Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.NC1C=CC=CC=1.[CH:37]1[N:41]=[CH:40][N:39]([C:42](N2C=NC=C2)=[NH:43])[CH:38]=1>C1COCC1>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:42]([N:39]3[CH:38]=[CH:37][N:41]=[CH:40]3)=[NH:43])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: N=C(n1ccnc1)n1ccnc1
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: N=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)n1ccnc1
Yield: 1.6 %

Procedure:
To imidazole (65 mg, 9.760 mmol) in CH2Cl2 (10 ml) at room temperature under nitrogen atmosphere bromonitrile (500 mg, 4.71 mmol) was added. The resulting mixture was heated at reflux for 1 hr. Cooling to room temperature, filtration and concentration in vacuo to a volume of approximately 10 ml. The resulting pale liquor was let stand at 0° C. for 15 hrs. Filtration afforded a pale white powder for C-(di-imidazol-1-yl)-methyleneamine (210 mg, 28% yield). To [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone (132 mg, 3.389 mmol), aniline (213 mg, 2.347 mmol) and C-(di-imidazol-1-yl)-methyleneamine (420 mg, 2.608 mmol) in THF (20 mg) was heated at reflux for 2.5 hrs. Concentration in vacuo and RP-HPLC (gradient water:acetonitrile) afforded the title compound as a yellow powder (20 mg, 14% yield). MS (ESI) m/z 486.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:12]([C:21]([OH:23])=[O:22])[N:11]=[N:10]1.[CH3:24][CH2:25]O>OS(O)(=O)=O>[CH2:24]([O:22][C:21]([C:12]1[N:11]=[N:10][N:9]([C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[OH:1])[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)=[O:23])[CH3:25]
Reactant: CCO
Reactant: O=C(O)c1nnn(-c2ccc(O)cc2O)c1-c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nnn(-c2ccc(O)cc2O)c1-c1ccc(F)cc1

Procedure:
1-(2,4-Dihydroxy-phenyl)-5-(4-fluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid (0.15 g, 0.48 mmol) was refluxed in EtOH (20 mL) in the presence of 5 drops of concentrated H2SO4 for 3 hours. After evaporation of the solvent, EtOAc (20 mL) was added. The organic layer was then washed with sat. NaHCO3 (2×10 mL) and brine (20 mL), dried with NaSO4 and filtered. After evaporation of the solvent, light brown semi-solids (93 mg, 57%) were obtained and purified by prep. TLC (Rf=0.73, EtOAc).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([Cl:11])[N:3]=1.S(Cl)([Cl:15])(=O)=O>ClC(Cl)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([C:9]([Cl:15])=[O:10])=[C:6]([Cl:8])[N:7]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Solvent: CC(Cl)Cl
Product: O=C(Cl)c1c(Cl)nc(Cl)nc1Cl
Temperature: 60 °C

Procedure:
To the subtitle product of step i) (5.0 g) in dichloroethane (25 ml) was added aza-bis-isobutyronitrile (25 mg) and the mixture heated to 60° C. Sulfuryl chloride (3.67 g) was then added and the reaction heated at 75° C. for 4 h. The same amount of aza-bis-isobutyronitrile (4×25 mg) and sulfuryl chloride (4×3.36 g) was added for 4 days on each day interval. The solvent was evaporated to give a yellow oil which was distilled under reduced pressure to yield the subtitle compound as a yellow oil. Yield 5.8 g.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([NH:22][NH2:23])=[O:21])=[CH:18][CH:17]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:23][NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:27])[F:26])=[CH:25][CH:24]=1
Reactant: NNC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Yield: 57 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3dione in acetic acid was added 4-(trifluoromethoxy)benzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 135 mg of the title compound (57%) as a yellow solid in 99.7% purity by HPLC (Rt: 6.39, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:25]([OH:27])[CH3:26].C(N(CC)C(C)C)(C)C.C(OC(N[C@@H]1CCN(CCO)C[C@@H]1C(OC)=O)=O)C1C=CC=CC=1>ClCCl.CO>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:14][CH2:13][N:12]([CH2:26][CH2:25][OH:27])[CH2:11][C@H:10]1[O:15][CH3:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(O)Br
Reactant: CO[C@@H]1CNCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: COC(=O)[C@H]1CN(CCO)CC[C@H]1NC(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CO[C@@H]1CN(CCO)CC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Temperature: 70 °C
Yield: 66.7 %

