Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[C:39](=[O:40])[N:38]2[CH2:41][C@@H:35]([CH2:36][C@H:37]2[C:42]([O:44][CH3:45])=[O:43])[O:34][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25](OS(C(F)(F)F)(=O)=O)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:46][C@H:9]2[O:8][C:7](=[O:47])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:48]([Sn](CCCC)(CCCC)C=C)[CH2:49]CC>O1CCOCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C@H:5]1[C:39](=[O:40])[N:38]2[CH2:41][C@@H:35]([CH2:36][C@H:37]2[C:42]([O:44][CH3:45])=[O:43])[O:34][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([CH:48]=[CH2:49])=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:46][C@H:9]2[O:8][C:7](=[O:47])[NH:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OS(=O)(=O)C(F)(F)F)O2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1c2c(nc3ccccc13)O[C@@H]1C[C@@H](C(=O)OC)N(C1)C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCC2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 244 step 1 (100 mg, 0.146 mmol) in dioxane (3 ml) was added tributyl(vinyl)stannane (92 mg, 0.292 mmol), copper (I) iodide (5.55 mg, 0.029 mmol) and tetrakis (33.7 mg, 0.029 mmol). After purging with N2 for 5 min, the reaction was stirred at 80° C. for 16 hours. After cooling to room temperature, water was added and the reaction was extracted with ethyl acetate, washed with brine, dried (Na2SO4) and concentrated. Purification by PTLC (30% EtOAc/hexane) provided the desired compound.
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O1CCOCC1.Cl>[OH-].[Na+]>[CH2:12]([O:19][C:20]([NH:1][C@H:2]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][C:4]([OH:6])=[O:5])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CC(=O)O)c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C[C@H](NC(=O)OCc1ccccc1)c1cccs1

Procedure:
(S)-3-amino-3-(thiophen-2-yl)propanoic acid (0.894 g) and benzyloxycarbonyl chloride 0.980 g) were stirred in 2M NaOH (8 mL) and dioxane (26 mL) at 0° C. for 24 hours. The reaction mixture was acidified with concentrated aqueous HCl, extracted twice with ethyl acetate, and the extracts were dried over MgSO4, filtered, concentrated, and chromatographed on silica gel with 50% ethyl acetate/hexanes.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH4+:10].[OH-]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH2:10])(=[O:8])=[O:7]
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1ccco1
Agent: [OH-]
Product: NS(=O)(=O)c1ccco1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Twenty-three g of 2-furansulfonyl chloride (138 mm) was added dropwise into 200 ml of conc. NH4OH at 0°-5°. After stirring overnight at room temperature, the water was removed under vacuum and the precipitate washed with ice water and dried. Yield: 14 g of 2-furansulfonamide, m.p. 120°-122° (literature m.p. 120°-122°: JOC 18, 894 (1953)). IR (Nujol) 3250 cm-1, 3100 cm-1, 1600 cm-1 (W), 1550 cm-1, 1310 cm-1, 1190 cm-1, 1140 cm-1, 1120 cm-1, 1055 cm-1, 1005 cm-1, 930 cm-1, 880 cm-1, 843 cm-1 (S).
Reaction SMILES: [CH:1]([N:3]([C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:19])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:2]>CO>[NH2:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:19])[C:10]=1[N:3]([CH:1]=[O:2])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CN(C=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: CO
Product: CCOC(=O)CN(C=O)c1c(C)cccc1N

