Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Br:12])=[CH:6][C:3]=1[CH:4]=O.[NH2:13][C:14](N)=[O:15]>>[Br:12][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][C:8]=1[O:10][CH3:11])[N:1]=[C:14]([OH:15])[N:13]=[CH:4]2
Reactant: COc1cc(N)c(C=O)cc1Br
Reactant: NC(N)=O
Product: COc1cc2nc(O)ncc2cc1Br
Temperature: 180 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
A mixture of 2-amino-5-bromo-4-methoxybenzaldehyde (3 g, 13.1 mmol) and urea (12 g, 196.5 mmol) was stirred at 180° C. for 2 h. LCMS showed the reaction was completed. The reaction mixture was cooled to RT and washed with water (3×100 mL). The precipitate was collected and dried to give the title compound (3 g, crude) as a yellow solid. MS (ES+) C8H7BrN2O2 requires: 254, 256. Found: 255, 257 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38](O)=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7].[C:50]1([C:102]2[CH:107]=[CH:106][CH:105]=[CH:104][CH:103]=2)[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[NH:56][C:57]([O:59][CH:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][N:68]([CH3:101])[C:69](=[O:100])[CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][N:75]([C:86]2[CH:91]=[CH:90][C:89]([N:92]([CH3:99])[C:93](=[O:98])[CH2:94][CH2:95][NH:96][CH3:97])=[CH:88][CH:87]=2)[C:76](=[O:85])[O:77][CH2:78][C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[CH2:62][CH2:61]1)=[O:58]>>[C:50]1([C:102]2[CH:107]=[CH:106][CH:105]=[CH:104][CH:103]=2)[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[NH:56][C:57]([O:59][CH:60]1[CH2:61][CH2:62][N:63]([CH2:66][CH2:67][N:68]([CH3:101])[C:69](=[O:100])[CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][N:75]([C:86]2[CH:87]=[CH:88][C:89]([N:92]([C:93](=[O:98])[CH2:94][CH2:95][N:96]([C:38](=[O:39])[CH2:37][O:36][C@@H:28]3[C:25]4([CH2:26][CH2:27][N:22]([CH2:21][CH2:20][C@:11]5([C:13]6[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=6)[O:10][CH2:9][N:8]([C:6](=[O:7])[C:5]6[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=[C:3]([C:2]([F:49])([F:1])[F:48])[CH:4]=6)[CH2:12]5)[CH2:23][CH2:24]4)[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29]3)[CH3:97])[CH3:99])=[CH:90][CH:91]=2)[C:76](=[O:85])[O:77][CH2:78][C:79]2[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=2)[CH2:64][CH2:65]1)=[O:58]
Reactant: O=C(O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Reactant: CNCCC(=O)N(C)c1ccc(N(CCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)C(=O)OCc2ccccc2)cc1
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN(C(=O)OCc1ccccc1)c1ccc(N(C)C(=O)CCN(C)C(=O)CO[C@H]2Cc3ccccc3C23CCN(CC[C@@]2(c4ccc(F)cc4)CN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CO2)CC3)cc1
Yield: 76.7 %

Procedure:
The compound (111 mg, 0.16 mmol) obtained in Example 1j and the compound (133 mg, 0.17 mmol) obtained in Example 97e were used to give the title compound (180 mg; yield, 73%) as a white solid according to the method described in Example 11e.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH2:28](Br)[CH:29]=[CH2:30]>CN(C=O)C>[CH2:30]([O:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 2-hydroxy-4-(1-tertbutyloxycarbonyl-4-piperidinyloxy)benzoate from Step XX of Example XX (2.50 g, 7.11 mmol) in DMF (50 mL) under N2 was added NaH (427 mg, 10.7 mmol). The reaction mixture was cooled, and allyl bromide (1.23 mL, 14.2 mmol) was added via syringe. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and aqueous NaHCO3. The ethyl acetate layer was dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified using pressurized silica gel column chromatography using a gradient elution of 10-15% ethyl acetate in hexanes. Methyl 2-allyloxy-4-(1-tertbutyloxycarbonyl-4-piperidinyloxy)benzoate was obtained as a thick colorless oil.
Reaction SMILES: I[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]=2[N:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([O:21][CH3:22])[CH:13]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH2:11][C:10]1[C:5]2[N:4]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([O:21][CH3:22])[CH:13]=3)[N:3]=[C:2]([C:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=3)[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: COc1cc(-n2nc(I)c3ncnc(N)c32)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-n2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c32)ccc1[N+](=O)[O-]
Temperature: 85 °C
Yield: 60.2 %

