Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:13](=[O:17])[C@H:14]([OH:16])[CH2:15][C:4]=2[CH:3]=1.ClCCl.C(N(C(C)C)CC)(C)C.[C:35](Cl)(=[O:46])[O:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1>>[C:35](=[O:46])([O:36][C:37]1[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=1)[O:16][C@H:14]1[C:13](=[O:17])[N:12]([CH2:18][C:19]([F:21])([F:20])[F:22])[CH2:11][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[C:2]([Cl:1])=[CH:3][C:4]=2[CH2:15]1
Reactant: O=C1[C@H](O)Cc2cc(Cl)c3[nH]ncc3c2CN1CC(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Reaction time: 48 h
Yield: 55.7 %

Procedure:
(R)-4-chloro-7-hydroxy-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one (1.2 g, 3.60 mmol) in dichloromethane (100.0 ml, 1554 mmol) was added diisopropylethyl amine (0.651 g, 5.03 mmol) followed by 4-nitrophenyl carbonochloridate (0.942 g, 4.67 mmol). After 48 h, the reaction mixture was washed with 1.0 M HCl and the crude product was purified by flash chromatography using 75% EtOAc in hexane to give (R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl 4-nitrophenyl carbonate (1.0 g, 2.005 mmol, 56% yield). MS (ESI) 499 (M+H) ; Rf=1.64.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C@@H:10]2[CH2:14][S:13][CH2:12][C@H:11]2[C:15]([OH:17])=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:58][C:59]1[CH:71]=[CH:70][C:62]([CH2:63][C@@H:64]2[CH2:69][CH2:68][CH2:67][NH:66][CH2:65]2)=[CH:61][CH:60]=1>ClCCl>[F:58][C:59]1[CH:60]=[CH:61][C:62]([CH2:63][C@@H:64]2[CH2:69][CH2:68][CH2:67][N:66]([C:15]([C@H:11]3[C@H:10]([NH:9][C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH3:8])[CH2:14][S:13][CH2:12]3)=[O:17])[CH2:65]2)=[CH:70][CH:71]=1
Reactant: C[C@@H](N[C@@H]1CSC[C@H]1C(=O)O)c1ccccc1
Reactant: Fc1ccc(C[C@@H]2CCCNC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](N[C@@H]1CSC[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Reaction time: 0.08 h
Yield: 94 %

Procedure:
A cloudy solution of (3R,4S)-4-[(R)-1-phenyl-ethylamino]-tetrahydrothiophene-3-carboxylic acid (containing sodium chloride; 928 mg, 2.54 mmol) in dichloromethane (20 mL) was treated with benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (1.59 g, 3.05 mmol) and triethylamine (814 μL, 5.84 mmol) and stirred for 5 minutes. A solution of the (S)-3-(4-fluorobenzyl)-piperidine prepared above in dichloromethane (5 mL) was added and the mixture was stirred at room temperature. After 21.5 h , the mixture was diluted with dichloromethane, washed with water and saturated NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (55% ethyl acetate/hexanes) to provide the product as a gum (1.05 g, 94%). 1H NMR (300 mHz, CDCl3) δ7.32 (m, 4H), 7.27 (m, 1H), 7.10 (m, 2H), 6.99 (m, 2H), 4.47 (m, 1H), 3.9-3.6 (m, 3H), 3.2 (m, 1H), 2.95 (m, 2H), 2.8-2.4 (m, 6H), 1.9-1.6 (m, 4H), 1.4 (m, 1H), 1.37 (m, 3H), 1.2 (m, 1H), ESI MS: (M+H)+=427.4.
Reaction SMILES: [NH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:8])=[CH:5][N:4]=1)[NH2:2].C(=O)([O-])[O-].[K+].[K+].C([O:27][CH:28]=[C:29]([C:35](OCC)=O)[C:30]([O:32][CH2:33][CH3:34])=[O:31])C.Cl>O>[OH:27][C:28]1[N:1]([C:3]2[CH:18]=[CH:17][C:6]([C:7](=[O:8])[NH:9][CH2:10][CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:5][N:4]=2)[N:2]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NNc1ccc(C(=O)NCC2CCOCC2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccc(C(=O)NCC3CCOCC3)cn2)c1O
Temperature: 100 °C
Reaction time: 14 h
Yield: 74.4 %

