Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH]Cl.[C:7]1([C:13]2[C:17]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]([NH2:26])[NH:15][N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Na+].[Cl-:28]>C(Cl)Cl>[Cl:28][C:18]1[C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:1][N:26]=[C:16]2[NH:15][N:14]=[C:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:17]=12
Reactant: Nc1[nH]nc(-c2ccccc2)c1C#Cc1ccccc1
Reactant: O=N[O-]
Reactant: [Cl-]
Agent: [CH]Cl
Agent: [Na+]
Solvent: ClCCl
Product: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 46.6 %

Procedure:
Sodium nitrite (2.88 g, 42 mmol) was added portionwise to cHCl (314 mL) at −15° C. and stirred for 15 min. 3-phenyl-4-(2-phenylethynyl)-1H-pyrazol-5-amine (5.4 g, 21 mmol) was added as a solid, followed by the addition of CH2Cl2 (10 mL). The reaction mixture was allowed to warm up and stirred at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2 (44 mL) and NaCl (2.7 g) was added. The reaction mixture was heated to 50° C. for 1 d. The layers were separated and the organic layer was washed with water, dried (phase separator cartridge) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, iso-hexanes/ethyl acetate 4:1, then CH2Cl2/ethyl acetate 1:0 to 4:1) yielding the title compound as a solid (3.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:13]#[N:14])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:15](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:13]#[N:14])[C:11]=1[O:12][CH3:15])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)c(O)c(C#N)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(Cl)c(OC)c(C#N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
Methyl 3-chloro-5-cyano-4-hydroxybenzoate (1.27 g) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (5.00 g) and dimethylsulfuric acid (1.70 mL) were added to the solution, and then the mixture was stirred at room temperature for 18 hours. The reaction solution was filtered and water was added, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.03 g) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH:15](C)CN4C(=O)C5=CC=CC=C5C4=O)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])[C:6]=2[CH:36]=1.O.[NH2:38]N.[CH2:40](O)[CH3:41]>>[NH2:38][CH:40]([CH3:41])[CH2:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:36][C:6]=3[C:7]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])=[N:8][CH2:9][C:10]2=[N:14][N:13]=1
Reactant: CC(CN1C(=O)c2ccccc2C1=O)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reactant: NN
Reactant: CCO
Solvent: O
Product: CC(N)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
In the manner given in Example 21, a solution of N-[2-[8-chloro-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepin-1-yl]propyl]phthalimide in ethanol is heated with hydrazine hydrate to give 1-(2-aminopropyl)-8-chloro-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:7]=1.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[NH2:14][C:3]1[N:4]=[CH:5][C:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:24](=[O:26])[CH3:25])[CH2:12][CH2:13]2)=[N:7][C:2]=1[Br:1]
Reactant: CC(=O)Cl
Reactant: Nc1ncc(C2CCNCC2)nc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(c2cnc(N)c(Br)n2)CC1
Reaction time: 0.5 h

