Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][N:4]([CH2:13][CH2:14][CH2:15][NH2:16])[CH:3]3[CH2:2]1.C([O-])(O)=O.[Na+].[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(Cl)Cl>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][N:4]([CH2:13][CH2:14][CH2:15][NH:16][C:22](=[O:24])[CH3:23])[CH:3]3[CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: NCCCN1CCc2cccc3c2C1CC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCCCN1CCc2cccc3c2C1CC3
Reaction time: 1.5 h
Yield: 86.6 %

Procedure:
3-(2,2a,4,5-Tetrahydro-1H-3-aza-acenaphthylen-3-yl)-propylamine (516 mg, 2.39 mmol) was disolved in a vigorously stirred mixture of CH2Cl2 (2.7 ml) and NaHCO3 (sat. solution, 2.7 ml). After the addition of acetic anhydride (348.9 mg, 3.42 mmol), stirring was applied for 90 min at room temperature. Then, the layers were separated. Water (6 ml) was added to the bicarbonate layer and was extracted with CH2Cl2 (3×6 ml). The combined organic layers were dried with Na2SO4, filtered and evaporated too dryness to afford as slightly brown solid identified as the acetylated compound (535 mg, 87% yield).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[CH:28]=3)[CH:23]=2)=[O:21])=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].CCS>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]4)[CH:28]=3)[CH:23]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc3cc(OCCN4CCCCC4)ccc3c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: O=C(c1ccc2cc(OCCN3CCCCC3)ccc2c1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Yield: 42.9 %

Procedure:
In a manner similar to that used in Example 2, 1.4 g (2.54 mmol) of [2-(4-methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][6-[2-(1-piperidinyl)ethoxy]naphth-2-yl]methanone, 1.4 g (10.2 mmol) of AlCl3, and 2 mL (12.7 mmol) of EtSH was converted to 570 mg of the title compound as a yellow powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.O>[Fe].CC(O)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 80 °C
Reaction time: 1.75 h

Procedure:
Iron powder (5.4 g, 97 mmol, 4 equiv) is added portionwise to an 80° C. mixture of 1-benzyl-4-(4-nitro-phenyl)-piperazine (7.2 g, 24.2 mmol), EtOH (150 mL), H2O (40 mL), and AcOH (20 mL). The reaction mixture is stirred for 1.75 h at 80° C., allowed to cool to RT, and concentrated. The residue is diluted with EtOAc and an aqueous saturated solution of Na2CO3. The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic phase is washed with brine, dried (Na2SO4), filtered and concentrated to afford the title compound: ES-MS: 268.3 [MH]+; single peak at tR=1.30 min (system 1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:8][C:9]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:7])[CH3:6]>S(=O)(=O)(O)O>[C:5]([NH:8][C:9]1[CH:18]=[C:17]([F:19])[C:16]([N+:1]([O-:4])=[O:2])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(F)cc1NC(C)=O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(F)cc1NC(C)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a three-neck flask (2,000 ml) was added concentrated nitric acid (500 ml). The mixture was cooled in an ice-water bath. Concentrated sulfuric acid (500 ml) was dropwise added to the mixture under mechanical stirring. After addition, the temperature of the resulting mixture was maintained below 15° C. Methyl 2-acetylamino-4-fluoro-benzoate (105.5 g, 0.5 mol) was slowly added. The resultant mixture was kept in an ice-water bath for 40 min with stirring. Then the mixture was poured into ice water (8 L). A large number of yellow solids precipitated. The mixture was stood for 10 min and filtered in vacuo. The filter cake was washed with lots of water and then transferred in water (2 L). The pH of the solution was adjusted to 7 with ammonia liquor under stirring and filtered in vacuo. The filter cake was dried by baking and recrystallized with ethyl acetate.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[C:5]1[CH2:6][S:7][C@@H:8]2[CH:28]([NH:29][C:30](=[O:69])/[C:31](=[N:57]\[O:58][C:59]([CH3:68])([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH3:60])/[C:32]3[N:33]=[C:34]([NH:37][C:38]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[S:35][CH:36]=3)[C:27](=[O:70])[N:9]2[C:10]=1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[I-:71].[Na+]>CC(C)=O.C(OCC)(=O)C>[I:71][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH2:6][S:7][C@@H:8]2[CH:28]([NH:29][C:30](=[O:69])/[C:31](=[N:57]\[O:58][C:59]([CH3:68])([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH3:60])/[C:32]3[N:33]=[C:34]([NH:37][C:38]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[S:35][CH:36]=3)[C:27](=[O:70])[N:9]2[C:10]=1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
A mixture of diphenylmethyl 3-[(Z)-3-chloro-1-propen-1-yl]-7-[(Z)-2-(1-methyl-1-t-butoxycarbonylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxy-late (IXa) (488 mg, 0.5 mmol) and sodium iodide (225 mg, 1.5 mmol) in acetone (5 ml) was stirred at room temperature for 2 hours and diluted with ethyl acetate. The organic layer was washed with an aqueous sodium thiosulfate, dried over anhydrous MgSO4 and concentrated to afford 546 mg (yield, quantitative) of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[SH:16][CH2:17][CH2:18]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:9][N:10]3[CH:14]=[N:13][CH:12]=[N:11]3)[S:16][CH2:17][CH2:18][O:15]2)=[CH:4][CH:3]=1
Reactant: O=C(Cn1cncn1)c1ccc(Br)cc1
Reactant: OCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: Brc1ccc(C2(Cn3cncn3)OCCS2)cc1
Yield: 15.3 %