Procedure:
Combined 6-hydrazinyl-N-((tetrahydro-2 H-pyran-4-yl)methyl)nicotinamide (1.0 g, 4.00 mmol) and potassium carbonate (2.209 g, 15.98 mmol) in water (25 mL) and added diethyl 2-(ethoxymethylene)malonate (0.807 mL, 4.00 mmol) at 23° C. The reaction mixture was stirred at 100° C. for 14 hours, then 3N HCl (10 mL, 7.5 eq) was added to give a tan suspension. The solid was filtered, rinsed with water (3×5 mL), and dried in vacuo to give the title compound (1.114 g, 74.5% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.24 (m, 2 H) 1.26 (t, J=7.07 Hz, 3 H) 1.56-1.68 (m, 2 H) 1.81 (qdd, J=11.16, 11.16, 11.16, 6.95, 3.79 Hz, 1 H) 3.19 (t, J=6.32 Hz, 2 H) 3.27 (td, J=11.75, 2.02 Hz, 2 H) 3.82-3.90 (m, 2 H) 4.18 (q, J=7.24 Hz, 2 H) 8.12 (br. s., 1 H) 8.13-8.24 (m, 1 H) 8.46 (dd, J=8.84, 2.27 Hz, 1 H) 8.76 (t, J=5.68 Hz, 1 H) 8.89 (dd, J=2.27, 0.76 Hz, 1 H) 13.73 (br. s., 1H). MS m/z [M+H]+ 329.3, 375.4.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[NH2:7][C:8]1[N:16]=[CH:15][C:14]([Br:17])=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11]>C1(C)C=CC=CC=1>[Br:17][C:14]1[CH:15]=[N:16][C:8]2[NH:7][C:2](=[O:3])[NH:12][C:10](=[O:11])[C:9]=2[CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1cc(Br)cnc1N
Solvent: Cc1ccccc1
Product: O=c1[nH]c(=O)c2cc(Br)cnc2[nH]1
Yield: 154.9 %

Procedure:
Oxalyl chloride (100 mL, 1.16 mmol) was added dropwise to a suspension of 2-amino-5-bromo-nicotinamide (500 mg, 2.31 mmol) in toluene (5 mL) and the resulting mixture was heated to reflux for 4 h. The reaction mixture was cooled and the mustard-colored solid which had formed was collected by filtration. The solid was washed with a small amount of water, MeOH, and then dried under high vacuum (40° C.) overnight to give the title compound (435 mg, 77%): 1H NMR (300 MHz, DMSO-d6) δ 11.86 (s, 1H), 11.60 (s, 1H), 8.72 (d, J=2.5 Hz, 1H), 8.35 (d, J=2.5 Hz, 1H); 13C NMR (126 MHz, DMSO-d6) δ 161.4, 154.8, 151.2, 150.17, 137.8, 112.6, 111.6.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:11])[CH2:8][CH:9]=[CH2:10]>CCOCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:7]([O:11][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: C=CCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.6 %