Procedure:
To 3-bromo-5-(piperidin-4-yl)pyrazin-2-amine (50 mg, 0.194 mmol) in DCM (4 mL) in ice bath was added DIEA (0.136 mL, 0.778 mmol) and acetyl chloride (0.017 mL, 0.233 mmol). The reaction mixture was stirred at in ice bath 30 min. The reaction mixture was partitioned between DCM and water. The DCM layer was separated and washed with brine. Dried over sodium sulfate, filtered and evaporated. Proceed for next step. LCMS (m/z): 299.1/301.1 (MH+), 0.508 min. 1H NMR (400 MHz, CD3OD) δ ppm 7.81-7.69 (m, 2 H), 7.62-7.45 (m, 2H), 7.37-7.09 (m, 6H), 6.5 (dd, J=8.61, 2.35 Hz, 1H), 6.50 (dd, J=13.50, 2.15 Hz, 1H), 5.17-5.01 (m, 1H), 4.55 (d, J=13.30 Hz, 1H), 3.94 (d, J=13.69 Hz, 1H), 3.83-3.63 (m, 2H), 2.88 (tt, J=11.84, 3.62 Hz, 1H), 2.67 (td, J=12.91, 2.35 Hz, 1H), 2.03 (s, 3H), 1.96-1.79 (m, 2H), 1.78-1.50 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([C:22]([NH2:24])=[O:23])=[N:4][C:5]([C:18](O)([CH3:20])[CH3:19])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:7]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.FC(F)(F)C(O)=O.CN1CCCC1=O>O>[CH3:25][N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:38]=[CH:37][C:35]([NH:36][C:2]3[C:3]([C:22]([NH2:24])=[O:23])=[N:4][C:5]([C:18]([CH3:20])=[CH2:19])=[C:6]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=4)[N:7]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1
Reactant: CC(C)(O)c1nc(C(N)=O)c(Cl)nc1Oc1cccc([N+](=O)[O-])c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)c1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc([N+](=O)[O-])c1
Temperature: 160 °C
Yield: 56 %

Procedure:
A mixture of 3-chloro-6-(2-hydroxypropan-2-yl)-5-(3-nitrophenoxy)pyrazine-2-carboxamide (1.48 g), 4-(4-methylpiperazin-1-yl)aniline (883 mg), trifluoroacetic acid (385 μL), and N-methylpyrrolidone (14.8 mL) was heated to 160° C. for 5 hours. To the reaction mixture were added water and a saturated aqueous sodium hydrogen carbonate solution, and the precipitated solid was collected by filtration and then dried. The obtained solid was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-30:1:0.1) and washed with ethyl acetate to obtain 3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)-6-(prop-1-en-2-yl)pyrazine-2-carboxamide (1.15 g) as an orange solid.
Reaction SMILES: O(C)[Na].[C:4]([C:6]1[N:7]=[C:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[S:9][CH:10]=1)#[N:5].Cl.Cl.[C:22]1(N)[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].O>CO>[NH:5]1[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:28]=[C:4]1[C:6]1[N:7]=[C:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[S:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1nc(C#N)cs1
Reactant: Nc1ccccc1N
Agent: CO[Na]
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1nc(-c2nc3ccccc3[nH]2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In analogy to the preparation of 8, 1.89 g of a 30% NaOCH3 solution were added to tert-butyl (4-cyano-1,3-thiazol-2-yl)methylcarbamate (2.5 g; 10.45 mmol) in 25 ml of CH3OH, and the mixture was stirred at room temperature for 2 h. Addition of 1.9 g of 1,2-phenylenediamine bishydrochloride was followed by stirring overnight, and then the reaction mixture was added to 100 ml of H2O, and the solid resulting after filtration was dried in vacuo.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[O:29][C:14]3=[CH:15][N:16]=[C:17]([C:19]4[CH2:20][CH2:21][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23][CH:24]=4)[CH:18]=[C:13]3[CH2:12]2)[CH2:7][CH2:6]1)=[NH:4].[C:30](Cl)(=O)[CH2:31][CH2:32][CH3:33]>>[CH3:28][S:25]([N:22]1[CH2:21][CH:20]=[C:19]([C:17]2[CH:18]=[C:13]3[CH2:12][CH:11]([CH:8]4[CH2:9][CH2:10][N:5]([C:3]5[N:4]=[C:30]([CH2:31][CH2:32][CH3:33])[O:1][N:2]=5)[CH2:6][CH2:7]4)[O:29][C:14]3=[CH:15][N:16]=2)[CH2:24][CH2:23]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)CC1
Reactant: CCCC(=O)Cl
Product: CCCc1nc(N2CCC(C3Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)no1

