Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]Cl.[CH:4]([C:8]1[C:9]([CH3:16])=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])([CH2:6][CH3:7])[CH3:5].Cl.[CH:18]#[CH:19]>C1COCC1>[CH:4]([C:8]1[C:9]([CH3:16])=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]([OH:12])[C:18]#[CH:19])([CH2:6][CH3:7])[CH3:5]
Reactant: C#C
Reactant: CCC(C)c1cccc(C=O)c1C
Agent: C[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: C#CC(O)c1cccc(C(C)CC)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
50 ml of absolute THF is saturated under a nitrogen blanket at 0° C. with acetylene. While passing in further acetylene, 87 ml of methylmagnesium chloride solution (1.5 molar) is dripped in over a 45-minute period, and the whole is then stirred for 30 minutes at 0° C. At -20° C., a solution of 15.3 g of 3-sec-butyl-2-methylbenzaldehyde in 20 ml of absolute THF is dripped in. The mixture is stirred for 2 hours at -20° C., is allowed to stand overnight at room temperature, and is then poured into 300 ml of ice water. The mixture is acidified with dilute hydrochloric acid and extracted by shaking three times with ether. The combined ether extracts are washed with water, dried over sodium sulfate and concentrated. There is obtained 16.6 g of an oil (70% desired compound), which, after purification by column chromatography over silica gel using toluene as eluant, gives 5.1 g of the pure benzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][OH:12])=[C:4]([O:13][CH3:14])[CH:3]=1.[H][H]>C(OCC)(=O)C.O=[Pt]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C#CCCO
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COc1cc(Cl)ccc1CCCCO
Yield: 89.6 %

