Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[C:30](B(O)O)[C:25]=2[O:24][CH2:23]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:2]3[C:3]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[N:4][C:5]4[C:10]([N:11]=3)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=4)=[CH:30][C:25]=2[O:24][CH2:23]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: OB(O)c1cccc2c1OCO2
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccc4c(c3)OCO4)nc2c1
Yield: 41.1 %

Procedure:
A suspension of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (80 mg, 0.23 mmol, 1.00 equiv), benzo[d][1,3]dioxol-4-ylboronic acid (59 mg, 0.36 mmol, 1.50 equiv), tricyclohexylphosphine (9 mg, 0.03 mmol, 0.14 equiv), Pd2(dba)3 (13 mg, 0.01 mmol, 0.06 equiv), and K3PO4 (149 mg, 0.80 mmol, 3.00 equiv). in dioxane/H2O (1/0.5 mL) in a 10-mL sealed tube was allowed to react, with stifling, overnight at 95° C. The pH value of the solution was adjusted to 7 with HCl (1N). Purification via silica gel column (dichloromethane:methanol (1:10)) afforded 35 mg (40%) of 3-(benzo[d][1,3]dioxol-5-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Na].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].BrCCCCCCCCBr.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][C:24]1[CH:25]=[CH:26][C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=1
Reactant: CCCCCCCCOc1ccc2ccccc2c1
Reactant: Oc1ccc2ccccc2c1
Agent: BrCCCCCCCCBr
Agent: [Na]
Product: c1ccc2cc(OCCCCCCCCOc3ccc4ccccc4c3)ccc2c1

Procedure:
Using the method described in Example 1, the crude solids were prepared using 5.5 g (0.24 gram atoms) sodium metal, 34.6 g (0.24 mole) 2-naphthol, and 27.2 g (0.100 mole) 1,8-dibromooctane. Recrystallization from ethyl acetate gave 30.0 g, mp 128° C., and 0.8 g, mp 125°-126° C., of pure 1,8-bix (2-naphthoxy) octane. The NMR spectrum was consistent with the structure and showed the absence of impurities.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]([F:24])([F:23])[S:12]([O:15]S(C(F)(F)F)(=O)=O)(=[O:14])=[O:13].[CH2:25]([C:27]([C:45]1[CH:50]=[C:49]([CH3:51])[C:48](O)=[C:47]([CH3:53])[CH:46]=1)([C:30]1[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([CH2:42][CH3:43])([OH:41])[CH2:39][CH3:40])=[C:32]([CH3:44])[CH:31]=1)[CH2:28][CH3:29])[CH3:26].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:25]([C:27]([C:45]1[CH:46]=[C:47]([CH3:53])[C:48]([O:15][S:12]([C:11]([F:24])([F:23])[F:10])(=[O:14])=[O:13])=[C:49]([CH3:51])[CH:50]=1)([C:30]1[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([CH2:39][CH3:40])([OH:41])[CH2:42][CH3:43])=[C:32]([CH3:44])[CH:31]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(O)c(C)c2)cc1C)CC
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(OS(=O)(=O)C(F)(F)F)c(C)c2)cc1C)CC
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
Diisopropylethylamine (2.2 mL, 12.92 mmol) and trifluoromethanesulfonic anhydride (1.3 mL, 7.75 mmol) were added to a solution of 4-{1-ethyl-1-[(E)-4-(3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-2,6-dimethyl-phenol (Example 38-(4); 2.55 g, 6.46 mmol) in dichloromethane (30 mL) at −40° C., and the mixture was stirred at −40° C. for 10 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, which was then heated to room temperature and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50, 40 minutes) to give the target compound as a colorless oil (2.92 g, 86%).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[N:29]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]5[CH:35]=[CH:34][C:33]([C:30]6[N:29]=[C:28]([CH3:27])[O:32][N:31]=6)=[CH:41][CH:40]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: Cc1nc(-c2ccc(C(=O)O)cc2)no1
Agent: Cl
Product: Cc1nc(-c2ccc(C(=O)N[C@H]3CC[C@H](CCN4CCC(c5cccc6c5CCO6)CC4)CC3)cc2)no1