Procedure:
A mixture of 3-iodo-1-(3-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (300 mg, 0.728 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydro-1-pyridinecarboxylate (270 mg, 0.874 mmol), sodium carbonate (185 mg, 1.75 mmol) and tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.044 mmol) in 1,2-dimethoxy ethane (6 mL) and water (3 mL) was heated in an 85° C. oil bath for 1.75 hours. tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydro-1-pyridinecarboxylate (45 mg, 0.146 mmol) was added to the mixture and then it was heated in the 85° C. oil bath for another 16 hours. The solvents were evaporated under reduced pressure then the residue was partitioned between water (10 mL) and ethyl acetate (15 mL). The layers were separated and then the aqueous layer was extracted with ethyl acetate (10 mL), dichloromethane (20 mL) and then a 10% solution of methanol in dichloromethane (20 mL). The organic solutions thus obtained were combined and evaporated to a residue which was purified by flash chromatography on silica gel using ethyl acetate as an eluent to provide the title compound as a yellow solid (205 mg, 60%): 1H NMR (DMSO-d6, 400 MHz) δ 8.40 (s, 1H), 8.10 (d, 1H), 7.50 (m, 1H), 7.42 (s, 1H), 7.31 (d, 1H), 7.1 (bs, 2H), 4.13 (m, 2H), 3.99 (s, 3H), 3.58 (m, 2H), 2.67 (m, 2H), 1.44 (s, 9H) RP-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 21.42 min; MS: M−H+ 466.3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[C:13]([CH3:18])=[N:14][O:15][C:16]=2[CH3:17])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20].O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:9]([C:12]2[C:13]([CH3:18])=[N:14][O:15][C:16]=2[CH3:17])(=[O:10])=[O:11])=[C:6]([N+:19]([O-:21])=[O:20])[CH:7]=1
Reactant: Cc1noc(C)c1S(=O)(=O)Nc1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: Cc1noc(C)c1S(=O)(=O)Nc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 64.4 %

Procedure:
To a solution of N-(4-Chlorophenyl)-3,5-dimethyl-4-isoxazolesulfonamide (1.10 g (3.84 mmol)) in acetic acid (4.0 ml), fuming nitric acid (0.20 ml (4.68 mmol)) was added dropwise with stirring at room temperature, and the mixture was heated at 50° C. for one hour with stirring. Water (20.0 ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydroxide solution and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with acetone-chloroform-hexane(1:3:8) as eluent, to give 0.82 g (64%) of N-(4-chloro-2-nitrophenyl)-3,5 dimethyl-4-isoxazolesulfonamide as yellow crystals.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]#[N:15]>C1COCC1>[NH2:15][C:14]([C:10]1[O:9][CH:13]=[CH:12][CH:11]=1)=[CH:2][C:1]#[N:3]
Reactant: N#Cc1ccco1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CC=C(N)c1ccco1
Reaction time: 0.25 h