Procedure:
A solution of 4-(4-chloro-2-methoxy-phenyl)-but-3-yn-1-ol (2.2 g, 10.4 mmol) and PtO2 (200 mg) in ethyl acetate (15 mL) was hydrogenated under 50 psi hydrogen atmosphere until no more hydrogen uptake was observed. The reaction mixture was then filtered and concentrated in vacuo. The crude product was subjected to column chromatography on silica gel (gradient elution with 0%-40% EtOAc/hexane) to give 4-(4-chloro-2-methoxy-phenyl)-butan-1-ol as a colorless oil (2 g, 89.7%). 1H NMR (300 MHz, CDCl3) δ ppm 7.03 (d, J=8.2 Hz, 1H), 6.86 (dd, J=8.2, 1.6 Hz, 1H), 6.81 (d, J=1.6 Hz, 1H), 3.81 (s, 3H), 3.66 (t, J=6.0 Hz, 2H), 2.49-2.65 (m, 2H), 1.50-1.72 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH2:19])=[CH:11]2)[C:4]=1[CH3:20].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH:46]1([CH2:49][C:50](O)=[O:51])[CH2:48][CH2:47]1>ClCCl.O>[CH:46]1([CH2:49][C:50]([NH:19][C:12]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:18]3[N:10]([CH2:9][C:5]3[C:4]([CH3:20])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=3)[CH:11]=2)=[O:51])[CH2:48][CH2:47]1
Reactant: COc1ncnc(Cn2cc(N)c3ncccc32)c1C
Reactant: O=C(O)CC1CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ncnc(Cn2cc(NC(=O)CC3CC3)c3ncccc32)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-amine (25d) (0.1 g, 0.37 mmol) in dichloromethane (10 mL) were added triethylamine (0.15 mL, 1.11 mmol), T3P (0.35 g, 1.11 mmol) and 2-cyclopropylacetic acid (0.037 g, 0.37 mmol and the mixture was stirred for 16 h at room temperature. Then the reaction mixture was poured into water (20 mL) and extracted with dichloromethane (2×50 mL). The combined organic layer was washed with brine and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using 50% ethylacetate in hexane to afford 2-cyclopropyl-N-(1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide as off-white solid; yield: 25 mg (19%). ES+MS m/z: 352 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.25 (s, 3H), 3.67-3.69 (m, 1H), 3.73-3.76 (m, 1H), 4.50-4.52 (m, 1H), 4.62-4.64 (m, 1H), 5.49 (s, 2H), 6.94-6.96 (m, 3H), 7.27-7.30 (m, 1H), 8.08 (d, J=8.2 Hz), 8.45 (s, 1H), 8.50 (d, J=3.88 Hz), 8.92 (t, J=5.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][N:10]=[C:9]2[CH:13]=O)=[CH:4][CH:3]=1.C(OP([CH2:23][C:24]([O:26]CC)=[O:25])(OCC)=O)C.[H-].[Na+].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[N:11][N:10]=[C:9]2/[CH:13]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1nncn1-c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1nncn1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
A mixture of 4-(4-fluorophenyl)-4H-1,2,4-triazole-3-carbaldehyde (3.83 g), ethyl diethylphosphonoacetate (5.60 g), sodium hydride (60% in oil, 0.88 g) and tetrahydrofuran (130 ml) was stirred at 0° C. for 1 hr. The reaction mixture was poured into an aqueous dilute hydrochloric acid solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in a 6N aqueous hydrochloric acid solution (100 ml) and stirred for 2 hrs. with heating under reflux. Disodium hydrogen phosphate was added to neutralize the reaction mixture. The precipitated solids were collected by filtration, washed with water and dried to give (2E)-3-[4-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl]acrylic acid (3.60 g, yield 76%) as pale-yellow crystals. melting point: 226-229° C. (recrystallized from ethyl acetate-hexane).
Reaction SMILES: [Mg].Br[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:4]=1[CH3:11].[B:12](OCC)([O:16]CC)[O:13]CC>O1CCCC1>[B:12]([OH:16])([OH:13])[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:4]=1[CH3:11]
Reactant: CCOB(OCC)OCC
Reactant: Cc1cc(C)c(Br)c(C)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(C)c(B(O)O)c(C)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
Magnesium (60.27 mmol) and tetrahydrofuran (30 mL) were put in a three-necked round bottom flask and stirred. To the solution, bromomesitylene (13.07 mmol) was added, and the reaction mixture was heated. After that, bromomesitylene (32.02 mmol) dissolved in tetrahydrofuran (30 mL) was added dropwise to the solution. The reaction mixture was heated and refluxed for 4.5 hours. Then, the mixture was cooled to −78° C. (EtO)3B (111.66 mmol) was added dropwise over 15 minutes. After that, the mixture was warmed to room temperature and stirred for additional 5 hours. Then the mixture was cooled to 0° C. The reaction was quenched by the addition of 1 M hydrochloric acid and stirring for additional 2 hours. The reaction mixture was extracted with diethyl ether three times. The combined extracts was washed with brine and dried over anhydrous sodium sulfate. After the drying, the extract was filtered. The filtrate was concentrated to give a solid, which was recrystallized in benzene to give GA33 (26.10 mmol, yield: 58%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:6][N:7]([O:19][CH3:20])[C:8](=[O:18])[CH:9]=[C:10]1[C:14](=[O:15])[O:13][C:12](C)(C)[O:11]1)#[N:2]>CO>[CH3:12][O:13][C:14](=[O:15])[C:10]([OH:11])=[CH:9][C:8](=[O:18])[N:7]([CH2:6][C:5]1[CH:21]=[CH:22][C:23]([F:24])=[C:3]([C:1]#[N:2])[CH:4]=1)[O:19][CH3:20]
Reactant: CON(Cc1ccc(F)c(C#N)c1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)c(C#N)c1)OC
Yield: 47 %

Procedure:
N-(3-Cyano-4-fluorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (47% yield); mp 125–126° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.75 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.81 (2H, s, NCH2), 6.44 (1H, s, CH), 7.18 (1H, m, aromatic), 7.56–7.61 (2H, m, aromatics). Anal. calcd for C14H13FN2O5: C, 54.54; H, 4.25; N, 9.08. Found: C, 54.76; H, 4.29; N, 9.04.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11]OC1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+]>>[CH2:1]([N:8]1[CH2:13][C:12]([CH3:11])([CH3:14])[CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)COC(=O)N(Cc2ccccc2)C1
Agent: [Cl-]
Agent: [Li+]
Product: CC1(C)CN(Cc2ccccc2)C1
Temperature: 245 °C
Reaction time: 5 h
Yield: 83.3 %