Procedure:
The title compound, white solid (98 mg, 77%), MS (ISP) m/z=515.4 [(M+H)+], mp 256.5° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and 4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzoic acid.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.O.N(C(NC1C=CC=CC=1)C)C1C=CC=CC=1.C(O)(=O)C>COCCOCCOC.CO>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[CH:14]=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CC(C(=O)Cl)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: CC(Nc1ccccc1)Nc1ccccc1
Solvent: CO
Solvent: O
Solvent: COCCOCCOC
Product: CC(C=O)c1ccc2c(=O)c3ccccc3ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.25 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionyl chloride (as prepared in Preparation 10 above) is dissolved in 4 ml. of diglyme and the solution cooled to -78° C. 3.5 Ml. of 0.045 molar lithium aluminum tri-tertiary butoxy hydride in diglyme is added, in 0.5 ml. portions over the course of 1 hour, to this solution. The mixture is warmed to room temperature and poured into water and extracted with ether. The extract is washed, dried and evaporated to give a crude product to which is added a solution of 0.106 g. of dianilinoethane and 0.072 g. of acetic acid in 5 ml. of methanol. The mixture is left for 1 hour then decanted from the insoluble product, α-(1,3-diphenyl-2-imidazolidinyl) 2-ethyl-5-oxo-5H-dibenzo[a,d]cycloheptene [a gum; nmr spectrum in deuterochloroform relative to tetramethylsilane: 1.47 (doublet, CHCH3), 5.77 (singlet, N--CH--N) acid 6.90 ppm (singlet, 10H, 11H)]. This compound is dissolved in 10 ml. of ether and the solution shaken with dilute hydrochloric acid. The ethereal layer is dried and evaporated to give 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propanal [a gum; nmr spectrum in deuterochloroform relative to tetramethylsilane: 0.98 (doublet, CHCH3), 3.78 (quartet, CHCH3), 7.02 (singlet, 10H, 11H) and 9.72 ppm (doublet, CHO); mass spectrum: 262 (M+) 233, 205].
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].Cl.Cl.[NH2:7][C@@H:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:24]=1)[C@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[CH:14]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][NH:11][CH2:10][C@@H:9]([OH:21])[C@@H:8]([NH:7][C:1](=[O:4])[CH3:2])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:24]=1)[CH3:20]
Reactant: CC(=O)O
Reactant: CCCCCCOc1cccc(C[C@H](N)[C@H](O)CNCc2cccc(CC)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCOc1cccc(C[C@H](NC(C)=O)[C@H](O)CNCc2cccc(CC)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.7 %

Procedure:
To a stirred solution of acetic acid (15 pg, 0.2 mmol), amine 92 (100 mg, 0.2 mmol), and HATU (80 mg, 0.2 mmol) in methylene chloride (3 mL) was added N,N-diisopropylethylamine (130 μL, 0.7 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, gradient 95:5 to 90:10 methylene chloride/methanol) provided N-{(1S,2R)-3-[(3-ethylbenzyl)amino]-1-[3-(hexyloxy)benzyl]-2-hydroxypropyl}acetamide 93B (20 mg): mp 102–105° C.; IR (KBr) 3304, 2929, 1637, 1603, 1550 cm 1; 1H NMR (500 MHz, CD3OD)δ 7.26–7.11 (m, 5H), 6.75–6.70 (m, 3H), 4.03–3.60 (m, 6H), 3.10–3.05 (m, 1H), 2.80–2.55 (m, 5H), 1.78–1.72 (m, 2H), 1.78 (s, 3H), 1.46–1.44 (m, 2H), 1.36–1.33 (m, 4H), 1.24–1.21 (m, 3H), 0.93–0.91 (m, 3H); ESI MS m/z 441 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][C:32]([F:35])([F:34])[F:33])[CH:25]=2)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.IC.[C:38](=O)([O-])[O-].[K+].[K+]>O>[OH:1][C:2]1([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:38])=[C:26]([O:31][C:32]([F:34])([F:35])[F:33])[CH:25]=2)[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2ccc(O)c(OC(F)(F)F)c2)C2(O)CCCCC2)CC1
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1ccc(C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)C2(O)CCCCC2)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
A solution of tert-butyl 4-{(1-hydroxycyclohexyl)[4-hydroxy-3-(trifluoromethoxy)phenyl]acetyl}piperazine-1-carboxylate (0.35 g 0.72 mmol) (See Example 400, step 1) and iodomethane (0.16 g, 1.08 mmol) in N-N′-dimethylformamide (5 mL) was treated with potassium carbonate (0.12 g, 0.86 mmol), and the solution was stirred at room temperature for 16 hours. The reaction was then poured into water and extracted 3 times with ethyl acetate. The combined extracts were washed twice with water, then dried over magnesium sulfate and concentrated to afford 0.31 g of tert-butyl 4-{(1-hydroxycyclohexyl)[4-methoxy-3-(trifluoromethoxy)phenyl]acetyl}piperazine-1-carboxylate). The product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[N:21]O)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1>[Pd].C(O)C>[NH2:21][CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=1)[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=1)[OH:10]
Reactant: O=C(C(=NO)c1ccnc(F)c1)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: NC(c1ccnc(F)c1)C(O)c1cccc(C(F)(F)F)c1
Reaction time: 10 h

