Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[N+:31]([O-])=O)[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CCOC(C)=O.O=[Pt]=O>[NH2:31][C:21]1[CH:22]=[CH:23][C:24]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:20]=1[CH2:19][N:15]1[C@@H:14]([CH3:34])[C@@H:13]([C:5]2[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=[C:3]([C:2]([F:1])([F:35])[F:36])[CH:4]=2)[O:17][C:16]1=[O:18]
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1N
Reaction time: 1 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-nitro-5-(trifluoromethoxy)benzyl]-1,3-oxazolidin-2-one (1.07 g, 2.01 mmol) in EtOAc (30 mL) was added PtO2 (100 mg, 0.44 mmol). The reaction was placed under a H2 atmosphere (balloon) and stirred vigorously. After 1 hour, the catalyst was removed by filtration, and the filtrate was concentrated. Purification of the residue by flash chromatography (5 to 40% EtOAc/hexanes) afforded (4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.45 (40% EtOAc/hexanes). LCMS=503.2 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 7.89 (s, 1H), 7.75 (s, 2H), 7.03 (dd, J=8.7, 2.0 Hz, 1H), 6.90 (d, J=2.1 Hz, 1H), 6.67 (d, J=8.7 Hz, 1H), 5.67 (d, J=8.5 Hz, 1H), 4.73 (d, J=15.4 Hz, 1H), 4.35 (bs, 2H), 4.09 (d, J=15.4 Hz, 1H), 4.04 (m, 1H), 0-78 (d, J=6.6 Hz, 3H).
Reaction SMILES: [C:1]([CH:4](C)[C:5](=O)[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=O)C.Cl.[NH2:16][CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18](OCC)=O.[C:28]([O-])(=O)C.[Na+].C(=O)=O>C(O)(=O)C>[CH2:26]([O:25][C:23]([C:17]1[NH:16][C:4]([CH3:1])=[C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:18]=1[CH3:28])=[O:24])[CH3:27]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: CCOC(=O)CCC(=O)C(C)C(C)=O
Reactant: CC(=O)[O-]
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CCc1c(C)[nH]c(C(=O)OCC)c1C
Temperature: 99 °C
Yield: 68.6 %

Procedure:
To a 5 L three-neck flask, equipped with a thermometer and a mechanical stirrer and heated on a steam bath, was added 350 g of ethyl 5-acetyl-4-oxohexanoate, 329 g of diethyl aminomalonate hydrochloride, 133 g of sodium acetate, and 1.2 L of acetic acid. The mixture was heated to 99° C. over 37 minutes. By 62° C., carbon dioxide evolution was already rapid. After a total of 35 minutes at 99° C., gas evolution had greatly slowed. After another hour, the mixture was cooled, the sodium chloride removed by vacuum filtration, and the solvent evaporated. The residue was mixed with 1 L of cold water. The precipitate was collected by vacuum filtration, washed with 400 mL of water, and dissolved in 1 L of hot 95% ethanol. The solution was treated with 20 g of Darco G-60, hot-filtered, and cooled to room temperature. The crystalline solid was collected by vacuum filtration, washed twice on the filter with 200 mL of 50% ethanol each time, and dried under vacuum at 70° C. to give 285 g (64% yield) of 2-ethoxycarbonyl-4-(2-ethoxycarbonylethyl)-3,5-dimethylpyrrole. The filtrate was refrigerated overnight to give another 53.1 g (11.9% yield) of product, for a total yield of 75.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19]Cl)=[CH:7]2.[N-:21]=[N+]=[N-].[Na+].CP(C)C>CN(C=O)C.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH2:21])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Agent: CP(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: NCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl

Procedure:
Prepared according to Procedure E using 8-chloro-3-(chloromethyl)-2-(2-chloro-phenyl)quinoline (0.685 g, 2.12 mmol) and sodium azide (1.10 g, 17 mmol, 8 eq) in DMF (10 mL). The resulting intermediate was submitted to trimethyl phosphine (1.0M) in THF (2.5 mL, 2.5 mmol, 1.2 eq) in THF (8 mL) and water (2 mL). (8-Chloro-2-(2-chlorophenyl)quinolin-3-yl)methanamine was obtained as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (1 H, s), 8.05 (1 H, dd, J=8.6, 1.2 Hz), 8.00 (1 H, dd, J=7.4, 1.2 Hz), 7.63-7.73 (2 H, m), 7.47-7.62 (3 H, m), 3.90 (1 H, s), 3.75 (1 H, s) Mass Spectrum (ESI) m/e=303.1 and 305.0 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:53]=[CH:52][C:13]([CH2:14][O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH2:22][CH2:23][N:24]([CH2:40][CH2:41][C:42]4[CH:47]=[CH:46][C:45]([C:48]([O:50]C)=[O:49])=[CH:44][CH:43]=4)[CH:25]4[CH2:34][CH2:33][CH2:32][C:31]5[N:30]=[C:29]([C:35]([O:37]CC)=[O:36])[CH:28]=[CH:27][C:26]4=5)=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:54]=1.O.[OH-].[Li+]>C1COCC1.O>[C:48]([C:45]1[CH:46]=[CH:47][C:42]([CH2:41][CH2:40][N:24]([CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]2[CH:12]=[CH:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:54][C:6]=4[N:7]=3)=[CH:53][CH:52]=2)[CH:25]2[CH2:34][CH2:33][CH2:32][C:31]3[N:30]=[C:29]([C:35]([OH:37])=[O:36])[CH:28]=[CH:27][C:26]2=3)=[CH:43][CH:44]=1)([OH:50])=[O:49]
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1ccccc1OCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCN(CCc2ccccc2OCc2ccc(-c3nc4cc(Cl)ccc4o3)cc2)C2CCCc3nc(C(=O)O)ccc32)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
45 mg (0.06 mmol) of ethyl 5-([2-(2-{[4-(5-chloro-1,3-benzoxazol-2-yl)benzyl]oxy}-phenyl)ethyl]-{2-[4-(methoxycarbonyl)phenyl]ethyl}amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 64A) were taken up in 4 ml of THF and 2 ml of water, and 8 mg (0.18 mmol) of lithium hydroxide monohydrate were added. The reaction was stirred at 60° C. overnight. After the reaction had gone to completion, the THF was removed on a rotary evaporator and the mixture that remained was diluted with water. The mixture was then acidified to pH 4-5 using acetic acid and extracted repeatedly with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated to dryness. This gave 13 mg (0.02 mmol, 32% of theory) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH:5]1[CH2:10][CH:9]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][C:7]([CH3:20])([CH3:19])[O:6]1>[OH-].[Na+].CO>[CH3:19][C:7]1([CH3:20])[O:6][C@@H:5]([CH2:4][C:3]([OH:21])=[O:2])[CH2:10][C@@H:9]([CH:11]=[CH:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:8]1
Reactant: COC(=O)CC1CC(C=Cc2ccccc2)OC(C)(C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)O[C@@H](CC(=O)O)C[C@@H](C=Cc2ccccc2)O1
Yield: 89 %

Procedure:
A solution of 2,2-dimethyl-6-(2-phenylethenyl)-1,3-dioxane-4-acetic acid methyl ester (8.5 g, 29.3, mmol) in 1 N NaOH (32 mL) and methanol (64 mL) was heated to reflux for 45 minutes. After evaporation under reduced pressure, the aqueous solution was washed once with diethyl ether and acidified with 1 N HCl (33 mL). The precipitate was collected and recrystallized from ethyl acetate/isopropyl ether to afford 7.2 g (90%) of the title compound as a colorless solid; m.p.=153°-155° C.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:23]=[CH:22][O:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:26]>CN(C=O)C>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([Cl:26])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:23]=[CH:22][O:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The carboxylic acid of example 2 (0.550 g, 1.8 mmol) was dissolved in SOCl2 (20 mL) and DMF (˜0.1 mL). The reaction mixture was stirred at room temperature for 20 h and then concentrated to dryness and co-evaporate with EtOAc to give a 1-cyclohexyl-2-furan-3-yl-1H-benzoimidazole-5-carbonyl chloride as a brown solid (580 mg). The acid chloride (0.050 g, 0.16 mmol) was dissolved in DMF (1 mL) and reacted with 1-carnosine (0.036 g, 0.159 mmol) in the presence of DIEA (82 μL, 0.476 mmol). The reaction mixture was stirred for 3 days at room temperature before it was acidified with AcOH (1 mL) and purified by reversed phase C18 preparative HPLC. The title compound of example 145 was obtained as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[OH:19][CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[OH:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:16]([C:13]2[S:14][CH:15]=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[N:12]=2)=[O:17])[CH2:21]1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: OC1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCCC(O)C3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (200 mg, 0.66 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 3-Hydroxypiperidine (Fluka)(67.0 mg; 0.66 mmol; 1 eq.) and triethylamine (0.19 ml; 1.33 mmol; 2 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is crystallized in MeOH, affording Compound (26) as a brown solid (103 mg; 42%). M− (ESI): 365.20; M+ (ESI): 367.16. HPLC (method A), Rt: 2.35 min (purity: 99.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(OP([CH2:33][C:34]#[N:35])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:33][C:34]#[N:35])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(=CC#N)c2cc(OC)c(OC)c(OC)c2)cc1OC
Yield: 76 %

