Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(#N)C.[BrH:15].N([O-])=O.[Na+]>O.[Cu]Br>[Br:15][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Br
Reactant: Nc1c(F)cccc1C(=O)O
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cccc(F)c1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
In a 1 L, three necked flask fitted with a dropping funnel and thermometer, were charged 2-amino-3-fluorobenzoic acid (20.0 g, 0.13 mol) and acetonitrile (160 mL). After cooling to 0° C., HBr (47%, 160 mL) was added drop wise over 10 min. To the resulting solution a solution of NaNO2 (10.0 g, 0.14 mol) in water (20.0 mL) was added drop wise over 1 h. After addition, the reaction mixture was stirred at 0° C. for 5 min, and copper(I) bromide (22.0 g, 0.15 mol) was added portionwise over 30 min. Stirring was continued at 70° C. in a an oil bath for 1 h. After cooling to 0° C., 700 mL of water was added and the precipitate was filtered, washed with cold water and dried under vacuum to give 28.23 g (100%) of the title compound as a white solid. The crude product was used in the next step without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1.[NH3:17].C1COCC1>S(Cl)(Cl)=O.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([NH2:17])=[O:16])[CH2:10][CH2:9]1
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2ccccn2)CC1
Reactant: N
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: NC(=O)[C@H]1CC[C@@H](Nc2ccccn2)CC1
Reaction time: 1 h

Procedure:
cis-4-(pyridin-2-ylamino)cyclohexanecarboxylic acid (0.22 g, 1.00 mmol) was dissolved in thionyl chloride (2 ml) at room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to yield the crude acid chloride, which was added to liquid ammonia/THF (1:1, 15 ml) and allowed to stir at room temperature. The reaction mixture was diluted with DCM and filtered. The filtrate was concentrated under reduced pressure to afford 100 mg of cis-4-(pyridin-2-ylamino)cyclohexanecarboxamide as off white solid.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=1[F:18].[Cl-].[NH4+].[CH3:21][C:22]([CH3:24])=[O:23]>>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH2:21][C:22](=[O:23])[CH3:24])=[CH:12][C:11]=1[F:18]
Reactant: CC(C)=O
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(=O)CC(O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
Proline (23 mg, 0.20 mmol) was added to a solution of 4-chloro-3-fluorobenzaldehyde (159 mg, 1.00 mmol) in acetone (2.5 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then treated with saturated ammonium chloride. After partitioning, the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:4) to afford 4-(4-chloro-3-fluorophenyl)-4-hydroxybutan-2-one (160 mg, 73% yield) as a solid. 1H NMR (500 MHz, CDCl3) δ 7.36 (m, 1H), 7.19 (m, 1H), 7.06 (m, 1H), 5.13 (t, J=6.5 Hz, 1H), 3.43 (br s, 1H), 2.82 (d, J=6.5 Hz, 1H), 2.21 (s, 3H).
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](=[O:36])[CH3:35].[OH-].[Na+].O>C(O)C>[O:36]=[C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[NH2:27])/[CH:35]=[CH:13]/[C:9]1[N:8]([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=[CH:11][N:10]=1
Reactant: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1C(=O)/C=C/c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.2 %

Procedure:
1-Triphenylmethyl-2-imidazole carbaldehyde (4) (25.0 g, 74 mmol) and 2'-aminoacetophenone (10.0 g, 74 mmol) were suspended in 700 ml of ethanol, and a 25% aqueous solution (120 ml) of sodium hydroxide was added to the suspension, The mixture was stirred at room temperature for 12 hours. Water (3,000 ml) was added to the resultant reaction mixture, and crystals deposited were collected by filtration, washed with water and dried. The thus-obtained crystals were recrystallized from ethanol to obtain 17.6 g (yield: 52%) of 2-[(E)-3-oxo-3-(2-aminophenyl)-1-propenyl]-1-triphenylmethylimidazole.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](Cl)=[N:9]2)=[CH:4][CH:3]=1.[CH3:13][N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([C:17]3[CH:16]=[N:15][N:14]([CH3:13])[CH:18]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1cnc2ccc(Br)cc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2cnc3ccc(Br)cc3n2)cn1
Yield: 89.4 %

