Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:21]([O-])=O)[CH:9]=2)[N:4]=1.Cl>[H][H].[C].[Pd]>[F:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:21])[CH:9]=2)[N:4]=1
Reactant: Cc1ccccc1-n1c(CF)nc2ccc([N+](=O)[O-])cc2c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: Cc1ccccc1-n1c(CF)nc2ccc(N)cc2c1=O
Yield: 71.9 %

Procedure:
A mixture of 2.0 g of 2-fluoromethyl-3-(o-tolyl)-6-nitro-4(3H)-quinazolinone, 0.2 g of 5 % palladium-carbon and 100 ml of 10 % hydrochloric acid is shaken at 40°C for 1.5 hours in hydrogen gas. The initial pressure of hydrogen gas is adjusted to 48 lb. After said reaction, the mixture is cooled and filtered to remove the catalyst. The filtrate is neutralized with sodium bicarbonate, and the precipitate is extracted with benzene. The benzene solution is dried and then evaporated to remove solvent. The residue thus obtained is recrystallized from isopropanol. 1.3 g of 2-fluoromethyl-3-(o-tolyl)-6-amino-4(3H)-quinazolinone are obtained.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:67]([C:69]1[CH:70]=[C:71]([CH:81]=[CH:82][CH:83]=1)[CH2:72][NH:73][C:74](=[O:80])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=O>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:67]([C:69]3[CH:70]=[C:71]([CH:81]=[CH:82][CH:83]=3)[CH2:72][NH:73][C:74](=[O:80])[O:75][C:76]([CH3:79])([CH3:77])[CH3:78])[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C=O)c1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)c1
Reaction time: 18 h
Yield: 73.3 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (200 mg, 0.51 mmol), DMF (0.45 mL), ethanol (2.55 mL), 1M Na2S2O4 (3 eq, 1.53 mmol, 1.53 mL) and tert-butyl N-(3-formylbenzyl)carbamate (1.1 eq, 0.21 mmol, 132 mg). After 18 h, concentration in vacuo and column chromatography (CH2Cl2-MeOH, 95:5) gave the product (89 mg, 30%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.38 (s, 9H, C(CH3)3), 2.62 (s, br, 4H, piperazine N(CH2)2), 3.61 (s, 2H, NCH2Ar), 3.66 (s, br, 4H, piperazine N(CH2)2), 4.22 (d, J=6.0 Hz, 2H, CH2NH—BOC), 7.36 (d, J=7.7 Hz, 1H, phenyl H-4 or H-6), 7.39 (dd, J=7.7, 2.7 Hz, 1H, pyridine H-5), 7.45 (t, br, J=5.7 Hz, 1H, NH—BOC), 7.48 (t, J=7.7 Hz, 1H, phenyl H-5), 7.78 (d, J=7.6 Hz, 1H, pyridine H-4), 8.01 (d, J=7.7 Hz, 1H, phenyl H-4 or H-6), 8.10 (s, br, 1H, phenyl H-2), 8.25 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.50 (d, br, J=3.5 Hz, 1H, pyridine H-6), 8.57 (s, br, 1H, pyridine H-2), 13.52 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: Br[C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([CH:33]=[O:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([S:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1.O>C(OCC)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([CH:33]([C:2]5[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=5)[OH:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([S:35]([C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:45])[F:46])=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1
Reactant: O=C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Reactant: Cn1ccnc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Cn1ccnc1C(O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Temperature: -75 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
2-Bromo-1-methyl-1H-imidazole (47 μL, 0.48 mmol) was dissolved in diethyl ether (2 mL) and cooled to −75° C. under argon. Butyl lithium (2.5 M in hexanes; 192 μL, 0.48 mmol) was added dropwise and the mixture stirred at −75° C. for 1 hour. A solution of (R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde (252 mg, 0.5 mmol) in diethyl ether (2 mL) was added dropwise. The reaction mixture was stirred for 16 hours whilst warming slowly to room temperature. The reaction mixture was cooled and treated with water (10 mL) and the phases separated. The organic phase was extracted with further diethyl ether (×2) followed by dichloromethane (×2). The combined organic phases were dried over sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient: 17.5 to 25% acetone in cyclohexane) to afford (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)-(R/S)-methanol as a white powder (82 mg) LCMS (Method A, ESI): RT 2.74 min, m+H=588.1
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:29])[CH2:25][C:26](O)=[O:27])[CH2:20][CH2:19]1.CC(C)N=C=NC(C)C>C1COCC1>[Cl:14][C:15]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:29])[CH2:25][C:26]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][N:11]=2)=[O:27])[CH2:20][CH2:19]1
Reactant: O=C(O)CC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1
Reactant: Nc1ccc(-c2ccccc2)cn1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(CC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1)Nc1ccc(-c2ccccc2)cn1
Yield: 18.7 %