Procedure:
To a chilled solution (0° C.) of 3,4-dihydro-2H-pyran (117 g, 1.4 mol) in anhydrous ether (600 mL) were added p-toluensulfonic acid (0.5 g) and 3-buten-1-ol (25.0 g, 0.35 mol). The resulting mixture was stirred at room temperature for 5 h and was then quenched by the addition of concentrated ammonium hydroxide (5 mL) and methanol (50 mL). The solvent was evaporated in vacuo, and ether was added to the residue. The precipitated ammonium p-toluenesulfate was filtered, the filtrate was concentrated, and the crude product was purified by flash column chromatography on silica gel (0-5% ethyl acetate in hexanes) to give 2-(3-butenyloxy)tetrahydropyran (49 g, 90%) as colorless viscous liquid: 1H-NMR (CDCl3, 300 MHz,) δ 5.80-5.89 [m, 1H, ═CH—C], 5.02-5.06 [m overlapping, 2H, ═CH2], 4.59-4.60 [m, 1H, 2-H of THP], 3.77-3.83 [m, 2H, —CH2O], 3.44-3.50 [m, 2H, CH2O of THP], 2.33-2.38 [m, 2H, CH2—CH═CH2], 1.51-1.71 [m, 6H, Hs of THP].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][C:19]1[C:20]([C:26](O)=[O:27])=[N:21][CH:22]=[C:23]([F:25])[CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:20]3[C:19]([F:18])=[CH:24][C:23]([F:25])=[CH:22][N:21]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1ncc(F)cc1F
Product: C[C@]1(c2cc(NC(=O)c3ncc(F)cc3F)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 3,5-difluoro-pyridine-2-carboxylic acid (CAS 745784-04-7) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=383.3 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]([CH2:10][OH:11])=[CH:8][N:7]=[C:6]1S.OO.[OH-].[Na+]>CO.O.O[W](O)(=O)=O>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]([CH2:10][OH:11])=[CH:8][N:7]=[CH:6]1
Reactant: OCCCn1c(CO)cnc1S
Agent: O=[W](=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCCCn1cncc1CO
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
1-(3-Hydroxypropyl)-2-mercapto-5-hydroxymethylimidazole(5.0 g, 23.1 mmol) and tungstic acid(H2WO4, 58 mg, 1 mol %) were mixed in 25 ml of methanol and 25 ml of distilled water. The mixture was warmed to 40° C. and 3.6 g of 30% hydrogen peroxide was added dropwise thereto. The whole mixture was stirred for 15 minutes and cooled and then, neutralized with 1 N sodium hydroxide solution. The resulting mixture was extracted twice with 25 ml of n-butanol and the solvent was distilled under reduced pressure to give 3.45 g(Yield 80.7%) of the title compound. 1H NMR (500 MHz, CDCl3) δ 7.46 (1H, s), 6.91 (1H, s), 4.61 (2H, s), 4.15 (2H, t, J=7 Hz), 3.52 (2H, t, J=7 Hz), 2.01 (2H, m).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][C:16]([Br:21])=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1S(C)(=O)=O)(=O)C.[OH-].[Na+]>O>[Br:21][C:16]1[CH:15]=[C:14]2[C:19]([C:20]3[N:8]4[CH2:7][CH2:6][CH2:5][O:4][C:9]4=[N:10][C:11]=3[CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: CC(=O)OCCCn1c(S(C)(=O)=O)nc2cnc3cc(Br)ccc3c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Brc1ccc2c(c1)ncc1nc3n(c12)CCCO3
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.5 %

Procedure:
To a round-bottomed flask containing 3-[7-bromo-2-(methylsulfonyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl acetate (15.7 g, 36.8 mmol) was added 2 N NaOH (300 mL) and the reaction was stirred at ambient temperature for 72 h. To the stirred reaction mixture was added additional 2 N NaOH (80 mL) and after 2 h more 2 N NaOH (100 mL) was added. After 1 h the reaction was diluted with water (1.1 L) and transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (3×800 mL). The aqueous layer was then extracted with ethyl acetate (3×800 mL) and the ethyl acetate extracts were combined, dried (MgSO4), filtered, and the solvent evaporated to afford a solid. The solid was washed with diethyl ether to afford 3-bromo-10,11-dihydro-9H-[1,3]oxazino[3′,2′:1,2]imidazo[4,5-c]quinoline (3.41 g) as a white solid. The dichloromethane extracts were combined and concentrated under reduced pressure. The residue was treated with 2 N NaOH to afford additional product.
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)O1.[H-].[Na+].[CH2:25]1[CH2:29]O[CH2:27][CH2:26]1>>[N:10]1([C:6]2[CH:5]=[C:4]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:6]3[C:5]4[C:26](=[CH:25][CH:29]=[CH:16][CH:4]=4)[CH2:27][C:2]=3[C:7]=2[C:8]#[N:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(-c2cc(N3CCCCC3)c(C#N)c(=O)o2)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(-c2cc(N3CCCCC3)c(C#N)c3c2-c2ccccc2C3)cc1