Procedure:
A mixture of cis(±)N,N-dibenzyl-3-methoxypiperidin-4-amine (1.7 g, 5.5 mmol) (WO 2005/068461), bromoethanol (0.5 mL, 7.1 mmol), and N,N-diisopropylethylamine (1.4 mL, 8.3 mmol) were reacted as described for Intermediate 37, but heating for one hour at 70° C. Chromatography on silica gel with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide gave 1.3 g (68%) of product as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:15])([CH3:14])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(N)cc1
Reaction time: 0.25 h

Procedure:
A solution of ethyl 2-(4-aminophenyl)-2-methylpropanoate (30 mg, 0.145 mmol) in THF (1 mL) was treated with LiAlH4 (1M solution in THF, 0.226 mL, 0.226 mmol) at 0° C. and stirred for 15 min. The reaction was treated with 0.1N NaOH, extracted with EtOAc and the organic layers were dried over Na2SO4. The solvent was removed under reduced pressure to yield 2-(4-aminophenyl)-2-methylpropan-1-ol (G-2), which was used without further purification: 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=8.5 Hz, 2H), 6.67 (d, J=8.5 Hz, 2H), 3.53 (s, 2H), 1.28 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([CH2:14]Cl)[CH:13]=1>>[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([CH2:14][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[CH:13]=1
Reactant: Cc1ncc[nH]1
Reactant: ClCc1cncc(Br)c1
Product: Cc1nccn1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates B-1 [B], 2-methyl-imidazol has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as a light brown solid. MS: 251.9, 254.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@H:18](O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1C(COC(/N=N\C(OCC2C=CC(Cl)=CC=2)=O)=O)=CC=C(Cl)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@@H:18]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: O=C(/N=N\C(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cncc(Br)c2)C1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-7, 5-bromopyridin-3-ol was reacted with (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as a white solid. MS: 343.1 and 345.1 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([N:12]2[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:17][C@@H:14]1[CH2:15][CH2:16][N:12]([C:3]2[C:2]([C:22]3[CH:23]=[N:18][CH:19]=[N:20][CH:21]=3)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=2)[CH2:13]1
Reactant: OB(O)c1cncnc1
Reactant: COC(=O)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
(R)-Methyl 5-bromo-6-(3-hydroxypyrrolidin-1-yl)nicotinate (Stage 170.3, 930 mg, 3.1 mmol) and pyrimidin-5-ylboronic acid (765 mg, 6.2 mmol) were dissolved in a solution of DME (5 mL) and EtOH (0.7 mL). A solution of 2 M Na2CO3 (4.63 mL, 9.26 mmol) was added, the mixture was flushed with argon, Pd(PPh3)2Cl2 (260 mg, 0.371 mmol) was added and the RM was stirred at 95° C. in a pressure safe vial for 1.5 h. After cooling at RT, the RM was treated with brine and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue that was purified by flash chromatography (RediSep® Silica gel column, (DCM/MeOH 98:2)/MeOH, from 0 to 5% MeOH) a treated with Si-Thiol (1 g) in MeOH to afford the title compound as a grey foamy powder. HPLC (Condition 4) tR=2.95 min, UPLC-MS (Condition 7) m/z=301.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][C:13]([C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])=[C:12]3[NH:24][C:25]2[CH:26]=[N:27][N:28]([CH:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)[CH:29]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][C:13]([C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])=[C:12]3[NH:24][C:25]2[CH:26]=[N:27][N:28]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:29]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5ccc(O)c(Cl)c5)cc34)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cnc2ccc(-c3ccc(O)c(Cl)c3)cc2c1Nc1cnn(C2CCNCC2)c1)C1CC1
Yield: 55.3 %