Procedure:
10% palladium on carbon (3.0 g) was added to a solution of the 1-(2-fluoropyridin-4-yl)-2-(3-trifluoromethylphenyl)-ethane-1,2-dione 1-oxime (4) (8.0 g, 27 mmol) in ethanol (400 mL) at ambient temperature. The reaction vessel was vacuum purged with hydrogen and vigorously stirred for 10 hrs. After the reaction was complete, the solution was filtered through a pad of celite, and concentrated to give a yellow solid. The residue could be purified by recrystalization from methylene chloride and hexane. Alternatively, non polar impurities could be removed by filtration though silica gel starting with 5% methanol in methylene chloride to 5% methanol, 0.5% ammonium hydroxide in methylene chloride. Colorless solid (91%): mp 128-129° C.; 1H NMR (300 MHz, CD3OD) d 8.01 (d, J=5.0 Hz, 1 H, Ar), 7.53 (m, 1 H, Ar), 7.49 (m, 2 H, Ar), 7.43 (s, 1 H, Ar), 7.06 (d, J=5.0 Hz, 1 H, Ar), 6.86 (s, 1 H, Ar), 4.96 (d, J=5.0 Hz, 1 H, CH), 4.12 (d, J=5.0 Hz, 1 H, CH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH2:20])=[CH:15][C:14]([N+:21]([O-:23])=[O:22])=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:15][C:14]([N+:21]([O-:23])=[O:22])=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCN)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCNC(=O)c2ccccc2)c1
Reaction time: 0.33 h

Procedure:
To a solution of 2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]ethylamine (3.0 g in 80 mL dry methylene chloride) at 0° C. was added 4.0 mL triethylamine followed by 1.4 mL benzoyl chloride and the mixture stirred at low temperature. After 20 minutes, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with water and concentrated in vacuo to give the crude title compound (1.43 g).
Reaction SMILES: [I-:1].[Na+].[C:3]([O:24][CH2:25]Cl)(=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(#N)C.[Al]>[C:3]([O:24][CH2:25][I:1])(=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: [I-]
Reactant: CCCCCCCCCCCCCCCCCCCC(=O)OCCl
Agent: [Al]
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCCC(=O)OCI
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
Sodium iodide (8.31 g, 0.0555 mol) was added to a solution of chloromethyl arachidate (6.7 g, 0.0185 mol) in acetonitrile (67 ml) at 25° C. The flask was covered in aluminum foil to protect from light and stirred at 25° C. for 16 hours. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with aqueous saturated NaHCO3, aqueous sodium sulfite (10% solution), and brine, then dried with sodium sulphate and concentrated in vacuo to provide the desired product (5.9 g, 71% yield) as a white solid which was not purified any further.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:34].N1C=CC=CC=1>C(Cl)Cl>[N+:42]([C:39]1[CH:38]=[CH:37][C:36]([O:35][C:33]([N:2]2[CH2:7][CH2:6][CH:5]([C:8]3[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]4[N:18]=[C:19]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:20][C:21]=4[C:22]([F:23])([F:24])[F:25])=[O:16])=[CH:12][CH:13]=3)[CH2:4][CH2:3]2)=[O:34])=[CH:41][CH:40]=1)([O-:44])=[O:43]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide hydrochloride salt (2.0 g, 4.43 mmol) in methylene chloride (20 mL) at room temperature was added p-nitrophenyl chloroformate (1.11 g, 5.52 mmol) followed by pyridine (1.1 mL, 13.6 mmol). The mixture was stirred at room temperature overnight. The slurry was filtered and the filtrate was evaporated to give a crude material (2.4 g). The crude was triturated with methanol and filtration gave 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid 4-nitro-phenyl ester (850 mg, crude) as a white solid, which was directly used in the next step without further purification. LCMS calcd for C29H23F3N4O6 (m/e) 580, obsd 581 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl.Cl[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:29][C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3cccnc3)C2=O)CC1
Yield: 78 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride (2.4 equivalents) and 3-(chloromethyl)pyridine hydrochloride, to give the desired product as a white solid (78%).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH:5]2[C:10]([NH2:12])=O)[CH2:3][CH2:2]1.[ClH:13]>C1COCC1>[ClH:13].[CH:1]1([N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH:5]2[CH2:10][NH2:12])[CH2:3][CH2:2]1
Reactant: NC(=O)C1COCCN1C1CC1
Agent: Cl
Solvent: C1CCOC1
Product: NCC1COCCN1C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Under an inert atmosphere, 13.6 ml (13.6 mmol) of a solution (1N) of triborohydride complexed with tetrahydrofuran, in THF, are added dropwise to a solution of 0.58 g (3.4 mmol) of the compound obtained from step 5.1 in anhydrous THF, cooled to 0° C. The reaction mixture is heated at 70° C. for 3 hours. 15 ml of HCl solution (1N) are added to the reaction mixture cooled to room temperature. After stirring for 30 minutes, the aqueous phase is separated out by settling and extracted twice with ether (15 ml) and then basified by addition of sodium hydroxide solution (1N). The aqueous phase is then extracted 4 times with ethyl acetate (20 ml) and 4 times with dichloromethane (20 ml). The combined organic phases are dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is taken up in methanol (4 ml), and 3.4 ml of a solution of HCl in ether are added. The solution is stirred for 30 minutes, and 5 ml of ether are then added. The solid formed is collected by filtration and dried under vacuum over P2O5. 0.51 g of product is obtained, in the form of a white powder. Yield 78%. MH+: 157.2 (tr: 0.4 min., condition 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:44][C:45]1[N:50]=[CH:49][C:48]([CH2:51][NH2:52])=[CH:47][CH:46]=1>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([NH:52][CH2:51][C:48]1[CH:49]=[N:50][C:45]([CH3:44])=[CH:46][CH:47]=1)=[O:7]
Reactant: Cc1ccc(CN)cn1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1C(=O)NCc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Methoxy-4-nitrobenzoic acid (293 mg, 1.49 mmol) is dissolved in DMF (2 mL) and 4-methylmorpholine (220 μL, 3.0 mmol) and TBTU (1.79 g, 1.7 mmol) are added. The mixture is stirred at rt for 30 min and C-(6-methylpyridin-3-yl)methylamine (400 mg, 3.27 mmol) is added. Stirring is continued at rt for 12 h. DCM (10 mL) is added and the organic phase is washed with Na2CO3 (5% aq.), HCl (3% aq.) and water, and then dried over Na2SO4. After evaporation of the solvents, the residue is triturated with ether-hexane to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30]([NH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)(=[O:32])=[O:31]
Reactant: COC(=O)c1ccc(CSc2ccc(F)cc2N)cc1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(CSc2ccc(F)cc2NS(=O)(=O)c2cc3ccccc3o2)cc1
Yield: 65.9 %

