Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15]2)[N:10]([CH3:24])[C:9]1=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(OC)(=O)=O)=CC=1.[NH2:38][C:39]1[CH:40]=[C:41]([C:48](=[O:50])[CH3:49])[CH:42]=[CH:43][C:44]=1[NH:45][CH2:46][CH3:47]>>[C:48]([C:41]1[CH:42]=[CH:43][C:44]([NH:45][CH2:46][CH3:47])=[C:39]([N:38]=[C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12](=[O:13])[C:11](=[C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[S:15]3)[N:10]2[CH3:24])[CH:40]=1)(=[O:50])[CH3:49]
Reactant: CCNc1ccc(C(C)=O)cc1N
Reactant: CN1C(=S)N(Cc2ccccc2)C(=O)C1=C1Sc2ccccc2N1C
Agent: COS(=O)(=O)c1ccc(C)cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1N(C)C(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 1, intermediate 3-benzyl-1-methyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-thioxoimidazolidin-4-one was alkylated with methyl p-toluenesulfonate and condensed with 3′-amino-4′-ethylaminoacetophenone to yield the title compound. 1H-NMR (CDCl3): δ 8.11 (1H, d), 7.84 (1H, dd), 7.51 (1H, dd), 7.31 (1H, m), 7.16 (1H, m), 6.95–7.12 (7H, m), 6.08 (1H, br t), 4.46 (2H, hs m), 3.99 (2H, m), 3.78 (3H, s), 3.50 (3H, s), 2.65 (3H, s), 1.06 (3H, t); MS(ESI): 512 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([OH:12])(=O)[C:8]([CH3:10])=[O:9].CN(C=O)C.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C1COCC1>[O:21]1[CH2:22][CH2:23][N:18]([C:7](=[O:12])[C:8](=[O:9])[CH3:10])[CH2:19][CH2:20]1
Reactant: CC(=O)C(=O)O
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (8.75 mL) was added to a solution of pyruvic acid (6.96 mL) and DMF (77 μL) in THF (200 mL) at room temperature, and the mixture was stirred at room temperature for 20 min. Under a nitrogen atmosphere, morpholine (18.4 mL) was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, the solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (11.0 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[C:26](=O)[CH3:27])[C:21]4=[O:30])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:33]>[Pd].CCCCO.CCCCO.CCCCO.CCCCO.[Ti].S1C=CC=C1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[CH:26]([NH:33][CH:32]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH3:31])[CH3:27])[C:21]4=[O:30])=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Reactant: C[C@@H](N)c1ccccc1
Agent: [Pd]
Agent: [Ti]
Solvent: c1ccsc1
Solvent: CCCCO
Product: CC(NC(C)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O)c1ccccc1
Reaction time: 48 h

Procedure:
A mixture of (±)-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methyl-2-oxopropyl)-3H-1,2,4-triazol-3-one (0.05 mol) (prepared as described in EP-A-0,228,125 and (+)-(R)-α-methylbenzenemethanamine (0.1 mol) in TBF (500ml) was hydrogenated at 50° C. for 48 hours with Pd/C 10% (10 g) as a catalyst in the presence of titanium(IV) n-butoxide (28.4 g) and thiophene solution (10 ml). The catalyst was filtered off. Pd/C 10% (10 g) was added again. Hydrogenation was continued at 50° C. for 48 hours. After uptake of H2, the mixture was cooled, then the catalyst was filtered off and the filtrate was evaporated. The residue was stirred in CH2Cl2 (500 ml) and H2O (50ml) was added. The mixture was acidified with a concentrated HCl solution, alkalized with a concentrated NH4OH solution and filtered over dicalite. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE, filtered off and dried, yielding 23.5 g (91%) of [(R*,R*)(R)+(R*,S*)(R)]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-[2-[( 1 -phenylethyl)amino]-1 -methylpropyl]-3H-1,2,4-triazol-3-one (interm. 1).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([F:10])[C:5]([O:8][CH3:9])([F:7])[F:6].[CH2:11]([Mg]Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH3:9][O:8][C:5]([F:7])([F:6])[C:4]([F:10])=[CH:3][CH2:2][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC[Mg]Br
Reactant: COC(F)(F)C(F)=CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCC=C(F)C(F)(F)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 118.9 %