Procedure:
The title compound is prepared from N-hydroxy-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl]-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxamidine and butyryl chloride following a procedure analogous to that described in Example 8. LC (method 5): tR=1.10 min; Mass spectrum (ESI+): m/z=474 [M+H]+.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH:12]1([C:18]([O:20][CH:21]([O:25][C:26](ON2C(=O)CCC2=O)=[O:27])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CC(OC)(C)C.CC(C)=O.O>[CH:12]1([C:18]([O:20][CH:21]([O:25][C:26]([NH:11][CH2:10][C@H:2]2[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]2)=[O:27])[CH:22]([CH3:23])[CH3:24])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(C)C(OC(=O)ON1C(=O)CCC1=O)OC(=O)C1CCCCC1
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)C(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)C1CCCCC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (1.4 g, 8.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]-2-methylpropyl cyclohexanecarboxylate (1.0 g, 2.9 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 48 (300 mg, 27% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.83-0.92 (br. m, 8H), 1.15-1.35 (br. m, 8H), 1.54-1.95 (br. m, 10H), 2.08 (tt, J=12.0, 3.6 Hz, 1H), 2.27-2.32 (br. m, 1H), 2.74-2.83 (br. m, 2H), 6.41 (d, J=5.2 Hz, 1H), 7.39 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 406.14 (M+Na)+; 382.17 (M−H)−.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[NH2:5].O.[NH2:16][NH2:17]>CO>[NH2:5][C@@H:4]([C:3]([NH:16][NH2:17])=[O:2])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](N)Cc1ccc(O)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)[C@H](N)Cc1ccc(O)cc1
Yield: 93.3 %

Procedure:
D-Tyrosine methyl ester (30 g, 129 mmol, 99% ee) was dissolved in 150 mL of methanol and stirred until dissolved. Hydrazine hydrate (23 ml, 453 mmol) was then added and solution stirred overnight. Methanol was removed at reduced pressure and saturated NaHCO3 was added (150 ml). The product was precipitated, filtered and dried to yield the title compound as a white powder (23.5 g, 93%). 1H NMR (CD3OD, 400 MHz) δ 7.03 (ad, J=8.8 Hz, 2H), 6.72 (ad, J=8.8 Hz, 2H), 3.44 (t, J=6.8 Hz, 1H), 2.91-2.86 (m, 1H), 2.76-2.71 (m, 1H). ESI-MS (m/z): 196.1 [M+1]+.
Reaction SMILES: [C:1]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(OCC)=O.[OH-:17].[Na+]>>[C:7]1(=[O:16])[N:6]([CH2:1][C@@H:13]2[CH2:14][CH2:15][CH:8]=[CH:7][O:17]2)[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]12
Reactant: [OH-]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1CCC=CO1

