Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([CH2:11][CH2:12][CH3:13])[CH:3]=1.[ClH:14]>CO.[OH-].[OH-].[Pd+2]>[ClH:14].[NH2:10][CH2:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[CH:3][C:4]=1[CH2:11][CH2:12][CH3:13]
Reactant: CCCc1cc(C)[nH]c(=O)c1C#N
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(C)[nH]c(=O)c1CN
Reaction time: 48 h
Yield: 60 %

Procedure:
To a stirred solution of 6-methyl-2-oxo-4-propyl-1,2-dihydropyridine-3-carbonitrile (15.0 g, 85.1 mmol) in methanol (600 mL) and concentrated HCl (15 mL) was added Pd(OH)2 (15.0 g). The mixture was stirred for 48 hours under H2 atmosphere. The reaction mixture was filtered and filtrate was concentrated in vacuo. Ethanol was added to the residue, the resulting precipitate was collected and dried to give the titled compound as a white solid (13.0 g, 60% yield). 1H-NMR (400 MHz, CDCl3) δppm; 11.86 (br. s., 1H), 6.00 (s, 1H), 3.78 (q, J=5.5 Hz, 2H), 3.61 (br. s., 2H), 2.46 (m, 2H), 2.17 (s, 3H), 1.50 (sxt, J=7.4 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Si:24]([CH3:36])([CH3:35])[CH2:25][CH2:26][O:27][CH2:28][N:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)(Cl)Cl.O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:34][C:31]3[CH:32]=[CH:33][N:29]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:36])([CH3:35])[CH3:23])[N:30]=3)[N:17]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(Cc2cccc(Br)n2)CCN(Cc2ccccc2)CC1
Reactant: C[Si](C)(C)CCOCn1ccc(N)n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc(Nc2cccc(CC3(O)CCN(Cc4ccccc4)CC3)n2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 469 mg of 1-benzyl-4-((6-bromopyridin-2-yl)methyl)piperidin-4-ol, 332 mg of 1((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (WO2006/046734, page 132, Reference 2), 150 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 134 mg of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, 827 mg of potassium phosphate and 10 ml of 1,4-dioxane was stirred at 100° C. overnight, followed by cooling to room temperature. The reaction mixture was diluted with chloroform. An insoluble matter was filtered off using Celite, washed with chloroform, and the filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=10/1) to give the title compound as a pale yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.CO.Cl>C1COCC1.O1CCOCC1>[Cl:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)=[N:15][CH:16]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: NC1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Reaction time: 48 h
Yield: 128.5 %

