Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]C)=[CH:6][N:5]=[C:4]([C:10]([NH:12][C@@H:13]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[C:23]([F:32])[CH:22]=2)[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:11])[CH:3]=1.[Li+].[Cl-].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.CCOC(C)=O>[NH2:1][C:2]1[C:7]([OH:8])=[CH:6][N:5]=[C:4]([C:10]([NH:12][C@@H:13]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[C:23]([F:32])[CH:22]=2)[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:11])[CH:3]=1
Reactant: COc1cnc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Nc1cc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)ncc1O
Temperature: 180 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-4-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl) (3-fluoropyridin-2-yl)methyl)-5-methoxypicolinamide (600 mg, 0.0013 mol) in NMP (10 mL) was added LiCl (168 mg, 0.0039 mol, Aldrich) followed by pTSA (754 mg, 0.0039 mol, Aldrich) at rt. The reaction mixture was stirred at 180° C. for 2 h. After completion of the reaction (monitored by TLC, 50% EtOAc in petroleum ether), the reaction mixture was cooled to room temperature and sat'd NaHCO3 (50 mL) was added and the aqueous solution was extracted with EtOAc (25 mL×2). The combined organic layers were washed with water (25 mL×2), saturated NaCl (25 mL) and dried over anhydrous sodium sulfate. The product thus obtained was purified by silica gel (60-120 mesh) column chromatography eluting with 60-70% EtOAc in petroleum ether to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.90 (s, 1H), 9.51 (d, J=8 Hz, 1H), 8.55 (d, J=4.8 Hz, 1H), 7.82-7.78 (m, 2H), 7.56-7.50 (m, 2H), 7.46 (d, J=1.6 Hz, 10.4 Hz, 1H), 7.30 (d, J=12.8, 2H), 6.48 (d, J=4.4 Hz, 1H), 5.78 (s, 2H). MS (ESI, positive ion) m/z: 441.3 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][N+:19]#[C-:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH-].[K+].O>COCCOC>[CH:2]([C:1]1[O:5][CH:20]=[N:19][C:18]=1[S:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1)(=[O:16])=[O:17])([CH3:4])[CH3:3]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(OC)cc1
Reactant: CC(C)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(S(=O)(=O)c2ncoc2C(C)C)cc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
1.1 g (0.0103 mole) of isobutyryl chloride in 10 ml of 1,2dimethoxyethane is added rapidly at a temperature between 15° and 20° C. to a mixture of 2.1 g (0.01 mole) of 4-methoxy benzenesulfonyl methylisonitrile in 10 ml of 1,2-dimethoxyethane in the presence of 0.65 g (0.0116 mole) of potassium hydroxide. The mixture is stirred for 3 h at about 20° C., cooled in an ice bath and water is added. An oil precipitates which solidifies in the presence of a little methanol. In this manner, 0.45 g of 5-isopropyl 4-(4-methoxy benzenesulfonyl)oxazole is obtained which is recrystallized from 5 ml of isopropanol to give 0.4 g, i.e. a yield of 14.2%. M.p.: 98°-100° C.
Reaction SMILES: [C:1]1([CH2:7]N2C3C=CC=CC=3N=N2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH:27]=NC2C=CC=CC=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>CO>[C:1]1([C:7]#[C:27][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(=Nc1ccccc1)c1cccc2ccccc12
Reactant: c1ccc(Cn2nnc3ccccc32)cc1
Solvent: CO
Product: C(#Cc1cccc2ccccc12)c1ccccc1
Yield: 88 %

Procedure:
In a procedure similar to that of Example 16 using [phenylmethyl]-1H-benzotriazole (10 mmol) and N-([1-naphthalenyl]methylene)benzenamine (10 mmol): 88% yield: mp 51°-53° C. (MeOH) (lit1 oil); 1H NMR (300 MHz, CDCl3) δ7.39-7.69 (m, 8H), 7.77-7.90 (m, 3H), 8.46 (br d, 2.7H, 1H); IR (CDCl3) 3060 (s), 2245 (eyne), 1596, 1581, 1508, 1491 (s), 1442, 1398, 1333, 1215, 1070, 1017 cm1. MS (EI) m/e 228 (M+, 100).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:45][OH:46])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]#[N:29])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][CH:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1C[O:50]CC1>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:45][OH:46])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:29])=[O:50])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:40][CH2:41][O:42][CH2:43][CH2:44]5)=[O:38])=[CH:33][CH:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3CO)ncc2c1
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3CO)ncc2c1
Reaction time: 1 h
Yield: 76.1 %

