Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([OH:19])=O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O.N>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([NH2:22])=[O:19])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(-c2nc3cccnc3n2CC(=O)O)s1
Agent: N
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3cccnc3n2CC(N)=O)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.6 %

Procedure:
A mixture of 2-(5-methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for 2.5 hours with a stream of nitrogen bubbling through it. The reaction mixture was cooled in a dry ice/acetone bath, and liquid ammonia (50 ml) was added. The mixture was allowed to warm to room temperature and was stirred for 2 days under nitrogen atmosphere. The solvents were removed under reduced pressure and the resulting solid was triturated in water, collected by filtration, rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was recrystallized from hot methanol and dried under high vacuum at 40° C. to give 2.82 g (56%) of title compound, mp >250° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>CN(C)C=O.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
(2S,4S)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (CAS Reg. No. 227935-38-8)(300 mg, 1.2 mmol) and 60% sodium hydride mineral oil dispersion (61 mg, 1.5 mmol) were dissolved in anhydrous dimethylformamide (9 ml) at 0° C. under a nitrogen atmosphere. After 10 mins stirring benzylbromide (0.153 ml, 1.3 mmol) in CH2Cl2 (1 ml) was added drop wise and the reaction mixture stirred to room temperature for 1 hour. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate (25 ml), washed with water (2×25 ml), dried (magnesium sulphate), filtered and evaporated under reduced pressure. The residue was purified using flash chromatography eluting with a solvent gradient 4:1 heptane:ethyl acetate, yielding the title compound (167 mg, 42% yield) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=1[F:19].O.O.[Sn](Cl)Cl>CCO>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]([F:19])=[CH:11][C:12]([NH2:16])=[C:13]([F:15])[CH:14]=1
Reactant: O=[N+]([O-])c1cc(F)c(Oc2ccncc2Br)cc1F
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(F)c(Oc2ccncc2Br)cc1F
Temperature: 80 °C
Yield: 111.6 %

Procedure:
3-Bromo-4-(2,5-difluoro-4-nitrophenoxy)pyridine (0.414 g, 1.25 mmol) was dissolved in EtOH (30 ml). Tin (II) chloride dihydrate (1.129 g, 5.00 mmol) was added and the mixture was heated at 80° C. for 4 h. The solvent was removed under reduced pressure and the residue quenched with sat. NaHCO3 (aq). The mixture was diluted with EtOAc and filtered through Celite®. The Celite bed was washed with water (2×) and EtOAc (2×). The filtrate was extracted with EtOAc (2×). The combined organic extracts were dried and evaporated to yield 4-(3-bromopyridin-4-yloxy)-2,5-difluorobenzenamine (0.42 g, 112% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.68 (s, 1H), 8.33 (d, 1H), 7.28-7.23 (m, 1H), 6.76-6.71 (m, 2H), 5.56 (br s, 2H); MS (ESI) m/z: 301.0 (M+H+).
Reaction SMILES: [F:1][C:2]([C:13]1C=CC(C#N)=[CH:15][CH:14]=1)([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.[CH3:26][Mg]Br>CCOCC.O>[F:1][C:2]([C:13]1[CH:14]=[CH:15][C:24]([C:25](=[O:21])[CH3:26])=[CH:23][CH:22]=1)([F:12])[C:3]([F:10])([F:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C1CCOC1
Reactant: C[Mg]Br
Reactant: N#Cc1ccc(C(F)(F)C(F)(F)c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Product: CC(=O)c1ccc(C(F)(F)C(F)(F)c2ccccc2)cc1

Procedure:
