Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16](F)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]([NH:31][C@@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35])[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](N)C(O)C(C)C
Reactant: CC(C)n1cnc2c(NCc3ccccc3)nc(F)nc21
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC[C@H](Nc1nc(NCc2ccccc2)c2ncn(C(C)C)c2n1)C(O)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of benzyl-(2-fluoro-9-isopropyl-9H-purin-6-yl)-amine (40 mg, 1 eq, 0.14 mmol) in n-BuOH/DMSO (2.5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.24 mL, 4.9 eq, 1.38 mmol) followed by (3RS,4S)-4-amino-2-methyl-hexan-3-ol (39 mg, 2.12 eq, 0.30 mmol). The reaction mixture-was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×50 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with hexane:ether:MeOH (50:50:0→50:50:2) to afford the title compound as a white solid; Yield: 6.7 mg (12%). (50% de 45,3S: 50% de 4S,3R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.95-1.04 (m, 9H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 1.57 (d, 6H, J=6.79 Hz, —CH(CH3)2), 1.62-1.88 (m, 4H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 3.26-3.32 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 3.87-4.00 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 4.57-4.70 (m, 1H, —CH(CH3)2), 4.76-4.90 (m, 2H, —HNCH2-Bz), 5.25-5.55 (m, 1H NHCH(CH2CH3)CH(CH(CH3)2)OH), 7.26-7.45 (m, 6H, 5×Bz-H+HNCH2-Bz), 7.53 (s, 1H, —N═CH—N). FABMS m/z (relative intensity): 397 ([M+H]+, 95), 385 (20), 323 (100). Accurate Mass (M+H): Actual: 397.2716, Measured: 393.2724.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:20]=[C:19]([F:29])[CH:18]=2)=[CH:7][CH:6]=1.[OH:31][CH2:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:29][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:20]=1)[C:16]([NH:15][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([O:4][CH2:3][CH2:2][N:36]2[CH2:37][CH2:38][CH:33]([CH2:32][OH:31])[CH2:34][CH2:35]2)=[CH:6][CH:7]=1)=[O:30]
Reactant: O=C(Nc1ccc(OCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Reactant: OCC1CCNCC1
Product: O=C(Nc1ccc(OCCN2CCC(CO)CC2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from N-[4-(2-chloroethoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide and 4-hydroxymethylpiperidine according to conditions described in general procedure N. 1H NMR 300 MHz (CDCl3) 8.32(dd, 1H, J=1.5 and 8.4 Hz), 7.88(s, 1H), 7.83(d, 1H, J=8.4 Hz), 7.73(d, 1H, J=8.1 Hz), 7.54(m, 2H), 7.31(s, 1H), 6.98(d, 1H, J=8.4 Hz), 6.84(d, 1H, J=7.8 Hz), 6.76(d, 1H, J=11.7 Hz), 4.32(t, 2H, J=5.7 Hz), 3.51(d, 2H, J=6.3 Hz), 3.28(m, 4H), 3.1(m, 2H), 2.99 (t, 2H, J=5.7 Hz), 2.23(dt, 2H, J=2.7 and 11.4 Hz), 1.32-1.8(m, 11H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].C(N(CC)CC)C.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:26]1.[I-].[Na+]>CN(C)C=O>[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([N:34]2[CH2:35][CH2:36][N:37]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[C:12]5[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=45)[S:5]3(=[O:17])=[O:16])[CH2:38][CH2:39]2)=[N:26]1
Reactant: c1ccc2c(N3CCNCC3)noc2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCN(c2noc3ccccc23)CC1
Temperature: 20 °C
Yield: 26.9 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.3 g), triethylamine (3 cc) and 4-(1,2-benzisoxazol-3-yl)piperazine (4 g) and sodium iodide (3 g) in dimethylformamide (60 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on silica gel, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (22 cc), 2-{2-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2.3 g) is obtained m.p. 148° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([CH2:30][CH3:31])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26]C)=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>CCO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([CH2:30][CH3:31])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([OH:26])=[O:25])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(CC)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Solvent: CCO
Product: CCCCc1ccc(C#Cc2ccc(CN(CC)c3ccc(F)c(C(=O)O)c3)cc2)cc1

