Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=1[C:37](=[O:41])[C:38]#[C:39][CH3:40]>>[CH3:40]/[C:39](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:38]/[C:37](=[O:41])[C:30]1[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:29]=1[F:28]
Reactant: CC#CC(=O)c1cc(F)c(F)cc1F
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: C/C(=C/C(=O)c1cc(F)c(F)cc1F)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 12) from 677 mg (1.85 mmol) of Intermediate 45 and 366 mg (1.85 mmol) of Intermediate 38 to yield 482 mg (46% yield) of Example 16. TLC (DCM/MeOH (4:1): Rf=0.55; 1H NMR (DMSO-d6, 300 MHz) δ11.39 (d, 1H, J=8.9), 7.86 (m, 2H), 7.69-7.59 (m, 1H), 7.54-7.40 (m, 4H), 7.10 (d, 2H, J=8.5), 6.79 (d, 2H, J=8.5), 5.3 (s, 1H), 4.12 (t, 2H, J=6.5), 4.1 (m, 1H), 3.16 (m, 1H), 2.86 (t, 2H, J=6.5), 2.76 (dd, 1H, J=13.7, 8.9), 2.3 (s, 3H), 1.64 (s, 3H): low resolution MS (ES+)m/e 565.1 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:13])=[C:4]([C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(OC)(C)(C)C>[OH:1][C:2]1[C:3]([CH3:13])=[C:4]([C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1)=[O:6]
Reactant: Cc1c(O)cc(O)c(C)c1C(=O)O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Product: Cc1c(O)cc(O)c(C)c1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.3 %

Procedure:
To a solution of 91.1 g of 3,5-dihydroxy-2,6 -dimethylbenzoic acid and 108.0 g of p-nitrobenzyl bromide were added 165.9 g of potassium carbonate. The mixture was heated at reflux under stirring for 4 hours. After cooling to room temperature, the mixture was filtered, and the unsoluble material was washed with 0.5 l of ethyl acetate. The filtrate was diluted with 0.5 l of ethyl acetate and washed with ice-cold 3N hydrochloric acid and with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. To the remaining, crystallizing oil were added 0.6 1 of tert-butylmethylether, and the suspension was stirred for 1 hour. Unsoluble material was filtered off and the filtrate was evaporated in vacuo. The remaining oil was dissolved in 300 ml of methylene chloride. Upon crystallization, 200 ml of hexane were added and the crystals isolated by filtration. This material was suspended once more in 400 ml of tert-butylmethylether and the unsoluble material was removed by filtration. Evaporation of the filtrate in vacuo and crystallization of the residue from methylene chloride/hexane afforded 98.8 g of p-nitrobenzyl 3,5-dihydroxy-2,6-dimethylbenzoate as yellow crystals of m.p. 164°-166° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1([C:11]#[N:12])[CH2:10][CH2:9][CH2:8]1)=O.B.C1COCC1.C(N=[N+]=[N-])CCCCCCCC>O1CCCC1>[NH2:12][CH2:11][C:7]1([CH2:5][NH:4][CH2:3][CH2:2][NH2:1])[CH2:10][CH2:9][CH2:8]1
Reactant: N#CC1(C(=O)NCCN)CCC1
Agent: B
Agent: CCCCCCCCCN=[N+]=[N-]
Solvent: C1CCOC1
Product: NCCNCC1(CN)CCC1
Temperature: -2.5 °C