A solution of 3.3 g. (0.0118 mole) of 4-(α,α,β,β-tetrafluorophenethyl)-benzonitrile in 25 ml. of dry, peroxidefree tetrahydrofuran is added dropwise to a stirred solution of about 0.03 mole of methylmagnesium bromide in 25 ml. of absolute ether in a nitrogen atmosphere. The mixture is stirred at reflux for about 26 hours. After cooling in an ice-bath, the adduct is hydrolyzed by the dropwise addition of about 5 ml. of water and the mixture is diluted with about 50 ml. of ether. The organic phase is decanted and the gelatinous precipitate is washed thoroughly with ether. The combined ethereal extracts are washed once with water, extracted with 15 ml. of ice-cold 6N hydrochloric acid in several portions, and then washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure leaves the product as the oily solid residue. Sublimation at 95°-100°C. and 0.02 mm. gives purified material as white crystals, m.p. 128°-133°C. A sample for analysis, m.p. 134°-135.5 °C., is obtained by repeated recrystallization from hexane and resublimation.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[C:4]([CH3:9])[N:3]=1.[OH2:10].[CH3:11][O-].[Na+].CO>C1(C)C=CC=CC=1.C(OC)(C)(C)C>[CH3:11][O:10][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[C:4]([CH3:9])[N:3]=1
Reactant: O
Reactant: Cc1nc(Br)ccc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(Br)c(C)n1
Temperature: 70 °C
Yield: 96 %

Procedure:
A solution of 2,5-dibromo-6-picoline (30.6 kg, 122 mol, 1.00 eq) in toluene (154.2 kg) was dried by vacuum distillation at 40° C./75 mmHg to remove 105.7 kg of distillate to produce a solution containing 40 ppm water. This was mixed with 25 weight % sodium methoxide in methanol (124.1 kg, 574 mol, 4.71 eq) and the mixture was heated at 65-75° C. for 6 hours until reaction completion, (HPLC analysis indicated 1.6 area % starting material remained). The mixture was cooled to 5° C. and water (98 L) was charged to the mixture followed by t-butylmethylether (97 kg). The layers were separated and the organic phase washed twice with 5% brine (139 kg) and once with 20% brine (165 kg). The organic phase was clarified by filtration and 51 kg was removed by vacuum distillation at 40° C. to produce a 2-methoxy-5-bromo-6-picoline solution (58.4 kg) of 40.6 wt % purity (96% yield). Part of this was purified by distillation for the purposes of recording the 13C NMR spectrum: 13C NMR (400 MHz, CDCl3) δ 162.4, 154.4, 142.0, 111.8, 109.5, 53.6, 24.6.
Reaction SMILES: O1C=CC=C1[C:6]([CH2:8][C:9]#[N:10])=O.[O-]CC.[Na+].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][N:24]=[C:25](Br)[C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=1>C(O)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:6]=[C:8]([C:9]#[N:10])[C:25]([C:26]([F:29])([F:28])[F:27])=[N:24]2)=[CH:19][CH:18]=1.[O:16]1[CH:15]=[CH:19][CH:18]=[C:17]1[C:22]1[NH:24][N:23]=[CH:20][CH:21]=1
Reactant: N#CCC(=O)c1ccco1
Reactant: COc1ccc(NN=C(Br)C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2cc(C#N)c(C(F)(F)F)n2)cc1
Product: c1coc(-c2ccn[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
To a solution of 2-furoylacetonitrile (0.91 g, 6.73 mmol) in 20 mL of absolute ethanol was added sodium ethoxide (2.5 mL of a 21% weight solution in ethanol, 6.73 mmol) followed by 2,2,2-trifluoroacetoyl bromide-N-(4-methoxyphenyl)hydrazone (2.0 g, 6.73 mmol). This mixture was stirred at ambient temperature for 4 h. The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by recrystallization from hexane/ethyl acetate to afford 1.1 g (49%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:15]=1[O:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]([N:23]([O:25][CH3:26])[CH3:24])=[O:22])=[CH:19][CH:18]=1>>[Cl:33][C:31]1[CH:30]=[CH:29][C:15]([O:16][C:17]2[CH:28]=[CH:27][C:20]([C:21]([N:23]([O:25][CH3:26])[CH3:24])=[O:22])=[CH:19][CH:18]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:32]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CON(C)C(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Product: CON(C)C(=O)c1ccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (111 mg, 0.62 mmol) was reacted with the product from Example 128b (192 mg, 0.62 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (50.9 mg, 15%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.72 (s, 3H) 3.19 (s, 3H) 3.42 (s, 3H) 6.71 (d, J=6.99 Hz, 1H) 6.94 (d, J=8.82 Hz, 2H) 7.36 (d, J=8.82 Hz, 1H) 7.50 (d, J=8.82 Hz, 2H) 7.63 (dd, J=8.82, 2.57 Hz, 1H) 7.72 (d, J=8.82 Hz, 1H) 7.75 (d, J=2.57 Hz, 1H) 8.53 (d, J=6.99 Hz, 1H) 8.81 (d, J=8.46 Hz, 1H) 10.88 (s, 1H) 14.46 (s, 1H); MS (ESI+) m/z 449 (M+H−TFA)+.
