Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][C:6]([C:8]1[S:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:7].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.[Hg]>[CH3:1][Si:2]([CH3:14])([CH3:15])[CH2:3][CH2:4][O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][Br:16])=[CH:11][CH:12]=1)=[O:7]
Reactant: Cc1ccc(C(=O)OCC[Si](C)(C)C)s1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Hg]
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)CCOC(=O)c1ccc(CBr)s1

Procedure:
A solution of the title A compound, 5-methyl-thiophene-2-carboxylic acid 2-trimethylsilanyl-ethyl ester (34.15 g, 141 mmol) in CCl4 (200 mL) is treated with N-bromosuccinimide (NBS, 25.08 g, 141 mmol) and 2,2′-azobisisobutyronitrile (1.0 g, 6 mmol). The mixture is irradiated with a 450 W mercury lamp for 3 h. An additional 2.5 g of NBS is added and the mixture is further irradiated for 2 h. The mixture is filtered through Celite and a plug of silica gel. The solvent is evaporated to give 5-bromomethyl-thiophene-2-carboxylic acid 2-trimethylsilanyl-ethyl ester as a yellow liquid.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Al](C)C.[F:14][C:15]1([F:22])[CH2:21][CH2:20][CH2:19][CH:18]2[CH:16]1[O:17]2.[F-].[Na+]>ClCCl>[F:14][C:15]1([F:22])[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[C@@H:16]1[OH:17]
Reactant: FC1(F)CCCC2OC21
Reactant: C[C@@H](N)c1ccccc1
Agent: C[Al](C)C
Agent: [F-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](N[C@@H]1CCCC(F)(F)[C@H]1O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A solution of (1R)-1-phenylethanamine (30, 72 mL, 0.57 mol) in dichloromethane (200 mL) was cooled to 0° C. and treated with trimethylaluminum (260 mL, 0.52 mol) and the resulting solution was stirred for 1 hour at 0° C. To this solution was added a solution of 2,2-difluoro-7-oxabicyclo[4.1.0]heptane (66 g, 0.49 mol) in dichloromethane (200 mL) and the resulting mixture stirred at 0° C. for 3 hours. The reaction was then warmed to ambient temperature for 16 hours. The reaction was cooled to 0° C., treated with 103 g of sodium fluoride and then quenched with water (90 mL, slow addition). The reaction was warmed to ambient temperature, the solids filtered and the solution evaporated in vacuo. Purification by flash chromatography (50-100% ethyl acetate in hexanes) gave 36.3 g (29%) of (1S,6R)-2,2-difluoro-6-{[(1R)-1-phenylethyl]amino}cyclohexanol 31 (plus 32 g of 1R,6S diastereomer) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.32 (5H, s), 3.90 (1H, q, J=6.6 Hz,), 3.39 (1H, ddd, J=19.8, 9.8, 4.2 Hz), 2.70 (1H, m), 2.11 (1H, m), 1.80 (1H, m), 1.62 (2H, m), 1.43 (1H, m), 1.36 (3H, d, J=6.6 Hz), 0.96 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[C:10](N)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12](O)=[O:13]>Cl>[O:13]1[C:10]2=[CH:9][CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]2[N:1]=[CH:12]1
Reactant: O=CO
Reactant: Nc1cccc(C(=O)O)c1N
Agent: Cl
Product: O=C(O)c1cccc2ocnc12
Yield: 76 %

Procedure:
A mixture of 2,3-diaminobenzoic acid (0.5 g, 3.29 mmol) and formic acid (405 μl, 9.87 mmol) in hydrochloric acid (4M, 10 ml) was heated under reflux for one hour. The precipitate which formed on cooling was collected, redissolved in boiling methanol, and decolorised with activated charcoal. Evaporation of the solvent gave benzoxazole-4-carboxylic acid as a white powder (407.9 mg, 77%)
Reaction SMILES: NCC[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=2)[NH:6][CH:5]=1.OC1C=C2C(=CC=1)NC=C2.C([O-])([O-])=O.[K+].[K+].BrC(CCCC)CC1C=CC=CC=1>CC(=O)CC.C(Cl)Cl>[C:20]1([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[NH:6][CH:5]=[CH:4]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCc1c[nH]c2ccc(OCCCCCCc3ccccc3)cc12
Agent: CCCCC(Br)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: Oc1ccc2[nH]ccc2c1
Solvent: CCC(C)=O
Solvent: ClCCl
Product: c1ccc(CCCCCCOc2ccc3[nH]ccc3c2)cc1
Temperature: 25 °C