Procedure:
To a slurry of 27.8 g 1-(4-bromophenyl)-2-(1H-1,2,4-triazol-1-yl) ethanone in 350 ml dry toluene and 175 ml 1-butanol were added 15.6 g 2-mercaptoethanol and 24.7 g p-toluenesulfonic acid. The mixture was refluxed under a Dean-Stark trap for 50 hours. After cooling, a white solid was removed by filtration and the filtrate evaporated. The residue was taken up in chloroform and washed twice with 10% aqueous sodium hydroxide and once with water. The organic layer was dried, filtered and evaporated to leave a liquid residue. The 1-butanol in the residue was removed azeotropically three times with cyclohexane leaving a slurry. The solid was isolated by filtration to give 5.2 g of product.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][N:5]1[CH2:29][C@:28]2([C:30](=[O:36])[CH2:31][O:32]C(=O)C)[C@@H:7]([CH2:8][C@H:9]3[C@H:22]4[C@@:13]([F:26])([C@:14]5([CH3:25])[C:19]([C@@H:20]([F:23])[CH2:21]4)=[CH:18][C:17](=[O:24])[CH:16]=[CH:15]5)[C@@H:12]([OH:27])[CH2:11][C@@:10]32[CH3:37])[CH2:6]1.C1(CN2C[C@]3(C(=O)CO)[C@@H](C[C@H]4[C@H]5[C@@](F)([C@]6(C)C([C@@H](F)C5)=CC(=O)C=C6)[C@@H](O)C[C@@]43C)C2)CC1>>[CH3:1][C:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][N:5]1[CH2:29][C@:28]2([C:30](=[O:36])[CH2:31][OH:32])[C@@H:7]([CH2:8][C@H:9]3[C@H:22]4[C@@:13]([F:26])([C@:14]5([CH3:25])[C:19]([C@@H:20]([F:23])[CH2:21]4)=[CH:18][C:17](=[O:24])[CH:16]=[CH:15]5)[C@@H:12]([OH:27])[CH2:11][C@@:10]32[CH3:37])[CH2:6]1
Reactant: CC(=O)OCC(=O)[C@@]12CN(CCC(C)(C)C)C[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Agent: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3C[C@H]4CN(CC5CC5)C[C@@]4(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Product: CC(C)(C)CCN1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)C1
Yield: 69 %

Procedure:
The title compound is prepared from compound 56 following the procedure described in Example 10 for the synthesis of compound 45.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:5]=2[C:6]=1[N+:7]([O-:9])=[O:8].O.[OH-].[Na+]>C(OCC)(=O)C>[CH3:1][C:2]1[O:3][C:4]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:5]=2[C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: Cc1oc2ccc([N+](=O)[O-])cc2c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1oc2ccc(N)cc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 70 h
Yield: 44.9 %