Procedure:
A mixture of 8.97 g (0.04 mole) of tetrahydro-3-benzyl-5,5-dimethyl-1,3-oxazin-2-one and 0.084 g (0.002 mole) of lithium chloride was heated to 245° C. at a pressure of 100 torr in a 25-ml flask equipped with a mechanical stirrer and distillation head. The receiver was cooled with dry ice as the product slowly distilled. After 5 hours, an additional 0.084 g of lithium chloride was added and heating was continued for an additional 25 hours. At this time, 5.84 g (85 percent yield) of pure 1-benzyl-3,3-dimethylazetidine had collected. The material was redistilled at bp 107° C.-108° C. (15 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])[CH2:16][CH2:15][CH:14]([CH2:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC1C(O)=C(F)C(F)=C(F)C=1F.C1([N:51]=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])[CH2:16][CH2:15][CH:14]([CH2:17][S:18]([CH2:21][C:22]([NH2:51])=[O:23])(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CS(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCOC(C)=O
Product: NC(=O)CS(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 0 °C

Procedure:
To the product of Example 75 (100 mg, 0.2 mmol) in ethyl acetate (8 mL) was added pentafluorophenol (55 mg, 0.3 mmol). The solution was cooled to 0° C. and dicyclohexylcarbodiimide was added (62 mg, 0.3 mmol). After 2 h the reaction was filtered through Celite® and the filtrate concentrated to give a white solid (130 mg). This was dissolved in a 2 M solution of ammonia in methanol (10 ml) and heated to 50° C. in a sealed tube for 16 h. The mixture was concentrated and the residue purified by flash chromatography on silica eluting with dichloromethane/methanol (9:1) to give a white solid (45 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:10]([C:19]([O:21]CC)=[O:20])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[OH-].[K+]>CCO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:10]([C:19]([OH:21])=[O:20])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2)nc2c(cnn2CC)c1-c1cncc(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1ncc2c(-c3cncc(C)c3)c(C(=O)O)c(-c3ccccc3)nc21
Yield: 70.5 %

Procedure:
To a stirred solution of ethyl 1-ethyl-4-(5-methyl-3-pyridyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (257 mg) in a mixture of EtOH (2.5 ml) and water (2 ml) was added potassium hydroxide (1.32 g) and the mixture was refluxed for 12 hours. Another potassium hydroxide (439 mg) was added and the mixture was refluxed for 4.5 hours. After cooling, the reaction mixture was diluted with water and extracted with CHCl3. The aqueous layer was acidified to pH3-4 by adding HCl and extracted with CHCl3. The organic layer was washed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was crystallized from EtOAc and n-hexane to give 1-ethyl-4-(5-methyl-3-pyridyl)-6-phenyl-1H-pyrazolo [3,4-b]pyridine-5-carboxylic acid (168 mg) as a light yellow crystal.
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[F:12][C:13]1[C:18]([OH:19])=[C:17]([CH:20]=[O:21])[CH:16]=[CH:15][C:14]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:1][C:15]1[C:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[C:13]([F:12])[C:18]([OH:19])=[C:17]([CH:20]=[O:21])[CH:16]=1
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Reactant: O=Cc1ccc(-c2ccc(F)cc2F)c(F)c1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c(-c2ccc(F)cc2F)c(F)c1O
Reaction time: 3 h
Yield: 121.3 %

Procedure:
Dibromoisocyanuric acid (2.25 g) was added at room temperature to a DMF (90 mL) solution of 2,2′,4′-trifluoro-3-hydroxybiphenyl-4-carbaldehyde (3.29 g), and the mixture was stirred at the same temperature as above for 3 hours in a nitrogen atmosphere. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The organic layer was separated, then washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) and silica gel column chromatography (diol, hexane/ethyl acetate) to obtain the title compound (3.15 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:4][C:3]=1[C:19]([NH:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:20].[OH-].[K+].Cl>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[C:19]([NH:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:20]
Reactant: CCCCCCCCCCCCOCCCNC(=O)c1cc(OCC(=O)OCC)c2ccccc2c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCOCCCNC(=O)c1cc(OCC(=O)O)c2ccccc2c1O
Yield: 94.3 %

