Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].C[Si]([C:18]#[N:19])(C)C.C(OCC)C.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CO.[I-].[Zn+2].[I-]>[C:18]([C:10]1([N:28]2[CH2:29][CH2:30][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH2:27]2)[CH2:11][CH2:12][N:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[CH2:8][CH2:9]1)#[N:19]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCCS(=O)(=O)N1CCC(=O)CC1
Agent: [I-]
Agent: [Zn+2]
Solvent: CO
Solvent: CCOCC
Product: CCCS(=O)(=O)N1CCC(C#N)(N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a flask in an ice-bath was added 1-(propylsulfonyl)piperidin-4-one (5.0 g, 24.4 mmol), trimethylsilylcyanide (3.25 mL, 24.2 mmol) and diethyl ether (3 mL) followed by addition of zinc iodide (0.005 g). This gave a yellow suspension which turned to an orange solution after 20 min stirring at room temperature. To the solution was added a solution of tert-butyl piperazine-1-carboxylate (4.54 g, 24.4 mmol) in methanol (35 mL). The solution was then refluxed overnight. The reaction was cooled and more trimethylsilylcyanide (0.5 eq) and zinc iodide (0.005 g) were added. The reaction was heated at reflux overnight and no starting material remained by TLC. The reaction mixture was evaporated to dryness and the product crystallised from ethyl acetate/iso-hexane to give tert-butyl 4-[4-cyano-1-(propylsulfonyl)piperidin-4-yl]piperazine-1-carboxylate as an off-white crystalline solid. 1H NMR (360 MHz, CDCl3): δ 3.80 (d, J=13.5 Hz, 2 H); 3.48 (t, J=4.9 Hz, 4 H); 3.15-3.09 (m, 2 H); 2.93-2.89 (m, 2 H); 2.60 (t, J=4.9 Hz, 4 H); 2.22 (d, J=13.4 Hz, 2 H); 1.91-1.81 (m, 4 H); 1.47 (s, 9 H); 1.07 (t, J=7.4 Hz, 3 H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])(=O)=O)=CC=1.[C:23]([O-:26])([O-])=O.[K+].[K+].[C:29]([O:40][CH3:41])(=[O:39])[C:30]1[CH:38]=[C:36]([OH:37])[C:34]([OH:35])=[C:32]([OH:33])[CH:31]=1>CC(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:20]([CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:37][C:36]1[CH:38]=[C:30]([CH:31]=[C:32]([O:33][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])[C:34]=1[O:35][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:26][CH2:23][CH2:19][N:20]=[N+:21]=[N-:22])[C:29]([O:40][CH3:41])=[O:39])=[N+:21]=[N-:22]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCN=[N+]=[N-])cc1
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCCOCCOCCN=[N+]=[N-])c(OCCOCCOCCN=[N+]=[N-])c(OCCOCCOCCN=[N+]=[N-])c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a solution in which the 2-(2-(2-azidoethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (4.80 g, 14.57 mmol) compound of Chemical Formula 9 was dissolved in acetone (15 mL), K2CO3 (2.05 g, 14.85 mmol), the methyl gallate (650.9 mg, 3.53 mmol) compound of Chemical Formula 10 and tetrabutylammonium bromide (25 mg) were added consecutively at room temperature. The reaction mixture was heated under reflux for 17 hours, cooled to room temperature, and partitioned to distilled water (40 mL) and ethyl acetate (150 mL). The organic layer was separated, washed with saturated salted water (15 mL), dried with anhydrous sodium sulfate, filtered and vacuum distilled, and the residue obtained was column chromatographed on silica gel (hexane/ethyl acetate (1:1.5)) to give methyl 3,4,5-tris(2-(2-(2-azidoethoxy)ethoxy)ethoxy)benzoate (2.18 g, 94%). 1H NMR (500 MHz, CDCl3) δ 7.29 (s, 2H), 4.18-4.23 (m, 6H), 3.86-3.88 (m, 7H), 3.81 (t, 2H, J=5.0 Hz), 3.70-3.74 (m, 6H), 3.63-3.67 (m, 12H), 3.36-3.39 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][OH:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]([CH3:22])[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1.O[C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]([CH3:22])[CH:13]=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1)[CH2:23][O:24][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]=1
Reactant: COc1cc(CO)ccc1OCc1nc(-c2ccccc2)cn1C
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)cn1C
Reaction time: 15 h
Yield: 51.2 %