Procedure:
1-(3-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-3-(4-(morpholine-4-carbonyl)phenylamino)-1H-pyrazole-4-carbonitrile (46 mg, 0.074 mmol) was dissolved in 4 mL of THF and 0.5 mL of water. Then dihydrogen tris(dimethylphosphinito)hydroplatinate (3 mg, 0.0069 mmol) was added and the mixture was stirred under fluxing. After 1 hr, TLC indicated complete consumption of the starting material. LC/MS indicated clean desired product formed. The mixture was evaporated and the residue was dissolved in dichloromethane and dried over sodium sulfate, filtered through micron filter and evaporated. The residue was purified through flash column chromatography using methanol in methylene chloride (1.5% to 5% methanol in 10 minutes, 12 g silica gel) to give 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazole-4-carboxylic acid amide as a white solid (36 mg, 76.1% yield). LC/MS clacd for C34H34FN7O5 (m/e) 639.26, obsd 640.1 (M+H, ES+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (s, 9H), 3.50 (br., 4H), 3.59 (br., 4H), 4.38 (br. s., 2H), 4.78 (t, J=5.2 Hz, 1H), 7.36 (d, J=8.6 Hz, 3H), 7.52-7.69 (m, 5H), 7.76 (d, J=13.1 Hz, 2H), 7.88 (s, 1H), 8.54 (m, 2H), 9.44 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)#[N:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)(N)[C@@H:22]([NH2:28])[CH2:23][O:24][CH2:25][O:26][CH3:27])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH2:12]([O:11][C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]2[NH:28][C@@H:22]([CH2:23][O:24][CH2:25][O:26][CH3:27])[C:21]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)([C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=3)[N:2]=2)[N:8]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)c1ccnc(C#N)n1
Reactant: COCOC[C@H](N)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccnc(C2=NC(c3ccc(F)cc3)(c3ccc(F)cc3)[C@H](COCOC)N2)n1
Temperature: 110 °C
Reaction time: 4 h
Yield: 61.4 %