Procedure:
(3,4-Dimethoxy-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (3.3 g, 10 mmol), cyanomethylphosphonic acid diethyl ester (2.4 ml, 15 mmol) in anhydrous THF (50 ml), and potassium bis(trimethylsilyl)amide (3.0 g, 15 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified by flash column chromatography to give 3-(3,4-dimethoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile as a solid (2.7 g, 77%): mp, 119-121° C.; 1H NMR (DMSO-d6) 07.14-7.07 (m, 1H), 7.00-6.77 (m, 2H), 6.66 (d, J=3 Hz, 2H), 6.25 (s, 0.5H), 6.19 (s, 0.5H), 3.84-3.71 (m, 15H); 13C NMR (DMSO-d6) □ 161.38, 161.31, 152.65, 150.99, 150.14, 148.64, 148.18, 139.44, 138.44, 133.69, 132.47, 130.01, 128.88, 122.66, 122.43, 118.66, 118.62, 112.75, 111.31, 111.22, 110.94, 106.88, 106.27, 94.23, 93.53, 60.08, 56.02, 55.98, 55.60, 55.55, 55.48; Anal. Calcd. For C20H21NO5: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.66; H, 5.98; N, 3.88.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6](=[O:20])[CH2:7][CH2:8][NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH3:2].C1C=C[NH+]=CC=1.[Br:28][Br-]Br.O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6](=[O:20])[CH:7]([Br:28])[CH2:8][NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH3:2]
Reactant: CCOC(=O)CC(=O)CCNC(=O)OCc1ccccc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)C(Br)CNC(=O)OCc1ccccc1
Reaction time: 16 h

Procedure:
5-Benzyloxycarbonylamino-3-oxo-pentanoic acid ethyl ester (1.0 g, 3.4 mmol) is dissolved in glacial acetic acid (10 mL) and pyridinium bromide perbromide (1.1 g, 3.4 mmol) of is added. The reaction stirred 16 hrs and then poured into H2O (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers are combined and washed with H2O (2×100 mL) and with brine (2×100 mL). The organic layer is dried over MgSO4, filtered and reduced to an oil by rotary evaporation. The crude product is purified by flash chrom-atography on silica gel using 25% ethyl acetate/hexane as the eluent to provide 5-benzyloxycarbonylamino-4-bromo-3-oxo-pentanoic acid ethyl ester. 1H NMR (300 MHz, CDCl3) δ 7.34 (s, 5H), 5.27 (m, 1H), 5.09 (s, 2H), 4.67 (t, 1H), 4.17 (q, 2H), 3.72 (m, 4H), 1.27 (t, 3H); MS (ion spray) 372 (M+H)+.
Reaction SMILES: [BH4-].[Na+].II.[C:5]([C:8]1[CH:9]=[CH:10][C:11]2[C:17](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[CH2:14][O:13][C:12]=2[CH:28]=1)(O)=[O:6]>C1COCC1.C(OCC)(=O)C>[OH:6][CH2:5][C:8]1[CH:9]=[CH:10][C:11]2[C:17](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[CH2:14][O:13][C:12]=2[CH:28]=1
Reactant: CCOC(=O)C=C1c2ccccc2COc2cc(C(=O)O)ccc21
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C=C1c2ccccc2COc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Sodium borohydride (2.22 g) was dissolved in 300 ml of THF, and 7.45 g of iodine was added to the solution under ice cooling. Then, 300 ml of a solution of 7.63 g of Compound 1-a in THF was added under the same conditions and the mixture was stirred at room temperature overnight, followed by addition of ice chips. The mixture was then diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: chloroform] to give 6.58 g (90.2%) of the product as a colorless oily substance.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[NH2:13])[C:6]([O:8][CH3:9])=[O:7].O.N1C=CC=CC=1.[C:21](Cl)(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>C(#N)C>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([NH:2][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=2[NH2:13])[C:6]([O:8][CH3:9])=[O:7])=[O:30])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(N)c(NC(=O)c2ccc(OC)cc2)c1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
A solution of methyl 3,4-diaminobenzoate hydrochloride (1.43 g, 6.00 mmol) in acetonitrile (100 mL) was cooled to 0° C. and treated with water (15 mL), pyridine (0.97 mL, 12 mmol), and a solution of p-anisoyl chloride (1.03 g, 6.00 mmol) in acetonitrile (25 mL). The reaction mixture was allowed to slowly warm to room temperature over 16 h. The resulting precipitate was collected and washed with acetonitrile to provide 1.07 g (59%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:25]=[CH:24][C:18]([CH2:19][C:20]4([NH2:23])[CH2:22][CH2:21]4)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[N:38]1[C:42](=[O:43])[CH2:41][S:40]/[C:39]/1=[N:44]\[C:45](=O)[O:46]C1C=CC([N+]([O-])=O)=CC=1)([CH3:30])[CH3:29]>>[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[N:38]1[C:42](=[O:43])[CH2:41][S:40]/[C:39]/1=[N:44]\[C:45]([NH:23][C:20]1([CH2:19][C:18]2[CH:24]=[CH:25][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:26])[F:27])=[CH:9][CH:8]=4)[N:11]=3)=[CH:16][CH:17]=2)[CH2:21][CH2:22]1)=[O:46])([CH3:30])[CH3:29]
Reactant: NC1(Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)CC1
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NC2(Cc3ccc(-c4ncn(-c5ccc(OC(F)(F)F)cc5)n4)cc3)CC2)c1