Procedure:
To compound 2 (5.37 g, 0.083 mol) under N2, tetrahydrofuran (THF, 50 ml) was added by syringe. The mixture was cooled to −5 to 0° C., 1M BH3.THF (50 ml) added by syringe, and then the mixture gradually warmed up and brought to reflux for 36 h. Then the solution was evaporated, the residue dissolved in C2H5OH (100 mL) and 6N HCl (10 mL), and the resulting solution refluxed for 12 h. The solution was evaporated, the residue dissolved in 20 mL of distilled water, acidulated with HCl to pH 2 and the solution applied to an AG 50W×8 cation exchange resin column (200-400 mesh, H+ form, 100 mL of resin, 3.0 cm column diameter). The column was eluted first with H2O and then with a gradient HCl. The 3.5-4 N HCl solution containing the product was evaporated to dryness, yielding 2.98 g (50.0%). MS (ESI): m/z: 158.23 [M+H]+. Anal. Calcd (Found) for C9H19N3: C, 61.10 (60.83); H, 12.18 (12.41); N, 26.72 (26.36). 1H NMR (D2O, 400 MHz), δ (ppm): 3.39-3.33 (m, 4H, —NHCH2CH2NH2), 3.25 (s, 2H, —NH2CH2CCH2NH—), 3.16 (s, 2H, —NH2CH2CCH2NH—), 1.95-1.86 (m, 6H, —CCH2CH2CH2—). 13C NMR (D2O, 400 MHz), δ (ppm): 52.73, 45.51, 43.64, 38.32, 35.50, 26.64, 14.16.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:36]([NH2:39])([CH3:38])[CH3:37]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:39][CH:36]([CH3:38])[CH3:37])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)N
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CC(C)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (490 mg, 0.97 mmol) and isopropylamine (175 mg, 3.00 mmol) as starting materials.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:17][C:18]1[O:22][N:21]=[C:20]([C:23]([NH2:30])([CH3:29])[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[N:19]=1.Br>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH2:15][F:16])=[CH:6][C:7]([C:10]([NH:30][C:23]([C:20]3[N:19]=[C:18]([CH3:17])[O:22][N:21]=3)([CH3:29])[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCCF)c(C2CC2)cn1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Agent: Br
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCCF)c(C3CC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(2-fluoroethoxy)pyridine-2-carboxylic acid (example 146b) and 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-methylsulfonyl-propan-2-amine;hydrobromide (enantiomer B) (example 125b) as starting materials and isolated (56 mg, 59%); MS (ESI, m/z): 427.2 (M+H+).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][N:9]=1)(=O)C.O1CCCC1.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2ncccc2O)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ncc(Sc2ncccc2O)s1
Yield: 68.2 %

Procedure:
A mixture of 2-acetylamino-5-(3-hydroxypyridin-2-ylthio)thiazole (2 g) in a mixture of ethanol (40 ml), tetrahydrofuran (20 ml) and aqueous 6N-hydrochloric acid (13 ml) was refluxed for 5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8.5 using aqueous sodium bicarbonate and extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1). The organic layer was washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give 2-amino-5-(3-hydroxypyridin-2-ylthio)thiazole (1.15 g, yield: 68.9%). mp: 128°-130° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[N:2]=1.N1C=CC=CC=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(#N)C.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:2]=1
Reactant: Nc1cc2ccccc2cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1cc2ccccc2cn1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Isoquinolin-3-amine (300 mg, 2.08 mmol) was dissolved in acetonitrile. To the reaction mixture was added pyridine (0.20 mL, 2.50 mmol) and phenyl chloroformate (0.27 mL, 2.18 mmol), respectively and stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give phenyl isoquinolin-3-ylcarbamate (456 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH3:23])=[O:21].Cl>ClCCl>[CH3:23][O:22][C:20](=[O:21])[NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1
Reactant: COc1cccc2sc(N)nc12
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1nc2c(OC)cccc2s1
Reaction time: 0.17 h

Procedure:
2-Amino-4-methoxybenzothiazol (23.6 g, 131 mmol) and pyridine (12.6 ml, 157 mmol) in dichloromethane (230 ml) are slowly treated with methyl chloroformate (10.6 ml, 137 mmol) at 0° C. After 10 minutes, further methyl chloroformate (1.0 ml, 13 mmol) and pyridine (1.0 ml, 12 mmol) are added. After 10 minutes, the mixture is poured into 200 ml 1M aqueous hydrochloric acid, the organic layer is separated, diluted with dichloromethane (250 ml) and washed with brine (50 ml). The organic phase is dried and the solvent evaporated in vacuo. 31.0 g (99.4%) white solid. MS: m/e=238 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:22])([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[SH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[CH3:32].COC1C=CC(N)=C(C)C=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[S:21][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[CH3:32])([OH:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)ccc2S)CC1
Reactant: COc1ccc(I)c(C)c1
Agent: COc1ccc(N)c(C)c1
Product: COc1ccc(Sc2ccc(F)cc2C2(O)CCN(C(=O)OC(C)(C)C)CC2)c(C)c1

Procedure:
Prepared from 4-hydroxy-4-(2-mercapto-5-fluoro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester and 1-iodo-4-methoxy-2-methyl-benzene (prepared from 4-methoxy-2-methyl-phenylamine by diazotization according to the general procedure by Tunney and Stille J. Org. Chem. 1987, 52, 748-753).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([C:12]([O:14]CC)=O)=[CH:8][C:7]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:6]2)[CH2:3][CH2:2]1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>C1(C)C(C)=CC=CC=1>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([C:12](=[O:14])[NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:8][C:7]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[N:6]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CC2CC2)c1=O
Reactant: NCc1ccccn1
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2cc(C(=O)NCc3ccccn3)c(=O)n(CC3CC3)n2)cc1
Yield: 84.2 %