Procedure:
2-Cyano-4-ethoxycarbonylpyrimidine (207.3 mg) and scandium trifluoromethanesulfonate (48.8 mg) were added to a solution of (2R)-1,1-bis(4-fluorophenyl)-3-methoxymethoxy-1,2-propanediamine (303.5 mg) in toluene (2.0 mL), and the mixture was stirred at 110° C. for 4 hours. The reaction mixture was concentrated in vacuo, and then the residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=1:1Δ1:2) to give (5R)-2-(4-ethoxycarbonyl-2-pyrimidyl)-4,4-bis(4-fluorophenyl)-5-[(methoxymethoxy)methyl]-2-imidazoline (279 mg). The obtained ester compound was dissolved in methanol (2 mL), and ammonia gas was passed through the solution at −78° C. for 20 minutes. Then the solution was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo, and then the residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=1:1→chloroform: methanol=9:1) to give the corresponding amide compound (273 mg). Triethylamine (0.75 mL) and trifluoroacetic anhydride (0.26 mL) were added at −78° C. to a solution of the obtained amide compound in tetrahydrofuran (2 mL), and the temperature of the mixture was raised up to room temperature, followed by stirring for 7 hours. Water was added to the reaction mixture, and the mixture was extracted by ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then sodium sulfate was removed by filtration. Then the organic solvent was evaporated in vacuc. The residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=1:1→1:2) to give the corresponding cyano compound (178 mg). The obtained cyano compound was dissolved in tetrahydrofuran (6 mL), and 6N hydrochloric acid (6 mL) was added to the solution. Then the mixture was stirred at room temperature for 5 hours. Saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture carefully, and the mixture was extracted by ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then sodium sulfate was removed by filtration. The organic solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (C-300; chloroform: ethyl acetate=2:1) to give the title compound (74.7 mg).
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[CH:21][N:22]=2)[CH:19]=1)=[O:13]>C(#N)C>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([I:1])=[CH:21][N:22]=2)[CH:19]=1)=[O:13]
Reactant: COC(=O)c1ccc2nccn2c1
Reactant: NC(=O)CCC(=O)NI
Solvent: CC#N
Product: COC(=O)c1ccc2ncc(I)n2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
N-iodosuccinamide (1.55 g, 6.89 mmol) was added to a solution of imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (1.1 g, 6.24 mmol) in acetonitrile (50 mL) which had been cooled to 0° C. under a nitrogen atmosphere. The reaction stirred for 1 hr, then concentrated in vaccuo to a residue. The residue was dissolved in ethyl acetate (50 mL) and washed with 10% sodium bisulfate (2×10 ml) and brine (1×20 mL), then the organic layers were dried over MgSO4 and evaporated to give 3-iodo-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester as a pale yellow solid (1.79 g, 95%). 1H NMR (250 MHz, CDCl3): δ 8.91 (s, 1H), 7.85 (dd, 1H, J=2.5, J=10), 7.80 (s, 1H), 7.69 (d, 1H, J=10), 4.01 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH2:10]([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([CH:20]([CH3:22])[CH3:21])[C:16]=1[CH:23](Cl)[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)=[O:14])[CH3:11].CCN(CC)CC>CCOC(C)=O>[CH2:10]([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([CH:20]([CH3:22])[CH3:21])[C:16]=1[CH:23]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([F:9])=[C:2]([Cl:1])[CH:3]=1)[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(Cl)c1ccc(C#N)cc1
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccn(C(C)C)c1C(Nc1ccc(F)c(Cl)c1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Chloro-4-fluoroaniline (6.40 mmol) was added at 0° C. to a solution of 2-[chloro-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step H3) (3.20 mmol). Then Et3N (9.60 mmol) was added and the mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc. The organic layer was washed successively with H2O (2×), brine, dried (Na2SO4), filtered and concentrated. The product was purified by flash chromatography to afford the title compound. tR: 5.96 min (HPLC 4); ESI-MS: tR=1.35 min, [M+H]+ 440/442 (LC-MS 1).
Reaction SMILES: [C:1](=[NH:25])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([O:13][C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][CH:19]=2)=[C:8]([F:24])[CH:7]=1)[NH2:2].FC(F)(F)C([O-])=O.[CH:33]([CH:35]([CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[N:45][CH:46]=1)[C:36](OC)=O)=[O:34].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[F:12][C:10]1[CH:11]=[C:6]([CH:7]=[C:8]([F:24])[C:9]=1[O:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:21])([F:22])[F:23])=[N:16][CH:15]=1)[CH2:5][CH2:4][O:3][C:1]1[NH:2][CH:36]=[C:35]([CH2:40][C:41]2[CH:46]=[N:45][CH:44]=[N:43][CH:42]=2)[C:33](=[O:34])[N:25]=1
Reactant: COC(=O)C(C=O)Cc1cncnc1
Reactant: N=C(N)OCCc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1nc(OCCc2cc(F)c(Oc3cnc(C(F)(F)F)nc3)c(F)c2)[nH]cc1Cc1cncnc1
Temperature: 80 °C
Yield: 33.8 %

Procedure:
To the solution of 3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenethyl carbamimidate, trifluoroacetate (100 mg, 0.210 mmol) and methyl 2-formyl-3-(pyrimidin-5-yl)propanoate (60 mg, 0.309 mmol) in 1,4-dioxane (1 mL) was added K2CO3 (116 mg, 0.842 mmol). The mixture was heated with a microwave reactor at 80° C. for 0.5 h. Purification via MDAP then afforded the title compound (36 mg, 0.071 mmol, 33.8% yield). LCMS: rt=2.82 min, [M+H]=507
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[C:13]([NH2:16])(=[O:15])[CH3:14]>>[C:13]([NH:16][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1)(=[O:15])[CH3:14]
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Reactant: CC(N)=O
Product: COC(=O)c1cc(C)nc(NC(C)=O)n1
Yield: 68 %