Procedure:
A mixture of 2-oxo-4-(piperidin-1-yl)-6-p-tolyl-2H-pyran-3-carbonitrile (294 mg), indanone-2, (132 mg) and NaH (29 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 162-164° C.; ESMS 365 (M++1); IR (KBr) 2213 cm−1 (CN); HRMS calcd. for C26H24N2 364.1940 found 364.1936.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:10][C:11](=[O:12])[CH:13]=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1]
Reactant: CC(C)=O
Reactant: O=Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccccc1F)C=Cc1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.5 %

Procedure:
2-Fluorobenzaldehyde (it, 0.5 ml, 4.7 mmol) and acetone (19, 0.18 ml, 2.4 mmol) were combined in ethanol (20 ml) and stirred for 10 min at room temperature. A solution of sodium hydroxide (0.29 g, 7.3 mmol) and water (15 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting mixture was filtered and chromatographed on silica gel with ethyl acetate/hexane to give a solid. The crude solid was recrystallized from ethanol to afford 0.27 g (41%) of yellow crystals: mp 68-72° C. [expected mp 68-70° C.]; 1H NMR: δ 7.13 (m, 6H), 7.36 (m, 2H), 7.61 (dt, 2H, J=7.6 Hz, 1.4 Hz), 7.84 (d, 2H, J=16.3 Hz); 13C NMR: δ 116.2, 122.8, 124.4, 127.6, 129.3, 131.8, 135.9, 161.5, 188.7.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][N:19]=1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14](=[O:16])[NH:17][C:18]2[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][N:19]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCOC(C(=O)Nc2cc(C(C)(C)C)on2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cold (0° C.) solution of morpholine-2,4-dicarboxylic acid 4-tert-butyl ester (1 g; 4.424 mmol) and 3-amino-5-t-butylisoxazole (606 mg; 4.324 mmol) and N,N-diisopropylethylamine (1.521 mL; 8.732 mmol) in anhydrous acetonitrile (12 mL) is added phosphorous oxychloride (0.39 mL; 4.424 mmol). The reaction mixture is stirred at room temperature for 18 hours. After this time, the reaction mixture is quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using ethyl acetate/Hexanes provides the title compound, m/z 354 [M+H+].
Reaction SMILES: C(OC([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:17])=O)C.C(O)C>[OH-].[K+].O>[C:11]1([C:10]2[CH:6]=[C:7]([NH2:17])[S:8][CH:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-4-phenyl-thiophene-3-carboxylic acid ethyl ester (5 g, 20.2 mmol) was suspended in 20% potassium hydroxide solution (100 ml) and heated to reflux. Ethanol (100 ml) was added to aid dissolution. The reaction was stirred overnight and then cooled to room temperature and diluted with water (250 ml). The precipitated solid was collected by filtration and dissolved in DCM/ethyl acetate before drying over magnesium sulfate. The solvent was removed in vacuo to give 4-phenyl-thiophen-2-ylamine. Yield 1.05 g (30%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:10][CH:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:9])=[O:8].[ClH:19].Cl.[CH2:21]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[ClH:19].[ClH:19].[CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:10][CH:11]([N:33]1[CH2:34][CH2:35][N:30]([CH2:21][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH2:31][CH2:32]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(CC(Br)c1ccccc1)c1ccccc1
Reactant: O=C(CN1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CN1CCN(C(CS(=O)(=O)c2ccccc2)c2ccccc2)CC1)c1ccccc1
Yield: 99.6 %