Procedure:
To a mixture of {3-methoxy-4-[(1-methyl-4-phenyl-1H-imidazol-2-yl)methoxy]phenyl}methanol (1.00 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.64 g), tributylphosphine (0.95 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.19 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(1-methyl-4-phenyl-1H-imidazol-2-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (0.78 g, yield 51%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 126-127° C.
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].[CH3:17][O:18][C:19](=[O:36])[C@@H:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:21]1[C:32](=[O:35])[CH2:33][NH2:34]>CCCCCC.C(OCC)(=O)C>[CH3:17][O:18][C:19](=[O:36])[C@@H:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:21]1[C:32](=[O:35])[CH2:33][NH:34][C:6](=[O:8])[CH:5]([S:4][C:1](=[O:3])[CH3:2])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: COC(=O)[C@@H]1CCC(c2ccccc2O)N1C(=O)CN
Reactant: CC(=O)SC(Cc1ccc(Cl)cc1)C(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCC(c2ccccc2O)N1C(=O)CNC(=O)C(Cc1ccc(Cl)cc1)SC(C)=O
Yield: 53 %

Procedure:
Condensation of 2-acetylthio-3-(para-chlorophenyl)propanoic acid with N-glycyl-5-(ortho-hydroxyphenyl)proline methyl ester, obtained in accordance with the same protocols as those described in Preparation G, yields the expected product in the form of an oil after chromatography in an n-hexane/ethyl acetate mixture, 1:1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][NH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[C:23](O)(=[O:25])[CH3:24]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][N:21]([C:23](=[O:25])[CH3:24])[C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC1c2[nH]ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Reactant: CC(=O)O
Product: CC(=O)n1ccc2c1C(C)N(C(=O)c1cc3ncc(Cl)cn3n1)CC2

Procedure:
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridin-6-yl)-methanone is reacted with acetic acid to provide the title compound.
Reaction SMILES: C(O[CH:5]1[O:21][C@H:20]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:11]([CH:31]=[CH2:32])([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[NH:33]1[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]1=[O:35].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>C(#N)C>[C:8]([O:7][C@@H:6]1[C@:11]([CH:31]=[CH2:32])([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:20]([CH2:22][O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:21][C@H:5]1[N:33]1[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]1=[O:35])(=[O:10])[CH3:9]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)OC(OC(C)=O)[C@@H]1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Yield: 82.9 %

Procedure:
To a stirred solution of compound 22 (4.24 g, 9.6 mmol) and thymine (2.43 g, 19.3 mmol) in anhydrous acetonitrile (100 cm3) was added N,O-bis(trimethylsilyl)acetamide (11.9 cm3, 48.1 mmol). The reaction mixture was stirred at reflux for 30 min. After cooling to 0° C., trimethylsilyl triflate (3.2 cm3, 16.4 mmol) was added dropwise and the solution was stirred for 24 h at room temperature. The reaction was quenched with cold saturated aqueous sodium hydrogencarbonate (100 cm3) and the resulting mixture was extracted with dichloromethane (3×50 cm3). The combined extract was washed with saturated aqueous sodium hydrogencarbonate (2×50 cm3) and brine (2×50 cm3) and dried (Na2SO4). The extract was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1, v/v) as eluent to give nucleoside 23 as a white foam (4.03 g, 83%). δH (CDCl3) 8.78 (1H, br s, NH), 7.75 (1H, s, 6-H), 7.38-7.26 (10H, m, Bn), 6.49 (1H, d, J 8.1, 1′-H), 5.99-5.88 (2H, m, 2′-H and 1″-H), 5.54-5.48 (2H, m, 2″-Ha, 2″-Hb), 4.91-4.50 (4H, m, Bn), 4.34 (1H, s, 4′-H), 3.80 (1H, m, 5′-Ha), 3.54 (1H, m, 5′-Hb), 2.11 (3H, s, COCH3), 1.48 (3H, s, CH3). δC (CDCl3) 170.1 (C═O), 163.8 (C-4), 151.0 (C-2), 138.9, 136.9 (Bn), 136.1 (C-6), 132.0 (C-1″), 128.7, 128.5, 128.2, 127.8, 127.7, 127.5, 127.5, 127.1 (Bn), 120.7 (C-2″), 111.3 (C-5), 85.4 (C-1′), 85.2 (C-3′), 84.3 (C-4′), 76.0 (C-2′), 73.7 (C-5′), 69.3, 67.6 (Bn), 20.6 (COCH3), 11.7 (CH3). Found: C, 66.3; H, 6.0; N, 5.1; C28H30N2O7 requires C, 66.4; H, 6.0; N, 5.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH:15]2[CH2:42][CH2:41][C:18]3[N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:20]=[N:21][C:17]=3[CH2:16]2)=[O:12])=[CH:4][CH:3]=1.ClC1C=CC(CCCC(NCC2CCC3N=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3C2)=O)=CC=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH:15]2[CH2:42][CH2:41][C:18]3[NH:19][CH:20]=[N:21][C:17]=3[CH2:16]2)=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(CCCc1ccc(Cl)cc1)NCC1CCc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: O=C(CCCc1ccc(Cl)cc1)NCC1CCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C1
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCCc1ccc(Cl)cc1)NCC1CCc2[nH]cnc2C1
Temperature: 90 °C