Procedure:
Synthesis of 3-(2-aminoethyl)-5-(6-phenylhexyloxy)indole was based on the protocols of example 1. A stirred mixture of 5-hydroxyindole (0.5 g, 3.8 mmol), anhydrous K2CO3, (2-bromohexyl)benzene, and a catalytic amount of KI in 2-butanone (40 ml) was heated at reflux overnight under nitrogen. After allowing to cool to room temperature, the reaction mixture was filtered, the filtrate concentrated under reduced pressure to give an oil. The oil was taken up in CH2Cl2 (50 ml) and washed successively with 2N-NaOH (1×20 ml) and water (1×20 ml). The organic portion was dried (MgSO4) and the solvent was removed under reduced pressure to give an oil. The oil was purified by column chromatography using a solvent system of CH2Cl2 /Hexane (40:60) to give 5-(6-phenylhexyloxy)indole as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.[NH:43]1[CH2:46][CH2:45][CH2:44]1>C1COCC1>[N:43]1([CH2:31][C@H:28]2[CH2:29][CH2:30][C@H:25]([C:8]3[N:4]4[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]4=[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:12]=4)[N:9]=3)[CH2:26][CH2:27]2)[CH2:46][CH2:45][CH2:44]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](c3nc(-c4cccc(OCc5ccccc5)c4)c4c(N)nccn43)CC2)cc1
Reactant: C1CNC1
Solvent: C1CCOC1
Product: Nc1nccn2c1c(-c1cccc(OCc3ccccc3)c1)nc2[C@H]1CC[C@H](CN2CCC2)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
General procedure to Examples 33 and 34: A THF solution (3 mL) of trans-toluene-4-sulfonic acid 4-[8-amino-1-(3-benzyloxy-phenyl)imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl ester (200 mg, 0.34 mmol) in a sealed tube was charged with azetidine (8.92 mmol, 510 mg) and stirred at 50° C. for 24 h. The reaction mixture concentrated in vacuo and partitioned b/w EtOAc and sat. NaHCO3. The organic layer was washed with sat. NaHCO3 (2×), water (1×), brine (1×), dried over Na2SO4, filtered, and concentrated to a yellow oil. The crude material was purified by silica gel column chromatography [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 to 2% ˜7 N NH3 in MeOH/CH2Cl2] to afford trans-3-(4-azetidin-1-ylmethyl-cyclohexyl)-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-8-ylamine as a white solid (130 mg, 82%).
Reaction SMILES: [CH:1]([O:3][CH:4]=[CH2:5])=[CH2:2].[CH3:6][O:7][C:8](=[O:15])[CH2:9][C:10]1CCCC=1.C([O-])(=O)C.[Na+].C(OO)(=O)C>C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:6][O:7][C:8](=[O:15])[CH2:9][CH:10]1[CH2:2][CH:1]2[O:3][CH:4]2[CH2:5]1
Reactant: C=COC=C
Reactant: COC(=O)CC1=CCCC1
Agent: CC(=O)OO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)CC1CC2OC2C1
Temperature: 35 °C
Yield: 66.5 %