Procedure:
The title compound was prepared following the procedure described in Example 23 step c) using methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}(ethyl)amino)-2-fluorobenzoate (293 mg, 0.66 mmol) in EtOH. The title compound was obtained as a white powder (258 mg, 91%). HPLC, Rt: 5.0 min (purity: 99.2%). LC/MS, M−(ESI): 428.0. 1H NMR (CDCl3) δ: 7.48 (d, J=7.9 Hz, 2H), 7.44 (d, J=7.9 Hz, 2H), 7.32 (m, 1H), 7.22 (d, J=7.9 Hz, 2H), 7.16 (d, J=7.9 Hz, 2H), 6.99 (dd, J=10.2, 9.4 Hz, 1H), 6.84 (m, 1H), 4.51 (s, 2H), 3.50 (q, J=6.8 Hz, 2H), 2.62 (t, J=7.6 Hz, 2H), 1.61 (m, 2H), 1.36 (m, 2H), 1.22 (t, J=6.8 Hz, 3H), 0.93 (t, J=7.4 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=O)[C:13]([O:15]CCCCCC)=O)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[NH2:23][C:24]1[C:33]([NH2:34])=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>C(O)CCCCC.CO>[OH:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13](=[O:15])[NH:34][C:33]3[CH:32]=[C:31]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]4=[CH:25][C:24]=3[N:23]=2)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]
Reactant: CCCCCCOC(=O)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: Nc1cc2ccccc2cc1N
Solvent: CO
Solvent: CCCCCCO
Product: O=c1[nH]c2cc3ccccc3cc2nc1-c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A solution of 1.07 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 696.3 mg of 2,3-diaminonaphthalene in 3 ml of 1-hexanol is heated to boiling under reflux for 3 hours. The reaction mixture is then cooled and diluted with methanol. The crude product is filtered under suction and recrystallized from N,N-dimethylformamide/water. There is obtained 3-(3,4-dihydroxy-5-nitrophenyl)-benzo[g]quinoxalin-2(1H)-one of m.p. >300°.
Reaction SMILES: Cl[Mg][CH2:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:5].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[C@@H:22]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C@@:23]([OH:27])([CH2:3][C:4](=[CH2:5])[CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:22]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Reactant: C=C(COc1ccccc1)C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(COc1ccccc1)C[C@]1(O)CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(chloromagnesio)-2-(phenoxymethyl)-1-propene in THF (0.91M, 3 ml) (Louw et. al., Tetrahedron, 48, 6087-6104, 1992, prepared from 2.74 mmol of 3-chloro-2-(phenoxymethyl)-1-propene) was slowly added to a solution of (2S)-1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Preparation 1) in THF (3 ml). The mixture was stirred at room temperature for 1 hours, then saturated aqueous ammonium chloride (20 ml) was added and the mixture was extracted with ethyl acetate (20 ml). The organic phase was washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (100:0 increasing to 80:20) to give the title compound. 1H NMR (360 MHz, CDCl3) δ7.48 (2H, d, J=6.9 Hz), 7.35-7.2 (6H, m), 6.9-6.88 (3H, m), 5.4 (1H, s), 5.15 (2H, d, J=13.7 Hz), 4.61 (2H, s), 4.11 (2H, m), 3.17 (1H, m), 2.66 and 2.59 (2H, AB d, J=14.0 Hz), 1.95 (2H, m), 1.79 (2H, m), and 1.36 (9H, s). m/z (ES+) 424 (M+1).
Reaction SMILES: [C:1]1([O:7][C:8]([C:10]2([Si](C)(C)C)[C:23]3[CH:22]=[C:21]([O:24][Si](C(C)(C)C)(C)C)[CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1>CC#N>[OH:24][C:21]1[CH:20]=[CH:19][C:18]2[O:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:8]([O:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])[C:23]=2[CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)C(C(=O)Oc1ccccc1)([Si](C)(C)C)c1ccccc1O2
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(Oc1ccccc1)C1c2ccccc2Oc2ccc(O)cc21
Temperature: 25 °C