Procedure:
To a stirred solution of 5-phenyl-pyridin-2-ylamine (0.041 g, 0.00024 mole) in THF (3 mL) was added 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid (0.08 g, 0.00025 mole) followed by DIC (0.036 g, 0.00028 mole). The mixture was heated to reflux for 3 hours, and then concentrated under educed pressure. The resulting residue was stirred with cold ether. The organic layers were removed by filtration and concentrated under reduced pressure to afford 0.021 g (18%) of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-N-(5-phenyl-pyridin-2-yl)-propionamide. LC-MS purity: 468.14 (M+1)+, 98%, 1H NMR (DMSO-d6) δ 11.2 (bs, 1H), 8.2 (t, 2H), 8.0 (d, 1H), 7.4 (m, 4H), 7.1 (t, 1H), 6.6 (d, 2H), 4.6 (s, 1H), 4.0 (d, 1H), 3.7 (m, 1H), 3.6 (m, 3H), 2.1 (bs, 9H), 1.8 (t, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(C2=CCC3(CC2)OCCO3)cc1
Yield: 81 %

Procedure:
A mixture of 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol (2.0 g, 7.9 mmole) and a catalytic amount of p-toluenesulfonic acid in 50 ml toluene was heated at reflux for 1.5 hr. The mixture was cooled and washed with saturated sodium bicarbonate solution. The toluene was removed in vacuo and the residue recrystallized from hexane to give the product (81%, mp: 84-85° C.). Calc'd for C14H15FO2 : C, 71.78%; H, 6.46%. Found: C, 71.33%; H, 6.33%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.B(O)O>>[N:7]1[CH:8]=[CH:9][C:4]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][NH:7][CH2:6][CH2:5]3)=[CH:5][CH:6]=1
Reactant: Brc1ccc2c(c1)CCNC2
Agent: OBO
Product: c1cc(-c2ccc3c(c2)CCNC3)ccn1

Procedure:
In close analogy to the procedure described above, 6-Bromo-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][Si:26]([C:29]#[C:30][C:31]1[NH:35][C:34]([C@@H:36]2[CH2:41][C@@H:40]3[C@@H:38]([CH2:39]3)[NH:37]2)=[N:33][CH:32]=1)([CH3:28])[CH3:27].[CH3:42][O:43][C:44]([NH:46][C@@H:47]([CH:51]([CH3:53])[CH3:52])[C:48](O)=[O:49])=[O:45].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:52][CH:51]([CH3:53])[C@H:47]([NH:46][C:44](=[O:45])[O:43][CH3:42])[C:48](=[O:49])[N:37]1[C@H:36]([C:34]2[NH:35][C:31]([C:30]#[C:29][Si:26]([CH3:27])([CH3:28])[CH3:25])=[CH:32][N:33]=2)[CH2:41][C@@H:40]2[C@H:38]1[CH2:39]2
Reactant: C[Si](C)(C)C#Cc1cnc([C@@H]2C[C@H]3C[C@H]3N2)[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(C#C[Si](C)(C)C)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
HATU (428 mg, 1.125 mmol) was added to a stirred solution of (1R,3S,5R)-3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (212 mg, 0.865 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (197 mg, 1.125 mmol) in DMF (3 mL) and DIPEA (1.2 mL, 6.9 mmol) and the reaction was stirred at rt overnight. The reaction was concentrated to dryness and then purified with a BIOTAGE® Horizon (25 g SiO2, 40-60% EtOAc/hexanes) to yield methyl (S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate (203 mg) as a yellow glass. LC-MS retention time 3.095 min; m/z 403.29 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 7.17 (br. s., 1H), 5.04-5.11 (m, 1H), 4.54 (d, J=6.8 Hz, 1H), 3.65 (s, 3H), 3.54-3.61 (m, 1H), 2.82 (s, 1H), 2.39-2.50 (m, 1H), 2.27-2.36 (m, 1H), 2.04-2.15 (m, 1H), 1.94-2.04 (m, 1H), 1.11 (dt, J=8.7, 5.6 Hz, 1H), 0.95 (d, J=6.8 Hz, 3H), 0.90 (d, J=6.8 Hz, 3H), 0.73-0.79 (m, 1H), 0.21 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[CH:6]=1)[OH:4].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1.CCOCC.O>[C:27]1([C:26]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([C:3]([OH:4])([C:5]4[C:13]5[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=5)[N:7]([CH3:14])[CH:6]=4)[C:2]([F:1])([F:24])[F:25])=[CH:23][CH:22]=3)[CH:18]=[N:19]2)=[O:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cn1cc(C(O)(c2ccc3[nH]ncc3c2)C(F)(F)F)c2ccccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: Cn1cc(C(O)(c2ccc3c(cnn3C(=O)c3ccccc3)c2)C(F)(F)F)c2ccccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
A mixture of 2,2,2-trifluoro-1-(1H-indazol-5-yl)-1-(1-methyl-1H-indol-3-yl)ethanol (0.162 mmol) and benzoyl chloride (0.324 mmol) in 1 mL pyridine was heated at 100° C. After 2 hours, the mixture was cooled to room temperature and diluted with ether and water. The organic layer was washed with aqueous HCl and brine and dried over magnesium sulfate. The volatiles were removed in vacuo and the residue purified by flash silica gel chromatography using 33% ethyl acetate in hexanes. The product-rich fractions were concentrated in vacuo to provide 0.093 mmol of the title compound, m.p. 102° C.-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([NH:14][C:15](=[O:18])OC)[NH:11][C:10]=2[CH:19]=1.[N:25]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN1CCCC1=O.C(OCC)C>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([NH:14][C:15]([NH:33][CH2:32][CH2:31][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:18])[NH:11][C:10]=2[CH:19]=1
Reactant: COC(=O)Nc1nc2ccc(OCc3c(Cl)cccc3Cl)cc2[nH]1
Reactant: NCCN1CCOCC1
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: O=C(NCCN1CCOCC1)Nc1nc2ccc(OCc3c(Cl)cccc3Cl)cc2[nH]1
Reaction time: 0.42 h
Yield: 76 %