Procedure:
tert-Butyl{1-[3-chloro-5-(trifluoromethyl)pyridine-2-yl]piperidin-4-yl}carbamate (2.5 g, 6.4 mmol) was stirred in a mixture of THF (25 ml), MeOH (5 ml) and HCl in dioxane (4M, 6.5 ml) over night at rt. HCl in dioxane (4M, 4 ml) was added and after 4 h a third portion of HCl in dioxane/4M, 4 ml) was added. Stirring was continued for 48 h at rt. The solvent was evaporated, and the residue was dissolved in EtOAc. The resulting mixture was washed with aqueous saturated Na2CO3, water and dried over Na2SO4. Concentration of the organic phase yielded the title compound (2.3 g, 128%), which contained some impurities. 1H NMR (500 MHz, CDCl3): δ 1.50-1.54 (m, 2H), 1.88-1.94 (m, 2H), 2.93-3.00 (m, 3H), 4.01-4.04 (m, 2H), 7.74 (s, 1H), 8.38 (s, 1H); Mass Spectrum: M+H+ 280.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[S:6][C:7]([CH2:9][OH:10])=[CH:8][C:4]=2[CH:3]=1.C(OCC)(=O)C>C(Cl)Cl.CCCCCC.O=[Mn]=O>[F:1][C:2]1[CH:12]=[CH:11][C:5]2[S:6][C:7]([CH:9]=[O:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: OCc1cc2cc(F)ccc2s1
Agent: O=[Mn]=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1cc2cc(F)ccc2s1
Temperature: 52 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
MnO2 (4.298 g, 49.45 mmol) was added to a solution of (5-fluorobenzo[b]-thiophen-2-yl)methanol (I-50b: 1.8 g, 9.89 mmol) in DCM (50 mL) and the resulting reaction mass was stirred at 52° C. for 2 hours. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mass was cooled to room temperature, filtered off the catalyst through a celite bed and washed the celite bed with DCM. The filtrate was concentrated under reduced pressure and dried under vacuum to afford 1.5 g of the product (88.23% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([NH:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]2)[N:14]=[CH:13]3)[CH2:3][CH2:2]1.Br[CH2:27][CH2:28][F:29].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C>[F:29][CH2:28][CH2:27][NH:25][C@H:22]1[CH2:23][CH2:24][C@H:19]([NH:18][C:15]2[N:14]=[CH:13][C:12]3[C:17](=[C:8]([O:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:9]=[CH:10][CH:11]=3)[N:16]=2)[CH2:20][CH2:21]1
Reactant: N[C@H]1CC[C@H](Nc2ncc3cccc(OC4CCOCC4)c3n2)CC1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FCCN[C@H]1CC[C@H](Nc2ncc3cccc(OC4CCOCC4)c3n2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of trans-N-[8-(tetrahydro-2H-pyran-4-yloxy)quinazolin-2-yl]cyclohexane-1,4-diamine (0.4 g, 1.168 mmol) and 1-bromo-2-fluoro-ethane (0.178 g, 1.4 mmol) in anhydrous DMF (10 mL) were added anhydrous K2CO3 (0.4035 g, 2.92 mmol) and NaI (0.0174 g, 0.1168). The resulting mixture was stirred at room temperature for 72 h. The mixture was concentrated and CH2Cl2 (40 mL) was added to the residue. The mixture was washed with H2O (3×30 mL) and brine (30 mL), dried over Na2SO4 and concentrated in vacuo to give crude solid, which was purified by chromatography (CH2Cl2: MeOH=40:1) to give the title compound (0.150 g, 33.3%) as a yellow solid. 1H NMR (CDCl3, 400 Hz): 8.872 (s, 1H), 7.273 (d, 1H), 7.130 (d, 1H), 7.038 (t, 1H), 5.129 (s, 1H), 4.568 (s, 1H), 4.556 (t, 1H), 4.449 (t, 1H), 3.995 (m, 2H), 3.897 (m, 1H), 3.493 (m, 2H), 2.925 (t, 1H), 2.854 (t, 1H), 2.491 (m, 1H), 2.201 (s, 2H), 1.970 (m, 6H), 1.214 (m, 5H).
Reaction SMILES: C([C@H]([C@@H:14]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:15]([NH:17][N:18](S(C)(=O)=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])CCCC1C=CC=CC=1)(O)=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CC([Si](ON)(C)C)(C)C>CN(C)C=O>[CH3:31][CH:30]([CH3:32])[CH2:29][CH2:14][C:15]([NH:17][NH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16]
Reactant: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](CCCc1ccccc1)C(=O)O
Agent: CC(C)(C)[Si](C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)CCC(=O)NNc1ccccc1