Procedure:
To a solution of 1.0 g (4.5 mmol) 4-bromo-1-methoxy-1,1,2,-trifluoro-2-butene in 15.0 mL tetrahydrofuran at -60° C. in a 50 mL round-bottom flask was added a solution of n-hexylmagnesium bromide (2M, 5.0 mL, 10.0 mmol) in diethyl ether and followed by addition of 100 mg dilithiumcupric tetrachloride. The reaction mixture was stirred for two hours at 0° C. The contents of the flask were poured into a large excess of an aqueous ammonium chloride solution, and the liquid extracted twice with diethyl ether. The ether layers were combined, washed once with brine, then dried over anhydrous magnesium sulfate. Evaporation of solvent gave 1.20 g of 1-methoxy-1,1,2,-trifluoro-2-decene. 1H NMR (CDCl3 300 MHz): 0.85(3H,t), 1.23(10H,bs), 2.12(2H,m), 3.60(3H,s), 5.39(1H,dt,J=8,34Hz). Without further Purification this crude oil was transformed to the ester as follows.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](Cl)[N:17]=2)[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1.[CH3:25][O:26][N:27]=[C:28]1[C:32]2([CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]2)[CH2:31][NH:30][CH2:29]1.C(#N)C>C(N(CC)CC)C>[C:39]([O:38][C:36]([N:34]1[CH2:35][C:32]2([C:28](=[N:27][O:26][CH3:25])[CH2:29][N:30]([C:16]3[N:17]=[C:18]4[C:13]([C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10][N:9]4[C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])=[CH:14][C:15]=3[F:20])[CH2:31]2)[CH2:33]1)=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reactant: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CON=C1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2F)CC12CN(C(=O)OC(C)(C)C)C2
Temperature: 50 °C
Reaction time: 4 h
Yield: 84.3 %

Procedure:
110 mg of 1-(2,4-difluorophenyl)-6-fluoro-7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 120 mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate were added to 10 ml of acetonitrile and thereto 0.5 ml of triethylamine was added dropwise. The resulting mixture was stirred for 4 hours at 50° C. and then for 2 hours at the room temperature. The precilitated solid was filtered and dried to give 150 mg of the titled compound(yield: 79.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]([OH:17])=O)[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][N:18]=4)=[CH:29][N:28]=3)=[O:17])[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(-c2cnccn2)cn1
Reactant: Cc1cc(-c2cc(CC(=O)O)ccn2)ccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(CC(=O)Nc3ccc(-c4cnccn4)cn3)ccn2)ccn1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2-(2′-methyl-2,4′-bipyridin-4-yl)acetic acid 238-3 (46 mg, 0.2 mmol), 5-(pyrazin-2-yl)pyridin-2-amine 86-3 (34 mg, 0.2 mmol), 1,3-dicyclohexylcarbodiimide (50 mg, 0.24 mmol) and 4-(dimethylamino)pyridine (4 mg, 0.04 mmol) in DMF (0.9 mL) was stirred at room temperature for 10 hours. The crude product was filtered to remove the insoluble and the filtrate was submitted directly for reverse phase HPLC purification to give 2-(2′-methyl-2,4′-bipyridin-4-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 238 as white solid. MS m/z 383.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.14 (s, 1H), 9.30 (d, 1H), 9.11 (dd, 1H), 8.73-8.71 (m, 1H), 8.67 (d, 1H), 8.62 (d, 1H), 8.56 (d, 1H), 8.52 (dd, 1H), 8.21 (d, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.84 (dd, 1H), 7.45 (dd, 1H), 3.95 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[OH:34][CH:35]([CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)[CH3:36]>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][CH:37]([CH:35]([OH:34])[CH3:36])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: CC(O)C1CCNC1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)C1CCN(c2ccc3c(C(=O)NC[C@@]4(O)CCC[C@@H](C)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-(1-hydroxyethyl)-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.69 (m, 1H), 4.16 (s, 1H), 3.89 (m, 1H), 3.70 (m, 2H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.15 (m, 3H), 1.03 (m, 1H), 0.83 (d, 3H), 0.74 (m, 1H). m/z: 446 [M+H]
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH3:12]>[Cu]I>[NH2:12][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: N
Agent: [Cu]I
Product: Nc1nc(Cl)ccc1C(=O)O
Temperature: 115 °C
Yield: 72 %