Procedure:
Following the method of Gupta et al. (Tetrahedron 1990, 46, 3703) and Bullock and Gregory (Can. J. Chem. 1965, 43, 332), to a stirred solution of 0.53 ml (10.0 mmol) acetonitrile in 25 ml dry THF under argon at −78° C. was added 6.25 ml (10.0 mmol) n-butyllithium solution (1.6M in hexane) and stirring continued for 15 minutes. 0.87 ml (10.0 mmol) 2-furonitrile was then added dropwise and stirring continued for 45 minutes at −78° C. The reaction mixture was quenched at 0° C. with 3 ml water and then partitioned between ether and water. The organic phase was then washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 1.10 g (82%) (E or Z)-3-amino-3-furan-2-yl-acrylonitrile as a yellow crystalline solid which was stored in the refrigerator. EI-MS m/e (%): 134 (M+, 100).
Reaction SMILES: [CH:1]1([C:4]2([F:25])[CH2:7][N:6]([C:8]3[N:13]=[C:12]([S:14]([CH3:17])(=O)=O)[N:11]=[C:10]([NH:18][C:19]4[NH:23][N:22]=[C:21]([CH3:24])[CH:20]=4)[CH:9]=3)[CH2:5]2)[CH2:3][CH2:2]1.[NH2:26][C:27]1[N:32]=[CH:31]C(S)=[CH:29][CH:28]=1>CN(C=O)C.C(OC(=O)C)C.C([O-])(O)=O.[Na+]>[NH2:26][C:27]1[N:32]=[CH:31][C:17]([S:14][C:12]2[N:11]=[C:10]([NH:18][C:19]3[NH:23][N:22]=[C:21]([CH3:24])[CH:20]=3)[CH:9]=[C:8]([N:6]3[CH2:7][C:4]([CH:1]4[CH2:3][CH2:2]4)([F:25])[CH2:5]3)[N:13]=2)=[CH:29][CH:28]=1
Reactant: Nc1ccc(S)cn1
Reactant: Cc1cc(Nc2cc(N3CC(F)(C4CC4)C3)nc(S(C)(=O)=O)n2)[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(N3CC(F)(C4CC4)C3)nc(Sc3ccc(N)nc3)n2)[nH]n1
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (880 mg, 2.4 mmol) and 6-aminopyridine-3-thiol) (300 mg, 2.4 mmol) in DMF (10 ml) was heated to 80° C. and stirred for 2 hrs. The reaction was diluted with ethylacetate (150 ml) and Sat. NaHCO3 (50 ml) and the organic layer washed with brine (50 ml), dried (MgSO4) and concentrated to give an oil. The residue was purified by flash column chromatography eluting with Pentane/EtOAc (5% MeOH) 0 to 100%. The resulting compound was triturated in 10:1 DCM:MeOH and filtered to give the title compound as a white solid (300 mg, 30%). 1H NMR (DMSO, 400 MHz) 0.42-0.44 (2H, m), 0.55-0.60 (2H, m), 1.35-1.45 (1H, m), 2.11 (3H, s), 3.81-3.90 (4H, m), 5.55-5.80 (2H, m), 6.35 (2H, s), 6.49-6.52 (1H, d), 7.46-7.49 (1H, d), 7.97 (1H, s), 9.30-9.35 (1H, s). ES+ 413
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:24]2[CH:23]=[C:22]([C:21]3[CH2:20][C:19](=[O:35])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:27]=[CH:26][CH:25]=2)[CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M24) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (151 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][CH2:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)=[O:26]>>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([NH:27][C:25](=[O:26])[CH2:24][NH:23][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH:33]=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: COc1ccc(NC(=O)CN)cc1OC
Product: COc1ccc(NC(=O)CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1OC

Procedure:
N-[2-(3,4-Dimethoxyphenylamino)-2-oxoethyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2 -yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4 oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 2-amino-N-(3,4-dimethoxyphenyl)acetamide using method I.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c([N+](=O)[O-])ccc(F)c1F
Yield: 106.7 %