Procedure:
A suspended mixture of 2-tert-butyldimethylsiloxy-9-trimethylsilyl-9-xanthene-carboxylic acid phenyl ester, 6 (570 mg, 1.13 mmole), in CH3CN (10 ml) and pyridine (2 ml) became a clear yellow solution after a brief stirring at room temperature. The mixture was treated with 20 drops of 48% HF from a pipette and stirred for 3 hrs at room temperature. The reaction mixture was quenched with dilute HCL solution, followed by two extractions with 30% EtOAc-hexanes. The combined organic layers were washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was dissolved in a minimum amount of 2% MeOH-CH2Cl2 and chromatographed on a silica gel column, eluting with CH2Cl2 to 2% MeOH-CH2Cl2. The relatively clean fractions were pooled and concentrated. The impure yellow product was further purified by trituration first with 5% EtOAc-hexanes followed by hexanes, yielding pure phenyl 2-hydroxy-9H-9-xanthene-carboxylate 7 ((173.5 mg, 48.3%) as a slightly yellow solid: mp 182-184° C.; 1H NMR (DMSO-d6): delta 7.33-7.40 (3H, m), 7.24 (1H, m), 7.13-7.17 (2H, m), 7.04 (1H, d, J=8.8 Hz), 6.95-6.98 (2H, m), 6.90 (1H, d, J=2.6 Hz), 6.78 (1H, dd, J=8.8, 2.6 Hz) and 5.40 (1H, s).
Reaction SMILES: [F:1][C@:2]12[CH:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][SH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1.[C:29]([NH:32][C@H:33]([C:38](O)=[O:39])[CH2:34][S:35][CH2:36][CH3:37])(=[O:31])[CH3:30]>>[C:29]([NH:32][CH:33]([CH2:34][S:35][CH2:36][CH3:37])[C:38](=[O:39])[S:18][CH2:17][C:16](=[O:19])[C@:15]1([OH:25])[C@:20]2([CH3:24])[C@H:12]([C@H:11]3[C@:2]([F:1])([C@@H:22]([OH:23])[CH2:21]2)[C@:3]2([CH3:28])[C:8](=[CH:7][C:6](=[O:27])[CH:5]=[CH:4]2)[CH2:9][CH2:10]3)[CH2:13][C@@H:14]1[CH3:26])(=[O:31])[CH3:30]
Reactant: CCSC[C@H](NC(C)=O)C(=O)O
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)C(O)C[C@]2(C)[C@@]1(O)C(=O)CS
Product: CCSCC(NC(C)=O)C(=O)SCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Yield: 29.5 %

Procedure:
The title compound (0.21 gm) was prepared from 9-fluoro-11 ,17-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-21-thiol (0.5 gm) and N-acetyl-S-ethylcysteine (0.70 gm) in the same manner as in Synthetic Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.Cl.[CH2:12]([O:14][NH2:15])[CH3:13].C(N(CC)CC)C>C(Cl)Cl.CCOCC>[CH2:12]([O:14][NH:15][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[S:10])[CH3:13]
Reactant: CCON
Reactant: Fc1ccc(N=C=S)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCONC(=S)Nc1ccc(F)cc1

Procedure:
4-Fluorophenyl isothiocyanate (306 mg, 2.0 mmol), O-ethyl hydroxylamine hydrochloride (585 mg, 6.0 mmol), and triethylamine (1.5 mL, 11.0 mmol) are stirred in CH2Cl2 (50 mL) for 2 h. The reaction mixture is diluted with ether, washed with water and 1 M HCl, dried (MgSO4), and concentrated. The residue is purified by column chromatography with hexane-EtOAc yielding a colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH:9]=1)(=O)[CH3:2].Cl.[NH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][CH:29]2[S:33][C:32](=[O:34])[NH:31][C:30]2=[O:35])=[CH:26][CH:25]=1>>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[N:19][O:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:28][CH:29]3[S:33][C:32](=[O:34])[NH:31][C:30]3=[O:35])=[CH:36][CH:37]=2)[CH3:2])=[CH:9][N:8]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(=O)c1ccc(OCc2ccccc2)nc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(OCc2ccccc2)nc1
Yield: 78 %

Procedure:
Following a procedure similar to that described in Example 40(f), 130 mg of 5-acetyl-2-benzyloxypyridine were reacted with 182 mg of 5-[4-(2-aminooxyethoxy)-benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure, to give 219 mg of the title compound, melting at 160°-161° C.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>C1COCC1.CCO>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:13](=[C:14]2[CH2:15][C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH2:19]2)[C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][CH:9]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)COc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(OCC(=O)O)cc2)CC(C)(C)C1
Yield: 92.7 %