Procedure:
The title compound was prepared as described in Example 95 using 1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanamine (CB30) and (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as red oil (0.104 g, 37%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH2:17][CH2:18][OH:19]>O1CCCC1.C(OCC)(=O)C>[F:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1Cl
Reactant: NCCCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1NCCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
To a stirred solution of 2-chloro-5-fluoro-1,3-dinitrobenzene (3.24 g, 14.7 mmol) in tetrahydrofuran (50 mL) was added 3-amino-1-propanol (2.80 mL, 36.8 mmol) at 0° C. After being stirred for 3 h at room temperature, the mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo to give the title compound as a yellow solid (3.59 g, 13.8 mmol, 94%).
Reaction SMILES: [O:1]([CH2:8][C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([C:15]#[N:16])(C)C>C1(C)C=CC=CC=1>[NH2:10][CH:9]([CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:15]#[N:16]
Reactant: N#CCOc1ccccc1
Reactant: C[Si](C)(C)C#N
Solvent: Cc1ccccc1
Product: N#CC(N)COc1ccccc1
Temperature: 0 °C
Yield: 20 %

Procedure:
10 millimoles (1.33 g) of phenoxyacetonitrile are dissolved in 10 ml of anhydrous toluene at 0° C., under an argon atmosphere. A solution of vitridenide (NaH2AL1 [0-CH2 -CH2OCH3 ]2) at 70% in toluene (1,4 ml viz 0.5 eq) in 3 m of anhydrous toluene is added, dropwise, at this temperature. The stirring is maintained for 1 hour at 0° C., then 2 ml (1.5 eq) of trimethylsilyl cyanide are added. The reaction mixture is maintained at room temperature for 3 hours, while stirring, then hydrolyzed by usual way. After purification by acid base extraction, there are obtained 0.300 g of 2-amino-3-phenoxy propionitrile with a yield of 20%.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].Cl[C:7]1[N:12]2[C:13]([CH:16]([CH3:18])[CH3:17])=[N:14][CH:15]=[C:11]2[CH:10]=[C:9]([Cl:19])[N:8]=1.O>C(O)C>[Cl:19][C:9]1[N:8]=[C:7]([O:1][CH2:2][CH3:3])[N:12]2[C:13]([CH:16]([CH3:18])[CH3:17])=[N:14][CH:15]=[C:11]2[CH:10]=1
Reactant: CC(C)c1ncc2cc(Cl)nc(Cl)n12
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOc1nc(Cl)cc2cnc(C(C)C)n12