Procedure:
A mixture of (2-benzenesulfonylmethyl)-benzyl bromide (0.5 g, 1.54 mmol), N-phenacyl piperazine dihydrochloride (0.32 g, 1.54 mmol) and K2CO3 (0.74 g, 5.38 mmol) in 40 ml of acetone was treated according to general preparation 2 to give 0.4 g of compound (IV-26), yield 50%. M+ 448.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=O)=[O:4].C(N(CC)CC)C.ClC(OCC)=O.[NH2:30][C@H:31]([C:39]([NH:41][C@H:42]([C:47]([O:49][CH3:50])=[O:48])[CH2:43][CH2:44][S:45][CH3:46])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:30][C@H:31]([C:39]([NH:41][C@H:42]([C:47]([O:49][CH3:50])=[O:48])[CH2:43][CH2:44][S:45][CH3:46])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:9])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@@H](N)Cc1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4.43 g of Boc-Gly-Gly-OH, A (2) is dissolved in 30 ml DMF and cooled to 0° C., after which 1 equivalent TEA (triethylamine) is added. The mixture is cooled further to about -10° C., after which 1 equivalent (eq) ethyl chloroformate is added and the whole is stirred for about 10 minutes. 6.6 g H-Phe-Met-OMe.HCl (A.1) in 30 ml DMF and 1.1 eq TEA is then added to the mixture, which is stirred for about 30 minutes at about -10° C. and for a further 20 hours at room temperature. After cooling to about -10° C., TEA.HCl is separated by filtration and the filtrate is evaporated to dryness. The residue is dissolved in 235 ml EtOAc and 55 ml water and is subsequently washed with 30% NaCl solution, 0.1 N HCl, 30% NaCl solution, 5% NaHCO3 solution and 30% NaCl solution. The solution is then dried over Na2SO4 filtered and evaporated to dryness. Melting point 100°-101° C.; Rf in CHCl3 :CH3OH:Wa (70:30:5)=0.94 on SiO2.
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].BrC1C=CC=C([N+]([O-])=O)C=1[NH:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][NH:23][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=[N+]([O-])c1cccc(Br)c1NCCO
Reactant: N#Cc1cccc([N+](=O)[O-])c1Cl
Product: N#Cc1cccc([N+](=O)[O-])c1NCCO

Procedure:
2-[(2-hydroxyethyl)amino]-3-nitrobenzonitrile was prepared starting from 2-chloro-3-nitrobenzonitrile [prepared as described in WO 97/38983] (0.89 g) according to the procedure described for the synthesis of 2-[(2-bromo-6-nitrophenyl)amino]ethanol. Yield 1.06 g (99 %). 1H NMR (400 MHz, CD3CN) δ ppm: 3.00 (t, J=4.8 Hz, 1H), 3.68 (q, J=4.7 Hz, 2H), 3.81 (m, 2H), 6.70 (dd, J=8.6, 7.6 Hz, 1H), 7.75 (dd, J=7.6, 1.5 Hz, 1H), 8.28 (dd, J=8.6, 2.0 Hz, 1H), 8.41 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[C:4]2([CH3:12])[O:10][C:7]([CH3:11])([C:8]=1Cl)[CH:6]=[CH:5]2.[CH3:14][OH:15].C[O-].[Na+]>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3](=[O:13])[C:4]2([CH3:12])[O:10][C:7]([CH3:11])([C:8]=1[O:15][CH3:14])[CH:6]=[CH:5]2
Reactant: CC12C=CC(C)(O1)C(Cl)=C(Cl)C2=O
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC1=C(Cl)C(=O)C2(C)C=CC1(C)O2
Temperature: 25 °C
Yield: 52.9 %