Procedure:
Preparation of a vinyl ether compound having the formula: ##STR48## A) 43.46 g (0.31 mol) of cyclopentenylacetic acid methyl ester are dissolved in 80 ml of chloroform. After the addition of 4 g of sodium acetate, 82.51 g of a 40% solution of peracetic acid in acetic acid are added dropwise thereto, with stirring, the temperature being maintained at about 35° C. The reaction mixture is then stirred for a further 5 hours at 35° C. The reaction mixture is extracted with 5% sodium hydrogen carbonate solution and then twice with water. The organic phase is then separated off and dried and residual peroxide is destroyed with sodium sulfite. After distillation of the organic phase there are obtained 32.3 g of 3,4-epoxycyclopentylacetic acid methyl ester (66.5% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([CH2:13][CH3:14])([O-:12])=[O:11].N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:13](/[N+:10]([O-:12])=[O:11])\[CH3:14])=[CH:4][CH:3]=1
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: C/C(=C\c1ccc(Cl)cc1)[N+](=O)[O-]
Reaction time: 8 h
Yield: 58 %

Procedure:
A solution of 4-chlorobenzaldehyde (28.57 g, 203 mmol), nitroethane (44.0 mL, 610 mmol) and piperidine (4.01 mL, 40.6 mmol) in toluene (200 mL) was stirred at reflux (Dean-Stark) for 6 h and the mixture was stored at room temperature overnight. The solvent was removed under reduced pressure and the product was recrystallised from absolute EtOH. The crystals were filtered off, washed with a small amount of absolute EtOH and dried to give 23.25 g of the desired product. The mother liquor was concentrated, heated, cooled. Another batch of crystals was filtered off, washed with a small amount of absolute EtOH and dried in vacuo, to afford 3.95 g of the desired product. Total yield: 27.20 g (68%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@H:14]([C:27]([N:29]([CH2:39][C:40]1[C:41]2[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=2[S:43][CH:44]=1)[C@@H:30]([CH3:38])[CH:31]([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34])=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>>[S:43]1[CH:44]=[C:40]([CH2:39][N:29]([C@@H:30]([CH3:38])[CH:31]([O:32][CH2:33][CH3:34])[O:35][CH2:36][CH3:37])[C:27](=[O:28])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:41]2[CH:48]=[CH:47][CH:46]=[CH:45][C:42]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CCNC(=O)NN(C)CC(=O)O
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N(Cc1csc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 50 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-((benzo[b]thiophen-3-ylmethyl)((S)-1,1-diethoxy-propan-2-yl)amino)-6-oxohexylcarbamate (Compound IV-15) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH2:22][NH:23][C:24](=[O:30])[NH:25][CH2:26][CH2:27][CH2:28]Cl)=[CH:4][C:3]=1[F:31].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][NH:25][C:24]2=[O:30])=[CH:4][C:3]=1[F:31]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)NCCCCl)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN2CCCNC2=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 114.8 %

Procedure:
To a solution of tert-butyl (6R,7R)-7-(4-chloro-3-fluorophenyl)-6-({[(3-chloropropyl)carbamoyl]amino}methyl)-1,4-oxazepane-4-carboxylate (531 mg) in DMF (22 mL) was added sodium hydride (48.8 mg, 60% in oil) under ice-cooling, and the mixture was stirred at 0° C. for 2 hr. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (563 mg).
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].CS([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[O:20])[CH2:14][CH2:13]1)(=O)=O>>[CH2:1]([S:4]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)=[O:20])[CH2:14][CH2:13]1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Yield: 63 %