Procedure:
A solution of a mixture of 4-(4-chlorophenyl)-N-((1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)methyl)butyramide and 4-(4-chlorophenyl)-N-((3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)methyl)butyramide (0.43 g, 0.72 mmol) in acetic acid (5 ml) and water (0.6 ml) was heated to 90° C. for 2 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 0.21 g of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]2([CH3:19])[CH3:18])=O.[NH:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)[NH2:21].[CH3:31]N(C)C=O>>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([N:20]2[CH2:2][CH2:3][C:4]([C:6]3[CH:15]=[CH:14][C:13]4[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=4[CH:7]=3)=[N:21]2)=[CH:30][CH:29]=1)([O:28][CH3:31])=[O:27]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CCCl)ccc21
Reactant: CN(C)C=O
Reactant: NNc1ccc(C(=O)O)cc1
Product: COC(=O)c1ccc(N2CCC(c3ccc4c(c3)C(C)(C)CCC4(C)C)=N2)cc1

Procedure:
2.8 g (10 millimoles) of 6-3-chloropropionyl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (for preparation see Example 9) and 1.5 g (10 millimoles) of 4-hydrazinobenzoic acid in 40 ml of dimethylformamide was stirred until the reaction was complete (check by thinlayer chromatography). The mixture was poured onto water and the resulting crystals were filtered off under suction and washed with water and ethanol. Drying gave 2.2 g of the title compound of melting point 276°-278° C.
Reaction SMILES: [CH3:1][C@:2]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][C:5](=[O:7])[N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:3]1.P(OCC)(OCC)[O:24]CC.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[OH:24][CH:6]1[C:5](=[O:7])[N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:3][C@@:2]1([CH3:1])[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17]
Reactant: CCOP(OCC)OCC
Reactant: C[C@H](c1ccccc1)N1C[C@@](C)(C(=O)OC(C)(C)C)CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@@](C)(C(=O)OC(C)(C)C)C(O)C1=O
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a solution of tert-butyl (3S)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (10.0 g, 33.0 mmol) and triethyl phosphite (6.78 mL, 39.6 mmol) in anhydrous tetrahydrofuran (165 mL), lithium bistrimethylsilylamide (46.1 mL, 46.1 mmol, 1.0M solution in tetrahydrofuran) was added at −5° C., and the mixture was stirred at the same temperature for 30 minutes. After bubbling oxygen gas into the reaction mixture for 2 hours, saturated aqueous solution of ammonium chloride (150 mL) was added to the mixture in an ice bath, and the mixture was concentrated under reduced pressure. Water (100 mL) was added to the residue and the mixture was extracted with ethyl acetate (200 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (200 mL), and dried with anhydrous sodium sulfate. After removing the solvent by distillation under reduced pressure, the residue was purified by silica gel column chromatography (hexane : ethyl acetate=1:1→1:4) to obtain 9.61 g (91.3%) of the title compound as a pale yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[C:3]=1[N+:12]([O-:14])=[O:13].S(=O)(=O)(O)O.[CH3:20]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:20])=[O:7])=[C:4]([CH3:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Cc1c(C(=O)O)ccc(N)c1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N)c([N+](=O)[O-])c1C
Temperature: 60 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
A mixture of 4-amino-2-methyl-3-nitrobenzoic acid (synthesized in reagent preparation 22, step 1) (500 mg, 2.6 mmol) methanol (25 mL) and concentrated sulfuric acid (1.25 mL) was stirred at 60° C. for 18 hours. The reaction mixture was cooled concentrated, diluted with ethyl acetate (50 mL), washed with water (50 mL), saturated aqueous sodium bicarbonate solution (2×30 mL), brine (30 mL), dried over sodium sulfate, filtered and concentrated to give the methyl 4-amino-2-methyl-3-nitrobenzoate (400 mg, 75% yield), MS (EI) for C9H10N2O4: 211 (MH+).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:13]=CC=CC=1.C(C(=O)C(=NO)C)C.[F:29][C:30]([F:40])([F:39])C1C=CC=CC=1C=O>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:30]([F:40])([F:39])[F:29])[O:6][C:7]=1[CH2:8][CH3:13]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CCC(=O)C(C)=NO
Product: CCc1oc(-c2ccccc2C(F)(F)F)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, 1-ethyl-1,2-propanedione-2-oxime and 2-trifluoromethylbenzaldehyde gave 4-iodomethyl-5-ethyl-2-(2-trifluoromethylphenyl)oxazole.
Reaction SMILES: [CH2:1]1[CH:3]([CH:4]([OH:7])C#N)[CH2:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].C(N(CC)CC)C>CO>[N+:8]([CH2:11][CH:4]([CH:3]1[CH2:1][CH2:2]1)[OH:7])([O-:10])=[O:9]
Reactant: C[N+](=O)[O-]
Reactant: N#CC(O)C1CC1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=[N+]([O-])CC(O)C1CC1

