Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH2:3](OC1C=CC(C2(O)CCCCC2CCN2CCN(C)CC2)=CC=1F)C1C=CC=CC=1.Cl.Cl.[CH2:36]([O:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]([C:58]2([OH:64])[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]2)[CH2:51][N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:46][C:45]=1[F:65])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[ClH:1].[ClH:1].[CH2:36]([O:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]([C:58]2([OH:64])[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63]2)[CH2:51][N:52]2[CH2:57][CH2:56][N:55]([CH3:3])[CH2:54][CH2:53]2)=[CH:46][C:45]=1[F:65])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: OC1(C(CN2CCNCC2)c2ccc(OCc3ccccc3)c(F)c2)CCCCC1
Reactant: CN1CCN(CCC2CCCCC2(O)c2ccc(OCc3ccccc3)c(F)c2)CC1
Agent: Cl
Product: CN1CCN(CC(c2ccc(OCc3ccccc3)c(F)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 24, 1-[1-[4-(benzyloxy)-3-fluorophenyl]-2-(4-methylpiperazin-1-yl)ethylcyclohexanol dihydrochloride was prepared from 1-{1-[4-(benzyloxy)-3-fluorophenyl]-2-piperazin-1-ylethyl}cyclohexanol dihydrochloride (See Example 413). MS (ES) m/z 427.1; HRMS: calcd for C26H35FN2O2+H+, 427.27553; found (ESI, [M+H]+), 427.2756.
Reaction SMILES: [CH2:1]([O:10][C:11](=[O:27])[C@H:12]([C@@H:24]([CH3:26])[OH:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[C:28]([N:35]([CH3:49])[C@H:36]([C:46](O)=[O:47])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1CCC(N=C=NC2CCCCC2)CC1.NC(N)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:10][C:11](=[O:27])[C@H:12]([C@@H:24]([CH3:26])[O:25][C:46](=[O:47])[C@H:36]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=1)[N:35]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH3:49])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: C[C@@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(=O)c1ccccc1
Reactant: COc1ccc(C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: NC(N)=O
Solvent: ClCCl
Product: COc1ccc(C[C@@H](C(=O)O[C@H](C)[C@H](NC(=O)OCc2ccccc2)C(=O)OCC(=O)c2ccccc2)N(C)C(=O)OC(C)(C)C)cc1
Temperature: -30 °C
Reaction time: 8 h

Procedure:
2.00 g (5.38 mmol) of (8), 1.67 g (5.4 mmol) of (9) and 70 mg (0.54 mmol) of DMAP were dissolved in 20 ml of CH2Cl2 and cooled to -30° C., and 1.13 g (5.5 mmol) of DCC were added. The mixture .was allowed to reach RT overnight, the urea was filered off, the filtrate was concentrated, the residue was taken up in ether and left to stand for 1 h, and the urea was again filtered off. Sufficiently pure peptolide (10) was obtained by filtration through silica gel with PE/EA 7/3. Yield: 3.5 g (5.28 mmol, 98%), α!D20 =28.7° (c=0.96, CHCl3)
Reaction SMILES: C([O:8][C:9]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:10]=1[C:11]([NH:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1)=[O:12])C1C=CC=CC=1>C(O)C.[Pd]>[F:25][C:23]([F:24])([F:26])[C:20]1[CH:21]=[CH:22][C:9]([OH:8])=[C:10]([CH:19]=1)[C:11]([NH:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1)=[O:12]
Reactant: O=C(Nc1nnn[nH]1)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1nnn[nH]1)c1cc(C(F)(F)F)ccc1O
Yield: 41.9 %

Procedure:
2-Benzyloxy-5-trifluoromethyl-N-(tetrazol-5-yl)benzamide (2.7 g) was dissolved in ethanol (500 ml), and the solution was hydrogenated at 25° C. and 5 kg/cm2 pressure, using a 5% palladium on charcoal catalyst. The reaction mixture was then filtered, and evaporated under vacuum. The resulting solid was recrystallized from isopropanol, with the aid of charcoal, to give 5-trifluoromethyl-2-hydroxy-N-(tetrazol-5-yl)benzamide (0.85 g), m.p. 245°-246° C. (with decomposition).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[CH3:14][C:15]([CH3:19])([CH3:18])[CH:16]=O>C1COCC1>[CH2:6]([C@@H:4]1[NH:5][C@H:16]([C:15]([CH3:19])([CH3:18])[CH3:14])[N:2]([CH3:1])[C:3]1=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)C=O
Solvent: C1CCOC1
Product: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Temperature: 25 °C
Reaction time: 36 h
Yield: 23.4 %