Procedure:
To a solution of 2-methyl-3,5-dinitrobenzofuran (4.4 g, 19.8 mmol) in ethyl acetate (250 mL) was added stannous chloride (dihydrate, 8.99 g, 39.8 mmol). The mixture was stirred at room temperature for 70 hours. Water (100 mL) and 1N NaOH (100 mL) were added. The mixture was extracted with ethyl acetate (4×150 mL). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographed (silica, 20-30% ethyl acetate in hexanes) to give 2-methyl-3-nitro-5-benzofuranamine as a yellow solid (1.71 g, 45%): 1H-NMR (270 MHz, CDCl3) δ 7.38 (d, 1H, J=2.8 Hz), 7.25 (d, 1H, J=8.8 Hz), 6.72 (dd, 1H, J=8.8, 2.8 Hz), 2.87 (s, 3H); HPLC (Method A) tR=1.36 min.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([OH:17])[C:8]([C:14](=[O:16])[CH3:15])=[CH:9][C:10]=1[C:11](=[O:13])[CH3:12])(=O)C.Cl>C(O)C>[C:11]([C:10]1[CH:9]=[C:8]([C:14](=[O:16])[CH3:15])[C:7]([OH:17])=[CH:6][C:5]=1[NH2:4])(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1cc(O)c(C(C)=O)cc1C(C)=O
Agent: Cl
Solvent: CCO
Product: CC(=O)c1cc(C(C)=O)c(O)cc1N
Yield: 91 %

Procedure:
3-Acetamido-4,6-diacetylphenol (250 g) was suspended in ethanol (2 l) containing conc. hydrochloric acid (200 ml) and heated on a steam bath for 5 hours. The mixture was allowed to cool, and the crystalline product isolated by filtration. Yield 91%, mp 227°-230° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](Cl)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=1.N1C=CC=CC=1.O>ClCCl>[Cl:1][C:2]1[C:3]([C:12]([NH:15][C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:18][CH:17]=2)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1nc2ccccc2nc1Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)c2nc3ccccc3nc2Cl)cc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A solution of 3-chloroquinoxaline-2-carbonyl chloride (1.0 g, 4.40 mmol) in dichloromethane (9.2 mL) was added dropwise to a mixture of tert-butyl 4-aminobenzoate (851.0 mg, 4.40 mmol), pyridine (1.07 mL, 13.21 mmol) and dichloromethane (13.8 mL) at 0° C. The reaction was stirred and allowed to warm up to room temperature over 40 minutes. To the reaction, water (10 mL) was added. The two layers were separated. The organic layer was washed with water (2×10 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The product was slurried in hexanes at 40° C., and the solid was isolated by filtration to yield tert-butyl 4-[(3-chloroquinoxaline-2-carbonyl)amino]benzoate (1.34 g, 79%) as a yellow solid. ESI-MS m/z calc. 383.10, found 384.4 (M+1)+; Retention time: 1.88 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.27 (dd, J=7.5, 2.1 Hz, 1H), 8.22-8.11 (m, 1H), 8.11-8.01 (m, 2H), 7.97 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.7 Hz, 2H), 1.56 (s, 9H) ppm.
Reaction SMILES: [ClH:1].[CH3:2][CH2:3][OH:4].[F:5][C:6]1[C:19]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[N:28][C:29]([N:32]4[CH2:35][CH:34]([O:36][CH3:37])[CH2:33]4)=[N:30][CH:31]=3)[CH2:22][CH2:21]2)=[CH:18][CH:17]=[CH:16]C=1CNC(NC(=O)[O-])=N.C[CH2:39][OH:40]>>[ClH:1].[ClH:1].[ClH:1].[C:29]([NH:32][C:39](=[O:40])[O:4][CH2:3][C:2]1[CH:16]=[CH:17][CH:18]=[C:19]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:31]=[N:30][C:29]([N:32]4[CH2:35][CH:34]([O:36][CH3:37])[CH2:33]4)=[N:28][CH:27]=3)[CH2:24][CH2:25]2)[C:6]=1[F:5])(=[NH:28])[NH2:30]
Reactant: COC1CN(c2ncc(N3CCN(c4cccc(CNC(=N)NC(=O)[O-])c4F)CC3)cn2)C1
Reactant: CCO
Agent: Cl
Product: COC1CN(c2ncc(N3CCN(c4cccc(COC(=O)NC(=N)N)c4F)CC3)cn2)C1
Temperature: 25 °C