Procedure:
205 g (0.4 mol) of 1-hydroxy-4-ethoxycarbonylmethyloxy-N-(3-n-dodecyloxypropyl)2-naphthamide was dispersed in 600 ml of methanol at the room temperature. A solution containing 105 g of potassium hydroxide in 250 ml of methanol was added slowly with stirring, followed by stirring for 1 hour. After being neutralized by adding concentrated hydrochloric acid, the precipitated crystals were filtered off and dried to obtain 184 g (94% yield) of 1-hydroxy-4-carboxymethyloxy-N-(3-n-dodecyloxypropyl)2-naphthamide. Melting point: 150° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15][N:11]2[C:12](=[O:14])[N:13]=1)#[N:2]>CN(C=O)C>[O:14]=[C:12]1[N:11]2[CH2:15][CH2:16][NH:17][C:10]2=[CH:9][C:8]([O:7][CH2:6][C:5]2[CH:25]=[CH:26][C:27]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=3)=[C:3]([CH:4]=2)[C:1]#[N:2])=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccnc(C(F)(F)F)c3)c(C#N)c1)nc2=O
Solvent: CN(C)C=O
Product: N#Cc1cc(COc2cc3n(c(=O)n2)CCN3)ccc1Oc1ccnc(C(F)(F)F)c1

Procedure:
Prepared in a manner similar to that described for E71 tert-butyl 7-((3-cyano-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimi-dine-1(5H)-carboxylate (80 mg, 0.151 mmol) in DMF (2 mL) and silica gel.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:22])[CH2:8][CH:9]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[CH2:10][C:11]=1[OH:12])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:23][O:24]C(Cl)Cl>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([C:6]1[C:11](=[O:12])[CH2:10][CH:9]([C:13]2[C:14]([CH3:21])=[CH:15][C:16]([CH3:20])=[C:17]([CH:23]=[O:24])[C:18]=2[CH3:19])[CH2:8][C:7]=1[OH:22])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COC(Cl)Cl
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(C=O)c2C)CC1=O
Yield: 26.7 %

Procedure:
To a solution of 2-butyryl-3-hydroxy-5-mesitylcyclohex-2-en-1-one (1.20 g) in dichloroethane (20 ml) at 0° C. was added titanium tetrachloride (300 g) over a period of 3 minutes. While the solution was stirred and cooled dichloromethyl methyl ether (0.46 g) in dichloroethane(20 ml) was added dropwise over a 25 minute period. After the addition was complete, the mixture was stirred for 5 minutes at 0° C., for 30 minutes at room temperature and for 2 hours under reflux. The cooled reaction mixture was poured into a separatory funnel containing crushed ice and was shaken thoroughly. The organic layer was separated, and the aqueous solution was extracted with methylene chloride. The combined organic solution was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give a crude brown oil (0.70 g). Purification by column chromatography over silica gel (eluant dichloromethane) gave 2-butyryl-3-hydroxy-5-(3-formyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.35 g) as a pale yellow oil. Proton nuclear magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.0 (3H, t); 1.68 (2H, m); 2.43 (3H, s); 2.48 (3H, s); 2.61 (3H, s); 2.65-4.20 (7H, m); 6.94 (1H, s); 10.54 (1H, s); 18.33 (1H, s).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:25])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([O:28]C)=[O:27])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].O>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:25])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([OH:28])=[O:27])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]nnc4c3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]nnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of (S)-methyl 2-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (130 mg, 0.33 mmol) in methanol (30 mL) was added sodium hydroxide (40.2 mg, 1.00 mmol) and water (1 mL) with stirring for overnight at room temperature. The resulting mixture was concentrated under vacuum and dissolved in water (25 mL), and adjusted to pH 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford (S)-2-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (90.3 mg, 72%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]([CH3:43])([CH3:42])[CH2:22][N:23]4[C:26](=[O:41])[CH2:27][N:28]([CH:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)C(=O)OC(C)(C)C)=[CH:19][CH:18]=3)[C:10]2=[O:44])[CH:5]=[CH:4][N:3]=1.[NH2:45][C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1.CC1(C)C2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:36]1([NH:28][CH2:27][C:26]([N:23]2[C:24]3[C:20](=[CH:19][CH:18]=[C:17]([N:11]4[C:12](=[O:16])[C:13]([CH3:15])([CH3:14])[N:9]([CH2:8][C:6]5[CH:5]=[CH:4][N:3]=[C:2]([NH:45][C:46]6[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=6)[CH:7]=5)[C:10]4=[O:44])[CH:25]=3)[C:21]([CH3:43])([CH3:42])[CH2:22]2)=[O:41])[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: Nc1cccnc1
Reactant: CC(C)(C)OC(=O)N(CC(=O)N1CC(C)(C)c2ccc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)cc21)C1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2ccc(P(c3ccccc3)c3ccccc3)cc2Oc2cc(P(c3ccccc3)c3ccccc3)ccc21
Solvent: C1COCCO1
Product: CC1(C)CN(C(=O)CNC2CCCC2)c2cc(N3C(=O)N(Cc4ccnc(Nc5cccnc5)c4)C(C)(C)C3=O)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.3 %

Procedure:
To a solution of 0.312 g of tert-butyl [2-(6-{3-[(2-chloropyridin-4-yl)methyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]cyclopentylcarbamate obtained in stage 1) of Example 3 in 12 mL of dioxane are successively added, under argon, 0.094 g of 3-aminopyridine, 0.028 g of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) (Xantphos), 0.022 g of palladium acetate and 0.65 g of caesium carbonate. The reaction mixture is refluxed for 4 hours and then filtered, and the filtrate is concentrated under reduced pressure. The residue is taken up in 10 mL of dioxane, 12 mL of a 4N solution of hydrogen chloride in dioxane are then added and the reaction mixture is stirred at room temperature for 15 hours. After concentrating under reduced pressure, the residue is taken up in 40 mL of water, neutralized by addition of sodium hydrogen carbonate and extracted with three times 25 mL of dichloromethane. The combined organic phases are then washed with water, dried over magnesium sulphate filtered and concentrated under reduced pressure. The residue is triturated with diethyl ether and the solid obtained is filtered off and dried to give 0.12 g of 3-[1-(N-cyclopentylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethyl-1-{[2-(pyridin-3-ylamino)pyridin-4-yl]methyl}imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]([CH2:10][CH3:11])[C:8]#[N:9])=[CH:3][CH:2]=1.[CH2:13](N)[CH2:14][NH2:15]>>[C:1]1([CH3:12])[CH:2]=[CH:3][C:4]([CH:7]([C:8]2[NH:9][CH2:13][CH2:14][N:15]=2)[CH2:10][CH3:11])=[CH:5][CH:6]=1
Reactant: NCCN
Reactant: CCC(C#N)c1ccc(C)cc1
Product: CCC(C1=NCCN1)c1ccc(C)cc1

Procedure:
rac-2-(1-p-Tolyl-propyl)-4,5-dihydro-1H-imidazole was prepared from rac-2-p-tolyl-butyronitrile and ethylene diamine in analogy to Example 22: colourless powder; MS (ISP): 203.0 ((M+H)+.).
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH2:24][CH2:25][CH3:26])[C:4]1=[O:27])[CH3:2].C([C@H]1N(C(=O)C2C=CC(O)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH2:24][CH2:25][CH3:26])[C:4]1=[O:27])[CH3:2]
Reactant: CCCN1C(=O)[C@@H](CC)N(C(=O)c2ccc(OC)cc2)c2cc(F)ccc21
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Product: CCCN1C(=O)[C@@H](CC)N(C(=O)c2ccc(O)cc2)c2cc(F)ccc21
Yield: 81 %

Procedure:
(3R)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-1-propyl-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-3-ethyl-6-fluoro-4-(4-hydroxybenzoyl)-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (81%). [α]D25=−298° (c=0.0102 G/ML, CHCl3); MS (ESI) m/z 357 ([M+H]+); MS (ESI) m/z 355 ([M−H]−); HRMS: calcd for C20H21FN2O3, 356.1536; found (ESI_FT), 357.16057.