Procedure:
In xylene, 2-cyclopropylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 2-(aminomethyl)pyridine were reacted at 140° C. for 1 hour. Post-treatments were conducted as in Example 58-(3), whereby the title compound was obtained in a yield of 84.2%.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)[N:4]=1>C(Cl)Cl.O=[Mn]=O>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[N:5]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]=[O:19])=[CH:16][CH:17]=2)[N:4]=1
Reactant: OCc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Yield: 75.5 %

Procedure:
A solution of [4-(3,5-bis-trifluoromethyl-pyrazol-1-yl)-phenyl]-methanol (2 g) and MnO2 (excess) in DCM (30 mL) was stirred at room temperature for 24 hours. Solid materials were removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (SiO2, 4:1 hexane/EtOAc) to give 4-(3,5-bis-trifluoromethyl-pyrazol-1-yl)-benzaldehyde (1.5 g, 76% yield) as a colorless syrup.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:17](=O)[O:16]C(C)(C)[O:14][C:13]=2[CH:12]=[C:11]([O:22][CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:22][CH3:23])[CH:12]=[C:13]([OH:14])[C:18]=1[CH:17]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OCc2ccccc2)c2c(c1)OC(C)(C)OC2=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(O)c(C=O)c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
A solution of 5-(benzyloxy)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (Example 1B, 6.76 g, 21.5 mmol) in dichloromethane (120 mL) was cooled to −78° C. and treated with 43 mL (64.5 mmol) of a 1.5 M solution of diisobutylaluminum hydride in toluene added dropwise over 20 min. The resulting mixture was then stirred at −78° C. for 3 h. The reaction mixture was quenched by the careful addition of methanol (5 mL) added dropwise over 15 min, followed by 1N hydrochloric acid (50 mL) added dropwise over 15 min. The cooling bath was then removed and an additional 150 mL of 1N hydrochloric acid was added over 20 min. The mixture was then stirred at 22° C. for 2 h and diluted with dichloromethane (400 mL). The organic phase was collected and the aqueous phase (pH ˜1) was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residual oil was diluted with tetrahydrofuran (70 mL), treated with 10 mL of 0.1N hydrochloric acid and stirred at 20° C. for 2 h. The reaction mixture was diluted with ethyl acetate (300 mL), washed with brine, dried over anhydrous magnesium sulfate, evaporated in vacuo to give a clear oil. Chromatography on silica gel (4×13 cm, elution toluene) gave 4.08 g (73% yield) of the title aldehyde as a clear oil which solidified on standing. LC (Method C): 2.237 min. HRMS (ESI) calcd for C15H15O4 [M+H]+ m/z 259.0965. found 259.1153. 1H NMR (CDCl3, 600 MHz) δ 3.80 (s, 3H), 5.07 (s, 2H), 5.97 (d, J=2.1 Hz, 1H), 6.01 (d, J=2.1 Hz, 1H), 7.3-7.4 (m, 5H), 10.15 (s, 1H), 12.49 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([CH2:17][CH2:18]OS(C)(=O)=O)[CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:24]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([CH2:17][CH2:18][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:24]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(CCN3CCOCC3)ccc2Nc2cc(Cl)ccc21
Temperature: 50 °C

Procedure:
A mixture of Example 767A (360 mg, 0.98 mmol) in DMF (5 mL) was treated with morpholine (200 μL) and heated at 50° C. for 24 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by column chromatography on silica gel to provide the desired product. MS (ESI) m/e 358 (M+H)+; 1H NMR (300 MHz, DMSO-d.6 □ 9.84 (s, 1H), 7.97 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.91 (dd, J=8.5, 2.0 Hz, 1H), 6.81-6.89 (m, 3H), 3.55-3.58 (m, 4H), 2.57-2.62 (m, 2H), 2.37-2.45 (m, 6H).
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][CH:6]=2.[ClH:16]>>[Cl:16][C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][CH:6]=2
Reactant: CC(=O)c1cccc2nc(C)c(F)nc12
Reactant: Cl
Product: CC(=O)c1cccc2nc(C)c(Cl)nc12
Yield: 99 %

Procedure:
1-(3-Fluoro-2-methylquinoxalin-5-yl)ethanone (126g, 2.00 g, 9.79 mmol) was treated with HCl (4.0 M solution in 1,4-dioxane; 24.49 ml, 98 mmol), and the homogeneous reaction was fitted with a drying tube. After 6 h the reaction was concentrated in vacuo, and the solid was taken up in DCM. Solid NaHCO3 was added cautiously with rapid stirring; and saturated aq. NaHCO3 was sequentially added cautiously with rapid stirring. The mixture was partitioned between saturated NaHCO3 and DCM. The aq. layer was extracted with DCM (2×), and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 1-(3-chloro-2-methylquinoxalin-5-yl)ethanone (254a, 99% yield) as an orange-brown solid. MS (ESI, pos. ion) m/z: 221.0 (M+1).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)CCC>>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]4[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]4)[N:8]=3)=[CH:4][CH:3]=2)[CH:30]=1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)s3)n2)CC(C)(C)N1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Product: CC1(C)CC(Nc2nccc(-c3ccc(-c4cccnc4)s3)n2)CC(C)(C)N1
Yield: 38 %