Procedure:
Hydrochloride salt of (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one (1): To a solution of ethanolic MeNH2 (8.0 M, 50 ml) was added (S)-phenylalanine methyl ester (23.0 g, 130 mmol). The resulting solution was stirred at room temperature until the amino ester was judged to be consumed by TLC analysis. The resulting solution was then concentrated to provide (S)-phenylalanine N-methyl amide (18 g, 82% yield) as a white solid. To a flask containing (S)-phenylalanine N-methyl amide (8.9 g, 50 mmol) was added THF (100 ml), trimethylacetaldehyde (5.4 g, 50 mmol), FeCl3 (1.7 g, 10 mmol) and 4 Å MS (5.0 g). The resulting mixture was stirred at room temperature for 36 h, then washed with H2O (3×100 mL). The combined organics were concentrated and the resulting residue was treated with HCl (27 mL, 1N in ether). The resulting heterogeneous mixture was filtered to removed the undesired trans isomer.HCl salt and the resulting solution was concentrated. The residue was recrystallized (9:1 pentane/CH2Cl2) to provide the product (1) as a crystalline solid (2.88 g, 23% yield, >99% ee). IR (film) 3343, 2958, 1605, 1028 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.31-7.17 (m, 5H, ArH), 4.04 (s, 1H, NCHN), 3.72-3.65 (m, 1H, CHCH2), 3.13 (dd, J=4.1, 13.7 Hz, 1H, CH2), 2.92 (dd, J=7.7, 13.7 Hz, 1H, CH2), 2.90 (s, 3H, NCH3), 0.82 (s, 9H, C(CH3)3); 13C NMR (75 MHz, CDCl3) δ 175.3, 138.0, 129.8, 128.7, 126.8, 82.7, 77.8, 77.4, 76.9, 59.7, 38.6, 35.4, 31.0, 25.7; [α]D=−39.6 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC using a Chiralpak OD-H and OD guard column (3.0% i-PrOH/hexanes, 1 mL/min); (5S) isomer tr=16.7 min, (5R) isomer tr=20.1 min.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].[F:15][CH:16]([F:20])[C:17](O)=[O:18]>>[O:9]=[C:8]1[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3](=[O:14])[CH:2]1[NH:1][C:17](=[O:18])[CH:16]([F:20])[F:15]
Reactant: O=C(O)C(F)F
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Product: O=C(NC1C(=O)Nc2ccccc2NC1=O)C(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using the method of Example 62, using 3-amino-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione and difluoroacetic acid, stirring overnight at ambient temperature after the addition of the acid, and washing reaction solid with dichloromethane instead of isopropanol: chloroform (3:1) gives the title compound: mass spectrum (APCI, m/e): 270 (M+1); NMR (1H, 300 MHz, DMSO-d6): δ 10.88 (s, 2H), 9.13 (d, 1H, J=6.9 Hz), 7.29-7.13 (m, 4H), 6.49 (t, 1H, 2J(H,F)=53.7 Hz), 4.79 (d, 1H, J=6.9 Hz).
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH:23]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:24]2=[O:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.O1CCCC1>[OH:29][CH:24]1[C:25]2[C:20](=[C:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH:23]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C1CCc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C1CCc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cccc2C1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.3 %

Procedure:
To a solution of 5-t-butyldiphenylsilyloxy-2-ethoxycarbonyl-1-oxo-1,2,3,4-tetrahydronaphthalene (17 g) in a mixture of ethanol (100 ml) and tetrahydrofuran (100 ml) was added NaBH4 (1.4 g) at 0° C. After the mixture was stirred for 6 hours at room temperature, the solvent was removed in vacuo. The residue was dissolved in a mixture of ethyl acetate and water and the organic solution was washed with 1N--HCl solution, sat. NaHCO3, and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give 1-hydroxy-2-ethoxycarbonyl-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (7.9 g).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=O.S([O-])([O-])(=O)=O.[Mg+2]>>[CH2:1]([N:6]=[CH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN
Reactant: O=Cc1ccccn1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CCCCCN=Cc1ccccn1