Procedure:
2,6-Dichloronicotinic acid (0.38 g, 2 mmol) and copper (I) iodide (720 mg, 3.8 mmol) were added to liquid ammonia (approx. 20 mL) in a sealed tube at −78° C., which was heated for 25 hours (oil bath temperature: 115° C.). The oil bath temperature was raised to 125° C. followed by additionally heating for 14 hours 30 minutes. The reaction mixture was allowed to return to room temperature followed by distilling off the ammonia. The insoluble material that precipitated following addition of methanol was filtered out and the filtrate was concentrated to obtain the title compound (0.25 g, 1.45 mmol, 72%) as a solid.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:25][CH2:26][CH3:27])[N:18]([CH2:19][CH2:20][CH2:21][C:22](=O)[CH3:23])[C:14]=2[C:13]2[CH:12]=[CH:11][C:10]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:9][C:8]=2[N:7]=1>C(O)C.O>[CH3:3][O:2][N:4]=[C:22]([CH2:21][CH2:20][CH2:19][N:18]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:9][C:8]=3[N:7]=[C:6]([NH2:5])[C:15]=2[N:16]=[C:17]1[CH2:25][CH2:26][CH3:27])[CH3:23]
Reactant: CON
Reactant: CCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CCCC(C)=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CCCC(C)=NOC
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
Methoxylamine hydrochloride (0.98 g, 11.79 mmol) was added to a solution of 5-(4-amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one (3.8 g, 9.83 mmol) in ethanol (50 mL) and water (10 mL) and stirred at ambient temperature for 3 hours. The mixture was then concentrated under reduced pressure, diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 5% methanol in dichloromethane) and recrystallized from methanol and water to afford 3.6 g of 5-(4-amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one O-methyloxime as a tan solid, mp 191-192° C. MS (APCI) m/z 416.2 (M+H+); C25H29N5O
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@:12]([F:15])([CH3:14])[CH2:11][N:10]1[C:16](=[O:38])[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27]CC3C=CC=CC=3)[CH:25]=2)[C:20]([C:35](=[O:37])[CH3:36])=[CH:19]1)=[O:8].C(O)(C(F)(F)F)=O.C1(SC)C=CC=CC=1>>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@:12]([F:15])([CH3:14])[CH2:11][N:10]1[C:16](=[O:38])[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=2)[C:20]([C:35](=[O:37])[CH3:36])=[CH:19]1)=[O:8]
Reactant: CC(=O)c1cn(CC(=O)N2C[C@](C)(F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(OCc3ccccc3)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CC(=O)c1cn(CC(=O)N2C[C@](C)(F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(O)ccc12

Procedure:
The title compound was prepared in a similar manner as described above for Example 577 from (2S,4R)-1-[2-(3-acetyl-6-benzyloxy-indol-1-yl)-acetyl]-4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide (96.0 mg, 0.137 mmol), TFA (2 mL) and thioanisole (0.162 mL, 1.374 mmol). Solid. MS (LC/MS): 504 [M+H]+; tR (HPLC, conditions k): 3.26 min.
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:17]1[C:22](=[O:23])[N:21]([O:24][C:25](ON2C(=O)CCC2=O)=[O:26])[C:19](=[O:20])[CH2:18]1>C(#N)C>[C:25](=[O:26])([O:24][N:21]1[C:22](=[O:23])[CH2:17][CH2:18][C:19]1=[O:20])[O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1
Reactant: OC1CCC=CCCC1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Agent: O=C(OC1CC/C=C/CCC1)ON1C(=O)CCC1=O
Agent: OC1CC/C=C/CCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(OC1CCC=CCCC1)ON1C(=O)CCC1=O
Temperature: 25 °C

Procedure:
50 mg of (E)-cyclooct-4-enol (major isomer) and 0.2 mL triethylamine were added to 3 mL anhydrous acetonitrile. To this solution was slowly added 250 mg of N,N-disuccinimidyl carbonate. The reaction mixture was stirred at room temperature until thin layer chromatography revealed that the reaction was complete (approximately 48 hours). The acetonitrile was removed by rotary evaporation and the remaining residue was suspended in ether, washed with 0.1M HCl followed by brine, and dried with magnesium sulfate. The ether was evaporated and the resulting oil was purified by column chromatography (1:1 Ethyl Acetate:Hexane) yielding 80 mg (75% yield) of the title compound. 1H NMR (400 MHz CDCl3): δ 5.65-5.54 (m, 1H), 5.5-5.4 (m, 1H), 4.5-4.4 (m, 1H), 2.88-2.78 (s, 4H), 2.45-2.3 (m, 2H), 2.2-1.5 (m, 8H).
Reaction SMILES: C1(N2C3N=CN=C(N)C=3[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[N:20][C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:22]4)=[CH:17][CH:16]=3)=C2)CCC1.Br[C:32]1[N:33]=[C:34]([CH:42]2[CH2:45][CH2:44][CH2:43]2)[N:35]2[CH:40]=[CH:39][N:38]=[C:37]([NH2:41])[C:36]=12>>[CH:42]1([C:34]2[N:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH2:41])[C:36]3=[C:32]([C:15]3[CH:7]=[C:19]4[C:18]([C:17]([CH3:16])=[N:22][C:21]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[N:20]4)=[CH:23][CH:24]=3)[N:33]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: Nc1nccn2c(C3CCC3)nc(Br)c12
Reactant: Nc1ncnc2c1c(-c1ccc3cnc(-c4ccccc4)nc3c1)cn2C1CCC1
Product: Cc1nc(-c2ccccc2)nc2cc(-c3nc(C4CCC4)n4ccnc(N)c34)ccc12