Reaction SMILES: [CH3:1][C:2](O)([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3]>O>[CH3:1][C:2]1([CH3:3])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)(O)CCCc1ccccc1
Solvent: O
Product: CC1(C)CCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 18 ml of ice-cold concentrated H2SO4 was added 17.8 g (0.1 mol) of 2-methyl-5-phenyl-2-pentanol over 10 minutes. The mixture was then stirred at 0° C. for 15 minutes and at room temperature for 15 minutes. The mixture was treated with 50 ml of water and then extracted with ether. The ether extracts were combined and washed with water and saturated NaCl and NaHCO3 solutions and then dried (MgSO4). The solution was filtered and the solvent removed in-vacuo. The residue was purified by distillation (93° C.; 10 mm) to give the title compound as a colorless oil. PMR (CDCl3): δ 1.19 (6H, s), 1.45-1.53 (2H, m), 1.62-1.73 (2H, m), 2.62 (2H, t, J~6.1 Hz), 7.14-7.30 (4H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[OH2:18].[OH:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[N:9][NH:10][C:3]=23)=[CH:13][CH:14]=1.[OH:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[N:9][NH:10][C:3]=23)=[CH:13][CH:14]=1
Reactant: Clc1ccnc2cn[nH]c12
Reactant: Nc1ccc(O)cc1
Solvent: Cc1ccccc1C
Product: O
Product: Oc1ccc(Nc2ccnc3cn[nH]c23)cc1
Yield: 33.9 %

Procedure:
A mixture of 7-chloro-1H-pyrazolo[4,3-b]pyridine (0.50 g, 3.26 mmol) and 4-aminophenol (0.71 g, 6.52 mmol) in xylene (10 ml) was heated under reflux under nitrogen for 5 h. After cooling the reaction mixture, the solid was collected and washed well with ethyl acetate and water. The solid was then dissolved in warm aqueous methanol, and the solution was adjusted to pH 8 with saturated sodium bicarbonate solution. The product separated as needles, which were recrystallised from aqueous methanol to give the title compound (260 mg, 35%), mp 286°-296° C.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([Li])[CH2:10][CH2:11][CH3:12].C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33]1(=[O:40])[CH:38]=[CH:37][C:36](=[O:39])[CH:35]=[CH:34]1>C1COCC1.CN1C(=O)N(C)CCC1>[OH:39][C:36]1([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:37]([CH2:12][CH2:11][CH:10]=[CH2:9])[CH2:38][C:33](=[O:40])[CH:34]=[CH:35]1
Reactant: C#Cc1ccccc1
Reactant: [Li]CCCC
Reactant: O=C1C=CC(=O)C=C1
Solvent: CN1CCCN(C)C1=O
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCCC1CC(=O)C=CC1(O)C#Cc1ccccc1
Temperature: 25 °C

Procedure:
Phenylacetylene (0.61 g, 0.006 mole) was added to a dry 25 mL flask containing dry THF (5 mL), n-butyllithium (4 mL of 1.48 M) and a few crystals of triphenylmethane. After stirring for several min at RT, the reaction was cooled to about 0 C., added to a flask containing benzoquinone (0.63 g, 0.006 mole) dissolved in dry THF (10 mL) and cooled to -78° C. The reaction was maintained at -35° C. to -25° during the addition. After stirring for about 15 min at -30° C., 4.6 mL of DMPU was added. The dialkylmagnesium product of Example 6a was filtered under nitrogen into the reaction mixture and the filter cake washed with ether. After stirring at -35° C. for 5 min, the reaction was allowed to warm to RT and stirred overnight. The reaction was quenched into saturated ammonium chloride solution and extracted with ether. The ether extracts were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield 1.1 g of a mixture which was purified by flash chromatography on silica gel using 4:1 hexane/EtOAc to yield two major fractions. The first compound-bearing fraction, 0.63 g (39%) represented the desired 1,2-1,4 product. A second compound-bearing fraction, 0.51 g (32%) was the 1,2-1,2 adduct.