Procedure:
A solution of 0.165 g of 2(R)-[1(S)-(carboxy)-4-phenylbutyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide in 4 ml of dry dimethylformamide was cooled to 0° C. while stirring under nitrogen and 0.09 g of 1-hydroxybenzotriazole and 0.09 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added in succession. After stirring for 40 minutes at 0° C. the solution was treated with 0.18 g of 0-(tert-butyldimethylsilyl)hydroxylamine and the mixture was left to come to room temperature and then stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was washed in succession with water, 2M sulphuric acid, water and brine and then dried over anhydrous magnesium sulphate. The solvent was evaporated to give a pale pink gum which on crystallization from ether gave 0.05 g of 2(R)-[1(S)-(hydroxycarbamoyl)-4-phenylbutyl]-2′-methanesulphonyl)-4-methyl-2′phenylvalerohydrazide in the form of an off-white solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[CH2:22][S:19](=[O:21])(=[O:20])[O:18][CH2:17]1>C1(C)C=CC=CC=1>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:17][CH2:16][CH2:22][S:19]([OH:21])(=[O:20])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=S1(=O)CCCO1
Solvent: Cc1ccccc1
Product: O=S(=O)(O)CCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of dibenzylamine (9.8 mL, 50.8 mmol) in toluene (50 mL) was added 1,3-propane sultone (6.50 g, 53.3 mmol). The mixture was stirred at reflux for 3 h. A sticky paste was formed at the bottom of the flask. The reaction mixture was cooled to room temperature. The top layer was decanted; and the paste was partially dissolved in EtOAc with heating. The mixture was poured in a 10% EtOAc/Hexanes (200 mL). The mixture was heated and the paste was spread on the walls of the conical flask. The solvent was removed. This process was repeated twice. MeOH (75 mL) was added to the paste. The mixture was heated until a white solid appeared. The solid was collected by filtration, washed with cold MeOH, and dried in vacuo, affording compound AV, 7.03 g (43%).
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[N:19]1([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH:23]=[N:22][CH:21]=[N:20]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[CH:32][CH:31]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-n2cncn2)cc1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Product: CC(C)c1noc(N2CCC(N(C(=O)c3ccc(-n4cncn4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 4-[1,2,4]triazol-1-yl-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=3.71 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].Cl[C:10]1[N:11]=[N+:12]([O-:23])[C:13]2[C:22]3[CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=[CH:16][C:14]=2[N:15]=1>COCCOC>[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][C:10]1[N:11]=[N+:12]([O-:23])[C:13]2[C:22]3[CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:2]
Reactant: CCN(CC)CCN
Reactant: [O-][n+]1nc(Cl)nc2ccc3c(c21)CCC3
Solvent: COCCOC
Product: CCN(CC)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCC3
Yield: 89.9 %

Procedure:
N,N-Diethyl-1,2-ethanediamine (0.41 mL, 2.9 mmol) was added to a stirred solution of chloride 5 (215 mg, 1.0 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 5 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 8 (271 mg, 93%) as a pale yellow solid: mp (MeOH/EtOAc) 126-130° C.; 1H NMR δ 7.54 (d, J=8.4 Hz, 1H, H-6), 7.39 (d, J=8.4 Hz, 1H, H-5), 5.93 (br s, 1H, NH), 3.63 (br dd, J=7.5, 7.4 Hz, 2H, H-9), 3.52-3.57 (m, 2H, CH2N), 2.97 (br dd, J=7.8, 7.6 Hz, 2H, H-7), 2.74 (br t, J=6.0 Hz, 2H, CH2N), 2.63 (q, J=7.4 Hz, 4H, 2×CH2N), 2.16 (br p, J=7.6 Hz, 2H, H-8), 1.07 (t, J=7.1 Hz, 6H, 2×CH3); 13C NMR δ 158.4, 149.0, 142.0, 137.3, 132.2, 129.2, 124.6, 51.2, 46.6 (2), 38.5, 35.3, 32.8, 24.8, 11.5 (2). Anal. calcd for C16H23N5O.¼H2O: C, 62.8; H, 7.7; N, 22.9. Found: C, 63.0; H, 7.6; N, 22.9%.
Reaction SMILES: O[CH2:2][C:3]1[NH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][N:7]=1.[NH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[SH:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[NH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[S:24][CH2:2][C:3]1[NH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1nnc(CO)[nH]1
Reactant: Nc1cc(Cl)ccc1S
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nnc(CSc2ccc(Cl)cc2N)[nH]1

Procedure:
A solution of tert-butyl (5-(hydroxymethyl)-4H-1,2,4-triazol-3-yl)carbamate (190 mg, 0.888 mmol), 2-amino-4-chlorobenzenethiol (213 mg, 1.332 mmol), PPh3 (466 mg, 1.776 mmol) and di-tert-butylazodicarboxylate (409 mg, 1.776 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 2 days. The solvent was then removed and the crude residues was loaded on silica gel column to get the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:15][C@@H:16]1[CH2:23][C@H:22]2[C@H:18]([CH2:19][C:20](=[O:24])[O:21]2)[C@H:17]1/[CH:25]=[CH:26]/[C@@H:27]([OH:33])[CH2:28][C:29]#[C:30][CH2:31][CH3:32])(=O)C1C=CC=CC=1.Cl>CO>[OH:33][C@@H:27]([CH2:28][C:29]#[C:30][CH2:31][CH3:32])/[CH:26]=[CH:25]/[C@H:17]1[C@H:16]([OH:15])[CH2:23][C@H:22]2[C@@H:18]1[CH2:19][C:20](=[O:24])[O:21]2
Reactant: CCC#CC[C@H](O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCC#CC[C@H](O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
712 mg of anhydrous potassium carbonate are introduced into a solution of 4.3 g of the alcohol prepared in Example (23d) in 47 ml of methanol and the mixture is stirred at room temperature for 3 hours. While cooling with ice, 0.72 ml of concentrated hydrochloric acid are then added dropwise to the reaction solution and the whole is concentrated in vacuo. The residue is dissolved in methylene chloride, the solution is dried over magnesium sulphate and concentrated in vacuo. The crude product is chromatographed over silica gel by gradient elution in methylene chloride/acetone. 2.85 g of the title compound are obtained.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(O)C>[CH2:16]([N:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][N:10]=[N:9]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: CCCCCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCn1nnnc1-c1ccccc1
Reaction time: 4 h
Yield: 46 %