Procedure:
A solution of ethyl({4-[(4-fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetate (10) (0.290 g, 0.68 mmol) in THF/EtOH (1:1, 8 mL) was treated with 1 N NaOH (4 mL) at 70° C. for 1 h. The reaction mixture was acidified with 20% aqueous HCl, and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure to afford the crude product. The product was purified by flash column chromatography with chloroform and methanol as an eluent to afford 0.250 g (95%) of the title compound 11 as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.19-7.14 (m, 2H), 7.13 (d, J=9.3 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.7 Hz, 1H), 6.84 (d, J=8.7 Hz, 2H), 4.63 (s, 2H), 1.93 (s, 2H), 1.88 (s, 2H), 1.27 (s, 2H), 0.90 (s, 12H). LCMS (ESI): m/z 395 (M−H)−.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C@H:11]([N:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:12].C([BH3-])#N.[Na+].Cl>C(O)C.CCCCCCC>[CH2:14]([NH:13][C@@H:11]([C:2]1[C:1]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:5]=[CH:4][CH:3]=1)[CH3:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[C@@H](N=Cc1ccccc1)c1ccc2ccccc2c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCCC
Product: C[C@@H](NCc1ccccc1)c1cccc2ccccc12
Temperature: 47.5 °C
Reaction time: 5.5 h

Procedure:
To a stirred solution of (1R)-1-(2-naphthyl)-N-(phenylmethylene) ethanamine (4, 10 g, 0.038 mol) in ethanol (200 mL) was added sodium cyanoborohydride (3.63 g, 0.057 mol) at 25-30° C. The reaction mass was further stirred at 45-50° C. for 5-6 h. Upon completion of the reaction (by TLC), the reaction mass was cooled, quenched with water (100 mL), and extracted with n-heptane (100 mL). The organic layer was separated, washed with water (100 mL), and concentrated under reduced pressure to provide a thick oil. The oil was dissolved in n-heptane (90 mL) and stirred, and the pH of the solution was adjusted to 1-2 using concentrated hydrochloric acid. The precipitated solid was filtered, washed with n-heptane (10 mL), and dried under vacuum to yield the title compound as a white crystalline solid. Yield: 8.2 g, (81.42%); HPLC purity: 99.10%; IR (KBr) cm−1: 3445, 2965, 2759, 2728, 2682, 1596, 1457, 1378, 801, 781, 779; MS: m/z=262.07 [M+H]+; 1H NMR (400 MHz, CDCl3): δ=1.73-1.75 (d, J=8.8 Hz, 3H), 3.95-3.99 (br dd, 1H), 4.16-4.19 (br dd, 1H), 5.24-5.26 (q, J=8.8 Hz, 1H), 7.38-7.39 (m, 3H), 7.48-7.50 (t, 2H), 7.57-7.59 (m, 2H), 7.64-7.66 (d, 1H), 7.98-8.03 (m, 3H), 8.08-8.11 (d, J=9.2 Hz, 1H), 9.72 (bs, 1H), 10.48 (bs, 1H). 13C NMR (100 MHz, CDCl3): δ=21.15 (CH3), 48.34 (CH2), 51.48 (CH), 121.35, 125.04, 125.9, 126.69, 128.52, 129.0, 129.11, 129.61, 130.21, 130.76, 132.11, 133.60.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]([CH2:24][CH2:25][NH:26]C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:17][CH:24]=[CH:25][N:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: c1ccc(NCCNc2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: c1ccc(-c2nccnc2-c2ccccc2)cc1
Temperature: 130 °C
Yield: 160.8 %