Procedure:
n-Pentylamine (20.3 g, 0.23 mol) was added dropwise to pyridine-2-carboxaldehyde (25.0 g, 0.23 mol) with stirring in an ice bath. After complete addition of the amine, anhydrous magnesium sulfate (6 g) was added and the slurry stirred for 2 hours at 25° C. The solution was filtered, solvent removed, and the product purified by distillation under reduced pressure (0.5 mm Hg at 80° C.) to give a yellow oil. Yield: 29.6 g (73%). 1H NMR (CDCl3, 500 MHz): δ8.64 (m, 1H), 8.38 (s, 1H), 7.99 (m, 1H), 7.72 (m, 1H), 7.28 (m, 1H), 3.67 (t, 2H), 1.73 (sextet, 2H), 1.36 (overlapping quintets, 2H each), 0.90 (t, 3H), GCMS m/e 176.
Reaction SMILES: [I-:1].[CH3:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:6]=2[NH+:7]=1.[C:17]1(C)C=CC(S(OCC)(=O)=O)=C[CH:18]=1.[I-]>CO.C(O)C>[I-:1].[CH2:17]([N+:7]1[C:6]2[CH:8]=[C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:11][C:5]=2[O:4][C:3]=1[CH3:2])[CH3:18]
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1[nH+]c2cc(NS(C)(=O)=O)ccc2o1
Agent: [I-]
Solvent: CCO
Solvent: CO
Product: CC[n+]1c(C)oc2ccc(NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 121.4 %

Procedure:
Intermediate D (4.52 g) and ethyl p-toluenesulfonate (4.4 g) were combined in a large test tube and heated over a hot air gun with manual stirring for 5 minutes. A brownish melt formed, which solidified to a glass on cooling to room temperature. The glas was dissolved in 50 ml hot methanol, diluted with an 100 ml hot ethanol, and 9.0 g tetrabutylamonnium iodide dissolved in 20 ml ethanol was added. The brown, clear solution was cooled to room temperature and then ice cooled for 4 hours. Filtration of the resulting crystalline product gave 5.92 g of 3-ethyl-2-methyl-5-methylsulfonamidobenzoxazolium iodide (Intermediate E).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11](I)=[N:10][C:9]=1[C:14]1[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[N:16][N:15]=1.[CH3:27][C:28]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[N:32][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:29]2[C:28]([CH3:27])=[CH:33][N:32]=[C:31]([NH:34][C:35](=[O:37])[CH3:36])[CH:30]=2)=[N:10][C:9]=1[C:14]1[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[N:16][N:15]=1
Reactant: CC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)c(C)cn1
Reactant: C[Si](C)(C)CCOCn1cnnc1-c1nc(I)oc1-c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(-c2nc(-c3nncn3COCC[Si](C)(C)C)c(-c3ccccc3Cl)o2)c(C)cn1
Yield: 80.6 %

Procedure:
A mixture of 3-[5-(2-chlorophenyl)-2-iodo-1,3-oxazol-4-yl]-4-{[2-(trimethylsilyl)-ethoxy]methyl}-4H-1,2,4-triazole (0.39 g, 0.78 mmol), N-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]acetamide (0.36 g, 1.32 mmol), tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.16 mmol) and cesium carbonate (1.64 g, 5.04 mmol) in dioxane (13 mL) and water (1.8 mL) was subjected to microwave irradiation at 150° C. for 60 min. The reaction mixture was concentrated and the residue was purified by column chromatography to give N-{4-[5-(2-chlorophenyl)-4-(4-{[2-(trimethylsilyl)ethoxy]methyl}-4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (0.33 g, 81%). LCMS (AA): m/z=525.1 (M+H).
Reaction SMILES: C([NH:9][C:10]([NH:24][CH2:25][CH2:26][CH2:27][C:28]1[N:29]=[CH:30][NH:31][CH:32]=1)=[N:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][N:17]=1)(=O)C1C=CC=CC=1.[ClH:33]>O>[ClH:33].[ClH:33].[ClH:33].[CH3:23][O:22][C:21]1[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]([NH2:9])=[N:24][CH2:25][CH2:26][CH2:27][C:28]2[N:29]=[CH:30][NH:31][CH:32]=2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccnc1CCCCN=C(NCCCc1c[nH]cn1)NC(=O)c1ccccc1
Agent: Cl
Solvent: O
Product: COc1cccnc1CCCCNC(N)=NCCCc1c[nH]cn1

Procedure:
0.75 g (1.7 mmol) of N1 -benzoyl-N2 -[4-(3-methoxy-pyridin-2-yl)butyl]-N3 -[3-(1H-imidazol-4-yl)propyl]guanidine and 15 ml of conc. hydrochloric acid are boiled under reflux for 18 hours. After cooling, the reaction mixture is diluted to 30 ml with water and extracted with 4×25 ml diethylether. The aqueous phase is then filtered and concentrated by evaporation under vacuum. The residue is taken up twice with 20 ml of absolute ethanol and again concentrated by evaporation. 0.74 g (98%) of a colourless, amorphous, highly hygroscopic solid is obtained.
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].O[CH:12]1[CH:19]2[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:21][C:13]1([OH:22])[CH2:14]3)[CH2:18]2.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([O:6][CH2:7][C:8]([O:10][C:19]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:21][C:13]([OH:22])([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: OC1C2CC3CC(C2)CC1(O)C3
Reactant: C=C(C)C(=O)OCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCC(=O)OC12CC3CC(CC(O)(C3)C1)C2

Procedure:
Hydroxycarbonylmethyl methacrylate (30 g) and dihydroxyadamantane (16.8) were added into dichloromethane (500 ml), and p-toluenesulfonic acid (1 g) was added thereto. Then, the mixture was refluxed for 15 hours while removing water generated. After the reaction, conventional after-treatments were carried out to obtain oil (21.2 g), which was identified to be Monomer A described above.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[K].Cl[CH2:17][CH2:18][N:19]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][N:21]=[C:20]1[CH3:27].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:27][C:20]1[N:19]([CH2:18][CH2:17][N:9]2[C:10](=[O:11])[C:5]3=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][CH:12]=[C:6]3[C:7]2=[O:8])[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][N:21]=1
Reactant: O=C1NC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: Cc1ncc([N+](=O)[O-])n1CCCl
Agent: [K]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ncc([N+](=O)[O-])n1CCN1C(=O)c2cccc([N+](=O)[O-])c2C1=O

Procedure:
3-Nitrophthalimide is converted to the potassium salt by the procedure described in Example 13 and then reacted with 1-(2-chloroethyl)-2-methyl-5-nitroimidazole according to the procedure described in Example 1. The crude reaction mixture is digested with toluene and then filtered to remove some insoluble material. Evaporation of the solvent leaves a syrup which is diluted with chloroform and then filtered to remove some insoluble material. The filtrate is further diluted with toluene and again filtered to remove some precipitate. The solvent is then evaporated from the filtrate and the resulting residue is recrystallized first from ethanol and then from acetone to give N-[2-(2-methyl-5-nitro-1-imidazolyl)ethyl]-3-nitrophthalimide melting at about 175°-176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38]C)[CH:33]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCC[C@@H](Nc2nccc(-c3c(-c4cccc(O)c4)nc4sccn34)n2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-methoxy-phenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (6.98 g, 12.03 mmol) in methylene chloride (100 ml) was cooled to −78° C. and slowly treated with 1 molar solution of boron tribromide in methylene chloride (65 ml). The reaction mixture was kept at −78° C. for one hour then was allowed to warm to room temperature for two hours. The mixture was quenched by the addition of methanol (25 ml) at 0° C. and was stirred at room temperature for an additional hour. The mixture was diluted with methylene chloride (500 ml) and washed with three portions of 100 ml of saturated sodium bicarbonate solution, two portions of 100 ml of water and two portions of 100 ml of saturated sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated in vacuo, giving a yellow foam. The crude product was re-crystallized from methanol as a yellow solid (4.85 g, 71%). M.p.=174-177° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 9.4 (br. s, 1H), 8.70 (br. s, 1H), 8.12 (d, J=5.5 Hz, 1H), 7.8-7.7 (m, 2H), 7.7-7.65 (m, 2H), 7.40 (d, J=4.7 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.15 (d, J=7.4 Hz, 1H), 7.0-6.95 (m, 1H), 6.85-6.8 (m, 1H), 6.44 (d, J=5.5 Hz, 1H), 3.95 (br. s, 1H), 3.72 (dd, J=10.6 3.1 Hz, 1H), 3.40 (m, 1H), 2.5-2.4 (m, 1H), 2.35 (t, J=10.2 Hz, 1H), 2.0-1.8 (m, 2H), 1.65-1.5 (m, 1H), 1.46-1.32 (m, 1H). LCMS: 567 [M+H]. Calc. for C26H23N6O3S2Cl.0.5 water.1.0 methanol: C, 53.33; H, 4.64; N, 13.82. Found C, 53.32; H, 4.64; N, 13.82.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:17][C:18]1[C:23]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:21]=[C:20]([CH3:30])[N:19]=1>>[CH3:17][C:18]1[C:23]([N:24]2[CH2:29][CH2:28][N:27]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:16])=[CH:15][CH:14]=3)=[O:13])[CH2:26][CH2:25]2)=[CH:22][CH:21]=[C:20]([CH3:30])[N:19]=1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)n1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)c(C)n1
Yield: 34.3 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (270 mg) described in Preparation Example 16 and 1-(2,6-dimethylpyridin-3-yl)piperazine (215 mg) described in Preparation Example 94 and by the reaction and treatment in the same manner as in Example 87, the title compound (159 mg) was obtained.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[Br:28]>C(O)(=O)C.[Zn]>[Br:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[C:3]1[N:4]=[C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])[S:6][CH:2]=1
Reactant: COc1ccc(Br)c(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)c1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(Br)c(-c2csc(COc3ccc(F)c(C(N)=O)c3F)n2)c1