Procedure:
Following general procedure A-2, tert-butyl 4-(4-((6-(3-chloro-4-hydroxyphenyl)-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.10 mmol) was reacted with TFA (2 mL) to afford the desired product (27 mg, 55% over 2 steps) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.12 (s, 1H), 8.18 (d, J=2.2 Hz, 1H), 8.02-7.96 (m, 1H), 7.92-7.86 (m, 2H), 7.45 (d, J=2.3 Hz, 1H), 7.41 (s, 1H), 7.28-7.22 (m, 1H), 7.01 (d, J=8.5 Hz, 1H), 4.24-4.14 (m, 1H), 3.06-2.99 (m, 2H), 2.94-2.85 (m, 1H), 2.62-2.53 (m, 2H), 1.95-1.89 (m, 2H), 1.83-1.71 (m, 2H), 1.02-0.97 (m, 4H). ESI MS m/z 488 [C27H26ClN5O2+H]+; HPLC>99% (AUC), tR=9.30 min.
Reaction SMILES: [CH3:1][CH:2]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[CH3:13].II.[Br:22]Br.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][CH:2]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([Br:22])=[CH:8][C:7]=1[CH3:13]
Reactant: BrBr
Reactant: Cc1ccc(C)c(OCCC(C)CCCC(C)C)c1
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(OCCC(C)CCCC(C)C)c(C)cc1Br
Temperature: 0 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
Into a 300 ml four-necked flask was placed 31.68 g (0.12 mol) of 1-(3,7-dimethyloctyloxy)-2,5-dimethylbenzene and 10 ml of chloroform and 0.21 g (0.8 mmol) of iodine, and the flask was purged with nitrogen while stirring and the mixture was cooled to 0° C. Bromine in an amount of 19.18 g (0.12 mol) was added dropwise over 1 hour while keeping the temperature not more than 5° C. After addition, the mixture was heated to 30° C. and kept at the same temperature for 5 hours to complete the reaction. The mixture was cooled to room temperature, and the reaction mixture was added into 200 ml of a 5% sodium hydroxide aqueous solution. The mixture was stirred for 10 minutes, then, separated and extracted. The chloroform layer was washed with 200 ml of water, and the organic layer was dried over sodium sulfate. It was concentrated by an evaporator and the resulting residue was purified by column chromatography to obtain 1-(3,7-dimethyloctyloxy)-2,5-dimethyl-4-bromobenzene. The yield amount was 30 g (87.9 mmol) and the yield was 73%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([O-:11])(=[O:10])=[O:9])[N:3]=1.[Na+]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[N:3]=1
Reactant: O=S(=O)([O-])c1cccc(Cl)n1
Agent: Cl
Agent: [Na+]
Product: O=S(=O)(O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Into 0.82 g (3.8 mmol) of sodium 2-chloropyridine-6-sulfonate prepared in accordance with Example 1, 10 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature overnight. Then, the solvent was distilled off, and after an addition of 200 ml of 2-propanol, the residue was heated. Insoluble matters were removed by filtration, and the filtrate was distilled under reduced pressure to obtain 710 mg (96.6%) of 2-chloropyridine-6-sulfonic acid as crystalline solid. Purification was conducted by recrystallization from 2-propanol.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[CH2:4][N:3]1[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1.[ClH:29]>C(OCC)(=O)C>[ClH:29].[NH:19]1[CH2:20][CH2:21][CH:16]([CH2:15][CH2:14][N:3]2[C:2](=[O:1])[C:10]3[CH:9]=[C:8]4[O:11][CH2:12][O:13][C:7]4=[CH:6][C:5]=3[CH2:4]2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2Cc3cc4c(cc3C2=O)OCO4)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1c2cc3c(cc2CN1CCC1CCNCC1)OCO3
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a reaction vessel, 15 g (0.039 mol) compound XII and 300 ml 10% solution of hydrogen chloride in ethyl acetate were added, the reaction mixture was kept at room temperature for 30 min until the reaction was complete, concentrated to dry under reduced pressure, recrystallized with the mixed solution of ethanol and ethyl acetate, and 10.5 g compound II-2 was obtained, with yield of 84.3%. 1H NMR (D2O): δ 1.38-1.49 (m, 2H), 1.59-1.61 (m, 3H), 1.98 (d, 2H, J=13.5 Hz), 2.91-2.98 (m, 2H), 3.42 (d, 2H, J=12.8 Hz), 3.49 (t, 2H, J=7.0 Hz), 4.13 (s, 2H), 5.97 (s, 2H), 6.72 (s, 1H), 6.76 (s, 1H); MS (ESI): m/z 289 [M−Cl]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:20]C1C=CC=CC=1>>[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:20][CH2:7][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(Nc2ccccc2)c1C
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Product: Cc1cccc(NCc2cccc([N+](=O)[O-])c2)c1C