Procedure:
Propylsulfonyl chloride (70 mg, 0.487 mmol) was reacted with PTU (70 mg, 0.244 mmol) as the same manner as the synthesis of 1-(1-(methylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (60 mg, 0.153 mmol, 63% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.77 (s, 1H), 7.57 (s, 4H), 6.38 (d, J=7.5 Hz, 1H), 3.63 (m, 1H), 3.52 (d, J=12.4 Hz, 2H), 3.08 (m, 4H), 1.90 (d, J=9.6, 2H), 1.70 (m, 1H), 1.43 (m, 2H), 0.99 (t, J=7.2 Hz, 3H).
Reaction SMILES: CC(S([NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH2:19])=[O:18])[CH:12]=1)[CH2:9][CH3:10])=O)(C)C.Cl>CO>[NH2:7][C@H:8]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH2:19])=[O:18])[CH:12]=1)[CH2:9][CH3:10]
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1ccnc(C(N)=O)c1
Agent: Cl
Solvent: CO
Product: CC[C@H](N)c1ccnc(C(N)=O)c1
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a solution of 4-[(S)-1-(2-Methyl-propane-2-sulfinylamino)-propyl]-pyridine-2-carboxylic acid amide (5.50 g) in methanol (50 mL) was added hydrochloric acid (4 N in dioxane, 4.3 mL, 17.3 mmol) and the mixture was stirred for 2 h. Additional hydrochloric acid (4 N in dioxane, 0.5 mL, 2.0 mmol) was added. The mixture was stirred for another 1.5 h. The mixture was concentrated to remove methanol and then diluted with ethyl acetate (400 mL), washed with sat. sodium bicarbonate solution, The aqueous layer was extracted with ethyl acetate (4×100 mL). the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give 4-((S)-1-Amino-propyl)-pyridine-2-carboxylic acid amide (3.50 g, 100%)
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:21][O:20][C:16]([CH:17]=[CH:18][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)=[O:19]
Reactant: COC(=O)c1cc(C(=O)OC)c(Br)cn1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1cnc(C(=O)OC)cc1C(=O)OC

Procedure:
500 mg of dimethyl 5-bromo-pyridine-2,4-dicarboxylate (from Example 3) are heated at 140° C. in an autoclave with 10 ml of methyl acrylate, 0.5 ml of triethylamine, 11 mg of palladium diacetate and 22 mg of triphenylphosphine for 14 hours. After cooling, the mixture is diluted with ethyl acetate, the solid is filtered off and the solvent is evaporated together with the excess methyl acrylate. The product is chromatographed (silica gel) to give 330 mg of a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1.Cl.[NH2:20][CH2:21][C:22]1[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:20][CH2:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][N:23]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1
Reactant: Cc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccc(-c2nc(N)nc(NCc3ncc(C(F)(F)F)cc3Cl)c2C#N)o1

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, 2-aminomethyl-3-chloro-5-(trifluoromethyl)pyridine hydrochloride and DBU in DME. ES-MS m/e (%): 411 (M{37Cl}+H+, 45), 409 (M{35Cl}+H+, 100).
Reaction SMILES: C([NH:11][C@H:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(OCC1C=CC=CC=1)=O.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:11][C@H:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)[C@H](CCc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H](N)CCc1ccccc1

Procedure:
A solution of (N-carbobenzyloxy)-(L)-homophenylalanine, tert-butyl ester (100 mg, 0.281 mmol) in anhydrous ethanol (2 mL) and anhydrous ethyl acetate (2 mL) was degassed and the reaction flask filled with hydrogen. 10% Palladium on carbon catalyst (25 mg) was added and the mixture was hydrogenated under a balloon of hydrogen at room temperature for 2.3 hr. The catalyst was removed by filtration through a pad of celite, and solvent was removed from the filtrate by rotoevaporation. After pumping under reduced pressure at room temperature, the material thus obtained (homogeneous by TLC in 4/1 hexane/ethyl acetate) was used in the subsequent reaction without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[CH2:22]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH2:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:21])[CH2:6][CH2:7]2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: CCc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCc1ccc(CNC2CCN(CCn3c(=O)cnc4ccc(F)cc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5 mL of a chloroform solution containing 301 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 143 mg of 4-ethylbenzaldehyde, 60 μL of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 352 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=1:1], to give 1-(2-(4-(4-ethylbenzylamino)piperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one as pale yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]4[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=4[C:12]=3[CH3:13])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(C)O2
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: Cc1c(C)c(N2CCN(c3ccc(F)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 27.2 %