Procedure:
Synthesized as 7-cyclobutyl-5-(2-phenylquinazolin-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine from of 1-bromo-3-cyclobutylimidazo[1,5-a]pyrazin-8-amine (16 mg, 0.06 mmol). Crude material was purified by preparative TLC (silica gel, 5% MeOH in DCM) followed by a recrystallization (EtOAc) and trituration (hexanes) to afford the title compound as a light yellow solid; MS (ES+): m/z 407.1 (100); HPLC: tR (min) 2.44 (OpenLynx, polar 5 min).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O-])(O)=O.[Na+].[NH2:16][C:17]1[CH:22]=[C:21]([NH2:23])[N:20]=[CH:19][N:18]=1.O>CO>[C:5]1([C:3]2[N:16]=[C:17]3[CH:22]=[C:21]([NH2:23])[N:20]=[CH:19][N:18]3[CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1cc(N)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cc2nc(-c3ccccc3)cn2cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
ω-Bromoacetophenone (9.04 g, 45 mmol) and NaHCO3 (4.30 g, 50 mmol) were added to a solution of 4,6-diaminopyrimidine (5.00 g, 0.45 mmol) in methanol (80 ml), and the mixture was heated to reflux (3 h). Upon cooling, water (40 ml) was added, and the suspension was stirred at r.t. (15 min). The precipitated title compound (5.62 g, 59%) was isolated by filtration, washed with small amounts of water and methanol, and dried under vacuum. MS (m/e)=211.1 [M+H+].
Reaction SMILES: [CH2:1]1CCN2C(=NCCC2)CC1.[C:12]1([C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH3:22])[C:19]([OH:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CI>C(#N)C>[C:12]1([C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH3:22])[C:19]([O:21][CH3:1])=[O:20])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CI
Product: COC(=O)C(C)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
37.60 g (0.247 mol) of DBU are added dropwise to a suspension of 50.8 g (0.225 mol) of 2,2-diphenylpropionic acid and 200 mL of acetonitrile at 20° C. 70.10 g (0.494 mol) of methyl iodide are added dropwise to the resulting solution within 30 minutes. Then the mixture is stirred overnight at 20° C. The solvent is evaporated down, the residue is extracted with diethylether/water, the organic phase is washed with water, dried over Na2SO4, and evaporated to dryness. Yield: 48.29 g of viscous residue 3.1. (89% of theory).
Reaction SMILES: Cl.[CH:2]1[C:14]2[CH:13]([CH2:15][O:16][C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[C:32]([O:36][C:37](=[O:43])[NH:38][CH2:39][CH2:40][CH:41]=O)([CH3:35])([CH3:34])[CH3:33].C([BH3-])#N.[Na+]>CO>[CH:2]1[C:14]2[CH:13]([CH2:15][O:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:41][CH2:40][CH2:39][NH:38][C:37]([O:36][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:43])[CH2:21][CH2:20]3)=[O:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)NCCCN1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
Piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester hydrochloride (0.67 g, 1.93 mmole) was dissolved in methanol (5 ml), treated with diisopropylamine (0.34 m], 1.93 mmole) and allowed to stir at room temperature for 5 minutes. The product from Step 1 (0.50 g, 2.89 mmole) and sodium cyanoborohydride (133 mg, 2.12 mmole) were added and the mixture stirred under argon for 18 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate/hexane (1:1) to afford the title compound (0.71 g). 1H NMR (CDCl3) δ 7.78-7.75 (2H, d), 7.59-7.56 (2H, d), 7.41-7.31 (4H, m), 4.52-4.43 (2H, d), 4.27-4.20 (1H, t), 3.51-3.42 (4H, br m), 3.25-3.15 (2H, m), 2.45-2.35 (6H, m), 1.72-1.60 (2H, m), 1.45 (9H, s).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[N+:18]([C:21]1[CH:22]=[C:23]([NH:27][NH2:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].S(=O)(=O)(O)O>CO>[OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=[N:28][NH:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=[N+]([O-])c1cccc(NN=C(c2ccc(O)cc2)c2ccc(O)cc2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A solution of 4,4′-dihydroxybenzophenone (0.32 g, 1.5 mmol) in 10 mL of methanol was added to a solution of 3-nitrophenylhydrazine hydrochloride (0.43 g, 2.25 mmol), concentrated sulfuric acid (0.3 mL) in 10 mL of methanol at 50° C. It was stirred at 50° C. for additional 2 h. The reaction mixture was concentrated and diluted with 20 mL of water. The precipitates were separated by filtration and washed with 3% aqueous NaHCO3 and water. The crude product was recrystallized from ethanol to give 0.4 g (77% yield) of the desired compound as a yellow solid, mp 160-162° C. 1H NMR (300 MHz, d6-DMSO): δ 6.71 [d, 2H, J=8.8 Hz, Ar—H], 6.91 [d, 2H, J=8.1 Hz, Ar—H], 7.07 [d, 2H, J=8.8 Hz, Ar—H], 7.27 [d, 2H, J=8.8 Hz, Ar—H], 7.40 [dd, 1H, J=J2=8.1 Hz, Ar—H], 7.49 [d, 1H, J=8.1 Hz, Ar—H], 7.61 (dd, 1H, J1=8.4 Hz, J2=2.2 Hz, Ar—H], 7.99 [d, 1H, J=2.2 Hz, Ar—H], 9.25 [s, 1H, NH], 9.78 and 9.62 [s, 1H, OH].
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][N:7]([C:9]2[C:18]([F:19])=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]3[CH2:20][CH3:21])=[CH:11][C:10]=2[F:26])[CH2:6][CH2:5][O:4]1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.[I-].[Na+]>CN(C)C=O>[CH2:20]([N:16]1[C:17]2[C:12](=[CH:11][C:10]([F:26])=[C:9]([N:7]3[CH2:6][CH2:5][O:4][CH:3]([CH2:2][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:8]3)[C:18]=2[F:19])[C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15]1)[CH3:21]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CCl)C3)c(F)c21
Reactant: C1CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CN4CCCC4)C3)c(F)c21
Temperature: 150 °C
Reaction time: 7 h