Procedure:
A solution of ethyl N-formyl-N-(2-methyl-6-nitrophenyl)glycinate (154 mg, 0.58 mmol) in methanol containing 5% Pd/C (35 mg) was hydrogenated at 1 atmosphere for 1 h. The mixture was filtered through a pad of celite, and the solvent was removed in vacuo affording ethyl N-(2-amino-6-methylphenyl)-N-formylglycinate, 127 mg (93%) as an oil. MS (ESI) m/z 237 [M+H]. 1H NMR (400 MHz, CDCl3) δ ppm 1.30 (t, J=7.2Hz, 3H), 2.14 (s, 3H), 3.60 (d, J=17 Hz, 1H), 4.32-4.18 (m, 2H), 4.70 (br. s, 2 H), 4.77 (d, J=17 Hz, 1H), 6.60 (app t, J=8.0 Hz, 2H), 7.05 (t, J=7.8 Hz, 1H), 8.11 (s,
Reaction SMILES: CI.[C:3](=O)(O)[O-].[Na+].[O:8]=[C:9]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[NH:12][CH2:11][CH:10]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CO>[O:8]=[C:9]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[N:12]([CH3:3])[CH2:11][CH:10]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CN1CC(NC(=O)OC(C)(C)C)C(=O)Nc2ccccc21
Yield: 66.9 %

Procedure:
Methyl iodide (1.4 ml) and sodium bicarbonate (630 mg) were added to a solution of 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (832 mg) in methanol (20 ml), the mixture was refluxed for 2 days. The reaction mixture was concentrated under reduced pressure, Water (30 ml) was added to the residue and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodiun sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1), to thereby obtain 585 mg of the title compound (Yield: 66.9%) as brown amorphous.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([OH:20])=[C:12]([N+:21]([O-:23])=[O:22])[CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH:25]1([CH2:28]O)[CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:10]1[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[C:13]([O:20][CH2:28][CH:25]2[CH2:27][CH2:26]2)=[C:12]([N+:21]([O-:23])=[O:22])[CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: OCC1CC1
Reactant: CCOC(=O)C(CC(C)C)c1cc([N+](=O)[O-])c(O)c(C(F)(F)F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(C)C)c1cc([N+](=O)[O-])c(OCC2CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.5 %

Procedure:
To a solution of 2-(4-hydroxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (2.66 g, 7.62 mmol), cyclopropanemethanol (0.60 g, 8.38 mmol) and triphenylphosphine (2.40 g, 9.14 mmol) in anhydrous THF (32 mL) was added diethyl azodicarboxylate (40 wt % solution in toluene, 3.98 g, 9.14 mmol) dropwise. The reaction mixture was stirred at room temperature for two days and then concentrated under reduced pressure. The residue was triturated with THF/hexane (1:5, 3×15 mL). The combined extracts were concentrated under reduced pressure to give a yellow solid, which was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (60:1 and then 10:1) to give 2-(4-cyclopropylmethoxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (1.89 g, 61%) as a colorless oil: 1H NMR (300 MHz, CDCl3): δ 7.92 (s, 1H), 7.73 (s, 1H), 4.06 (m, 2H), 3.79 (d, 2H, J=7.2 Hz), 3.64 (t, 1H, J=7.5 Hz), 1.93 (m, 1H), 1.55 (m, 1H), 1.40 (m, 1H), 1.24 (m, 1H), 1.17 (t, 3H, J=6.9 Hz), 0.86 (m, 6H), 0.56 (d, 2H, J=6.6 Hz), 0.27 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 172.49, 149.98, 144.40, 135.55, 130.96 (q, J=5 Hz), 128.29, 126.77, (q, J=31 Hz), 122.37 (q, J=272 Hz), 82.03, 61.37, 48.74, 42.66, 26.04, 22.36, 22.32, 14.14, 10.66, 3.39.
Reaction SMILES: [C:1]([CH:9]([NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][CH:20]=O)[CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>CN1CCCC1=O>[C:2]1([C:1](=[O:8])[CH:9]([N:11]2[C:12](=[O:22])[C:13]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:19]=[CH:20]2)[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(NC(=O)c1ccccc1NC=O)C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CN1CCCC1=O
Product: CC(C(=O)c1ccccc1)n1cnc2ccccc2c1=O

Procedure:
A mixture of N-(1-benzoylethyl)-2-(formylamino)-benzamide in N-methyl-pyrrolidone (“NMP”) is dehydrated with concentrated sulfuric acid, cyclizing to provide 3-(1-phenyl-1-oxoprop-2-yl)-quinazolin-4-one.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=[N:11][CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1.O>O1CCCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:30])([F:29])[F:19])[CH:26]=1
Reactant: CN1CCC(N=Cc2nc3ccccc3[nH]2)CC1
Reactant: FC(F)(F)c1cccc([Mg]Br)c1
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(NC(c2cccc(C(F)(F)F)c2)c2nc3ccccc3[nH]2)CC1