Reaction SMILES: C(O)(=[O:3])C.[F:5][C:6]([F:23])([F:22])[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.OO.[OH2:26]>>[F:23][C:6]([F:5])([F:22])[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][S:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:3])=[O:26])=[CH:9][CH:8]=1
Reactant: O
Reactant: Oc1ccc(SCc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(=O)O
Agent: OO
Product: O=S(=O)(Cc1ccc(C(F)(F)F)cc1)c1ccc(O)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a 15 ml of acetic acid solution of 2.23 g of 4-(4-trifluoromethylbenzylsulfanyl)phenol was added slowly, 2.5 ml of 30% hydrogen peroxide solution at approximately 80° C. The reaction mixture was stirred for 3 hours at 90° C., then poured into water, and the resulted precipitate was collected by filteration. After washing with water, the precipitate was dried by heating under the reduced pressure to produce 2.34 g of the desired product.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[NH4+:23].[OH-]>CC(O)C>[NH2:23][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N
Temperature: 120 °C
Yield: 61 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 51 mg, 0.172 mmol) and NH4OH (670 μl, 17.21 mmol) in propan-2-ol (1.7 ml) and heating in a microwave reactor (Biotage Initiator) at 120° C. for 10 min. Purification by silica gel (100% DCM to 5% MeOH/DCM) provided 2-(3-amino-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (61% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52 (s, 3H) 2.94 (t, J=6.85 Hz, 2H) 3.44 (td, J=6.80, 2.25 Hz, 2H) 6.94 (br. s., 1H) 6.98 (d, J=2.15 Hz, 1H) 7.15 (br. s., 2H) 7.29 (t, J=7.82 Hz, 1H) 7.54 (dd, J=8.02, 0.98 Hz, 1H) 7.91 (dd, J=7.53, 1.08 Hz, 1H) 12.45 (br. s., 1H). MS (ESI, pos. ion) m/z: 294.0 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[N:15][C:8]=2[NH:7][C:6]2[N:16]=[CH:17][CH:18]=[CH:19][C:5]1=2.[H][H].[CH2:22](I)[CH3:23]>CN(C)C=O.O>[CH2:22]([N:7]1[C:8]2[N:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10](=[O:11])[N:4]([CH3:3])[C:5]2[CH:19]=[CH:18][CH:17]=[N:16][C:6]1=2)[CH3:23]
Reactant: CN1C(=O)c2cccnc2Nc2ncccc21
Reactant: [H][H]
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1c2ncccc2C(=O)N(C)c2cccnc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
2.00 g of a 50% dispersion of sodium hydride in mineral oil was added to a solution of 5.75 g (0.025 mol) of 5,11-dihydro-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one in 100 ml of dimethylformamide. When the evolution of hydrogen ceased, the mixture was heated to 50° C. for 30 min. and then cooled to room temperature. Then, 7.80 g of ethyl iodide (neat) was added dropwise over 15 minutes, and the resulting mixture was allowed to stir overnight at room temperature. The excess sodium hydride was decomposed by the careful addition of ice, followed by water. The product was extracted with ether, dried (anhydrous sodium sulfate), and evaporated to yield 4.5 g (70% of theory) of 5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, m.p. 130°-132° C.
Reaction SMILES: [CH3:1]I.[H-].[Na+].[Br:5][C:6]1[N:7]=[C:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22](=[O:27])[C:21]=3[CH:28]=2)=[O:16])[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12>CN(C=O)C>[Br:5][C:6]1[N:7]=[C:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]3[N:25]([CH3:1])[C:24](=[O:26])[O:23][C:22](=[O:27])[C:21]=3[CH:28]=2)=[O:16])[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12
Reactant: CI
Reactant: O=C(c1ccc2[nH]c(=O)oc(=O)c2c1)c1nc(Br)c2ccccn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc(=O)c2cc(C(=O)c3nc(Br)c4ccccn34)ccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
808 mg (5.7 mmol) of methyl iodide and 164 mg (3.42 mmol) of 50% sodium hydride are added, at ambient temperature under an inert atmosphere, to 1.1 g (2.85 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2H-3,1-benzoxazine-2,4(1H)-dione in 20 ml of DMF. After stirring for 3 hours, the reaction medium is poured into 200 ml of ice-cold water. The precipitate is filtered off, rinsed with water, and then dried under reduced pressure for 18 hours at 40° C. 1.13 g of a yellow solid are obtained.