Procedure:
Bis-phenyl pyrazine was prepared by heating at 130° C. for 12 hrs a suspension of benzoin (Aldrich, 1.25 g) and 1,2 dianilinoethane (Aldrich, 2.13 g) in xylene (20 ml). The mixture was cooled to room temperature and was purified by column chromatography (silicagel, hexane:ethyl acetate, 95:5) to give 2.2 grams of pure bis-phenyl pyrazine as pale yellow solid. NMR: (CDCl3) 7.2-6.8 (20H, m) and 3.6 (4H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].C(N(CC)CC)C.[CH2:20]([C:28]1([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:40]2[CH:39]=[C:38]([C:41](Cl)=[O:42])[CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>ClCCCl.CCCCCCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([NH:6][NH:7][C:41]([C:38]1[CH:37]=[CH:36][C:35]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:40]=2[CH:39]=1)=[O:42])=[O:5]
Reactant: NNC(=O)c1cc(Cl)ccc1Cl
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C(=O)Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CCCCCCC
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C(=O)NNC(=O)c3cc(Cl)ccc3Cl)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2,5-Dichlorobenzohydrazide (one equivalent) and triethylamine (one equivalent) were warmed in 500 mL of 1,2-dichloroethane until the solid material had dissolved. On cooling, 9,9-dioctyl-9H-fluorene-2-carbonyl chloride (one equivalent) was added and the mixture stirred at RT for two days. The insolubles were filtered off and the filtrate evaporated to give an oil. This was taken up in heptane and the precipitated solid filtered off. The remaining solution was dried (MgSO4) and concentrated to give the desired intermediate.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1)(=[O:3])[CH3:2]
Reactant: Nc1cnccn1
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cnccn2)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 13.7 %

Procedure:
To a stirred solution of 75 mg (0.261 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 37 mg (0.392 mmol) of aminopyrazine was added. The resulting mixture was stirred at room temperature during 3 days and the final product was collected by filtration and washed with diethylether to yield the title compound (12 mg, 13.6% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([C:22](O)=[O:23])=[CH:8][CH:9]=1.[NH2:25][CH:26]([CH2:29][OH:30])[CH2:27][OH:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:28][CH2:27][CH:26]([NH:25][C:22]([C:7]1[CH:6]=[C:5]2[C:10]([S:11](=[O:20])(=[O:21])[NH:12][C:13]3[C:4]2=[CH:3][C:2]([Cl:1])=[C:19]2[C:14]=3[N:15]=[CH:16][CH:17]=[CH:18]2)=[CH:9][CH:8]=1)=[O:23])[CH2:29][OH:30]
Reactant: NC(CO)CO
Reactant: O=C(O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NC(CO)CO)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 34.1 %

Procedure:
In a similar fashion using route 54 general procedure 123, 12-chloro-6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid 524 (100 mg, 0.27 mmol), serinol (50 mg, 0.55 mmol), EDC.HCl (80 mg, 0.41 mmol), HOBt (56 mg, 0.41 mmol), TEA (0.12 ml, 0.11 mmol) and DMF (1 ml) gave the title compound (40 mg, 33%) after purification by column chromatography with chloroform/MeOH (90:10) as the eluent.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][C:5]([N+:13]([O-])=O)=[C:4]([F:16])[CH:3]=1>[Pd].C(O)C>[F:16][C:4]1[CH:3]=[CH:2][C:7]([O:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][C:5]=1[NH2:13]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Oc1ccc(F)c(N)c1
Reaction time: 3 h
Yield: 47.3 %

Procedure:
4-Chloro-5-methoxycarbonyloxy-2-fluoronitrobenzene (1.2 g, 4.8 mmol), (as described in EP 61741 A2), and 10% palladium-on-charcoal catalyst (500 mg) in ethanol (100 ml) was stirred under hydrogen at 1 atmosphere pressure for 18 hours. A further batch of 10% palladium-on-charcoal catalyst (500 mg) was added and the mixture stirred under hydrogen for a further 3 hours. The catalyst was removed by filtration through diatomaceous earth and the solvent removed from the filtrate by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/hexane (1/4) to give 2-fluoro-5-methoxycarbonyloxyaniline (0.42 g, 47%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([F:12])[CH:3]=1.[H-].[Na+].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[CH2:19]([O:18][C:16]([N:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[F:12])=[O:17])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: Nc1c(F)cc(Br)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(C(=O)OCC)c1c(F)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a stirred solution of 4-bromo-2-fluoro-6-nitroaniline (1) (0.500 g, 2.12 mmol, 1.00 equiv) in THF (20 mL) was added NaH (0.250 g, 6.40 mmol, 3.00 equiv) portion wise at 0° C. After being stirred for 1 h at RT, ethyl chloroformate (1.00 mL, 10.6 mmol, 5.00 equiv) was added drop wise to the reaction mixture at 0° C. The reaction mixture was heated under reflux temperature for 36 h. After consumption of the starting material (by TLC), the reaction was quenched with saturated NH4Cl solution and extracted with EtOAc (2×100 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane 1:4) to furnish compound 2 (0.350 g, 43.0%) as yellow solid.