Procedure:
A 4M hydrogen chloride/EtOH solution (1.5 ml) was added to a mixture of 2-fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzylcarbamimidoylcarbamate (285 mg) and EtOH (5 ml), followed by stirring at room temperature. The precipitated yellow solid was collected by filtration and washed with EtOH. The obtained solid was dried at 40° C. under reduced pressure to obtain 2-fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzyl carbamimidoylcarbamate trihydrochloride (330 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:24])[CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=1>C1C=CC=CC=1>[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:24])[CH2:20][C:21]([Cl:3])=[O:22])=[CH:15][CH:14]=1
Reactant: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(CC(=O)Cl)c1ccc(-c2ccc(F)cc2F)cc1
Reaction time: 24 h

Procedure:
6 g. of thionyl chloride and 10 g. of 3-(2',4'-difluoro-4-biphenylyl)butyric acid in 80 ml. of benzene are allowed to stand at 25° for 24 hours and the mixture is evaporated under reduced pressure to give 3-(2',4'-difluoro-4-biphenylyl)butyryl chloride.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[CH3:12][S:13]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][CH:23]=[CH:22]2)(=[O:15])=[O:14].O[CH:27]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[CH:28]1[CH2:30][CH:29]1[C:31]#[N:32]>ClCCl>[CH3:39][C:36]1[CH:37]=[CH:38][C:33]([CH:27]([C:22]2[C:21]3[C:25](=[C:17]([CH2:16][S:13]([CH3:12])(=[O:15])=[O:14])[CH:18]=[CH:19][CH:20]=3)[NH:24][CH:23]=2)[CH:28]2[CH2:30][CH:29]2[C:31]#[N:32])=[CH:34][CH:35]=1
Reactant: Cc1ccc(C(O)C2CC2C#N)cc1
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(c2c[nH]c3c(CS(C)(=O)=O)cccc23)C2CC2C#N)cc1

Procedure:
195 mg (0.88 mmol) of indium(III) chloride and 0.11 ml (1.44 mmol) of trifluoroacetic acid were added to 168 mg (0.80 mmol) of the compound from Example 86A and 150 mg (0.80 mmol) of the compound from Example 158A under argon in 9 ml of dichloromethane, and the mixture was heated under reflux for 1 h. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 100 mg (33% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[NH:23])[NH:21][OH:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12])(C)(C)C.[CH2:25]([N:27]([CH2:30][C:31]1[S:35][C:34]([C:36](O)=O)=[CH:33][C:32]=1[CH3:39])[CH2:28][CH3:29])[CH3:26]>Cl.O1CCOCC1.O>[NH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:23]=[C:36]([C:34]3[S:35][C:31]([CH2:30][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[C:32]([CH3:39])[CH:33]=3)[O:22][N:21]=2)=[CH:18][CH:19]=1)(=[O:12])=[O:13]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(C(=N)NO)cc1
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(S(=O)(=O)NCCN)cc3)no2)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.5 %