Procedure:
To a solution of (1H-benzimidazol-2-ylmethylene)(1-methylpiperidin-4-yl)amine (70 mg) in tetrahydrofurane (3 mL) is added a 1.5M solution of 3-trifluoromethylphenylmagnesium bromide in tetrahydrofurane (0.77 mL) at room temperature. The mixture is then stirred at 40° C. for 1 h, hydrolyzed with water and extracted with ethyl acetate. The pooled organic extracts are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (gradient dichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/0.5) to give [(1H-benzimidazol-2-yl)(3-trifluoromethylphenyl)methyl](1-methylpiperidin-4-yl)amine as a yellow solid melting at 90° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7](O)=O.Cl.C(N(CC)CCCN=C=NCC)C.[NH2:27][C:28]1[C:29](=[O:40])[N:30]([CH2:38][CH3:39])[C:31](=[O:37])[N:32]([CH2:35][CH3:36])[C:33]=1[NH2:34].[OH-].[Na+]>O.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]1[NH:27][C:28]2[C:29](=[O:40])[N:30]([CH2:38][CH3:39])[C:31](=[O:37])[N:32]([CH2:35][CH3:36])[C:33]=2[N:34]=1
Reactant: O=C(O)C=Cc1cccc(Br)c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(Br)c3)nc2n(CC)c1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 51.1 %

Procedure:
3-Bromocinnamic acid (2.52 g, 11.1 mmol) and 3-(3-diethylaminopropyl)-1-ethylcarbodiimide hydrochloride (2.90 g, 15.2 mmol) were added to a solution of 5,6-diamino-1,3-diethyluracil (2.0 g, 10.1 mmol) in a dioxane (34 ml)-water (68 ml) mixture, and the resulting mixture was stirred at room temperature for 40 minutes while keeping the pH at 5.5. A 4N aqueous solution of sodium hydroxide was added thereto to adjust the pH to >14, and the mixture was heated under reflux for 20 minutes. After cooling, the mixture was neutralized and the precipitated crystals were collected by filtration. The obtained crude crystals were recrystallized from tetrahydrofuran/water to give 2.01 g (yield 37%) of Compound g as pale green plates.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1F.[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: Fc1ccc(C2=NOC(COc3ccon3)C2)cc1F
Reactant: c1nc[nH]n1
Product: Fc1cc(C2=NOC(COc3ccon3)C2)ccc1-n1cncn1

Procedure:
(5RS)-3-(3,4-Difluorophenyl)-5-isoxazol-3-yloxymethyl-4,5-dihydroisoxazole (140 mg, 0.5 mM) was treated with 1,2,4-triazole using essentially the conditions of Example 5. Crude product was chromatographed on a 5 g silica Mega Bond Elut® column, eluting with a gradient from 0–25% ethyl acetate in dichloromethane. Relevant fractions were combined to give the desired product (45 mg). MS (ESP): 330 (MH+) for C15H12FN5O3
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:10][O:11][C:12]=2[CH2:13]Br)[CH:5]=[CH:4][N:3]=1.[CH3:22][O-:23].[Na+]>[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:10][O:11][C:12]=2[CH2:13][O:23][CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccc(-c2noc(CBr)c2-c2ccnc(Br)c2)cc1
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COCc1onc(-c2ccc(F)cc2)c1-c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
To the above Compound 18b (200 mg, 0.485 mmol) was added NaOMe (0.5 M in MeOH, 2.0 mL, 1.0 mmol). The solution was stirred at 25° C. for 90 min. Then, the solution was poured into brine, extracted with EtOAc (4×15 mL), dried (MgSO4), filtered through a silica plug. Evaporation of the solvent provided the title compound (175 mg, 0.482 mmol, 99%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]([NH:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:14])=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: Nc1nc(-c2ccco2)c2ncn(CC(=O)O)c2n1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2ccco2)c2ncn(CC(=O)NCc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A suspension of 2-amino-6-(2-furyl)-9H-purine-9-acetic acid (129 mg, 0.5 mmol) in DMF (2 mL) was treated with carbonyl diimidazole (81 mg, 0.5 mmol), stirred at room temperature for 1 h, treated with benzylamine (55 μL, 0.5 mmol), stirred at room temperature for 2 h, diluted with water, filtered and dried to give the title compound (115 mg, 66%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][CH2:16][CH2:17]Cl)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][CH2:16][CH2:17][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(OCCCl)c2ccccc2)cc1
Reactant: C1CNCCN1
Product: Cc1ccc(C(OCCN2CCNCC2)c2ccccc2)cc1
Yield: 65 %