Procedure:
Example 319 A) To cyclopropyl carboxaldehyde in MeOH is added nitromethane and triethylamine. After stirring, the solvent is removed in vacuo and the residue is dissolved in CH2Cl2. The 2-nitro-1-cyclopropylethanol is isolated from the methylene chloride solution and added to a mixture of sodium acetate and acetic anhydride under N2After stirring, the mixture is diluted with water and extracted with EtOAc. The combined extracts are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. The 2-nitroethenylcyclopropane is used without further purification.
Reaction SMILES: [C:1](=O)([S:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[C:15]([F:17])[C:14]([C:18]2[CH:23]=[N:22][C:21]([NH2:24])=[CH:20][N:19]=2)=[CH:13][CH:12]=1)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:45]([O-])([O-:47])=[O:46].[K+].[K+].BrCC>CO>[CH:45]([OH:47])=[O:46].[CH2:1]([S:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([C:18]2[N:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=2)=[C:15]([F:17])[CH:16]=1)[CH3:2]
Reactant: CC(=O)SCc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCBr
Product: CCSCc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Product: O=CO
Reaction time: 16 h
Yield: 64.9 %

Procedure:
To a solution of S-(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methyl ethanethioate (100 mg, 0.28 mmol) in CH3OH (30 mL) were added Ph3P (147 mg, 0.56 mmol) and K2CO3 (78 mg, 0.56 mmol) followed by drop-wise addition of bromoethane (60 mg, 0.56 mmol). After 16 hours, the mixture was concentrated to dryness and the residue was purified by prep-TLC and followed by HPLC to give the title compound (70 mg HCOOH salt, 73%). MS (ESI): mass calcd. for C19H18FN3S, 339.12; m/z found, 340.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.38 (m, 1H), 8.07 (d, J=1.5, 1H), 7.89 (m, 1H), 7.48-7.40 (m, 1H), 7.37-7.21 (m, 5H), 3.71 (s, 2H), 2.42 (q, J=7.4, 2H), 1.13 (t, J=7.4, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1.O.O.Cl[Sn]Cl>C(O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([NH2:11])[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(Cl)c(N)c1
Temperature: 80 °C
Yield: 69.7 %

Procedure:
To a solution of 4-Chloro-3-nitro-benzoic acid methyl ester (5.0 g, 23.19 mmol) in 100 ml of ethanol was added SnCl2.2H2O (26.0 g, 115.96 mmol) and the reaction mixture was heated at 80° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. Water (100 mL) was added, basified the reaction mixture with NaOH solution and extracted with hot EtOAc (3×250 mL). The combined organics was dried over Na2SO4, filtered and concentrated to give the desired product (3.0 g, 69%).
Reaction SMILES: [B-](F)(F)(F)F.CC[O:8][C:9]([C:11](C#N)=NOC(N(C)C)=[N+](C)C)=[O:10].Cl.[C:24]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH:34]([CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[C:35]([NH:37][C@@H:38]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[C:39](O)=[O:40])=[O:36])=[CH:29][CH:28]=1)(=[NH:26])[NH2:25].Cl.Cl.[CH2:56]([NH:64][C:65](=[O:75])[C@@H:66]([NH2:74])[CH2:67][CH2:68][CH2:69][NH:70][C:71]([NH2:73])=[NH:72])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.C(N1CCOCC1)C>CN(C)C=O>[C:9]([OH:10])(=[O:8])[CH3:11].[CH2:56]([NH:64][C:65](=[O:75])[C@@H:66]([NH:74][C:39](=[O:40])[CH:38]([NH:37][C:35](=[O:36])[CH:34]([CH:48]1[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]1)[CH2:33][C:30]1[CH:31]=[CH:32][C:27]([C:24](=[NH:25])[NH2:26])=[CH:28][CH:29]=1)[CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:67][CH2:68][CH2:69][NH:70][C:71]([NH2:73])=[NH:72])[CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Reactant: N=C(N)c1ccc(CC(C(=O)N[C@H](C(=O)O)C2CCCCC2)C2CCCCC2)cc1
Reactant: N=C(N)NCCC[C@H](N)C(=O)NCCc1ccccc1
Agent: CCN1CCOCC1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)C(NC(=O)C(Cc1ccc(C(=N)N)cc1)C1CCCCC1)C1CCCCC1)C(=O)NCCc1ccccc1
Temperature: 22 °C
Reaction time: 15 h
Yield: 57 %