Procedure:
The amine tartrate (107.0 g, 407 mmol) was added to 4N sodium hydroxide (310 mL) and extracted with ether (3×100 mL). The ether was dried over anhydrous sodium sulfate and evaporated in vacuo. The amine which remained was dissolved in tetrahydrofuran (450 mL). With stirring, N-carboethoxyphthalimide (89.60 g, 409 mmol) was added to the solution. The mixture was refluxed overnight then evaporated in vacuo. The residue was taken up into benzene (660 mL) and water (180 mL). The layers were separated and the organic layer was washed with water (180 mL), 5% sodium hydroxide (180 mL), water (2×180 mL), and saturated brine (180 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo leaving the crude product (97.0 g) as a white solid. This was recrystallized from ether-petroleum ether (1:1). Yield 72.64 g (73%), m.p. 87°-88° C.; Anal. Calcd. for C14H13NO3 : C, 69.12 ; H, 5.39; N, 5.76. Found: C, 69.18; H, 5.36; N, 5.66.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1([CH2:11][C:12]2[CH:13]=[C:14]([CH:21]=[CH:22][CH:23]=2)[O:15][CH2:16][CH2:17][C:18](O)=[O:19])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CN(C)C=O>ClCCl>[ClH:3].[N:5]1([CH2:11][C:12]2[CH:13]=[C:14]([CH:21]=[CH:22][CH:23]=2)[O:15][CH2:16][CH2:17][C:18]([Cl:3])=[O:19])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(O)CCOc1cccc(CN2CCCCC2)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cl
Product: O=C(Cl)CCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (23.8 g) was added slowly to a cooled (0° C.) mixture of 3-[3-(piperidinomethyl)phenoxy]propionic acid and dimethylformamide (0.5 ml) in dichloromethane (100 ml). The resulting suspension was stirred at room temperature overnight, and solvent was removed under reduced pressure to give 3-[3-(piperidinomethyl)phenoxy]propionyl chloride hydrochloride (18.9 g) as an oil.
Reaction SMILES: [C:1]([NH:22][C@H:23]([C:36]([OH:38])=[O:37])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][P:32]([OH:35])([OH:34])=[O:33])=[CH:27][CH:26]=1)(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:39](O)(=O)[CH2:40]C/C=C\CC=CCC=CCC=CCC=CCC=CCC>>[C:1]([NH:22][C@H:23]([C:36]([OH:38])=[O:37])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][P:32]([OH:35])([OH:34])=[O:33])=[CH:27][CH:26]=1)(=[O:21])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:39][CH3:40]
Reactant: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCC(=O)O
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](Cc1ccc(OP(=O)(O)O)cc1)C(=O)O
Product: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCC(=O)N[C@@H](Cc1ccc(OP(=O)(O)O)cc1)C(=O)O

Procedure:
This compound was prepared as described above for (8) using 0.5 mmol (164 mg) of cis-4,7,10,13,16,19-docosahexaenoic acid; yield 74 mg, (26%); Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 2.0-2.1 (t, 2H, CH2CO); 2.2-2.4 (m, 4H, 2CH2CH═CH); 2.7-2.9 (br s, 10H, 5HC═CHCH2CH═CH); 2.9-3.1 (m, 2H, CH2Ar); 4.3-4.4 (m, 1H, NHCHCO); 5.2-5.4 (br s, 12H, 6HC═CH); 7.0-7.2 (q, 4H, Ar); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:10]=2[O:9][CH:8]([CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31]([NH2:33])=[NH:32])=[CH:24][CH:23]=2)[C:7]1=[O:34].O.[NH4+].[Cl-]>C(O)C.[Fe]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]2[O:9][CH:8]([CH2:19][CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][NH:30][C:31]([NH2:33])=[NH:32])=[CH:26][CH:27]=3)[C:7](=[O:34])[N:6]([CH2:5][C:4]3[CH:35]=[CH:36][CH:37]=[C:2]([Cl:1])[CH:3]=3)[C:11]=2[CH:12]=1
Reactant: N=C(N)NCCc1ccc(OCCC2Oc3ccc([N+](=O)[O-])cc3N(Cc3cccc(Cl)c3)C2=O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N=C(N)NCCc1ccc(OCCC2Oc3ccc(N)cc3N(Cc3cccc(Cl)c3)C2=O)cc1
Yield: 85 %