Procedure:
7-bromo-2-chloro-quinoxaline (502 g; 2.06 mol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (450.42 g; 2.16 mol), triphenylphosphine (10.82 g; 0.041 mol) and palladium(II)acetate were added to a mixture of sodium carbonate (240.37 g; 2.267 mol), 1,2-dimethoxyethane (5.48 L) and water (1.13 L). The reaction mixture was stirred at reflux for 20 hours, then 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (42.9 g; 0.206 mol) was added and the reaction mixture refluxed until complete conversion (4 hours). The reaction mixture was poured out in water, stirred for 2 hours at room temperature, filtered and the precipitate was washed with water. The precipitate was then triturated in methanol and filtered. The precipitate was washed with methanol and dried to give 532.2 g (89%) of 7-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-quinoxaline (off-white powder).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:5][CH:4]=1.[OH:14]O>C1C=CC=CC=1>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:5][CH:4]=1)=[O:14]
Reactant: CSc1ccc(-n2cnnn2)cc1
Reactant: OO
Solvent: c1ccccc1
Product: CS(=O)c1ccc(-n2cnnn2)cc1

Procedure:
1-[p-(Methylthio)phenyl]-1H-tetrazole (2 g.) and 0.9 ml. of 30% hydrogen peroxide were refluxed with stirring in benzene for 3 hours. The benzene was decanted and the precipitate washed with benzene and recrystallized from acetone, m.p. 175°-176° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[NH:5][C@@H:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[CH2:7][N:8]=[N+]=[N-])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[NH:5][C@@H:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=1)[CH2:7][NH2:8])[CH3:2]
Reactant: CCOC(=O)N[C@H](CN=[N+]=[N-])c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N[C@H](CN)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.3 %

Procedure:
To a solution of (S)-[2-azido-1-(3-trifluoromethyl-phenyl)-ethyl]-carbamic acid ethyl ester (4.60 g, 15.2 mmol) in EtOH (200 mL) is added 10% Pd/C (˜200 mg). The resulted mixture is then degassed and filled with H2 and stirred at room temperature under H2 for 14 h. The mixture is then filtered through a pat of Celite to remove the Pd/C and washed with EtOH (3×10 mL). The filtrate is concentrate to provide the crude (S)-[2-amino-1-(3-trifluoromethyl-phenyl)-ethyl]-carbamic acid ethyl ester (˜4.0 g, 95%), which is used for next step without further purification.
Reaction SMILES: COC[O:4][CH:5]1[CH2:8][C:7]([C:14]2[N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[N:16][N:15]=2)([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:6]1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:16]1[N:15]=[C:14]([C:7]2([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][CH:5]([OH:4])[CH2:8]2)[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:17]=12
Reactant: COCOC1CC(c2cccs2)(c2nnc3n2CCCCCC3)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1CC(c2cccs2)(c2nnc3n2CCCCCC3)C1
Temperature: 25 °C
Reaction time: 21 h
Yield: 71.6 %

Procedure:
3-[3-(Methoxymethoxy)-1-(2-thienyl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (6.14 g) was dissolved in methylene chloride (125 ml) and then trifluoroacetic acid (25 ml) was added thereto, followed by stirring at room temperature for 21 hours. The reaction solution was subjected to evaporation under reduced pressure and the resulting residue was diluted with a 1M aqueous sodium hydroxide solution (100 ml), followed by extraction with chloroform (100 ml×2). The organic layer was dried over anhydrous sodium sulfate, and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting solid washed with diethyl ether to obtain 3.84 g of 3-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocin-3-yl)-3-(2-thienyl)cyclobutanol (white solid).
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[CH2:3][C@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:5][O:6][C:7]1[C:8]([CH:23]=[CH2:24])=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1.[H][H]>[Pd].CO.C(OCC)(=O)C>[CH2:23]([C:8]1[C:7]([O:6][CH2:5][C@@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:3][CH:2]([CH3:1])[CH3:33])=[CH:22][C:11]2[N:12]([CH3:21])[C:13](=[O:20])[C:14]3[C:19]([C:10]=2[CH:9]=1)=[CH:18][CH:17]=[N:16][CH:15]=3)[CH3:24]
Reactant: [H][H]
Reactant: C=Cc1cc2c3ccncc3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1cc2c3ccncc3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Yield: 40.1 %

Procedure:
A mixture of (S)-tert-butyl (4-methyl-1-((6-methyl-5-oxo-9-vinyl-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.15 g, 0.332 mmol) and palladium on carbon (0.075 g, 0.070 mmol) in MeOH (3 mL) and ethyl acetate (3 mL) was stirred at RT under a balloon of hydrogen gas for 24 h. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure. The residue was purified by prep TLC (60% ethyl acetate and petroleum ether) to afford (S)-tert-butyl (1-((9-ethyl-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan 2-yl)carbamate (0.11 g, 0.133 mmol, 40% yield) as a yellow semi solid. LC/MS (ESI) m/e 454.4, [(M+H)+, calcd for C26H36N3O4, 454.3]; LC/MS retention time (method D): tR=0.96 min.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([C:24]2[N:25]=[C:26]([NH:29][C:30](=[O:32])[CH3:31])[S:27][CH:28]=2)=[O:23])=[CH:17][CH:16]=1)=[O:11])[NH:2]C(OC(C)(C)C)=O.O1CCOCC1.[ClH:39]>ClCCl>[ClH:39].[C:30]([NH:29][C:26]1[S:27][CH:28]=[C:24]([C:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][O:12][C:10]([NH:1][NH2:2])=[O:11])=[CH:20][CH:19]=2)=[O:23])[N:25]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Nc1nc(C(=O)Oc2ccc(CCOC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)Nc1nc(C(=O)Oc2ccc(CCOC(=O)NN)cc2)cs1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.1 %

Procedure:
To a suspension of 2-[4-({[2-(acetylamino)-1,3-thiazol-4-yl]carbonyl}oxy)phenyl]ethyl tert-butyl hydrazine-1,2-dicarboxylate (371.6 mg, 0.800 mmol) in anhydrous dichloromethane (4 ml) was added 4M hydrogen chloride dioxane solution (4 ml). After stirring at room temperature for 2.5 hr, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. The operation was performed twice to remove hydrogen chloride gas azeotropically. The residue was suspended in a mixture of ethanol (5 ml) and ethyl acetate (30 ml), and the suspension was filtered. The filtered product was washed twice with ethyl acetate and dried under reduced pressure to give the title compound (317.7 mg, 0.793 mmol, yield 99.1%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24](OS(C(F)(F)F)(=O)=O)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])(O)=O.[Na+]>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.COCCOC>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:38]3[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1
Reactant: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C)c1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(-c3ccncc3)cc2)c(C)c1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
A mixture trifluoromethanesulfonic acid 4-[2-methyl-4-(2,4,6-trimethylphenylamino)-pyrimidine-5-sulfonyl]-phenyl ester (72 mg, 0.14 mmol), prepared by the method described in Example 22, pyridine-4-boronic acid (34 mg, 0.28 mmol), 2 M Na2CO3 (1.0 mL, 2.0 mmol) and DME (2 mL) was deoxygenated with N2 for 10 min, and then Pd(PPh3)2Cl2 (20 mg, 0.028 mmol) and PPh3 (15 mg, 0.056 mmol) were added. The mixture was heated at reflux under N2 for 2 h and then cooled to room temperature. Saturated aqueous NaHCO3 was added, and the mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (50:50 hexanes/EtOAc) to provide the desired product (38 mg, 61%) as a white solid: mp 232–234° C.; 1H NMR (500 MHz, CDCl3) δ 8.79 (s, 1H), 8.73 (d, J=4.5 Hz, 2H), 8.28 (br s, 1H), 8.13 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.48 (d, J=4.5 Hz, 2H), 6.92 (s, 2H), 2.40 (s, 3H), 2.31 (s, 3H), 2.03 (s, 6H); APCI MS m/z 445 [(M+H)+, calcd for C25H25N4O2S, 445.2].
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[S:21][C:12]=2[N:13]=[C:14]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[O:20]1[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:23]=[C:22]([C:24]([F:26])([F:27])[F:25])[S:21][C:12]=3[N:13]=2)=[CH:17][CH:18]=[N:19]1
Reactant: NCc1ccccc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(isoxazol-5-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-benzylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl-].C([Al+]CC)C.[C:7]12([C:17](Cl)=[O:18])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.[CH3:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH2:27][N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1.[OH-].[Na+]>CCCCCC.C(Cl)Cl>[CH3:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH2:27][N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:17]([C:7]23[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]4)[CH2:8]2)[CH2:14]3)=[O:18])=[CH:29]1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CN1CCCCC1Cn1ccc2ccccc21
Agent: CC[Al+]CC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: CN1CCCCC1Cn1cc(C(=O)C23CC4CC(CC(C4)C2)C3)c2ccccc21

Procedure:
To the stirring solution of the diethyl aluminum chloride (1.5 ml 1 M soln. in hexane, 180.8 mg, 1.5 mmol) in 10 ml absolute methylene chloride was added at room temp. 298.0 mg (1.5 mmol) 1-adamantanecarbonyl chloride in 5 ml of methylene chloride and the reaction mixture was stirred 15 min. The solution of (N-Methyl-2-piperidinyl)methyl-1H-indole (228.3 mg, 1.0 mmol) in 5 ml of methylene chloride was added during 3 min and mixture was stirred and reflux 48 h. The reaction was work-up by addition of 20 ml 2M solution of sodium hydroxide and extracted by ethyl acetate (3×20 ml), washed to times by water and two times by brine. The combined extract dried by the mixture of sodium sulfate and potassium carbonate. After removing of solvents the rest was purified by chromatography (silica gel, methanol ethyl acetate 1:1).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][NH2:24])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([CH3:25])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26](OCC)=[O:27]>ClCCl>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][NH:24][CH:26]=[O:27])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([CH3:25])[CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(c1)c1c(OCCN)cccc1n2Cc1ccccc1
Reactant: CCOC=O
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(OCCNC=O)cccc1n2Cc1ccccc1
Temperature: 62 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A mixture of 2-[(9-benzyl-6-methyl-9H-carbazol-4-yl)oxy]ethylamine (0.2974 g, 0.90 mmol), dichloromethane (4 mL) and ethyl formate (4 mL) is heated at 62° C. Additional dichloromethane (6 mL) and ethyl formate (6 mL) are added. After 4 h, the mixture is concentrated to dryness and the residue is chromatographed on silica gel (100 mL) using methanol/dichloromethane (4/96). The resulting solids are recrystallized from ethyl acetate/dichloromethane/hexane to give 0.2716 g (84%) of the title compound; 1H NMR (CDCl3) δ2.55, 3.94, 4.36, 5.48, 6.11, 6.64, 6.99, 7.11, 7.24, 7.32, 8.06, 8.28.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].Br[CH2:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]2[S:25][C:24]3[N:26]=[CH:27][CH:28]=[N:29][C:23]=3[N:22]([CH2:30][O:31][CH3:32])[C:21]=2[CH:33]=1)=[O:16]>C(O)C.O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]2[S:25][C:24]3[N:26]=[CH:27][CH:28]=[N:29][C:23]=3[N:22]([CH2:30][O:31][CH3:32])[C:21]=2[CH:33]=1)=[O:16]
Reactant: Nc1ccccn1
Reactant: COCN1c2cc(C(=O)CBr)ccc2Sc2nccnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COCN1c2cc(C(=O)CNc3ccccn3)ccc2Sc2nccnc21
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To 3 ml of a solution of 140 mg of 2-aminopyridine in ethanol was added 130 mg of sodium hydrogencarbonate and the resulting mixture was stirred at room temperature. Next, 2 ml of a solution of 360 mg of bromomethyl(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)ketone in tetrahydrofuran was dropped thereinto and the resulting mixture was heated under reflux for 2 hours. Then the reaction mixture was brought back to room temperature and silica gel was added thereto. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 200 mg of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.[CH3:13][O:14][C:15](=[O:19])[CH:16](Br)[CH3:17]>C1COCC1.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9]([C:8]([CH:16]([CH3:17])[C:15]([O:14][CH3:13])=[O:19])=[CH:7][CH2:6]2)=[CH:10][CH:11]=1
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: COC(=O)C(C)Br
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)C(C)C1=CCc2cc(OC)ccc21
Temperature: 25 °C
Yield: 44.8 %