Procedure:
At 4° C. TOTU (48 mg, 0.14 mmol) was added to a solution of [3-(4-carbamimidoyl-phenyl)-2-(R,S)-cyclohexyl-propionylamino]-(S)-cyclohexyl-acetic acid hydrochloric acid salt (60 mg, 0.14 mmol), (S)-2-amino-5-guanidino-pentanoic acid phenethyl-amide dihydrochloride (51 mg, 0.14 mmol) and N-ethylmorpholine (56 μl, 0.42 mmol) in dimethylformamide (10 ml). The mixture was stirred at 22° C. for 15 hours. The solvent was evaporated and the residue was purified by column chromatography (Sephadex LH20, n-butanol/acetic acid/water 17:1:2) to give two stereoisomeric product mixtures. more polar diastereomeric mixture: 41 mg MS m/z 673.6 (M+H)+. less polar diastereomeric mixture: 21 mg MS m/z 673.6 (M+H)+. Total yield: 57%.
Reaction SMILES: [Na].S([CH2:6][CH2:7][CH2:8][CH2:9]OC1C=CC=CC=1C1C=CC(S(O)(=O)=O)=CC=1)(O)(=O)=O.[OH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1.Br[CH2:42][CH2:43][CH2:44][CH3:45].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:6]([O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:36][CH:35]=2)=[CH:32][CH:33]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCBr
Reactant: O=S(=O)(O)CCCCOc1ccccc1-c1ccc(S(=O)(=O)O)cc1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCOc1ccc(-c2ccc(OCCCC)cc2)cc1

Procedure:
In the same manner as in (1) above, 4,4′-dihydroxybiphenyl, 1-bromobutane and potassium carbonate were reacted in a proportion of 1:6:6 to prepare the objective compound. The reaction was conducted by heating under reflux at the refluxing temperature of acetone for 6 hours. The reaction solution thus obtained was cooled, potassium carbonate was filtered off, the filtrate was concentrated under reduced pressure and put into water, and the precipitate thus formed was collected by filtration and recrystallized from ethanol to obtain 4,4′-dibutoxybiphenyl.
Reaction SMILES: N(OCCC(C)C)=O.[CH2:9]([O:16][C:17]1[CH:44]=[CH:43][C:20]([O:21][C:22]2[CH:28]=[C:27]([N:29]3[C:34](=[O:35])[CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[N:31]([CH3:40])[C:30]3=[O:41])[C:26]([F:42])=[CH:25][C:23]=2N)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[ClH:45]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:45][C:23]1[CH:25]=[C:26]([F:42])[C:27]([N:29]2[C:34](=[O:35])[CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[N:31]([CH3:40])[C:30]2=[O:41])=[CH:28][C:22]=1[O:21][C:20]1[CH:43]=[CH:44][C:17]([O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:18][CH:19]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(OCc4ccccc4)cc3)c(N)cc2F)c1=O
Reactant: Cl
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(OCc4ccccc4)cc3)c(Cl)cc2F)c1=O
Reaction time: 1 h

Procedure:
0.46 g of isoamyl nitrite was added dropwise to a mixture of 1.0 g of 2-(4-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline, 0.38 g of copper (I) chloride, 0.78 g of copper (II) chloride, and 14 ml of acetonitrile at room temperature, and the mixture was stirred for 1 hour. This reaction solution was poured into 2% hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.73 g of ([4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene.