Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[C:30]1([O:40][C:41](=[O:71])[C@H:42]([CH2:44][CH2:45][CH2:46][N:47]([C:61]([O:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[O:62])[C:48](=[NH:60])[NH:49][C:50]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:51])[NH2:43])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[C:30]1([O:40][C:41](=[O:71])[C@H:42]([CH2:44][CH2:45][CH2:46][N:47]([C:61]([O:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[O:62])[C:48](=[NH:60])[NH:49][C:50]([O:52][CH2:53][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)=[O:51])[NH:43][C:20](=[O:22])[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: N=C(NC(=O)OCc1ccccc1)N(CCC[C@H](N)C(=O)Oc1cccc2ccccc12)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: N=C(NC(=O)OCc1ccccc1)N(CCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)Oc1cccc2ccccc12)C(=O)OCc1ccccc1
Yield: 43.1 %

Procedure:
In 8 ml of dimethylformamide (DMF) were dissolved 898 mg of benzyloxycarbonyl-L-phenylalanine and 2.05 g of Nδ,Nω -dibenzyloxycarbonyl-L-arginine 1-naphthyl ester trifluoroacetate, and to the resulting solution were added 681 mg of dicyclohexylcarbodiimide (DCC), 405 mg of 1-hydroxybenzotriazole (HOBt) and 304 mg of triethylamine (TEA) with ice-cooling and with stirring, after which the mixture was stirred for 3 hrs at the same temperature. The temperature was elevated to room temperature and the mixture was stirred for a further 24 hrs. After the reaction, the crystals of dicyclohexylurea (DCU) precipitated were removed by filtration, and ethyl acetate was added to the filtrate, after which the mixture was washed with 10% aqueous citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution in this order, dried over anhydrous magnesium sulfate, and thereafter evaporated under reduced pressure to removed the solvent. The white powder thus precipitated was collected and recrystallized from chloroform-diethyl ether to obtain 1.1 g (yield 43%) of benzyloxycarbonyl-L-phenylalanyl-Nδ,Nω -dibenzyloxycarbonyl-L-arginine 1-naphthyl ester, m.p. 125°-130° C.
Reaction SMILES: C[NH:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[CH:14]=[CH:13][O:12][N:11]=1)=S.[N:15]#CN.[Pb]>>[O:12]1[CH:13]=[CH:14][C:10]([CH2:9][S:8][CH2:7][CH2:6][N:5]=[C:3]([NH2:15])[NH2:2])=[N:11]1
Reactant: N#CN
Reactant: CNC(=S)NCCSCc1ccon1
Agent: [Pb]
Product: NC(N)=NCCSCc1ccon1

Procedure:
Reaction of N-methyl-N'-[2-(3-isoxazolylmethylthio)ethyl]thiourea with lead cyanamide by the procedure of Example 121 gives N-cyano-N'-methyl-N"-[2-(2-(3-isoxazolylmethylthio)ethyl]guanidine.
Reaction SMILES: C([NH:8][C@@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)[CH3:28])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(OC(C)(C)C)=O.CCOC(C)=O.[ClH:45].CCOC(C)=O>CCOCC>[ClH:45].[C:14]([NH:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)[CH3:28])=[O:25])[NH2:8])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1cccc2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[C@@H](NC(=O)[C@H](N)CCCNC(=O)OCc1ccccc1)c1cccc2ccccc12

Procedure:
Prepared according to the method described in Example 1(b) above from crude (R)-N2 -(Boc)-N5 -(Cbz)-(R)-N-[1-(1-naphthyl)ethyl]ornithine amide (7.5 g; from step (a) above), EtOAc (150 mL) and HCl/EtOAc (75 mL), 6 hours reaction time. The resulting heterogeneous solution was diluted with Et2O and the solids collected and dried to afford the sub-title compound as a white solid (4.8 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:6]#[N:7])[CH3:2].[ClH:13]>CO.[OH-].[OH-].[Pd+2]>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7])[CH3:2].[ClH:13]
Reactant: CCc1cc(C#N)ccc1OC
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CCc1cc(CN)ccc1OC
Reaction time: 8 h

