Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH3:44][S:45](Cl)(=[O:47])=[O:46].N1C=CC=CC=1.Cl>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:38]=[CH:39][C:40]([NH:43][S:45]([CH3:44])(=[O:47])=[O:46])=[CH:41][CH:42]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(N)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(NS(C)(=O)=O)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 108.7 %

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzene (126 mg) obtained in Example 197-(1) was dissolved in dichloromethane (3 ml) and added thereto were methanesulfonyl chloride (48 mg) and pyridine (48 mg). The mixture was stirred at room temperature for 3.5 hours. To the mixture was added 2N hydrochloric acid aqueous solution at 0° C. and extracted with ethyl acetate. The organic layer was washed with water, aqueous sodium hydrogen carbonate solution and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1-1:2) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylsulfonylaminophenyl)-2-thienylmethyl)benzene (154 mg) as yellow caramel. ESI-Mass m/Z 706/708 (M−H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:24])=[C:22]([OH:23])[C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25]C(C)([O-])C.[K+].IC>CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:24])=[C:22]([O:23][CH3:25])[C:17]=3[O:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2noc3c(O)c(F)ccc23)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CI
Product: COc1c(F)ccc2c(C3CCN(C(=O)OC(C)(C)C)CC3)noc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
To a stirred solution of 4-(6-fluoro-7-hydroxy-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.28 g, 3.80 mmol) in N-methyl-2-pyrrolidone (33 mL) was added potassium tert-butoxide (2.09 g, 17.12 mmoles). To the resulting deep red solution was added iodomethane (1.20 mL, 19.02 mmoles). The resulting yellow solution was stirred at room temperature for 6 hours when the reaction was quenched with water (55 mL) and acidified with HClaq. The resulting mixture was extracted with Et2O (4×110 mL). The combined extracts were washed with brine (110 mL), dried (MgSO4), filtered and evaporated. The residue was separated via column chromatography (1:1; Et2O/Pet. ether) yielding 1.2 g of the methyl ether. The white, solid product was further purified via recrystallization from 1:1; Et2O/Pet. ether yielding 963 mg (72%) as a white, crystalline solid, mp 94-96° C. Analysis calculated for C18H23N2FO4: 61.70% C, 6.62% H, 7.99% N. Found: 61.75% C, 6.73% H, 7.94% N.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1.[H-].[Na+].I[CH3:16]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][CH3:16])[CH2:7][CH2:6]1
Reactant: CI
Reactant: COC(=O)C[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1CC[C@H](OC)CC1
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
trans-(4-Hydroxy-cyclohexyl)-acetic acid methyl ester (500 mg, 2.90 mmol) were dissolved in 1.5 ml DMF and cooled to 0-5° C. Sodium hydride (190 mg, 4.35 mmol, 55%) and iodomethane (3.62 ml, 23.2 mmol) were added and the reaction mixture stirred for 4 hours at 0-5° C. The reaction mixture was quenched with saturated NaHCO3-solution and extracted with dichloromethane. The organic extract was washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product (561 mg, quant.) was obtained as a colourless oil and used without any further purification for the next step.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH:9](OCC)=[O:10]>>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][CH:9]=[O:10])=[CH:4][CH:5]=1
Reactant: NCc1ccncc1
Reactant: CCOC=O
Product: O=CNCc1ccncc1
Reaction time: 16 h

Procedure:
A solution of 4-(aminomethyl)pyridine (54.1 g, 0.5 mol) and ethyl formate (44.4 ml) was refluxed for two hours and then permitted to stand at ambient temperature for 16 hours. The reaction was distilled to produce 61.6 g of N-(4-pyridylmethyl)formamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([OH:17])[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].[CH3:20][S:21]([CH:24]=[CH2:25])(=[O:23])=[O:22]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:17][CH2:25][CH2:24][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[CH2:10]2)[C:6]=1[CH3:7]
Reactant: C=CS(C)(=O)=O
Reactant: Cc1c(Br)cnn1CC1(O)CCCC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Br)cnn1CC1(OCCS(C)(=O)=O)CCCC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of EXAMPLE 157B (0.218 g) in tetrahydrofuran (2.5 mL) was added sodium hydride (0.027 g) and the reaction mixture was stirred for 15 minutes at room temperature. Methylsulfonylethene (0.095 mL) was added and the reaction was stirred at room temperature overnight. The reaction was cooled and diluted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 1-20% ethyl acetate in hexanes provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:20])=O)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18](=[O:20])[N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:8][N:9]=2
Reactant: C1CCNCC1
Reactant: O=C(O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Product: O=C(Cc1cc(Cl)cc2c(-c3ccccc3)onc12)N1CCCCC1