Procedure:
By using 5-bromo-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran (269 mg, 0.999 mmol) synthesized in Reference example 4 and 1-(4-fluorophenyl)piperazine (541 mg, 3.00 mmol), the reaction was carried out in the same manner as Example 21 to synthesize the title compound 100 mg (yield 27%). Melting point was 175 to 177° C. (hexane).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:18]Br.CO>>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([Br:18])=[CH:4][CH:3]=1
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: BrBr
Solvent: CO
Product: Nc1ccc(Br)c2c1C(=O)c1ccccc1C2=O

Procedure:
halogenating said compound (B) by diluting the reaction mixture with a protic solvent and introducing a bromine/methanol mixture at -20° to +70° C. to give 1-amino-4-bromo-anthraquinone (C),
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.Br.Br[CH2:11][C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=O.ClCCl.C(N(CC)CC)C.[OH-].[Na+]>Cl[Ti](Cl)(Cl)Cl.C(Cl)(Cl)Cl>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:11]=[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:1]=2)[CH:4]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: Nc1ccc(F)cn1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Br
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc2nc(-c3cccnc3)cn2c1
Temperature: 110 °C

Procedure:
2-Amino-5-fluoropyridine (0.048 g, 0.427 mmol), 3-bromoacetylpyridine hydrobromide (0.10 g, 0.356 mmol) and chloroform (3.56 mL) were added to a microwave vial. To the resulting solution were added a solution of TiCl4 in dichloromethane (1.0 M, 0.267 mL, 0.267 mmol) and triethylamine (0.030 mL, 0.214 mmol). The reaction was then heated in a microwave at 110° C. for 30 minutes. The resulting mixture was poured into aqueous sodium hydroxide solution (1.0 N) and extracted with ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (50% to 100% ethyl acetate in hexanes) provided the title compound: LCMS m/z 214.09 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.13 (d, J=1.7 Hz, 1H), 8.59-8.58 (m, 1H), 8.29-8.28 (m, 1H), 8.10 (t, J=2.9, 2.9 Hz, 1H), 7.95 (s, 1H), 7.63 (dd, J=9.9, 5.1 Hz, 1H), 7.40 (dd, J=7.9, 5.0 Hz, 1H), 7.18-7.14 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([C@@H:12]2[CH2:16][C@H:15]([N:17]([CH3:19])[CH3:18])[CH2:14][N:13]2[CH3:20])=O)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.CC(C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C@H:12]3[N:13]([CH3:20])[CH2:14][C@@H:15]([N:17]([CH3:19])[CH3:18])[CH2:16]3)=[N:9][N:8]=2)[CH:7]=1
Reactant: CN(C)[C@H]1C[C@@H](C(=O)NNc2ccc(F)cn2)N(C)C1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CN(C)[C@H]1C[C@@H](c2nnc3ccc(F)cn23)N(C)C1
Temperature: 60 °C
Yield: 80.3 %

Procedure:
A solution of Intermediate 38b (1.73 g, 6.15 mmol) in THF (40 mL) was treated with triphenyl phospine (3.22 g, 12.3 mmol) and TEA (3.43 mL, 24.6 mmol). Hexachloroethane (2.91 g, 12.3 mmol) was added to the solution portion wise over a period of 5 minutes. The reaction mixture was heated at 60° C. for 16 hours. The reaction mixture was cooled down, treated with acetone to precipitate the triethylammonium chloride, which was then filtered; the filter cake was washed abundantly with acetone and the solvent was evaporated under reduced pressure. The residue was purified by SCX-2 cartridge eluting with DCM (40 mL), MeOH (40 mL) and 2M NH3 in MeOH (40 mL). The product containing fractions were evaporated under reduced pressure to give the title compound as a brown oil (1.3 g, 80%). 1H NMR (300 MHz, d6-DMSO): 201-2.13 (1H, m), 2.2 (3H, s), 2.29 (6H, s), 2.31-2.33 (1H, m), 2.34-2.39 (1H, m), 2.51-2.61 (1H, m), 2.88-2.98 (1H, m), 3.31-3.39 (1H, dd), 3.50 (1H, s), 4.17-4.27 (1H, m), 7.14-7.24 (1H, m), 7.67-7.77 (1H, m), 9.00-9.07 (1H, m).