Procedure:
20 g (0.114 mole) of 2,3-difluoro-6-nitrophenol (VI) were dissolved in 700 ml of acetone. 18.9 g (0.137 mole) of potassium carbonate and 34.1 g (0.24 mole) of methyl iodide were added to the solution, and the mixture was heated under reflux for 20 hours, whilst stirring. The solvent was then removed from the mixture by evaporation under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and the solvent was removed by evaporation under reduced pressure to give 23.0 g of 3,4-difluoro-2-methoxy-1-nitrobenzene (VII) as a yellow oil [Step (B1)].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:16])=[C:8]([CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14])[CH:9]=1)(=[O:3])[CH3:2].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[Cl:16][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[CH:19][N:20]([CH3:22])[CH3:21])=[CH:9][C:8]=1[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14]
Reactant: COC(=O)NCc1cc(C(C)=O)ccc1Cl
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: COC(=O)NCc1cc(C(=O)C=CN(C)C)ccc1Cl
Temperature: 135 °C
Yield: 81.2 %

Procedure:
To a solution of methyl N-[(5-acetyl-2-chlorophenyl)methyl]carbamate (10 g, 41.5 mmol) (prepared by the method given in European Patent Publication EP 1586552) in toluene was added N,N-dimethylformamide dimethyl acetal (9.88 g, 82.9 mmol) and the reaction mixture was heated at 135° C. for 2 days. TLC analysis (50% ethyl acetate/pet ether) showed the reaction was complete. The solvent was evaporated under vacuum and water was added to the residue. The water layer was extracted with ethyl acetate three times. The combined the organic phases were washed with water, brine, dried over Na2SO4 and concentrated under vacuum to give the title compound (10 g, 81% yield) as solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([CH:26]=O)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.Cl.[NH2:29][OH:30]>CO.N1C=CC=CC=1>[OH:30][N:29]=[CH:26][C:20]1([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:8][CH:9]=3)[CH:15]=2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: NO
Reactant: Cc1nccn1-c1ccc(Sc2cccc(C3(C=O)CCOCC3)c2)cc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1nccn1-c1ccc(Sc2cccc(C3(C=NO)CCOCC3)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.3 %

Procedure:
4-[3-[4-(2-Methylimidazol-1-yl)phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carbaldehyde (178 mg, 0.47 mmol) and hydroxylamine hydrochloride (210 mg, 3 mmol) were dissolved in a mixture of methanol (4 ml) and pyridine (1 ml) and the reaction mixture was stirred for 5 h at ambient temperature. Volatiles were removed in vacuo and the resultant residue was diluted with 0.1 N aqueous NaOH (20 ml) and extracted with ethyl acetate (30 ml×3). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried (MgSO4) and concentrated in vacuo. The residual solids were recrystallized from ethyl acetate to afford 130 mg (70%) of the titled compound as white solids.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(c1cnn(-c2ccccc2)c1)c1cc(Br)ccc1O
Product: CCOC(=O)COc1ccc(Br)cc1C(=O)c1cnn(-c2ccccc2)c1
Yield: 100 %

