield: 51 %

Procedure:
First, to a solution in which 1.36 g of dibenzo[f,h]quinoxaline was dissolved in 20 mL of dichloromethane was added 2.04 g of 3-chlorobenzoic acid (abbreviation: MCPBA) in a nitrogen atmosphere, followed by stirring at room temperature for 1 week. Water was added to this mixture, and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. Then, the resulting solution was filtered. The solvent of this solution was distilled off. The resulting residue was purified by silica gel column chromatography which uses a mixed solvent of dichloromethane and ethyl acetate as a developing layer. By recrystallization from dichloromethane, the object of the synthesis was obtained (as a white powder in a yield of 51%). The synthesis scheme of Step 1 is illustrated in the following (a″′-2-1).
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].[F:24][C:25]1([F:41])[O:29][C:28]2[CH:30]=[CH:31][C:32]([CH:34]=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:33][C:27]=2[O:26]1>>[F:41][C:25]1([F:24])[O:29][C:28]2[CH:30]=[CH:31][C:32]([C@H:34]3[C@H:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:2]3([CH3:4])[CH3:3])=[CH:33][C:27]=2[O:26]1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=Cc1ccc2c(c1)OC(F)(F)O2
Agent: [I-]
Product: CCOC(=O)[C@H]1[C@H](c2ccc3c(c2)OC(F)(F)O3)C1(C)C
Yield: 54.3 %

Procedure:
Isopropyltriphenylphosphonium iodide (4.32 g, 10 mmol) and ethyl 3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-acrylate (2.56 g, 10 mmol) were reacted as described under General Procedure B to furnish the title compound (1.62 g, 54%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 6.96 (d, J=7.1 Hz, 1H), 6.89 (s, 1H), 6.87 (d, J=7.1 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 2.66 (d, J=5.8 Hz, 1H), 1.88 (d, J=5.8 Hz, 1H), 1.36 (s, 3H), 1.30 (t, J=7.2 Hz, 3H), 0.92 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH:11]([NH:14][CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C.C1COCC1>O.CCOC(C)=O>[CH3:15][N:14]([CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: CNC(C)C
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C)Cc1ccc(C#N)cc1
Reaction time: 12 h
Yield: 87.6 %

Procedure:
Add 4-bromomethyl-benzonitrile (784 mg, 4 mmol) to a stirring mixture of N-isopropyl-methylamine (730 mg, 10 mmol), triethylamine (1.4 mL, 10 mmol) and THF (20 mL) at room temperature, and stir for 12 h. Dilute the mixture with water and EtOAc. Extract the aqueous layer with EtOAc and wash the organic phase with water and brine. Dry the organic solution over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel (12 g) eluting with a gradient of DCM to 9:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the desired compound (660 mg, 88%). MS (APCI+) m/z: 189 (M+H)+.
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].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:21]([C:18]2[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a stirring, 0° C. solution of piperazine-1-carboxylic acid tert-butyl ester (1.17 g, 6.29 mmol, 1.05 equiv) and TEA (1.67 mL, 11.98 mmol, 2.0 equiv) in DCM (10 mL) was added 4-bromo-benzenesulfonyl chloride (1.53 g, 5.99 mmol, 1 equiv). The reaction was allowed to warm to ambient temperature and stir for 3 h. The reaction solvents were evaporated and the resulting solids were dried, washed with water and filtered, yielding a white powder (2.24 g, 92% yield). MS (ESI+): m/z=306.9, LC retention time: 3.17 min. Rf=0.56 (30% EtOAc/hexanes).