Procedure:
4-(3-Chlorobenzyl)-3,4-dihydro-2-{2-[4-(2-guanidinoethyl)phenoxy]ethyl}-6-nitro-3-oxo-2H-1,4-benzoxazine (0.3 g) was warmed in ethanol (5 ml) and H2O (4 ml) until completely in solution. Iron powder (0.19 g, 6.8 eq) was stirred in followed by NH4Cl (0.02 g, 0.7 eq) and the reaction continued at reflux for 5 hours. While still hot, the mixture was filtered through celite and the yellow filtrate concentrated down to a yellow oil. After drying in vacuo at 80 C.°, the product was collected as a yellow solid in 85% yield, mp (dec)>94° C.; MS (Cl) MH+ 494; IR (KBr) 3332, 1667, 1614, 1512, 1467, 1396, 1243, 830, 774, 680 cm-1 ; 1H NMR (DMSO-d6 /CDCl3) δ 7.66 (br s, 1H), 7.58-6.50 (v br s, 3H), 7.36 (m, 4H), 7.20 (m, 3H), 6.91 (d, 2H, J=8.6 Hz), 6.74 (d, 1H, J=8.4 Hz), 6.26 (d, 1H, J=2.2 Hz), 6.21 (dd, 1H, J=2.2, 8.4 Hz), 5.08 (d, 1H, J=16.7 Hz), 4.99 (d, 1H, J=16.5 Hz), 5.12-4.78(v br s., 1H), 4.79 (dd, 1H, J=4.0, 8.9 Hz), 4.15 (m, 2H), 3.33 (m, 2H), 2.71 (t, 2H, J=7.5 Hz), 2.30 (m, 1H), 2.18 (m, 1H). Anal. Calc'd for C26H28ClN5O3.HCl.0.5 H2O: C 57.89, H 5.61, N 12.98. Found: C 57.64, H 5.48, N 12.63.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16].O(CCCC)CCCC.O>[Fe].CC(O)=O>[NH2:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCc1cccs1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCOCCCC
Product: COc1cc(N)c2nccc(C)c2c1OCCCCCc1cccs1

Procedure:
A mechanically stirred mixture of 6-methoxy-4-methyl-8-nitro-5-[5-(thienyl) pentoxy] quinoline (5.50 g, 0.014 mol), Fe-filings (6 g), Bu2O (15 ml), H2O (50 ml) and HOAc (1.5 ml) was heated at 105°-110° C. for 2.5 h, allowed to cool and filtered. The residue was well washed with Et2O (200 ml) and the filtrate and the washings were combined. The organic layer was separated and the aqueous layer was extracted with Et2O (2×75 ml). The combined organic layers were washed with saturated NaCl solution (2×50 ml), dried (K2CO3), treated with carbon (Darco G-60), and concentrated to a yellow oil which on trituration with pet. ether (20°-40° C., 20 ml), at -20° C., gave 8-amino-6-methoxy-4-methyl-5-[5-(2-thienyl)pentoxy] quinoline as a yellow solid, 4.07 g (80%), m.p. 42°-44° C. This material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH2:12][CH3:13])[N:3]=1.C[Si]([N-:18][Si](C)(C)C)(C)C.[Li+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[C:37]1([CH3:43])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:43]([NH:18][C:5]1[N:4]([CH2:11][CH2:12][CH3:13])[N:3]=[C:2]([Br:1])[C:6]=1[N+:7]([O-:9])=[O:8])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCCn1nc(Br)c([N+](=O)[O-])c1Br
Reactant: Cc1ccccc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Li+]
Product: CCCn1nc(Br)c([N+](=O)[O-])c1NCc1ccccc1

Procedure:
Treatment of 3,5-dibromo-4-nitro-1H-pyrazole 1 with 2-bromoethanol and NaH in DMF affords 2-(3,5-dibromo-4-nitro-1H-pyrazol-1-yl)ethanol 2. Reaction of the compound 2 with lithium bis(trimethylsilyl)amide in the presence of bis(dibenzylidene)palladium (0) and P(t-Bu)3 in toluene affords the bis-silylamine 3, which is readily converted to 2-(5-amino-3-bromo-4-nitro-1H-pyrazol-1-yl)ethanol 4 by addition of aqueous HCl and neutralization (Org. Lett. 2001, 3, 2729). Reduction of the compound 4 with Fe in acetic acid provides 2-(4,5-diamino-3-bromo-1H-pyrazol-1-yl)ethanol 5.
Reaction SMILES: [CH:1]1([O:7]/[N:8]=[C:9](/[C:15](=[O:17])[CH3:16])\[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:21])(=O)=O>>[Cl:21][CH2:16][C:15](=[O:17])/[C:9](=[N:8]/[O:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)/C(=N\OC1CCCCC1)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Product: CCOC(=O)/C(=N\OC1CCCCC1)C(=O)CCl
Temperature: 25 °C
Yield: 60 %