Procedure:
To a solution of 3-ethyl-4-methoxybenzonitrile (12-2, 0.12 g, 0.71 mmol) in MeOH (3.5 mL) was added Pearlman's catalyst (0.020 g, 0.036 mmol) and concentrated HCl (0.47 mL, 5.71 mmol). The system was then stirred under an atmosphere of hydrogen via a balloon overnight. The reaction contents were filtered through a pad of celite and solvents were removed in vacuo to yield the desired product (12-3) as a salmon colored crystalline solid in the form of a mono HCl salt. ESI+MS [M+H]+ C8H12N2O2: M-16 (—NH2), 149.07 found, 149.2 required.
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OCC)=O)[C@@H:6]([CH3:16])[CH2:5]1)[CH:2]=[CH2:3].[OH-].[K+].C(=O)=O.C1(C)C=CC=CC=1>C(O)C>[CH2:1]([N:4]1[CH2:5][C@@H:6]([CH3:16])[NH:7][CH2:8][C@@H:9]1[CH3:10])[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@H](C)N(C(=O)OCC)C[C@H]1C
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C=CCN1C[C@@H](C)NC[C@@H]1C
Temperature: 5 °C
Yield: 69 %

Procedure:
Ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate (630 g, 2.78 mol) was added to a solution of 87% potassium hydroxide pellets (2970 g, 46 mol) in 4300 mL of 95% ethanol and heated at reflux for 1.5 hours. Carbon dioxide evolution was observed for the first 0.5-1 hour of heating. The reaction was cooled below reflux temperature and 2000 mL of toluene was carefully added. Ethanol was removed by azeotropic distillation at 105 C, while adding an additional 4000 mL of toluene to the reaction flask during the course of the distillation. After collection of 9000 mL of distillate, the reaction was cooled to 100 C and 1000 mL of toluene was carefully added. The solution was slowly cooled to 5 C and maintained at 5° C. for 30 minutes. The solution was filtered, and the filter cake was washed with an additional 1500 mL of toluene. The filtrate was washed with 1000 mL of water, dried over magnesium sulfate, and the solvent was removed to give 296 g (69%) of trans-1-allyl-2,5-dimethylpiperazine as a dark liquid. NMR (300 MHz, DMSO-d6): δ 0.87 (d, J=6.3 Hz, 3H); 0.92 (d, J=6.3 Hz, 3H); 1.63 (t, J=11 Hz, 1H); 2.05 (m, 1H); 2.30 (t, J=11 Hz, 1H); 2.6-2.8 (m, 4H); 3.33 (dd, J1=5 Hz, J2=14 Hz, 1H); 5.09 (d, J=8.7 Hz, 1H); 5.13 (d, J=14 Hz, 1H) 5.8 (m, 1H).
Reaction SMILES: [Cl-].[NH2:2][C:3]1([CH2:33][CH2:34][OH:35])[CH2:7][CH2:6][C@@H:5]([C:8]([NH:10][C@H:11]([CH:30]([CH3:32])[CH3:31])[C:12]([N:14]2[CH2:19][CH2:18][C@@:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([OH:20])[C:16]([CH3:29])([CH3:28])[CH2:15]2)=[O:13])=[O:9])[CH2:4]1.[C:36](C1NC=CN=1)(C1NC=CN=1)=[O:37].C(N(CC)CC)C>C1COCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@@:17]2([OH:20])[CH2:18][CH2:19][N:14]([C:12](=[O:13])[C@H:11]([NH:10][C:8]([C@@H:5]3[CH2:6][CH2:7][C:3]4([CH2:33][CH2:34][O:35][C:36](=[O:37])[NH:2]4)[CH2:4]3)=[O:9])[CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2([CH3:29])[CH3:28])=[CH:22][CH:23]=1
Reactant: CC(C)[C@@H](NC(=O)[C@@H]1CCC(N)(CCO)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NC(=O)[C@@H]1CCC2(CCOC(=O)N2)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.33 %

Procedure:
To a solution of (1R)-3-amino-N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-(2-hydroxyethyl)cyclopentanecarboxamide (from step F, 30 mg, 0.061 mmol) in THF (1 mL) was added carbonyl diimidazole (14.77 mg, 0.091 mmol) and triethylamine (0.021 mL, 0.152 mmol). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and subjected preparative HPLC(Shimadzu VP-ODS 20×100 mm, 8 min. gradient, Solvent A: 10% MeOH, 90% H2O, 0.1% TFA; Solvent B: 90% MeOH, 10% H2O, 0.1% TFA; wavelength: 220 nM) to yield the desired product as a diastereomer mixture. The diastereomer mixture was subjected to chiral preparative HPLC (Column: ChiralPak ASH, 250×3 cm, 5 μm; Flow rate: 120 mL/min; Mobile Phase: CO2/MeOH=80/20; Inj. Vol.=2.0 mL, Wavelength=220 nM; isomer 1, retention time=5.75 min; isomer 2, retention time=9.10 min) to yield the individual diasteromers (2 mg for each isomer, 3.85 μmol, 6.33% yield) as a solid.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[N:11]=2)[C:5]([CH3:21])([CH3:20])[CH2:4][O:3]1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30].O>O1CCCC1>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:11]=[C:7]([N:6]3[C:5]([CH3:21])([CH3:20])[CH2:4][O:3]/[C:2]/3=[N:1]\[C:29](=[O:31])[CH3:30])[S:8][CH:9]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: CC(=O)Cl
Reactant: CC1(C)COC(=N)N1c1nc(-c2ccc(C#N)cc2)cs1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)/N=C1\OCC(C)(C)N1c1nc(-c2ccc(C#N)cc2)cs1
Reaction time: 4 h
Yield: 64.6 %