Procedure:
The title compound was prepared as described for Example 25, using [4-(5-bromo-thiophen-2-yl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (Step C of Example 5) and 3-tributylstannylpyridine. Yield: 38%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cccc(N)c1
Yield: 100.4 %

Procedure:
A solution of 3-nitro-benzoic acid t-butyl ester (3.77 g, 16.9 mmol) in absolute ethanol (50 mL) was combined with palladium on carbon (10 wt %, 0.30 g) and hydrogenated under a baloon of hydrogen gas for appoximately 3 hrs. The reaction mixture was filtered through a pad of diatomaceous earth and then concentrated in vacuo to an oil which crystallized when dried under high vacuum providing 3.28 g of the title compound as a tan solid. 1H NMR (300 MHz, CDCl3) d 7.38 (d, 1H, J=8.0 Hz), 7.29 (m, 1H), 7.19 (m, 1H), 6.83 (m, 1H), 1.58 (s, 9H); low resolution MS (Cl) m/e 194 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[N:15]([CH3:23])[C:14]2=[O:24])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Na].Cl[C:27]1C=CC(N2C(=O)C3CCCCC=3N(C)C2=O)=CC=1C(O)=O.C(Br)(C)C>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[N:15]([CH3:23])[C:14]2=[O:24])=[CH:9][C:3]=1[C:4]([O:6][CH:7]([CH3:27])[CH3:8])=[O:5]
Reactant: Cn1c2c(c(=O)n(-c3ccc(Cl)c(C(=O)O)c3)c1=O)CCCC2
Reactant: CCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)ccc1Cl
Agent: [Na]
Solvent: CC(C)Br
Product: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)ccc1Cl

Procedure:
using ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate via the sodium salt of the corresponding carboxylic acid and isopropyl bromide there is obtained isopropyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 148°-150° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:14]([O:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1)[CH2:15][CH2:16][CH3:17].O>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:20][CH:21]=2)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)O)cc1
Reactant: CCCCOc1ccc(O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCOc1ccc(C(=O)Oc2ccc(OCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
30.0 g of PPE, 5.00 g (28.1 mmol) of the compound (12) and 4.40 g (28.9 mmol) of p-butoxyphenol were dissolved in 100 ml of chloroform under an argon gas atmosphere and the whole was stirred at room temperature overnight. After addition of water to the reaction mixture, the whole was extracted with methylene chloride. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 8.30 g of p-butoxyphenyl p-allyloxybenzoate (13) (yield: 94.6%).
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17].[CH3:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][C:29](=[O:35])[NH:30]2.N1CCCCC1>C(O)C>[OH:1][C@@H:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][C:12](/[CH:15]=[C:28]3\[C:29](=[O:35])[NH:30][C:31]4[C:27]\3=[C:26]([CH3:25])[CH:34]=[CH:33][CH:32]=4)=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CCC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cccc2c1/C(=C/c1[nH]c3c(c1C)C(=O)N(C[C@@H](O)CN1CCOCC1)CCC3)C(=O)N2
Temperature: 45 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (40 mg, 0.12 mmol 1) and 4-methyl-1,3-dihydro-indol-2-one (18 mg, 0.12 mmol) were dissolved in 1.5 ml of ethanol, and added with 6 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred at 45° C. for 16 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (1 ml×2) and dried to obtain the title compound (S,Z)-5-(2-hydroxy-3-morpholinopropyl)-3-methyl-2-((4-methyl-2-oxoindolin-3-ylidene)methyl)-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 83 (35 mg, yield 63.6%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])[CH:2]=[CH2:3].[BH4-].[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:9])[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CCOc1cccc(CO)c1
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a solution of 3-allyloxybenzaldehyde (7.2 g) in methanol (50 ml) at 0° C. was added sodium borohydride (1 g) in portions. The mixture was stirred for 30 minutes, evaporated dissolved in 5% acetic acid and extracted with diethyl ether (3×100 ml) , washed with water (2×100 ml), and sodium bicarbonate (2×100 ml), dried (magnesium sulphate), filtered and evaporated to give 3-allyloxybenzyl alcohol (7.26 g).