Procedure:
6.0 g (27.39 mmol) of 3,4-dichloro-1,5-dimethyl-8-oxa-bicyclo[3.2.1]octa-3,6-dien-2-one is introduced into 39 ml of anhydrous methanol. At a temperature of 0° C., the reaction mixture is further diluted dropwise with a solution of 15.2 ml of 5.4M sodium methanolate (82.17 mmol) and treated with 10 ml of absolute methanol. The reaction mixture is then heated to ambient temperature with 35 minutes' stirring. Using thin-layer chromatography (hexane/ethyl acetate 8:2) it can be established that reaction of the starting material is complete. The reaction solution is then concentrated under reduced pressure. The residue is then extracted by means of carbon tetrachloride against water. The aqueous phase is extracted a further three times using fresh carbon tetrachloride. The combined organic extracts are dried over sodium sulfate and concentrated by evaporation under reduced pressure; with ice-cooling, the oily product that remains behind crystallises out in the form of a ˜1:1 mixture. The mixture is separated by means of column chromatography on silica gel (eluant: gradient from 1-5% ethyl acetate/hexane). 3.1 g (52.9%) of pure 3-chloro-1,5-dimethyl-4-methoxy-8-oxa-bicyclo[3.2.1]octa-3,6-dien-2-one are isolated.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]([O:13][CH3:14])=[O:12].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>C(O)(C)(C)C>[C:20]([O:19][C:17]([NH:16][CH2:15][C@H:10]([N:9]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:11]([O:13][CH3:14])=[O:12])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: BrCCCCCBr
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCCCC1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
1.8 ml (6.5 mmol) of triethylamine are added to a solution of 1 g (6.5 mmol) of commercial methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride in 20 ml of tert-butanol. The reaction medium is stirred for 30 min at 40° C. then filtered. Added to the filtrate thus obtained are 1.2 ml (8.6 mmol) of 1,5-dibromopentane and the reaction medium is heated at 60° C. for 3 days. After filtration of the insoluble fraction, the filtrate is concentrated under vacuum. The crude residue is purified by chromatography over silica gel eluted with a 70/30 heptane/ethyl acetate mixture. 600 mg (49%) of methyl (S)-3-tert-butoxycarbonylamino-2-piperidin-1-yl-propanoate are obtained in the form of a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14]CC)=[O:13])([O-:3])=[O:2].[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[OH:25].C(=O)([O-])[O-].[K+].[K+]>>[N+:1]([C:4]1[C:9]([O:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([OH:14])=[O:13])([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Reactant: Oc1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)Cc1cccc(Oc2cccc(Cl)c2Cl)c1[N+](=O)[O-]
Yield: 29.2 %

Procedure:
A mixture of ethyl 2-(2-nitro-3-chlorophenyl)acetate (10 g.), 2,3-dichlorophenol (7.4 g.), anhydrous potassium carbonate (8.5 g.) and cupric oxide (1 g.) was treated in a similar manner to the above to give 2-[2-nitro-3-(2,3-dichlorophenoxy)phenyl]acetic acid (4.1 g.). mp 178° to 183° C.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[N:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[C:21]#[N:22].[Na].[F:24][C:25]([F:29])([F:28])[CH2:26][OH:27]>>[F:24][C:25]([F:29])([F:28])[CH2:26][O:27][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[N:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[C:21]#[N:22]
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)C(F)(F)F)[nH]c2c1Cl
Reactant: OCC(F)(F)F
Agent: [Na]
Product: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)C(F)(F)F)[nH]c2c1OCC(F)(F)F

Procedure:
4-Chloro-7-nitro-5-cyano-2-pentafluoroethylbenzimidazole is reacted with the sodium salt of 2,2,2,-trifluoroethanol to obtain 4-(2,2,2-trifluoroethoxy)-7-nitro-5-cyano-2-pentafluoroethylbenzimidazole, m.w., 404.2.