Procedure:
4-[2-(2-Imino-4,4-dimethyl-1,3-oxazolidin-3-yl)-1,3-thiazol-4-yl]benzonitrile (0.075 g, 0.25 mmol), prepared in Example 63, was dissolved in tetrahydrofuran (2 mL) followed by triethylamine (0.069 mL, 0.5 mmol) and acetylchloride (0.039 g, 0.5 mmol). The mixture was stirred 4 h, poured into water, extracted with ethyl acetate, and dried over anhydrous MgSO4. The solvent was evaporated and residue triturated with hexane/ethyl acetate (95/5), collected and dried to give the title compound (0.055 g, 64%). HRMS: calcd for C17H16N4O2S+H+, 341.10667; found (ESI, [M+H]+), 341.1075; HPLC purity 96.5% at 210-370 nm, 9.4 min; 96.0% at 250 nm, 9.4 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][O:4][C:5]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][C:6]=1[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[CH3:17])=[O:8].[CH3:30][I:31]>>[I-:31].[F:29][C:2]([F:1])([F:28])[CH2:3][O:4][C:5]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][C:6]=1[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N+:12]1([CH3:30])[CH3:17])=[O:8]
Reactant: CI
Reactant: CN1CCCCC1CNC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: C[N+]1(C)CCCCC1CNC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: [I-]

Procedure:
A mixture of 2.7 g. (0.0063 mole) of finely divided 2.5-bis(2,2,2-trifluoroethoxy)-N-[(1-methyl-2-piperidyl)methyl]-benzamide and 6 ml. of methyl iodide is heated at 56° to 57° C. in a sealed tube for about 90 minutes. The mixture is extracted with methanol, and the methanol extracts are concentrated to provide a crystalline solid which is recrystallized from 50 ml. of ethyl acetate and about 2 ml. of isopropanol, with treatment by decolorizing charcoal. The resulting product is dried to provide white solid 2-[2,5-bis(2,2,2-trifluoroethoxy)benzamidomethyl]-1,1-dimethylpiperidinium iodide, m.p. 170°-172.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](OC)=O)=[CH:4][CH:3]=1.[C:13]1([NH2:20])[C:14]([NH2:19])=[CH:15][CH:16]=[CH:17][CH:18]=1>CO>[NH:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:20]=[C:9]1[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: Nc1ccccc1N
Solvent: CO
Product: Oc1ccc(Cc2nc3ccccc3[nH]2)cc1
Temperature: 150 °C

Procedure:
A mixture of methyl 2-(4-hydroxyphenyl)acetate (40.0 g, 241 mmol) and benzene-1,2-diamine (26.0 g, 241 mmol) in a sealed vessel was heated to 150° C. for 18 h. After cooling to room temperature, the mixture was diluted with MeOH and heated to 100 C for 1 h. The mixture was cooled to −20 C overnight, then filtered to collect 25.8 g (48%) of a lavender solid. MS (ESI, pos. ion) m/z: 225 (M+1).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1[C:34](O)=[O:35].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1[C:34]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:35]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)c1cc2ccccc2o1
Yield: 98.4 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (4.0 g), triethylamine (2.2 mL), benzofuran-2-carboxylic acid (3.1 g), WSC.HCl (3.6 g), and methylene chloride (100 mL), to give the captioned compound (5.6 g, 98%) as an oily product.
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>C(OC(=O)C)C>[Br-:15].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][N+:12]1[CH:11]=[CH:10][C:9]([CH:1]=[CH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:14][CH:13]=1
Reactant: BrCCCCBr
Reactant: C(=Cc1ccncc1)c1ccccc1
Solvent: CCOC(C)=O
Product: BrCCCC[n+]1ccc(C=Cc2ccccc2)cc1
Product: [Br-]