Procedure:
Crude (2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzenesulfonylamino}-ethyl)-carbamic acid tert-butyl ester (156 mg) is obtained starting from {2-[4-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]-ethyl}-carbamic acid tert-butyl ester (277 mg, 0.774 mmol) and 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (160 mg, 0.704 mmol) according to Method A; LC-MS: tR=0.61 min; [M+1]+=550.16. This material (156 mg, 0.284 mmol) is dissolved in 4 M HCl in dioxane (5 mL) and the mixture is stirred at rt for 18 h. The mixture is diluted with water and washed with EA. The organic washing is extracted with water. The combined aq. extracts are neutralised by adding sat. aq. NaHCO3 solution and extracted twice with EA. These organic extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC (XBridge, eluting with a gradient of acetonitrile in water containing 0.5% of aq. ammonia) to give the title compound (11 mg) as a pale yellow oil; LC-MS: tR=0.42 min; [M+1]+=449.64.
Reaction SMILES: C(OCC[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)(=O)C.[C:21](Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:21]([Br:22])[C:9]#[C:8][CH2:7][CH2:12][CH2:11][CH2:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCc1ccc(CCOC(C)=O)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCC#CCBr
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In a reaction vessel equipped with a calcium chloride tube, 8.465 g of the compound of (2) above was dissolved in 85 ml of dichloromethane and 15.683 g of carbon tetrabromide and 14.867 g of triphenylphosphine were added thereto under ice-cooling. The mixture was stirred at 0° C. for 5 minutes. The reaction mixture was concentrated under reduced pressure and the residue was extracted with hexane. The hexane extract obtained was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 7.964 g of 2-pentadecynyl bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](/[C:15](/[CH3:35])=[CH:16]/[CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([O:32][CH2:33][CH3:34])[C:27]([O:29]CC)=[O:28])=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](/[C:15](/[CH3:35])=[CH:16]/[CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([O:32][CH2:33][CH3:34])[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=3)=[CH:13][CH:14]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(Cl)cc(Cl)c3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(Cl)cc(Cl)c3)cc2)cc1)C(=O)O
Yield: 86.9 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 3-{4-[3-(3′,5′-dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate (example 125) (513 mg, 1.0 mmol) and sodium hydroxide (1M, 5.0 ml, 5.0 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-3-{4-[3-(3′,5′-dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid (422 mg, 87%) as a colourless glass.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1O.C[O:10][C:11](=[O:24])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:21]#N)=[CH:16][C:15]=1[CH3:23]>>[C:2]1([C:1]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH:7]=[CH:6][C:5]([CH2:21][S:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]([OH:10])=[O:24])=[C:15]([CH3:23])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1O
Reactant: COC(=O)COc1ccc(SC#N)cc1C
Product: Cc1cc(SCc2ccc(-c3ccccc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in a manner analogous to Example 1B from 2-methylphenol. 400 MHz 1H NMR (DMSO-d6) δ 10.09 (s, 1H), 7.36 (s, 1H), 7.30 (d, 1H, J=8.1 Hz), 6.83 (d, 1H, J=8.1 Hz), 2.08 (s, 3H); MS m/z 166 (M+1). Step 2. Preparation of (2-Methyl-4-thiocyanato-phenoxy)-acetic acid methyl ester (Compound 2B)
Reaction SMILES: CNCC[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.ClC1C=CC=C(Cl)C=1C(Cl)=[O:17]>>[C:9]([NH2:8])(=[O:17])[C:10]1[CH:5]=[CH:6][CH:7]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CNCCC#Cc1ccccn1
Product: NC(=O)c1ccccc1
Yield: 45 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2,6-dichlorobenzoyl chloride (85 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 47 mg of 2,6-dichloro-N-methyl-N-(4-pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 45%).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:9][CH:8]=1)C.O[C:24]1[CH:37]=[CH:36][C:27]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:29])=[CH:26][CH:25]=1>>[C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH3:21])[C:4]([OH:3])=[O:22])=[CH:12][CH:11]=2)=[CH:32][CH:31]=1)(=[O:29])[C:27]1[CH:36]=[CH:37][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCCO)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(6-Hydroxy-hex-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 49, Step A) and 4-hydroxybenzophenone via the standard Mitsunobu coupling-hydrolysis procedure (Standard Procedure A) to produce the title compound. MS(ES) for C29H28O5 [M+H]+: 457.2.
Reaction SMILES: [BrH:1].C(OC([NH:9][CH2:10][C:11]#[C:12][CH2:13][NH:14][C:15](=[NH:18])[CH2:16][F:17])=O)CCC.Br>C(O)(=O)C>[BrH:1].[BrH:1].[NH2:9][CH2:10][C:11]#[C:12][CH2:13][NH:14][C:15](=[NH:18])[CH2:16][F:17]
Reactant: CCCCOC(=O)NCC#CCNC(=N)CF
Agent: Br
Solvent: CC(=O)O
Product: N=C(CF)NCC#CCN
Reaction time: 1 h

Procedure:
1-Butoxycarbonylamino-4-(1-imino-2-fluoroethylamino) but-2-yne hydrobromide (500 mg) was deprotected by dissolving in glacial acetic acid (10 ml), cooling until the solution almost solidified and adding HBr in acetic acid (45% wv, 1.8 ml). The mixture was stirred with cooling for 1 h then at room temperature for 1 h. After this time the mother liquor was decanted off and the sticky residue subjected to an oil pump vacuum to remove residual solvent. The resulting material was triturated with dry diethyl ether (×2), filtered off and washed with more dry diethyl ether. The yellow solid was recrystallised from ethanol/diethyl ether and finally dried in a drying pistol to yield 1-amino-4-(1-imino-2-fluoroethylamino)but-2-yne dihydrobromide, Mpt 174°-176.5° C.(dec.), FAB M.S. M+1+144.