Reaction SMILES: C[O:2][C:3]1[N:4]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:6]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1.CO.Cl>O1CCCC1>[CH3:9][C:7]1[NH:8][C:3](=[O:2])[N:4]([C:25]([NH:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[CH:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:6]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11]
Reactant: COC1=NC(C)=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)N1C(=O)NCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)N(C(=O)NCc2ccccc2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A solution of 1,6-dihydro-2-methoxy-4-methyl-6-(3-nitrophenyl)-1-[[(phenylmethyl)amino]carbonyl]-5-pyrimidinecarboxylic acid, 1-methylethyl ester (3.00 g, 6.45 mmol) in tetrahydrofuran (50 ml)/methanol (25 ml) was treated with 1 N hydrochloric acid (6.0 ml, pH 1) and stirred at room temperature for 1 hour. The reaction was quenched with saturated sodium bicarbonate and partially evaporated. The residue was partitioned between chloroform and water. The organic phase was washed with saturated sodium chloride, dried (magnesium sulfate) and evaporated. The residue was crystallized from dichloromethane/isopropyl ether. The solids which precipitated were recrystallized to give the title compound as a colorless electrostatic solid (1.84 g), melting point 184°-185° C. TLC (5% ethyl acetate/dichloromethane) single spot, Rf =0.39.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:16]=3[CH:29]=2)=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:40]([O:42][CH2:43][CH:44]([CH3:46])[CH3:45])=[O:41].C(O)(C(F)(F)F)=O>ClCCl>[O:21]1[C:15]2[CH:14]=[CH:13][C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:2]4[N:3]([C:40]([O:42][CH2:43][CH:44]([CH3:46])[CH3:45])=[O:41])[CH:4]=[CH:5][N:1]=4)=[CH:7][CH:8]=3)=[CH:29][C:16]=2[CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(-c4ncc[nH]4)cc3)cc2C1
Reactant: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COC(=O)n1ccnc1-c1ccc(-c2ccc3c(c2)CNCCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
1,1-dimethylethyl 7-[4-(1H-imidazol-2-yl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (490 mg, 1.25 mmol) was taken into dichloromethane (20 mL) followed by sequential addition of DIPEA (0.4 mL, 2.3 mmol) and isobutyl chloroformate (0.18 mL, 1.4 mmol) and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated then partitioned with ethyl acetate and 10% aqueous citric acid. The organic solution was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated. The residue thus obtained was taken into TFA (5 mL) and allowed to stand for 30 minutes at room temperature. The mixture was concentrated and the residue was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate and the organic solution was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated to give 2-methylpropyl 2-[4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)phenyl]-1H-imidazole-1-carboxylate (361 mg, 65% yield). MS (EI) for C23H25N3O3: 392 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([C:15]1(C(OC(C)(C)C)=O)[CH2:17][CH:16]1[C:18]1[C:28]([F:29])=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([F:30])[C:19]=1[F:31])=[O:14])(C)(C)C.C(OCC)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:13]([CH:15]1[CH2:17][CH:16]1[C:18]1[C:28]([F:29])=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([F:30])[C:19]=1[F:31])([OH:14])=[O:12]
Reactant: CCOC(=O)c1cc(F)c(C2CC2(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1cc(F)c(C2CC2C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.7 %

Procedure:
18 ml of trifluoroacetic acid was added to 9.3 g of ethyl 4-(2,2-di-tert-butoxycarbonylcyclopropyl)- 2,3,5-trifluorobenzoate. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was directly heated with a burner for about 20 seconds to complete decarboxylation. To the reaction mixture were added 100 ml of diethyl ether and 200 ml of water in this order. The resulting mixture was adjusted to pH 9.5 with a 10% aqueous sodium carbonate solution. The aqueous layer was separated and 100 ml of diethyl ether was added thereto. The resulting mixture was adjusted to pH 1.5 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 3.30 g (yield: 54.7%) of ethyl 4-(2-carboxycyclopropyl)-2,3,5-trifluorobenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].CC[O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:18]([O:17][C:15]([C:14]1[C:13](=[O:12])[C:7]2[C:5](=[CH:4][C:3]([Cl:9])=[C:2]([Br:1])[CH:8]=2)[NH:6][CH:20]=1)=[O:16])[CH3:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(Br)c(Cl)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(Cl)c(Br)cc2c1=O
Yield: 88 %

Procedure:
A mixture of 4-bromo-3-chloroaniline (8.3 g) and diethyl ethoxymethylene malonate (8.9 g) was heated at 120°-130° C. for 1.5 hours. The mixture was added to diphenyl ether (140 ml) and refluxed for 30 minutes. The cooled mixture was filtered, the solid was washed with benzene and dried. The solid was recrystallized from DMF to give 6-bromo-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (11.7 g).