Procedure:
Starting with 3-nitrobenzaldehyde (0.50 g) and 2,3-dimethylphenylaniline (0.40 mL) the method described in Step 3. of Example 1 was used to prepare the above compound. NMR (300 MHz, CDCl3) δ 8.25 (1H, s), 8.12 (1H, d, J=7 Hz), 7.72 (1H, d, J=7 Hz), 7.50 (1H, t, J=8 Hz), 6.95 (1H, t, J=8 Hz), 6.62 (1H, d, J=7 Hz), 6.36 (1H, d, J=7 Hz), 4.50 (2H, s), 4.09 (1H, s), 2.30 (3H, s), 2.13 (3H, s).
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.Cl.[O:9]1[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[N:10]1.C(N(C(C)C)C(C)C)C>C(O)C>[O:9]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:2]2[CH2:6][S:5][C:4](=[O:7])[N:3]=2)=[N:10]1
Reactant: O=C1NC(=S)CS1
Reactant: NCc1ccon1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C1N=C(NCc2ccon2)CS1
Yield: 49.5 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (700 mg) in ethanol (20 mL) were added (isoxazol-3-ylmethyl)amine hydrochloride (707 mg) and N-ethyl-N-(1-methylethyl)propan-2-amine (1.42 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated, the residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the obtained powder was washed with ethyl acetate to give the title compound (513 mg).
Reaction SMILES: COC1C=C([C:11](=O)[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]3CCC[C@H:18]3[CH2:17]2)=O)C=CC=1OC.C(OC(N1CCCCC1C(O)=O)=O)(C)(C)C.[CH3:42][O:43][C:44]1[CH:56]=[CH:55][C:47]([C:48]([CH2:50][CH2:51][C:52]([OH:54])=O)=[O:49])=[CH:46][C:45]=1[F:57]>>[F:57][C:45]1[CH:46]=[C:47]([C:48](=[O:49])[CH2:50][CH2:51][C:52]([N:19]2[CH2:20][CH2:21][N:16]3[CH2:14][CH2:13][CH2:12][CH2:11][CH:17]3[CH2:18]2)=[O:54])[CH:55]=[CH:56][C:44]=1[O:43][CH3:42]
Reactant: COc1ccc(C(=O)CCC(=O)N2CCN3CCC[C@H]3C2)cc1OC
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1F
Agent: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Product: COc1ccc(C(=O)CCC(=O)N2CCN3CCCCC3C2)cc1F