Procedure:
5-Phenyltetrazole (29.2 g, 0.2 mole) was placed in 300 ml of ethanol and sodium methylate (11 g, 0.2 mole) added. On the addition of bromohexane (33 g, 0.2 mole), the solution cleared immediately. The mixture slowly became cloudy on four hours refluxing. Filtering followed by stripping gave 21.2 g of a yellow liquid.
Reaction SMILES: Cl.Cl.[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH:14]([NH2:18])[CH2:13]2)[N:11]=1)[C:4]([NH2:6])=[NH:5].C(N(CC)CC)C.[N-:26]([C:29]#[N:30])[C:27]#[N:28].[Na+]>C(O)CCC>[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:29]([NH2:30])=[N:26][C:27]#[N:28])[CH2:13]2)[N:11]=1)[C:4]([NH2:6])=[NH:5]
Reactant: N=C(N)Nc1nc(C2CCCC(N)C2)cs1
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: N#CN=C(N)NC1CCCC(c2csc(NC(=N)N)n2)C1

Procedure:
A mixture of 2-guanidino-4-(3-aminocyclohexyl)thiazole dihydrochloride (0.62 g.), triethylamine (0.56 ml.) and sodium dicyanamide (0.23 g.) in n-butanol (10 ml.) was heated under reflux for four hours. The filtered reaction mixture was evaporated and the residue subjected to preparative thin layer chromatography on silica GF 254 (Merck) plates using chloroform/methanol/ammonia (s.g. 0.88) 8:2:03 v/v/v for development. Isolation of the appropriate region of the chromatogram and elution with hot ethanol/chloroform (50:50 v/v) gave 2-guanidino-4-[3-(2-cyanoguanidino)cyclohexyl] thiazole as a glass. The n.m.r. spectrum in d6 dimethylsulphoxide included resonances at 1.28(m); 1.8(m); 6.3(s); 6.55(br s); 6.67(d); 6.9(br s) and showed resonances attributable to solvation by ethanol (~0.5 mole) and water.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][OH:27])[CH2:24][O:23][C:22]3=[O:28])=[CH:17][C:16]=2[F:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:31](I)[CH3:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][O:27][CH2:31][CH3:32])[CH2:24][O:23][C:22]3=[O:28])=[CH:17][C:16]=2[F:29])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)cc2F)CC1
Reactant: CCI
Product: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Yield: 71.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-4-[2-fluoro-4-(4-hydroxymethyl-2-oxooxazolidin-3-yl)benzoyl]piperazine-1-carboxylic acid tert-butyl ester (2.20 g) described in Preparation Example 156 and ethyl iodide (972 mg), the title compound (1.67 g) was obtained.
Reaction SMILES: Br[C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[Cl:20][C:17]([F:19])([F:18])[C:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:23]=[C:2]([C:34]3[CH:35]=[N:30][CH:31]=[N:32][CH:33]=3)[C:3]([N:24]3[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1)([F:22])[F:21]
Reactant: O=C(Nc1ccc(C(F)(F)C(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using (R)-5-bromo-N-(4-(2-chloro-1,1,2,2-tetrafluoroethyl)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 278.1) and pyrimidin-5-ylboronic acid to afford an amorphous white powder. HPLC (Condition 4) tR=5.21 min, UPLC-MS (Condition 3) tR=0.99 min, m/z=496.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.77 (m, 1H) 1.78-1.89 (m, 1H) 2.82-2.92 (m, 1H) 3.14-3.26 (m, 2H) 3.32-3.42 (m, 1H) 4.15-4.26 (m, 1H) 4.87 (d, J=3.13 Hz, 1H) 7.63 (d, J=8.99 Hz, 2H) 7.97 (d, J=8.60 Hz, 2H) 8.10 (dd, J=2.35, 0.78 Hz, 1H) 8.79 (dd, J=2.35, 0.78 Hz, 1H) 8.88 (d, J=0.78 Hz, 2H) 9.18 (d, J=0.78 Hz, 1H) 10.31 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from {5-ethoxy-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M166) (265 mg, 0.488 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (154 mg, 74%).