Procedure:
In an oven dried 3-neck 5.0 L flask fitted with a condenser, a thermometer, and an addition funnel was charged under argon, 5-methoxy-1-indanone (86.73 g, 0.52 mol) and THF (2.13 L). The mixture was stirred at rt and became an orange-colored solution. To this were added zinc granules (59.96 g, 0.92 mol, 30 mesh). The mixture was heated to ˜50° C. with simultaneous addition of a solution of methyl-2-bromopropionate (88.80 g, 0.79 mol) in THF (393 mL). The reaction mixture was heated for a period of 20 h, after which heating was stopped and the reaction mixture cooled to rt followed by cooling on an ice bath. The mixture was then slowly quenched with HCl (3.3 L, 1 N aqueous solution) maintaining the internal temperature at ˜18° C. The aqueous layer was extracted with EtOAc (3×500 mL). The organic layer was then washed with water (4×500 mL, a pH of ˜4.5 achieved), brine (500 mL), and dried over Na2SO4. The solvent was removed under vacuum to give a dark brown colored oil. The crude product was purified by silica gel chromatography (1-8% EtOAc/hexane gradient) to give 54.09 g (52%) of the title compound as a dark brown oil. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (1H, d), 7.09 (1H, s), 6.87 (1H, dd), 6.24 (1H, s), 3.82 (1H, q), 3.75 (3H, s), 3.58 (3H, s), 3.30 (2H, s), 1.21 (3H, d); LC-MS: RT=3.00 min, (M+H)+:233.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[Li+].[CH3:19]C([N-]C(C)C)C.IC>C1COCC1>[CH3:1][O:2][C:3]([C@:5]1([CH3:19])[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)[C@]1(C)[C@H](O)CCN1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
To a solution of (2S,3R)—N-tert-butyloxycarbonyl-3-hydroxy-2 pyrrolidinecarboxylic acid methyl ester (1D) (1.13 g, 4.61 mmol) in THF (73 mL) at −78° C. was slowly added a 1.8 M solution of LDA (7.70 mL, 13.86 mmol). After stirring for 1 h, iodomethane (2.87 mL, 46.10 mmol) was added, and the reaction was stirred for 1 h at −78° C., before warming gradually to −20° C. for 3 h, and then was stored at −40° C. overnight. After quenching with saturated aqueous NH4Cl, water and EtOAc were added and the layers were separated. The organic layer was washed with brine, and the aqueous layer was extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified using preparative HPLC (Luna C-18, 21.2×250 mm, eluting with 50-90% solvent B (A=90% H2O-10% MeOH and B=10% H2O-90% MeOH) over 30 min; Flow rate at 10 mL/min. UV detection at 220 nm) to provide a mixture of the starting material and its epimer as a yellow oil (490 mg) and the title compound as a yellow oil (362 mg); LC/MS m/z 260 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C@@H:6]([C:9]([NH:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[O:10])[CH2:7][OH:8])=[O:4].[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:8][CH2:7][C@H:6]([C:9]([NH:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[O:10])[NH:5][C:3](=[O:4])[C:2]([F:18])([F:1])[F:19])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NCc1nccs1)[C@@H](CO)NC(=O)C(F)(F)F
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H](NC(=O)C(F)(F)F)C(=O)NCc1nccs1
Temperature: 25 °C
Reaction time: 14 h
Yield: 92 %

Procedure:
To a solution of 1.965 g of the above-obtained 2-[(N-trifluoroacetyl-D-seryl)amino]methylthiazole in 20 ml of pyridine was added 2 ml of acetic anhydride. The mixture was stirred at room temperature for 14 hours, and then concentrated to dryness under reduced pressure. The residue was dissolved in 50 ml of methylene chloride, and the solution was washed with 30 ml of a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with 30 ml of methylene chloride. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 2.07 g (yield 92%) of 2-[(O-acetyl-N-trifluoroacetyl-D-seryl)amino]methylthiazole. NMR (CDCl3) d: 2.05 (3H, s), 4.36-4.41 (1H, m), 4.77-4.85 (2H, m), 7.33 (1H, d, J=3.3 Hz), 7.42-7.52 (1H, br), 7.6-7.7 (1H, br), 7.72 (1H, d, J=3.3 Hz) MS (EI, CHCl3, 160° C.): 339 (M+)