Procedure:
put a solution of 250 mg of methyl {6-[(2,6-dichlorobenzyl)oxy]-1H-benzimidazol-2-yl}carbamate and 178 mg of 2-morpholin-4-ylethanamine in 3 cm3 of 1-methylpyrrolidin-2-one in a microwave reactor. After the reactor has been sealed, it is put in the microwave cavity for 25 minutes at 125° C. The reaction mixture is then evaporated to dryness under reduced pressure (0.2 kPa) with a bath temperature of 85° C. The residue is taken up in 30 cm3 of water, then extracted three times with 180 cm3 of ethyl acetate. The combined organic phases are washed three times with 30 cm3 of water, dried over magnesium sulphate, filtered and evaporated under reduced pressure (2 kPa). After purification of the residue by silica-column flash chromatography [eluent: dichloromethane/methanol (90/10 by volume)], the product obtained is solidified in 20 cm3 of diethyl oxide, filtered, washed three times with 3 cm3 of diethyl oxide and dried under reduced pressure in the presence of potassium hydroxide. We obtain 241 mg of 1-{6-[(2,6-dichlorobenzyl)oxy]-1H-benzimidazol-2-yl}-3-(2-morpholin-4-ylethyl)urea in the form of a pink powder, which has the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][C:3]=1[OH:17].[CH2:18]([Li])CCC.[Cl-].[NH4+]>O1CCCC1.CS(C)=O.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=[CH2:18])[CH:5]=[CH:4][C:3]=1[OH:17]
Reactant: Cn1nccc1C(=O)c1ccc(O)c(Cl)c1Cl
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCCCCC
Product: C=C(c1ccc(O)c(Cl)c1Cl)c1ccnn1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2.71 g of 2,3-dichloro-4-(1-methyl-5-pyrazolylcarbonyl)phenol in tetrahydrofuran-dimethylsulfoxide is added dropwise to an ylide solution prepared from a solution of 8.57 g of methyltriphenylphophonium bromide in tetrahydrofurandimethylsulfoxide and 13.8 ml of 1.6M n-butyl lithium in hexane. The mixture is stirred at room temperature for 18 hours, and further stirred at 65° C. for 2 hours. The reaction mixture is poured into an aqueous saturated ammonium chloride solution and then extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography to give 2.41 g of 2,3-dichloro-4-[1-(1-methyl-5-pyrazolyl)vinyl]phenol.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:16]=[C:15]([CH3:17])[C:14]([Cl:18])=[C:13]([CH3:19])[C:9]=2[C:10](=[O:12])[CH:11]=1)=O)C.[NH3:20]>C(O)C>[Cl:18][C:14]1[C:15]([CH3:17])=[CH:16][C:8]2[O:7][C:6]([C:4]([NH2:20])=[O:3])=[CH:11][C:10](=[O:12])[C:9]=2[C:13]=1[CH3:19]
Reactant: CCOC(=O)c1cc(=O)c2c(C)c(Cl)c(C)cc2o1
Reactant: N
Solvent: CCO
Product: Cc1cc2oc(C(N)=O)cc(=O)c2c(C)c1Cl