Procedure:
Following a procedure similar to that described in Preparation 5(c), but using 2-[α-(4-methylphenyl)-benzyloxy]ethyl chloride and anhydrous piperazine, the title compound was obtained in a yield of 65%.
Reaction SMILES: [Si](N1C(CO[Si](C(C)(C)C)(C)C)CCC1=O)(C(C)(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].C(OC([N:37]1[CH2:41][C@@H:40]([S:42][C:43]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:39][C@H:38]1CI)=O)C=C>>[C:43]([S:42][CH:40]1[CH2:41][NH:37][CH2:38][CH2:39]1)([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CI
Agent: CC(C)(C)[Si](C)(C)OCC1CCC(=O)N1[Si](C)(C)C(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: c1ccc(C(SC2CCNC2)(c2ccccc2)c2ccccc2)cc1
Yield: 32.9 %

Procedure:
The same procedure as in Reference Example 22-1 was carried out by using N-tert-butyldimethylsilyl-5-tert-butyldimethylsiloxymethyl-2-oxopyrrolidine (10.67 g, 31.6 mmol), lithium diisopropylamide (2.1M tetrahydrofuran solution, 15.1 ml, 31.6 mmol) and (2S,4S)-N-allyloxycarbonyl-2-iodomethyl-4-tritylthiopyrrolidine (10 g, 17.6 mmol) to obtain (2R,4S)-N-allyloxycarbonyl-2-(5S)-5-hydroxymethyl-2-oxopyrrolidin-3-ylmethyl]-4-tritylthiopyrrolidine (2 g, yield: 21%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Br:12])[CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C.CO.O>C1(C)C=CC=CC=1>[Br:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[Cl:11])[CH2:4][OH:3]
Reactant: CCOC(=O)c1ccc(Cl)c(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: OCc1ccc(Cl)c(Br)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of ethyl-3-bromo-4-chlorobenzoate (3.25 g, 12.34 mmol) in toluene (70 mL) was added, at −78° C. under argon, diisobutylaluminum hydride (1.5M in toluene, 24 mL, 37.01 mmol). The reaction mixture was stirred at −78° C. for 1 hr then methanol (9 mL) and water (18 mL) was added. The solution was warmed up to room temperature and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 2.73 g of 3-bromo-4-chloro-benzyl alcohol.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][N:8]([CH2:22][C:23]2C=CC=CC=2)[CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClCC(Cl)=[O:32]>>[CH:1]1([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][N:12]([C:13]3[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)[C:23](=[O:32])[CH2:22]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ccc(NCCCN(CCC2CCCC2)Cc2ccccc2)cc1
Reactant: O=C(Cl)CCl
Product: O=C1CN(CCC2CCCC2)CCCN1c1ccc([N+](=O)[O-])cc1

Procedure:
In a manner similar to Preparation 13 react N-[2 (cyclopentyl)ethyl]-N'-(4-nitrophenyl)-N-(phenylmethyl)1,3-propanediamine with chloroacetyl chloride to obtain the title compound.
Reaction SMILES: [C:1]([C:3]([C:16](=[O:25])[NH:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[CH:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)#[N:2].[Na+].Cl>O.CO>[C:1]([C:3]([C:16](=[O:25])[NH:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:14][CH:15]=1)#[N:2]
Reactant: N#CC(=Cc1ccc(OCC(=O)[O-])cc1)C(=O)NCc1cccnc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CC(=Cc1ccc(OCC(=O)O)cc1)C(=O)NCc1cccnc1
Reaction time: 8 h