Procedure:
To a stirred solution of sodium ethoxide prepared in ethanol from 0.18 g (7.8 mmole) of sodium metal under nitrogen was added 1.50 g (6.52 mmole) of 5,7-dichloro-3-isopropylimidazo[1,5-c]pyrimidine (from Example 37). After three hours at room temperature the mixture was poured into 50 ml of water and extracted thrice with 30 ml portions of chlorofrom. The combined extracts were washed thrice with 40 ml portions of water, dried over magnesium sulfate and evaporated to provide crude 7-chloro-5-ethoxy-3-isopropylimidazo[1,5-c]pyrimidine.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][C@@H:6]2[CH2:8][C@:5]32[C@H:9]2[C@H:19]([CH2:20][CH2:21][C@:3]13[CH3:4])[C@:17]1([CH3:18])[C:12]3(O[CH:13]3[C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]2.[ClH:24].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:24][C:13]1[C:14](=[O:22])[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:12]=1[CH2:11][CH2:10][C@@H:9]1[C@@H:19]2[CH2:20][CH2:21][C@@:3]2([CH3:4])[C@@:5]31[CH2:8][C@H:6]3[CH2:7][C@@H:2]2[OH:1]
Reactant: Cl
Reactant: C[C@]12CCC(=O)C3OC31CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@@H]3C[C@]312
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C[C@]12CCC(=O)C(Cl)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@@H]3C[C@]312
Reaction time: 24 h

Procedure:
17β-hydroxy-4,5-epoxy-14α,15α-methylene-androstan-3-one (1.5 g) is dissolved in 150 mL of acetone and treated at 0° C. with 5.5 mL of concentrated hydrochloric acid. After 24 hours at 0° C., the reaction mixture is neutralized with sodium carbonate solution and the acetone is evaporated. The residue is extracted with dichloromethane. The organic extracts are dried and concentrated. After crystallization from ethanol, 4-chloro-17β-hydroxy-14α,15α-methylene-androst-4-ene-3-one is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][O:28][C:29]([CH2:31][CH2:32][C:33](Cl)=[O:34])=[O:30]>CC(C)=O>[CH3:27][O:28][C:29]([CH2:31][CH2:32][C:33]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16](=[O:17])(=[O:18])[NH2:19])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1)=[O:34])=[O:30]
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(O)cc2)s1
Reactant: COC(=O)CCC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)Oc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 5-[(4-hydroxyphenyl)sulfonyl]thiophene-2-sulfonamide (3.19 g; 0.1 mole) in acetone (60 ml) at -10° was treated with triethylamine (1.11 g; 0.011 mole). Then methoxycarbonylpropionyl chloride (1.66 g; 0.011 mole) was added, dropwise, during 5 minutes at -10°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[C:10]([CH3:15])=[N:11][O:12][C:13]=2[CH3:14])=[CH:4][C:3]=1[S:16]([NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)(=[O:18])=[O:17].C1N=CN([C:30](N2C=NC=C2)=[O:31])C=1>CN(C=O)C>[CH:20]1([NH:19][S:16]([C:3]2[C:2]3[NH:1][C:30](=[O:31])[NH:8][C:7]=3[CH:6]=[C:5]([C:9]3[C:10]([CH3:15])=[N:11][O:12][C:13]=3[CH3:14])[CH:4]=2)(=[O:17])=[O:18])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1noc(C)c1-c1cc(N)c(N)c(S(=O)(=O)NC2CCCC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2[nH]c(=O)[nH]c2c1
Temperature: 150 °C

Procedure:
2,3-Diamino-N-cyclopentyl-5-(3,5-dimethylisoxazol-4-yl)benzenesulfonamide (58 mg, 0.17 mmol) was dissolved in DMF (2 mL). To the solution was added CDI (360 mg, 4 mmol) and TEA (1 mL). The reaction was heated at 150° C. in microwave for 10 h. The solvent was evaporated and the residue was purified by preparative HPLC (0-100% CH3CN/H2O) to afford N-cyclopentyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-sulfonamide.
Reaction SMILES: [CH2:1]([CH:3]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([Cl:14])[C:9]=2[Cl:13])[C:4]1=[O:17])[CH3:2].[C:18](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH2:1]([C:3]1([CH3:18])[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([Cl:14])[C:9]=2[Cl:13])[C:4]1=[O:17])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCC1C(=O)c2cc(OC)c(Cl)c(Cl)c2C1=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCC1(C)C(=O)c2cc(OC)c(Cl)c(Cl)c2C1=O
Reaction time: 0.25 h

Procedure:
A stirred solution of 2-ethyl-4,5-dichloro-6-methoxyindan-1,3-dione (1.3 g.) in dimethylformamide (15 ml.) is treated with potassium carbonate (1.26 g.) and metyl iodide. After 15 minutes, the reaction is poured into water (75 ml.) affording 1.3 g. of 2-ethyl-2-methyl-4,5-dichloro-6-methoxyindan-1,3-dione which melts at 157°C. after recrystallization from ethanol.