Procedure:
The title compound is prepared by reacting the acid chloride of 5-chloro-3-phenyl-2,1-benzisoxazole-7-acetic acid with piperidine in an aprotic solvent and washing the reaction mixture with sodium bicarbonate solution.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH:24]4[CH2:26][CH2:25]4)=[CH:22][C:21]([CH:27]4[CH2:29][CH2:28]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:30]([N:33]1[CH2:37][CH2:36][NH:35][C:34]1=[O:38])(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:37][CH2:36][N:35]([C:2]2[CH:3]=[CH:4][C:5]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[C:23]([CH:24]5[CH2:26][CH2:25]5)=[CH:22][C:21]([CH:27]5[CH2:29][CH2:28]5)=[CH:20][N:19]=4)[CH2:14][CH2:13]3)=[O:11])=[C:6]([CH:9]=2)[C:7]#[N:8])[C:34]1=[O:38])(=[O:32])[CH3:31]
Reactant: CC(=O)N1CCNC1=O
Reactant: N#Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)c(C#N)c2)C1=O
Yield: 47.1 %

Procedure:
Using 5-bromo-2-[4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (1.35 g) described in Preparation Example 245 and 1-acetylimidazolidin-2-one (461 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (702 mg) was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)[OH:4].O=[C:21]([CH3:35])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:34][O:33][C:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH:21]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=2)[OH:4])[CH3:35])=[CH:29][CH:28]=1)=[O:32]
Reactant: CC(C)(C)c1cc(C(O)CN)cc(C(C)(C)C)c1O
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Yield: 45 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 3 g of 2-amino-1-(3,5-di-t-butyl-4-hydroxyphenyl)ethanol (prepared as described in Preparation 35), 2.2 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 100 ml of benzene, 60 ml of absolute methanol and 4 g of sodium cyanoborohydride were used, and that the product was purified by repeated column chromatography through silica gel, using as the eluent first ethyl acetate and then a 1:1 by volume mixture of benzene and ethyl acetate. 2.1 g of 2-[2-(4-methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3,5-di-t-butyl-4hydroxyphenyl)ethanol were obtained. This product was then mixed with 246 mg of fumaric acid, and the mixture was recrystallized from ethyl acetate, to give 1.5 g of the title compound as crystals, melting at 171°-174° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CCCCCCCCCCO
Reactant: CC(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOC(=O)C(C)O
Temperature: 145 °C
Yield: 13.9 %

Procedure:
A 500 mL one neck round bottom flask equipped with a Dean Stark trap, condensor and nitrogen inlet/outlet was charged with 22.52 g (0.75 moles) lactic acid, 47.46 g (0.98 moles) decyl alcohol, 3 ml sulfuric acid and 220 mL toluene. The mixture was heated to 145° C. for 20 hours and water was collected as the reaction proceeded. The acid was neutralized by washing three times with 50 ml saturated sodium bicarbonate solution. The organic layer was collected and dried over magnesium sulfate. Decyl lactate was distilled under high vacuum to yield 24.03 g (12.4% yield) of clear colorless liquid. According to GC the product is 97.78% pure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[Cl:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)[CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])=[O:15])[S:10][C:11]=1[Cl:12]
Reactant: Cn1ncc(Br)c1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1ncc(Br)c1-c1cc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid (183 mg, 0.54 mmol) [prepared according to the procedure of Example 167], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (201 mg, 0.52 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (298 mg, 0.64 mmol) in chloroform (5 mL). DIEA (470 μL, 2.69 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (246 mg, 0.36 mmol, 69%): LC-MS (ES) m/z=653 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].Cl[C:15]1[CH:20]=[CH:19][N:18]([C@@H:21]2[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:25]([O:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:22]2[O:23][CH3:24])[C:17](=[O:47])[N:16]=1>C1COCC1.[Cu]I>[C:8]([C:15]1[CH:20]=[CH:19][N:18]([C@@H:21]2[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:25]([O:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:22]2[O:23][CH3:24])[C:17](=[O:47])[N:16]=1)#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1ccc(Cl)nc1=O
Reactant: C#CCCCC
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC#Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC)c(=O)n1
Reaction time: 0.08 h

Procedure:
Bis-triphenylphosphine palladium (II) dichloride (422 mg, 4.3 mmole) and copper (I) iodide (114 mg, 4.3 mmole) were suspended in anhydrous THF (100 ml) and degassed with argon for 10 min. The orange suspension was treated with triethylamine (5 ml) and 1-hexyne (2.96 g, 41 mmole) and stirred for 5 min. A solution of 4-chloro-1-(2-O-methyl-3,5,-di-O-benzoyl-β-D-ribofuranosyl)pyrimidin-2-one (6.74 g, 13.9 mmole) in THF (25 ml) was added all at once. The reaction mixture was stirred for 2 hours at room temperature and evaporated to an oil. The residue was purified by silica gel column chromatography. Elution with chloroform (500 ml) and then chloroform/acetone (98:2, 21), pooling of appropriate fractions and evaporation gave a yield of 3.84 g (52.7%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[N:11]2[C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C:13]=3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[N:4]([CH3:23])[C:3]1=O.Cl.O>C1COCC1>[CH2:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:12]2[N:11]3[C:10]4[C:9]([C:13]=2[CH2:14]1)=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]([CH3:23])[CH2:3][C:2]3([CH3:1])[CH3:25])=[O:19])[CH3:22]
Reactant: CCOC(=O)N1CCc2c(c3cccc4c3n2C(C)(C)C(=O)N4C)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCc2c(c3cccc4c3n2C(C)(C)CN4C)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
To a solution of ethyl 1,1,3-trimethyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (240 mg, 0.7 mmol) in THF (20 mL) at 25° C. was added BH3/THF complex (0.7 mL, 0.7 mmol). The mixture was stirred at 80° C. for 5 hours then cooled to rt and added 6N HCl (10 mL) with stirred for another 1 hr. About 30 mL of H2O was added and then was extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to give ethyl-1,1,3-trimethyl-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate as an oil (152 mg, 66%). MS [M+H]+ 327. 1H NMR (CDCl3, 300 MHz) δ 7.01 (t, 1H, J=7.7 Hz), 6.97 (d, 1H, J=7.7 Hz), 6.41 (d, 1H, J=7.7 Hz), 4.68 (s, 2H), 4.23 (m, 2H), 3.84 (m, 2H), 3.11 (m, 2H), 2.99 (s, 3H), 1.54 (s, 6H), 1.27 (t, 3H, J=7.3 Hz) ppm.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[C:9]([C:11]([NH:13][C:14]2[O:15][C:16]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[N:17][N:18]=2)=[O:12])[CH:10]=1)(=[O:3])[CH3:2].[CH2:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)[CH3:26]>>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]([NH:13][C:14]2[O:15][C:16]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[N:17][N:18]=2)=[O:12])[CH:8]=[C:7]([C:36]2[CH:37]=[CH:38][C:33]([C:30]3[CH:29]=[CH:28][C:27]([CH2:25][CH3:26])=[CH:32][CH:31]=3)=[CH:34][CH:35]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Reactant: CC(=O)Nc1cc(Br)cc(C(=O)Nc2nnc(-c3ccco3)o2)c1
Product: CCc1ccc(-c2ccc(-c3cc(NC(C)=O)cc(C(=O)Nc4nnc(-c5ccco5)o4)c3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 5-acetylamino-3-bromo-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]benzenecarboxamide prepared in Reference Example 38 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [Na].[CH3:2][OH:3].[N+:4]([O:7][CH2:8][C:9]([CH2:17][O:18][N+:19]([O-:21])=[O:20])([CH2:12][O:13][N+:14]([O-:16])=[O:15])[CH2:10]Br)([O-:6])=[O:5]>O>[N+:4]([O:7][CH2:8][C:9]([CH2:17][O:18][N+:19]([O-:21])=[O:20])([CH2:12][O:13][N+:14]([O-:16])=[O:15])[CH2:10][O:3][CH3:2])([O-:6])=[O:5]
Reactant: CO
Reactant: O=[N+]([O-])OCC(CBr)(CO[N+](=O)[O-])CO[N+](=O)[O-]
Agent: [Na]
Solvent: O
Product: COCC(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Yield: 75 %

Procedure:
0.025 mol of sodium and 0.12 mol of absolute methanol are used to prepare the methylate solution. 0.02 mol of 3-nitryloxy-2,2-bis(nitryloxymethyl)propyl bromide is added and the mixture is refluxed for 5 hours, with stirring and with the exclusion of moisture. After cooling, the reaction mixture is added to 5 times the amount of water and the ether (Me-PETriN ether) is separated off, washed again with water, dried and purified by column chromatography. Yield: 75%. Elemental analysis: (C: conforms, H: conforms, N: conforms).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[C:4]([NH:7][C:8](=[O:21])[CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][C:11]2=[O:20])[S:5][CH:6]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:28]>>[Cl:1][C:2]1[C:3]([C:22]2[N:26]=[CH:25][N:24]([CH3:28])[N:23]=2)=[C:4]([NH:7][C:8](=[O:21])[CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][C:11]2=[O:20])[S:5][CH:6]=1
Reactant: O=C(CN1C(=O)CCc2ncccc21)Nc1scc(Cl)c1-c1nc[nH]n1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Product: Cn1cnc(-c2c(Cl)csc2NC(=O)CN2C(=O)CCc3ncccc32)n1

Procedure:
The titled compound was synthesized from N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide and TMSCHN2. HPLC purification afforded a white solid. LCMS method [11], retention time=7.322 min; MS(ESI) 403.2 (MH+, 35Cl); 1H NMR (300 MHz, CD3OD) δ 8.43 (s, 1H), 8.29 (d, J=5.3 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.59 (t, J=7.1 Hz, 1H), 6.94 (s, 1H), 4.98 (s, 2H), 3.98 (s, 3H), 3.36 (t, J=7.5 Hz, 2H), 2.97 (dd, J=8.2, 6.3 Hz, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[N:5]=1)[CH3:2].C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[C:27]=1[C:28](Cl)=[O:29]>C1COCC1>[F:25][C:26]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[C:27]=1[C:28]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[N:5]=1)=[O:29]
Reactant: CCNc1cccc(OC2CCN(C)CC2)n1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(C(=O)c1c(F)cc(F)cc1F)c1cccc(OC2CCN(C)CC2)n1
Temperature: 55 °C
Yield: 81.7 %

Procedure:
Dissolve ethyl-[6-(1-methyl-piperidin-4-yloxy)-pyridin-2-yl]-amine (preparation 74, 110 mg, 0.47 mmol) in THF (6 mL), add triethylamine (95 mg, 0.94 mmol) and 2,4,6-trifluorobenzoyl chloride (136 mg, 0.70 mmol) sequentially, heat at 55° C. overnight. Quench the reaction with 0.1N NaOH, extract with methylene dichloride three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 3.5% 2M NH3-methanol in methylene dichloride provides 151 mg (82%) of the title compound as an oil: mass spectrum (ion spray): m/z=394.1 (M+1); 1H NMR (CDCl3, ppm): 7.43 (t, 1H), 6.52 (m, 4H), 4.82 (m, 1H), 4.03 (q, 2H), 2.73 (m, 2H), 2.33 (s, 3H), 2.26 (m, 2H), 1.95 (m, 2H), 1.75 (m, 2H), 1.31 (t, 3H). Mono-hydrochloride salt: Anal calcd for C20H22F3N3O2.HCl.H2O: C, 53.63; H, 5.63; N, 9.38. Found: C, 53.66; H, 5.12; N, 9.29.
Reaction SMILES: [CH:1](=[O:8])[CH2:2][CH2:3][C:4]#[C:5][CH2:6][CH3:7].[CH:9]([C:11]([CH3:13])=[O:12])=[CH2:10].C(N(CC)CC)C>>[CH3:13][C:11](=[O:12])[CH2:9][CH2:10][C:1](=[O:8])[CH2:2][CH2:3][C:4]#[C:5][CH2:6][CH3:7]
Reactant: C=CC(C)=O
Reactant: CCC#CCCC=O
Solvent: CCN(CC)CC
Product: CCC#CCCC(=O)CCC(C)=O

Procedure:
22.0 g (0.2 mol) of hept-4-in-1-al, 14 g (0.2 mol) of methyl vinyl ketone, 5.4 g (0.02 mol) of Cat. 1 and 12.6 g (0.12 mol) of triethylamine are brought together in the manner described in Example 26. After 12 hours' reaction time at a surrounding temperature of 80° C in a nitrogen atmosphere, the mixture is worked up in the manner described in Example 21. On subsequent fractionation, undec-8-ine-2,5-dione is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:10](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl.CN(C)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:6][CH2:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCN1CCNCC1
Agent: CN(C)C
Solvent: ClCCl
Product: OCCN1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
2.6 g of 1-(2-hydroxyethyl)piperazine was dissolved in a mixture of 20 ml of dry methylene chloride and 10 ml of trimethylamine and stirred at room temperature during the slow addition of a solution of 5.6 g of trityl chloride in 20 ml of dry methylene chloride. When the addition was complete, the solution was stirred for a further 18 hours at room temperature and then evaporated to dryness. Basification with 5% aqueous sodium bicarbonate solution and extraction with methylene chloride gave 4.0 g of 1-(2-hydroxyethyl)-4-triphenylmethylpiperazine, m.p. 82°, used directly in the next stage.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[Cl:11][CH:12]([CH3:16])[C:13](O)=[O:14]>>[Cl:11][CH:12]([CH3:16])[C:13]([C:7]1[CH:8]=[CH:9][C:4]2[NH:3][C:2](=[O:10])[O:1][C:5]=2[CH:6]=1)=[O:14]
Reactant: CC(Cl)C(=O)O
Reactant: O=c1[nH]c2ccccc2o1
Product: CC(Cl)C(=O)c1ccc2[nH]c(=O)oc2c1

Procedure:
81.1 g (600 mmol) 2-benzoxazolinone are dissolved at 80° C. in 720 g polyphosphoric acid. Then 66.1 ml (720 mmol) 2-chloropropionic acid are added dropwise and the mixture is heated for 3 h to 125° C., then the reaction mixture is poured onto ice water, the precipitated product is suction filtered, washed with water and dried at 98° C. in the circulating air dryer.