Reaction SMILES: O1CC[C@H]([O:6][C:7](=[O:34])[NH:8][CH2:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=4)[N:19]=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])[N:17]=3)[CH2:11]2)C1.[ClH:35].[CH3:36][CH2:37][O:38][CH2:39][CH3:40]>C(Cl)Cl>[ClH:35].[O:38]1[CH2:39][CH2:40][C@H:36]([N:8]([CH2:9][C@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=4)[N:19]=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])[N:17]=3)[CH2:11]2)[C:7](=[O:34])[OH:6])[CH2:37]1
Reactant: CCOCC
Reactant: Cc1ccc2c(N3CCC[C@@H](CNC(=O)O[C@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC[C@H](CN(C(=O)O)[C@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
(S)-Tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (115 mg, 0.251 mmol) was suspended in 8 mL of anhydrous CH2Cl2 and gently heated until an homogenous solution was formed. After cooling to room temperature, a 2.0 M solution of HCl in Et2O (0.126 mL, 0.251 mmol) was added in one portion. The reaction mixture was diluted with 25 mL Et2O, and the product precipitated from the solution. The reaction was stirred for an additional 30 minutes before the solid was filtered and dried to obtain (S)-tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate hydrochloride (108 mg, 86%) as a light yellow solid. LC/MS: m/z 463.5 (M+H)+ at 2.37 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J=6.6 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.73 (s, 1H), 7.44-7.51 (m, 2H), 7.00-7.07 (m, 2H), 5.06-5.09 (m, 1H), 4.52-4.62 (m, 2H), 3.62-3.74 (m, 4H), 3.23-3.29 (m, 1H), 3.00 (d, J=6.8 Hz, 2H), 2.52 (s, 3H), 2.02-2.11 (m, 1H), 1.61-2.01 (m, 4H), 1.24-1.43 (m, 2H), 0.84-0.89 (m, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: C1COCCN1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: Brc1ccc(-c2nsc3cc(OCCCCN4CCOCC4)ccc23)cc1

Procedure:
According to the method in example 4, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and morpholine were converted to yield 3-(4-Bromo-phenyl)-6-(4-morpholin-4-yl-butoxy)-benzo[d]isothiazole, MS: 448 (MH+, 1Br).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N+:6]([O-:11])[CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[S:12]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=1)(=[O:14])=[O:13].[N+:24]([O-])([OH:26])=[O:25].CCOCC>C(O)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[N+:6]([O-:11])[CH:7]=[C:8]([N+:24]([O-:26])=[O:25])[CH:9]=2)[S:4][C:3]=1[S:12]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=1)(=[O:13])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1cc(F)cc(S(=O)(=O)c2sc3c(ccc[n+]3[O-])c2Br)c1
Solvent: CC(=O)O
Solvent: CCOCC
Product: N#Cc1cc(F)cc(S(=O)(=O)c2sc3c(cc([N+](=O)[O-])c[n+]3[O-])c2Br)c1

Procedure:
3-Bromo-2-(3-cyano5-fluorobenzenesulfonyl)-thieno[2,3-b]pyridin-N-oxide (prepared as described in WO 2007/072095) (7.97 g, 19.3 mmol) was boiled at 120° C. with 66% nitric acid (1.22 ml) in acetic acid (25 ml) for 4 hours. The reaction mixture was evaporated and the residue was purified by chromatography (Kieselgel 60, chloroform:methanol=5:0.1). First the starting material was isolated (3.7 g, 47%), than a yellow solid, which was treated with ether (5 ml). After filtration the title compound was isolated (0.72 g, 8.3%). LC-MS: (M+H)+ 459.1.