Procedure:
A mixture of 4-styrylpyridine (0.181 g) and 1,4-dibromobutane (0.432 g) in ethylacetate (5 ml) was stirred and refluxed for 24 hours, and then filtered. The crystals obtained were washed and dried to give 0.31 of N-(4-bromobutyl)-4-styrylpyridinium bromide λmax 344 nm (water). NMR (CDCl3, p.p.m.): 9.4(d.,2H), 8.0(d.,2H), 7.0-7.7(m.,7H), 4.9(T.,2H), 3.4(m.,2H), 2.0(m.,4H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[CH:4][C:3]=1[CH3:11].ClC1C=C[N:16]=CC=1[N+]([O-])=O.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.NC1C=CC=CN=1>>[F:22][C:23]1[CH:29]=[CH:28][C:26]([N:27]2[C:2]3[C:3]([CH3:11])=[CH:4][N:5]=[CH:6][C:7]=3[N:8]=[N:16]2)=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Nc1ccc(F)cc1
Reactant: Cc1cncc([N+](=O)[O-])c1Cl
Agent: Nc1ccccn1
Product: Cc1cncc2nnn(-c3ccc(F)cc3)c12

Procedure:
The title compound was prepared in a manner analogous to Intermediate 17, Step 1 through Intermediate 19, Step 3 substituting 4-chloro-3-methyl-5-nitro-pyridine for 4-chloro-3-nitropyridine and 4-fluoroaniline for 2-aminopyridine in the synthesis of Intermediate 17, Step 1. MS (ESI) mass calcd. C12H9FN4, 228.1. m/z found, 229.1 [M+H]+.
Reaction SMILES: B(Cl)(Cl)Cl.[F:5][C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[C:15]([NH:25][S:26]([CH:29]2[CH2:32][CH:31]([O:33]CC3C=CC=CC=3)[CH2:30]2)(=[O:28])=[O:27])=[C:16]2[S:24][CH2:23][CH2:22][N:17]2[C:18](=[O:21])[C:19]=1[CH3:20].CO>C(Cl)Cl.C(Cl)(Cl)Cl>[F:5][C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[C:15]([NH:25][S:26]([CH:29]2[CH2:32][CH:31]([OH:33])[CH2:30]2)(=[O:27])=[O:28])=[C:16]2[S:24][CH2:23][CH2:22][N:17]2[C:18](=[O:21])[C:19]=1[CH3:20]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(OCc3ccccc3)C2)c2n(c1=O)CCS2
Agent: ClB(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(O)C2)c2n(c1=O)CCS2
Temperature: -78 °C
Reaction time: 3 h
Yield: 17.4 %

Procedure:
1M BCl3 (0.46 mL, 0.468 mmol) was added to a solution of 3-benzyloxy-cyclobutanesulfonic acid [7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-8-yl]-amide (0.1 g, 0.156 mmol) in dry DCM (3 mL) at −78° C. The resulting mixture was stirred at −78° C. for 3 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was quenched with methanol, basified with saturated NaHCO3 solution and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (4% MeOH in CHCl3), followed by preparative HPLC afforded 0.015 g of the product (18% yield).
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[CH2:21][C@@]2(C)[C@@H:15]([CH2:16]C=C2)[C@H:14]2[C@H:5]1[C@:6]1([CH3:26])[C@@H:11]([CH2:12][CH2:13]2)[CH2:10][C@H:9]([OH:22])[C@@H:8]([O:23][CH2:24][CH3:25])[CH2:7]1)[CH3:3].[Br:27]N1C(=O)CCC1=O.Cl(O)(=O)(=O)=O.[O:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>O>[Br:27][C@@H:43]1[C@@H:44]([OH:40])[CH2:16][C@H:15]2[C@H:14]3[C@H:5]([C@H:4]([N:2]([CH3:3])[CH3:1])[CH2:21][C@:42]12[CH3:41])[C@:6]1([CH3:26])[C@H:11]([CH2:10][C@H:9]([OH:22])[C@@H:8]([O:23][CH2:24][CH3:25])[CH2:7]1)[CH2:12][CH2:13]3
Reactant: C1CCOC1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](N(C)C)C[C@]2(C)C=CC[C@@H]32)C[C@@H]1O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](N(C)C)C[C@]2(C)[C@H](Br)[C@@H](O)C[C@@H]32)C[C@@H]1O
Reaction time: 8 h

Procedure:
A solution of 11α-N,N-dimethylamino-2β-ethoxy-5α-androst-16-en-3α-ol (1.6 g) in tetrahydrofuran (40 ml) and water (16.5 ml) containing N-bromosuccinimide (1.05 g) and 60% perchloric acid (2 ml) was kept overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and potassium carbonate solution and the organic extract was washed, dried (Na2SO4) and evaporated in vacuo. Purification of the residue by preparative thin layer chromatography over silica (ethyl acetate:petroleum ether 1:1) and crystallization from ether afforded the title compound m.p. 173°-174°, [α]D -53.6°.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:10][CH2:9][C:7]([C:3]2[O:2][CH:6]=[CH:5][CH:4]=2)=[O:8])=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCC(=O)c1ccco1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NCC(=O)c1ccco1)c1ccc(F)cc1
Yield: 67 %