Procedure:
The title compound is prepared in 68% yield (0.76 g, a yellow solid) from methyl 2-chloro-6-methylpyrimidine-4-carboxylate (1.0 g, 5.4 mmol) and acetamide by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[CH3:14][O:15][C:16]([C@@:18]12[CH2:24][CH2:23][C@:22]1([CH2:25]O)[CH2:21][N:20]([C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[C:19]2=[O:35])=[O:17].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl.O>[CH3:14][O:15][C:16]([C@@:18]12[CH2:24][CH2:23][C@:22]1([CH2:25][F:11])[CH2:21][N:20]([C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[C:19]2=[O:35])=[O:17]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: COC(=O)[C@@]12CC[C@]1(CO)CN([C@H](C)c1ccccc1)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@]12CC[C@]1(CF)CN([C@H](C)c1ccccc1)C2=O
Temperature: 50 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
Bis(2-methoxyethyl)aminosulfur trifluoride (1.98 mL, 10.7 mmol) was added to a solution of (1S,5R)-5-hydroxymethyl-2-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane-1-carboxylic acid methyl ester (1.30 g, 4.30 mmol) in dichloromethane in a nitrogen atmosphere at room temperature. The mixture was heated to 50° C. and stirred for 12 hours. Then, a saturated sodium bicarbonate solution (10 mL) was added, and the mixture was stirred for 10 minutes. The reaction solution was poured into a mixture of ethyl acetate (50 mL) and water (30 mL), followed by extraction with ethyl acetate (200 mL). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→2:1→1.5:1) to give 1.26 g (96%) of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([CH3:30])=[C:14]([NH:19][C:20](=O)[C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]=2[CH3:31])=[CH:4][CH:3]=1>C(O)C>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]3[O:10][C:9]([CH3:31])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:12]=3[C:13]=2[CH3:30])=[CH:26][CH:25]=1
Reactant: COc1ccc(C(=O)Nc2c(C)c(C)c3oc(C)c(-c4ccc(F)cc4)c3c2C)cc1
Solvent: CCO
Product: COc1ccc(CNc2c(C)c(C)c3oc(C)c(-c4ccc(F)cc4)c3c2C)cc1
Yield: 75 %

Procedure:
By using N-[3-(4-fluorophenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-yl]-4-methoxybenzamide, the title compound was synthesized according to Example 2b. Yield: 75%. Melting point: 100-102° C. (Ethanol)
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[OH2:14]>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:14])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: O
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccccc1C(=O)O
Temperature: 7.5 °C
Yield: 80 %

Procedure:
To the so obtained solution, a solution of the acetylsalicylic acid chloride (16 g, 0.08 moles) in toluene (50 ml) is added under stirring at the temperature of 5-10° C. The mixture is maintained at a temperature within the above range, under stirring for 2 hours, then poured into water and then extracted with dichloromethane (2×100 ml). The organic phase is separated, washed in sequence with a solution of potassium carbonate at 25% w/v, with water, with a 3% hydrochloric acid solution and finally again with water, then anhydrified with sodium sulphate and the solvent evaporated under reduced pressure. The residue is crystallized from isopropanol. 3-hydroxymethyl phenyl ester of the 2-acetoxybenzoic acid (45.8 g, 0.16 moles, yield 80%) is obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C(O)(=O)C.S(=O)(=O)(O)O>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Yield: 103.9 %

Procedure:
A mixture of 94 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (7), 600 ml of glacial acetic acid, 450 ml of water and 70 ml of concentrated sulphuric acid is heated under reflux for 1.5 hours. Thereafter, the hot suspension is poured onto ice, and the precipitate is filtered off under suction, rinsed thoroughly with water and dried in vacuo at 100° C. In this manner, 88.9 g of pure 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid II of melting point 228°-230° C. (decomposition) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16](=O)[NH:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=O)[CH2:14][N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:40]>>[CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[N:40]=2)[CH2:14][N:13]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: [NH4+]
Reactant: COC(=O)NC(C(=O)N1CN(c2ccccc2)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CN(c2ccccc2)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
(1-{5-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-3-phenyl-imidazolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (90 mg) was dissolved in m-xylenes (3 mL) and heated at 135° C. Solid ammonium acetate (100 mg, 1.29 mmol) was added and the reaction was stirred at 135° C. After 120 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc/hexanes) to yield the product {1-[4-(4-Bromo-phenyl)-1′-phenyl-1′,2′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (40.2 mg, 0.0764 mmol): LCMS-ESI+: calc'd for C25H28BrN5O3: 526.4 (M+); Found: 526.4/528.3 (M+H+).
Reaction SMILES: OC[C:3]1[C:4]([C:9]2[C:14](C3C=CC=CN=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[H-].[Na+]>O1CCOCC1>[CH:8]1[CH:3]=[CH:4][N:5]=[C:6]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([C:4]3[CH:3]=[CH:8][CH:7]=[CH:6][N:5]=3)[N:10]=2)[CH:7]=1
Reactant: OCc1cccnc1-c1ncccc1-c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1ccc(-c2cccc(-c3ccccn3)n2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 0.9 g amount of hydroxymethyl terpyridine tetramer was dissolved in 20 ml of dioxane. Under Argon, 0.12 g of NaH were added and stirred for 15 minutes at room temperature. After adding 0.40 g of epoxide modified silica gel, the temperature was raised to 90° C. for 72 hours. Upon cooling, the mixture was filtered and the silica was washed with a large amount of CH3OH. The product was dried in a vacuum oven at 50° C. for 8 hours. The reaction is shown schematically below:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[Ca+2].[Br-:15].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl.CO>[Br:15][C:7]1[C:6]([CH3:9])=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[CH:8]=1
Reactant: Cc1ccc(F)c(N)c1
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N)c(F)cc1Br
Yield: 81.7 %

Procedure:
To a slurry of 2-fluoro-5-metylaniline (6.75 g, 54 mmol) and CaCO3 (10 g, 100 mmol) in CH2Cl2 (1 L) and MeOH (400 mL) was added a solution of Benzyltrimethylammonium tribromide (22.3 g, 57 mmol) in CH2Cl2 (180 mL) and MeOH (70 mL). The solution was added dropwise and the mixture was stirred over night. The solution was a light orange/tan color. The mixture was filtered and the solvent was removed under reduced pressure. The resulting slurry was diluted with H2O (100 mL) and extracted with Et2O (3×200 mL). The mixture was purified by flash column chromatography (Hex:Et2O 2:1 to Et2O) to provide (9 g, 69.5% yield) the product as a white solid. 1H-NMR (DMSO-d6) δ 7.23 (d, J=10.8 Hz, 1H), 6.74 (d, J=10.8 Hz, 1H), 5.27 (s, 2H), 2.20 (s, 3H).
Reaction SMILES: C(OC1C(=O)N=C(CC2(N3C4=NC=CC=C4C=C3)CCCC2)N2CCN(C)C(=O)C=12)C1C=CC=CC=1.[CH:37]1([N:41]([CH2:74][CH2:75]O)[C:42]([C:44]2[C:49]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[C:48]([OH:58])[N:47]=[C:46]([CH2:59][C:60]3([N:65]4[C:69]5=[N:70][CH:71]=[CH:72][CH:73]=[C:68]5[CH:67]=[CH:66]4)[CH2:64][CH2:63][CH2:62][CH2:61]3)[N:45]=2)=[O:43])[CH2:40][CH2:39][CH2:38]1>>[CH2:51]([O:50][C:49]1[C:48](=[O:58])[N:47]=[C:46]([CH2:59][C:60]2([N:65]3[C:69]4=[N:70][CH:71]=[CH:72][CH:73]=[C:68]4[CH:67]=[CH:66]3)[CH2:61][CH2:62][CH2:63][CH2:64]2)[N:45]2[CH2:75][CH2:74][N:41]([CH:37]3[CH2:38][CH2:39][CH2:40]3)[C:42](=[O:43])[C:44]=12)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=C(c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CCC1
Agent: CN1CCn2c(CC3(n4ccc5cccnc54)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(n4ccc5cccnc54)CCCC3)n2CCN1C1CCC1

Procedure:
9-Benzyloxy-2-cyclobutyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (427) was prepared following the same method as described for 9-benzyloxy-2-methyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (407) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclobutyl-(2-hydroxyethyl)-amide (426) (90 mg, 0.17 mmol) and was obtained as an off-white solid (65 mg, 75%).