Procedure:
A solution of 50.1 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester in 750 parts of warm ethanol was saturated with dry ammonia. After 2 hours a solid had precipitated out and the slurry was heated on the steam bath to remove excess ammonia. The solid was filtered off and crystallised from dimethylformamide to give 42.3 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carboxamide, melting point >300°C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N#N.CCOC(/N=N/C(OCC)=O)=O.BrCCBr.[F:38][C:39]1[CH:40]=[C:41]([OH:49])[CH:42]=[C:43]([S:45]([CH3:48])(=[O:47])=[O:46])[CH:44]=1.[C:50]([NH:57][CH2:58][CH2:59]O)([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]>C1COCC1.CCOC(C)=O.O>[F:38][C:39]1[CH:40]=[C:41]([CH:42]=[C:43]([S:45]([CH3:48])(=[O:46])=[O:47])[CH:44]=1)[O:49][CH2:59][CH2:58][NH:57][C:50](=[O:51])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CS(=O)(=O)c1cc(O)cc(F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: BrCCBr
Product: CC(C)(C)OC(=O)NCCOc1cc(F)cc(S(C)(=O)=O)c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 68.8 %

Procedure:
A mixture of triphenylphosphine (1.9 g, 7.3 mmol) in dry THF (20 ml) was flushed with N2(g) and DEAD (3.1 ml, 6.9 mmol) was added drop-wise, 1,2-dibromoethane followed by 3-fluoro-5-methylsulfonyl-phenol (1.1 g, 6.1 mmol) and then boc-glycinol (1.0 ml, 6.1 mmol) in portions. The mixture was stirred at 70° C. for 20 h, cooled to room temperature and water and EtOAc was added. The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic phase was washed with aqueous NaOH (3 M, 50 ml) and brine (75 ml), dried (Na2SO4) and evaporated. Purification by flash column chromatography (ethyl acetate/isooctane, 0:1 to 1:0) gave the title compound (1.4 g, 70%). MS m/z (relative intensity, 70 eV 298 (M+, 18), 296 (M+, 18), 109 (bp), 107 (99), 82 (15).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:7]=[CH:6][CH:5]=1)(=O)[NH2:2].P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)Cl.[OH-].[Na+]>CN(C)C=O>[C:1]([C:4]1[N:9]=[C:8]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: NC(=O)c1cccc(C=CC(=O)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cccc(C=CC(=O)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 3-(6-carbamoyl-2-pyridyl)-1-phenyl-2-propen-1-one (0.5 g) in N,N-dimethylformamide (5 ml) was added phosphorus oxychloride (0.46 g) under ice-cooling. After stirring for 30 minutes at same temperature, the solution was poured into a mixture of ice-water (50 ml) and chloroform (10 ml). The resultant solution was adjusted to pH 9 with 4N-sodium hydroxide. The organic layer was washed with water and brine and dried over magnesium sulfate. After evaporating the solvent to give 3-(6-cyano-2-pyridyl)-1-phenyl-2-propen-1-one (0.38 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:40])[C:15]([O:32]CC2C=CC=CC=2)=[C:16]2[C:29](=[O:30])[N:20]3[CH:21]4[CH2:28][CH2:27][CH2:26][CH2:25][CH:22]4[CH2:23][O:24][CH:19]3[CH2:18][N:17]2[CH:31]=1)=[O:12].[H][H].CO.ClCCl>O1CCCC1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:40])[C:15]([OH:32])=[C:16]2[C:29](=[O:30])[N:20]3[CH:21]4[CH2:28][CH2:27][CH2:26][CH2:25][CH:22]4[CH2:23][O:24][CH:19]3[CH2:18][N:17]2[CH:31]=1)=[O:12]
Reactant: O=C(NCc1ccc(F)cc1F)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1C(C2)OCC2CCCCC21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cc1F)c1cn2c(c(O)c1=O)C(=O)N1C(C2)OCC2CCCCC21
Yield: 67.3 %