Procedure:
Ethyl (Z)-2-(cyclohexyloxyimino)-3-oxobutyrate (1.0 g) was added to ice-cooled sulphuryl chloride (10 ml) with stirring. The mixture was allowed to warm to room temperature, stirred for 27 h, then evaporated under an argon stream. The residue was dissolved in diethyl ether, washed twice with water, then brine, dried (MgSO4) and evaporated. Purification by flash chromatography, eluting with dichloromethane/carbon tetrachloride gave the title compound (0.69 g, 60%) as a colourless liquid; νmax (film) 2950, 2860, 1750, 1720 cm-1 ; δH (CDCl3) 1.32 (3H, t), 1.2-2.0 (10H, br m), 4.3 (1H, br m), 4.34 (2H, q), and 4.53 (2H, s), (Found: MH+ 276.0998, C12H18NO4Cl requires M+H 276.1004).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:2]=1.[H-].[Na+].[H][H].[Cl:23][C:24]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:25]=1[CH2:26]Cl>CN(C=O)C.C(O)(=O)C>[Cl:23][C:24]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:25]=1[CH2:26][N:12]1[C:13]2[CH:1]=[N:2][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: [H][H]
Reactant: ClCc1cc(Cl)ccc1Cl
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Temperature: 25 °C
Yield: 986.8 %

Procedure:
A suspension of ethyl 9H-β-carboline-3-carboxylate (2.40 g, 10 mmol) in anhydrous DMF (20 mL) was cooled in an ice bath under nitrogen. Sodium hydride (420 mg of 60% NaH in mineral oil, 10.5 mmol) was added at once, and the mixture stirred until most of the solids dissolved and hydrogen evolution stopped (approx 10 min). The cool mixture was treated with 2,5-dichlorobenzyl chloride (2.15 g, 1.0 mmol) slowly with stirring, then allowed to warm to room temperature over two hours. The resulting cloudy solution was neutralized with acetic acid, then the solvent was removed in vacuo, affording a tan solid (3.94 g). The crude material was chromatographed on silica gel using a mixture of chloroform and ethyl acetate, affording the title product (1.96 g, 49%). 1H NMR (300 MHz, DMSO-d6) δ9.06 (s, 1 H), 8.96 (s, 1H), 8.48 (d, J=8.0, 1H), 7.55-7.64 (m, 3H), 7.35-7.42 (m, 2H), 6.60 (d,J=2.3, 1H), 5.89 (s, 2H), 4.36 (q, J=6.9, 1H), 1.35 (t, J=7.2, 3H); LRMS calcd for C21H16Cl2N2O2 (M+H) 399, found 399.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[C:24](Cl)(=[O:26])[CH3:25].Cl.[C:29](OCC)(=[O:31])[CH3:30]>ClCCl.CO>[C:24]([N:1]([C:29](=[O:31])[CH3:30])[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CCOC(C)=O
Reactant: Cc1ccc(-c2ccnc(N)c2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N(C(C)=O)c1cc(-c2ccc(C)cc2)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
2-Amino-4-(4-methylphenyl)pyridine (1.27 g) was dissolved in dichloromethane (50 ml). Under ice cooling, N,N-diisopropylethylamine (1.80 ml) and acetyl chloride (735 μl) were successively added dropwise to the resulting solution. After heating to room temperature, the reaction mixture was added again with N,N-diisopropylethylamine (0.90 ml) and acetyl chloride (800 μl). The mixture was stirred for 18 hours. Methanol was added to the reaction mixture. Dilute hydrochloric acid and ethyl acetate were then added to the residue obtained by distilling off the solvent in order to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, followed by concentration. The residue was dissolved in methanol. Crystals precipitated by the addition of water were collected by filtration and dried, whereby the title compound (1.39 g, 75%) was obtained.