Procedure:
To a solution of 3-[5-Bromo-4-(2-bromo-5-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.06 g, 0.0001 mol) in 6 ml of acetic acid was added zinc (0.06 g, 0.0001 mol). The reaction mixture was refluxed for 30 min. The reaction mixture was allowed to come at 25° C. The reaction mixture was filtered on celite bed; the product was precipitated by adding water to the filtrate. The white solid was filtered and dried (0.006 g, 12%). 1H NMR (DMSO, 400 MHz), 3.79 (s, 3H), 5.59 (s, 2H), 6.94 (dd, 1H, J=8.8 Hz (o-coupling), J=4.0 Hz), 7.09-7.15 (m, 1H), 7.27 (d, 1H, J-4.0 Hz), 7.40-7.43 (m, 1H), 7.63 (d, 1H, J=8.8 Hz (o-coupling), 7.89 (broad s, 1H), 8.11 (s, 1H), 8.18 (s, 1H); MS ES+ (455.08 & 457.08). HPLC (method 5) Rt=10.21 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([NH:14][C:15]1[C:20]([CH2:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:23][CH3:24])=[NH:13])[CH3:2].[Cl:25][CH:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([NH:14][C:15]1[C:20]([CH2:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:23][CH3:24])=[N:13][CH2:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][Cl:25])[CH:28]=1)[CH3:2]
Reactant: CCc1cccc(CC)c1NC(=N)Nc1c(CC)cccc1CC
Reactant: Cc1cccc(C(Cl)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1NC(=NCc1cccc(CCl)c1)Nc1c(CC)cccc1CC
Yield: 32.5 %

Procedure:
9.7 g (0.03 mole) of N,N'-bis-(2,6-diethylphenyl) guanidine, 5.7 g (0.033 mole) of α,α-dichloro-m-xylene and 2.1 g (0.015 mole) of anhydrous potassium carbonate were added to 50 ml of toluene. The thus-formed mixture was then refluxed under heating for 10 hours. After the mixture had been allowed to cool, the insoluble substance was removed by filtration. The thus-obtained filtrate was washed with water and then concentrated for the purpose of recovering the solvent and unreacted raw materials to obtain a slightly yellow crystal. The crystal was then recrystallized from benzene to obtain 4.5 g of white powder.
Reaction SMILES: Br[CH2:2][CH2:3][C@H:4]([NH:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[N:11]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2][CH2:3][C@@H:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:10]1
Reactant: CCOC(=O)[C@H](CCBr)NNC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)N1
Reaction time: 2 h
Yield: 51.7 %

Procedure:
To a solution of slightly impure tert-butyl 2-[(1S)-3-bromo-1-(ethoxycarbonyl)propyl]hydrazinecarboxylate (1.57 g, 4.83 mmol) in dry THF (50 mL) at 0° C. was added LiHMDS (1 M in THF, 4.83 mmol, 4.83 mL). The solution was allowed to attain rt and was then stirred for 2 h. The reaction was quenched by addition of saturated NH4Cl(aq) and diluted with TBME. The phases were separated, the organic phase was dried, filtered and evaporated. The residue was purified using flash chromatography (DCM/EtOAc 4:1, 1:1) to give the pure 1-tert-butyl 3-ethyl (3S)-pyrazolidine-1,3-dicarboxylate (610 mg, 52%) as an oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][O:13][Si](C(C)(C)C)(C)C)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].Cl.C[O-].[Na+]>CO>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCC(CO[Si](C)(C)C(C)(C)C)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N1CCC(CO)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
A solution of 1-allyloxycarbonyl-3-t-butyldimethylsilyloxymethylpyrrolidine (29.95 g) in a mixture of concentrated hydrochloric acid (15 ml) and methanol (150 ml) was stirred at ambient temperature for one hour. A 28% solution of sodium methoxide in methanol (35 ml) was added to the mixture. Insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (400 g) and eluted with ethyl acetate to give 1-allyloxycarbonyl-3-hydroxymethylpyrrolidine (19.01 g).