Procedure:
The filtrate and the remainder of the solid from Example 82 were dissolved in water (100 ml)/methanol (100 ml), and neutralized with 20 ml of 0.1 mol/l hydrochloric acid. Methanol was evaporated and impurities were removed by extraction with ethyl acetate. The aqueous layer was filtered to remove insoluble components, concentrated to about 50 ml, and then allowed to stand overnight. The precipitated solid was filtered, washed with a small amount of acetone, and then dried by heating under reduced pressure to give the compound of interest (102 mg, 19%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Brc1ccc(Br)nc1
Product: Clc1cccc(Nc2ccc(Br)cn2)c1
Temperature: 180 °C

Procedure:
A 1-dram vial was charged with 2,5-dibromopyridine (0.5 g, 2.1 mmol, 1.0 equiv) and 3-chlorophenyl amine (0.89 mL, 8.4 mmol. 4 equiv). The neat reaction mixture was heated to 180° C. for 3 hours. The reaction was cooled, then purified by flash chromatography to afford the title compound. (M+H)+ 285.0.
Reaction SMILES: N[C:2]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[Cl:26])=[CH:11][C:3]=1[C:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[O:5].C(O)(=O)C.[N+:31]([O-:34])(O)=[O:32].OO>O>[Cl:26][C:17]1[CH:18]=[C:19]([C:22]([F:23])([F:25])[F:24])[CH:20]=[CH:21][C:16]=1[O:15][C:12]1[CH:13]=[CH:14][C:2]([N+:31]([O-:34])=[O:32])=[C:3]([CH:11]=1)[C:4]([NH:6][S:7]([CH3:10])(=[O:8])=[O:9])=[O:5]
Reactant: CS(=O)(=O)NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1N
Reactant: O=[N+]([O-])O
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
A stirred solution is prepared containing 39.5 g of 2-amino-5-(2-chloro-4-trifluoromethylphenoxy)-N-methanesulphonyl benzamide of the formula (V), R1 =methyl, 1380 ml of glacial acetic acid and 1.0 g of concentrated nitric acid at about 40° C. To the solution is added 138 g of a 30% by weight hydrogen peroxide in water solution and the reaction mixture is raised to and maintained at about 70° C. for 20 hours. The solution is then poured slowly into about 3 liters of ice water with precipitation of crude product. After filtration, the product is isolated as a solid, m.p. 175°-183° C., containing 68% of the compound of formula (I), R1 =methyl, as determined by high pressure liquid chromatography, thin layer chromatography and its mass spectrum. Recrystallization from aqueous methanol yields the product 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitro-N-methanesulphonyl benzamide, m.p. 216°-218° C.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:25])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].[CH3:32][O:33][CH2:34][CH2:35]Cl>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:35][CH2:34][O:33][CH3:32])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COCCCl
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccc(F)cc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(OCCOC)cccc2c1Nc1ccc(F)cc1C
Yield: 10.3 %

Procedure:
A solution of 3-butyryl-4-(4-fluoro-2-methylphenyl-amino)-8-hydroxyquinoline (3.38 g,. 10 mmol) and potassium t-butoxide (1.68 g, 15 mmol) in tetrahydrofuran (75 ml) was warmed to near boiling, chloroethyl methyl ether (1.83 ml, 20 mmol) added, and the mixture heated at reflux for 3 days. The solvent was evaporated then the product taken up in dichloromethane, washed with water and brine, dried and evaporated. Chromatography (silica gel, ethyl acetate/2% acetic acid/0-5% methanol) and recrystallisation from ethyl acetate/petroleum ether gave 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-(2-methoxyethoxy)quinoline (0.41 g), m.p. 124°-5°.