Procedure:
A mixture of 397 mg of 7-(2-chloromethylmorpholino)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 156 mg of pyrrolidine, 150 mg of sodium iodide and 15 ml of dimethylformamide is stirred at 150° C. for 7 hours. The reaction mixture is concentrated under reduced pressure and to the residue is added water followed by extracting with chloroform. The organic layer is washed with water, dried over anhydrous magnesium sulfate and then the solvent is distilled off to give 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-[2-(1-pyrrolidinylmethyl)morpholino]quinoline-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([OH:7])=[C:5]([C:8]([O:10][CH2:11][CH2:12][CH3:13])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15].O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[Br:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>CC(C)=O>[CH3:1][C:2]1[C:6]([O:7][S:39]([C:36]2[CH:37]=[CH:38][C:33]([Br:32])=[CH:34][CH:35]=2)(=[O:41])=[O:40])=[C:5]([C:8]([O:10][CH2:11][CH2:12][CH3:13])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: CCCOC(=O)c1sc(C(=O)OCCC)c(O)c1C
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CCCOC(=O)c1sc(C(=O)OCCC)c(OS(=O)(=O)c2ccc(Br)cc2)c1C

Procedure:
A mixture of 2.3 g (8 mmol) of dipropyl 3-methyl-4-hydroxy-2,5-thiophene-dicarboxylate, 20 ml of dioxane, 40 ml of acetone, 1.6 g (12 mmol) of anhydrous potassium carbonate and 2.3 g (10 mmol) of 4-bromobenzene-sulfonyl chloride was refluxed for about 10 hours, removed of dioxane and acetone by distillation, added with ethyl ether, washed with water, and dried with anhydrous magnessium sulfate. The solvent was removed by distillation, and recrystallization was effected with use of methanol to give 3.8 g (94%) of the desired white crystalline compound, m.p. 73°-74° C.