Procedure:
23.4 g of (2-furylcarbonyl)methylamine hydrochloride, 29.3 g of sodium bicarbonate and 23.0 g of 4-fluorobenzoyl chloride are treated in the same manner as described in Preparation 1-(1). 24.0 g of N-(4-fluorobenzoyl)-(2-furylcarbonyl)methylamine are thereby obtained. Yield: 66.8%
Reaction SMILES: Cl.[CH2:2]([CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1)[CH3:3].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[CH:18]=[C:17]([S:19](Cl)(=[O:21])=[O:20])[S:16][C:15]=2[CH:23]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[CH:18]=[C:17]([S:19]([N:8]3[CH2:7][CH2:6][NH:5][CH:4]([CH2:2][CH3:3])[CH2:9]3)(=[O:21])=[O:20])[S:16][C:15]=2[CH:23]=1
Reactant: CCC1CNCCN1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a methylene chloride solution (30 ml) of 2-ethylpiperazine hydrochloride (307 mg) was added (6-chlorobenzo[b]thien-2-yl)sulfonyl chloride (438 mg) and triethylamine (498 mg). The resulting mixture was stirred at room temperature for 26 hours. Distilled water and methylene chloride were added and the water layer was extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column (methanol:methylene chloride=1:20), whereby the title compound (255 mg) was obtained as a pale yellow oil. MS (FAB) m/z: 345 [(M+H)+, Cl35], 347 [(M+H)+, Cl37]. 1H-NMR (CDCl3) δ: 0.95(3H,t,J=7.8 Hz), 1.24-1.46(2H,m), 2.16(1H,t,J=10.7 Hz), 2.54(1H,dt,J=2.9,11.2 Hz), 2.65-2.75(1H,m), 2.95(1H,dt,J=2.9,11.2 Hz), 3.04-3.10(1H,m), 3.65-3.72(2H,m), 7.43(1H,dd,J=8.8,2.0 Hz), 7.75(1H,s), 7.81(1H,d,J=8.8 Hz), 7.86(1H,s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1(C)[CH:27]=CC=C[CH:23]=1.COC(C)=C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@@H:10]([C:11]([O:13][CH3:14])=[O:12])[O:15][C:22]1([CH3:27])[CH3:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1
Reactant: COC(=O)[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 120 °C
Yield: 36 %

Procedure:
147.5 mg (0.50 mmol) of methyl (2S,3S)-3-t-butoxycarbonylamino-3-phenyl-2-hydroxypropionate and 2.5 cm3 of anhydrous toluene are introduced, under an argon atmosphere, into a 10 cm3 round-bottomed flask equipped with a magnetic stirrer system. 10 grains of 4 Åmolecular sieve, 188.5 μl (144.2 mg, 2.0 mmol) of 2-methoxypropene and 12.5 mg (0.05 mmol) of pyridinium p-toluenesulphonate are then added to the suspension obtained. The mixture is allowed to react for 1 hour at a temperature in the region of 20° C. and is then heated to 120° C. and allowed to react at this temperature for 2 hours. The resulting dark-brown reaction mixture is cooled to a temperature in the region of 20° C. 60 cm3 of dichloromethane are added. The organic phase is washed with 5 cm3 of a saturated aqueous sodium hydrogen-carbonate solution, 3 times with 5 cm3 of water and then once with 5 cm3 of a saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous sodium sulphate. After filtration and concentration to dryness under reduced pressure, a residue is obtained which is chromatographed on a column of silica gel, eluting with an ethyl ether/hexane (15/85 by volume) mixture. There are obtained, with a yield of 36%, 60 mg (0.18 mmol) of (4S,5S)-3-t-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].C(N(CC)CC)C.[CH2:19]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([O:26][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To 2-amino-benzoic acid methyl ester (0.51 mL) and triethylamine (0.69 mL) in dichloromethane (31 mL) at −50° C. was slowly added a solution of 4-benzyloxy-benzoyl chloride [1486-50-6] (1 g) in 31 mL of dichloromethane. The reaction mixture was then allowed to warm up to room temperature and stirred for an additional hour. After such time, the reaction mixture was washed with water. The aqueous phase was further extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (heptane-ethyl acetate: 0-50%) to yield 2-(4-benzyloxy-benzoylamino)-benzoic acid methyl ester (400 mg). MS (m/e): 362.5 (M+H+, 100%).