Procedure:
12 mg of the title compound were prepared as described for 1-(3,4-dimethoxyphenyl)-4-((S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl)butane-1,4-dione, using 1-(tert-butoxycarbonyl)piperidine 2 carboxylic acid instead of BOC-protected proline and 3-(4-methoxy-3-fluorobenzoyl)propanoic acid instead of 3-(3,4-dimethoxybenzoyl)propionic acid.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].CN(C=O)C.[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[O:3]=[C:2]([CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:1]=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=CC(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
Phenylpyruvic acid (25.0 g, 152.0 mmol) was coevaporated twice with dry pyridine and then redissolved in dry pyridine (250 mL). To this solution was added acetic anhydride (170 mL, 1.8 moles) and the solution was stirred at ambient temperature for 15 h. The reaction progress was monitored by TLC. When the reaction was complete, the solution was evaporated to a viscous syrup. The syrup was dissolved in dichloromethane (700 mL) and then washed three times with 0.1 M aqueous HCl solution (3×200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to an amber-colored syrup. This product was purified by flash chromatography on silica gel (250 g) using dichloromethane as mobile phase. Appropriate fractions were pooled and evaporated to afford 24 g of a dry solid. This material was dissolved in THF (150 mL) and the solution was cooled in an ice-water bath. To the solution was added dropwise oxalyl chloride (51 mL, 580 mmol). After 10 min DMF (7.5 mL) was added to the reaction mixture and the reaction was stirred for 4 h at 0° C. Toluene (100 mL) was added and the reaction mixture was evaporated to give a thick oil. This material was coevaporated twice with toluene and the crude product was dried under vacuum for 5 h. The dried product was dissolved in a 1:1 mixture of THF-dichloromethane (200 mL) and the solution was cooled to −78° C. (dry ice-isopropanol bath) under argon. Then, lithium tri-tert-butoxyaluminohydride (152 mL of a 1.0 M solution in THF, 152 mmol) was added at a rate such that the internal temperature of the reaction was below −60° C. After addition was complete, the reaction was stirred below −60° C. for 10 h. The reaction was quenched by the slow addition of 2 M aqueous HCl solution (100 mL) and the mixture was allowed to warm to ambient temperature. The reaction mixture was diluted with dichloromethane (500 mL) and then washed twice with 0.1 M aqueous HCl solution (2×100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to give an amber-colored syrup. This material was purified by flash chromatography on silica gel (250 g) starting with 95:5 heptane-ethyl acetate, then with 9:1 heptane-ethyl acetate as mobile phase. Appropriate fractions were pooled and evaporated to afford 13.5 g (80%) of the desired compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:16]([NH:20][CH2:21][C:22]1[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:24]([CH3:35])[CH:23]=1)[CH2:17][CH2:18][CH3:19].C(N(CC1C=CC(OCC(OCC)=O)=C(C)C=1)C1C(C)=C(C2C=CC(OC)=CC=2)N=CN=1)CCC>>[CH2:16]([N:20]([CH2:21][C:22]1[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:24]([CH3:35])[CH:23]=1)[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Reactant: Cc1c(Cl)ncnc1-c1ccc(Cl)cc1
Agent: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(OC)cc2)c1C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(Cl)cc2)c1C

Procedure:
Prepared from 4-chloro-6-(4-chlorophenyl)-5-methylpyrimidine and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate using the procedure of Intermediate 67.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3].[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[N:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH:26]=O)=[CH:19][CH:18]=1.COC1C=CC(NC2C(C=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=CC=CN=2)=CC=1.Cl>CO>[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[C:25]([CH:26]=[CH:1][C:2]([C:4]3[CH:5]=[C:6]([O:14][CH3:15])[C:7]([O:12][CH3:13])=[C:8]([O:10][CH3:11])[CH:9]=3)=[O:3])=[CH:28][CH:29]=[CH:30][N:31]=2)=[CH:19][CH:18]=1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=Cc1cccnc1Nc1ccc(F)cc1
Agent: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CO
Product: COc1cc(C(=O)C=Cc2cccnc2Nc2ccc(F)cc2)cc(OC)c1OC
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a solution of 3,4,5-trimethoxyacetophenone (194 mg, 0.925 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 ml) and stirred for 5 minutes followed by the addition of 2-(4-fluorophenylamino)nicotinaldehyde (200 mg, 0.925 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (6aj) (340 mg, 90% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[CH2:13]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:30])[C:27](O)=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C>[CH2:13]([CH:20]1[CH2:21][CH2:22][N:23]([C:26](=[O:30])[C:27]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=3[CH:12]=2)=[O:28])[CH2:24][CH2:25]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Solvent: CCOCC
Product: O=C1COc2ccc(NC(=O)C(=O)N3CCC(Cc4ccccc4)CC3)cc2N1

Procedure:
The title compound is prepared from 6-amino-4H-benzo[1,4]oxazin-3-one and (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) according to the method described in Example 1c. Melting Point: 186-187° C. (diethylether)