Procedure:
racemic-(4aR,6aR,14aS)—N-[(2,4-Difluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide (13 mg, 0.0236 mmol) was dissolved in tetrahydrofuran and 10 w.t. % Pd/C (13 mg) was added. Hydrogen was passed through the solution several times and the mixture was stirred at 1 atm hydrogen for 18 hours until the reaction was determined complete by TLC (5% methanol/dichloromethane). The mixture was filtered through Celtite, eluting with methanol/chloroform and the filtrate was concentrated under reduced pressure and purified by HPLC to yield the title compound (7.3 mg, 73%) 1H NMR (CDCl3) δ 12.45 (m, 1H), 10.38 (s, 1H), 8.30 (s, 1H), 7.32 (m, 1H), 6.83-6.76 (m, 2H), 5.23 (m, 1H), 4.75 (m, 1H), 4.63 (m, 2H), 4.26 (m, 1H), 4.12-4.01 (m, 2H), 3.83 (m, 1H), 2.30 (m, 1H), 1.91 (m, 1H), 1.80 (m, 1H), 1.67-1.40 (m, 5H), 1.20 (m, 1H); ES+ MS: 460 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][CH:7]([C:9]1[CH:10]=[C:11]([NH:16][C:17]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])[C:20]=2[C:32]([F:35])([F:34])[F:33])=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15])[CH3:8].N1C=CC=CC=1>C1COCC1>[Cl:15][C:14]1[CH:13]=[CH:12][C:11]([NH:16][C:17]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]([F:30])([F:31])[C:26]([F:27])([F:28])[F:29])[C:20]=2[C:32]([F:35])([F:34])[F:33])=[O:18])=[CH:10][C:9]=1[CH:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])[CH3:8]
Reactant: CCC(=O)Cl
Reactant: CC(N)c1cc(NC(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)ccc1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC(=O)NC(C)c1cc(NC(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)ccc1Cl
Reaction time: 28 h
Yield: 90.4 %

Procedure:
Propionyl chloride (21 mg, 0.22 mmol, 1.3 eq.) in THF (1 ml) was added to a solution of N-[3-(1-aminoethyl)-4-chlorophenyl]-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (80 mg, 0.17 mmol) and pyridine (18 mg, 0.22 mmol, 1.3 eq.) in THF (3 ml). After 28 h at room temperature, the mixture was concentrated under reduced pressure and purified by column chromatography (hexane/ethyl acetate) to give N-{4-chloro-3-[1-(propionylamino)ethyl]phenyl}-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (80 mg, 89%).
Reaction SMILES: Cl.CC(C1[NH:9][C:8](=[O:10])[CH2:7][NH:6]1)C.N1C2(CCCCC2)NCC1=O.C(=O)([O-])[O-].[K+].[K+].[O:28]1[CH2:36][CH:29]1[CH2:30][C:31]([O:33]CC)=O>O.CN(C=O)C.CC(C)=O>[CH2:30]1[C:31](=[O:33])[N:6]([CH2:7][C:8]([NH2:9])=[O:10])[CH2:36][CH:29]1[OH:28]
Reactant: CC(C)C1NCC(=O)N1
Reactant: CCOC(=O)CC1CO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C1CNC2(CCCCC2)N1
Solvent: CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CN1CC(O)CC1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 6.8 %

Procedure:
5.8 g of 2-(1-methylethyl)-4-imidazolidinone hydrochloride ((5); R4 =H, R5 =isopropyl) (0.035 moles) are shaken in 10 ml water and treated with 2.4 g potassium carbonate (0.0174 moles). 4.5 g ethyl 3,4-epoxybutanoate and 6 ml acetone are added, and stirring is maintained for 45 h at 70° C. After evaporation, the residue is chromatographed on silica, eluting with 8:2 ethyl acetate/methanol. The main fractions are collected and evaporated. The oil that remains is taken up with ethyl acetate. After being left to stand overnight the white compound obtained is filtered: 1.3 g ethyl 2-(1-methylethyl)-4-oxo-1-imidazolidine-β-hydroxybutanoate m.p. 118°-122° C. 0.95 g of this compound (3.7 mmoles) are heated to boiling for 15 h in 4 ml DMF and 1 ml water. After evaporation in vacuo, the residue is taken up with methanol, and the solution is filtered. 0.37 g oxiracetam is obtained as a white crystalline powder, m.p. 167°-70° C. (63.2%).