Procedure:
Following General Procedure B, the title compound (929 mg, 66%) was prepared from methyl 4-(((2-amino-4-fluorophenyl)thio)methyl)benzoate (873 g, 2.99 mmol) and benzofuran-2-sulfonyl chloride (646 mg, 2.99 mmol) in pyridine (5 ml).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[NH:19][C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH2:21](I)[CH2:22][CH2:23][CH2:24][CH3:25].[H-].[Na+]>CN(C)C=O>[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(c2nc3ccccc3c(=O)[nH]2)CC1
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCN(c2nc(OCCCCC)c3ccccc3n2)CC1
Temperature: 0 °C
Yield: 88.2 %

Procedure:
In 30 ml of N,N-dimethylformamide was suspended 3.6 g of 2-(4-allyl-l-piperazinyl)-4(3H)-quinazolinone obtained in Example 1. With stirring under ice cooling, 3.6 g of pentyl iodide and 0.95 g of sodium hydride (oily, 60 %) were added to the suspension. The mixture was then stirred at 60° C. for 2.5 hours. Ice water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [eluted with chloroform/methanol (30:1, v/v)] to give 4.0 g of 2-(4-allyl-l-piperazinyl)-4-pentyloxyquinazoline as a pale yellow oil.
Reaction SMILES: [C:1]1([C:16]([OH:17])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=[C:7]([N+:8]([O-:10])=[O:9])[C:5]=1[OH:6])[N+:2]([O-:4])=[O:3].N(C1C(O)=C(N=O)C=CC=1O)=[O:19]>>[C:1]1([C:5]([OH:6])=[C:7]([N+:8]([O-:10])=[O:9])[CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:16]=1[OH:17])[N+:2]([O-:4])=[O:3].[N+:13]([O-:15])([OH:19])=[O:14]
Reactant: O=Nc1ccc(O)c(N=O)c1O
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1O
Product: O=[N+]([O-])O

Procedure:
A process for the preparation of styphnic acid comprising adding a liquid suspension containing from about 4 to about 20 percent weight/volume of 2,4-dinitroso resorcinol over a period of time sufficient to form styphnic acid to a nitric acid solution containing between 45 and 100 percent by weight of nitric acid, said solution being maintained at a temperature in the range from about 45° to 100°C.