Procedure:
Prepared from (5-bromo-2-hydroxy-phenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone and ethyl bromoacetate according to GP2 to give 215 mg (100%) white crystals. The product was used without further purification: LC/MS (an 10p8): Rt 6.15 min, m/z 429 [M+H]+; 1H NMR (CDCl3): δ 1.26 (t, J=7.1 Hz, 3H), 4.24 (q, J=7.1 Hz, 2H), 4.64 (s, 2H), 6.72 (d, J=8.9 Hz, 1H), 7.34 (m, 1H), 7.46 (m, 2H), 7.53 (dd, J=8.9, 2.5 Hz, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.73-7.78 (m, 2H), 8.17 (s, 1H), 8.58 (s, 1H); 13C NMR (CDCl3): δ14.3, 61.9, 65.5, 114.0, 114.5, 119.8, 125.3, 127.7, 129.8, 131.8, 132.3, 132.7, 134.6, 139.6, 142.7, 154.1, 168.5, 186.9.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7]Cl)[O:4][N:3]=1.[CH3:9][N:10]([CH3:21])[C:11]([N:13]([CH3:20])[C:14]1[S:15][C:16]([SH:19])=[N:17][N:18]=1)=[O:12].C(N(CC)CC)C>O1CCCC1>[CH3:9][N:10]([CH3:21])[C:11]([N:13]([CH3:20])[C:14]1[S:15][C:16]([S:19][CH2:7][C:5]2[O:4][N:3]=[C:2]([CH3:1])[CH:6]=2)=[N:17][N:18]=1)=[O:12]
Reactant: CN(C)C(=O)N(C)c1nnc(S)s1
Reactant: Cc1cc(CCl)on1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(CSc2nnc(N(C)C(=O)N(C)C)s2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
In a 100 ml round bottom flask were mixed 3-methyl-5-chloromethylisoxazole (1.5 g, 11 mmol), tetrahydrofuran (50 ml), 1,1,3-trimethyl-3-(5-mercapto-1,3,4-thiadiazol-2-yl) urea (2.5 g, 11 mmol) and triethylamine (5.1 g, 50 mmol). This was stirred at room temperature overnight. The reaction mixture was filtered and the solvent was stripped from the filtrate on a rotary evaporator. The residue was dissolved in dichloromethane and this was washed with water (2×60 ml) and the organic solution was dried over MgSO4. This was treated with decolorizing carbon, was filtered and the solvent was removed to give a pale tan oil which was dried in vacuo, 2.9 g, 84.1% yield. NMR: (CDCl3) 6.2 (S, 1H), 4.5 (S, 2H), 3.55 (S, 3H), 2.95 (S, 6H), 2.25 (S, 3H). IR (neat) 3120, 2960, 2930, 1660, 1600, 1480, 1440, 1410, 1370 1305, 1265, 1125, 1080, 1060 cm-1. Calcd: C, 42.16; H, 4.82; N, 22.35. Found: C, 42.06; H, 4.90; N, 22.10.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4].[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>C(O)C>[C:17]([NH:21][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Solvent: CCO
Product: CC(C)(C)NCC(=O)c1ccc(O)c2[nH]c(=O)ccc12
Yield: 44.4 %

Procedure:
8.0 g of the 5-chloroacetyl-8-hydroxycarbostyril (IV) (IV) obtained Example 4 or 8 was suspended in 100 ml of ethanol, and 10 g of tert-butylamine was added dropwise to the resulting suspension while stirring followed by stirring at 55° to 60° C. for 5 hours. After the mixture was concentrated to half the volume, concentrated hydrochloric acid was added thereto to adjust the mixture to a pH of 2 to 3. The precipitated crystals were filtered, washed with acetone and recrystallized from ethanol to obtain 4.1 g of 5-tert-butylaminoacetyl-8-hydroxycarbostyril (II) having a melting point of 291° - 293° C. (with decomposition) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[O:21][CH2:22][CH3:23])=[N:10][CH:9]2[CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)([Cl:39])=[O:38]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([C:37]([Cl:39])=[O:38])[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[O:21][CH2:22][CH3:23])=[N:10][CH:9]2[CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a solution of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (160 mg, 0.387 mmol) in methylene chloride (15 mL) cooled to 0° C. were sequentially added triethylamine (108 μL, 0.774 mmol) and phosgene (589 μL, 1.161 mmol, 1.97 M in toluene). The reaction mixture was stirred at 0° C. under Argon for 30 min. The solvent and excess reagents were removed by rotovap, and the residue was purified by flash chromatography (Biotage system, KP-Sil™ 32–63 μm, 60 Å silica gel) eluting with 20–25% ethyl acetate in hexanes to give 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (132.6 mg, 72%) as white solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][OH:14])[CH2:7][CH2:6]2.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][O:14][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(CO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(COS(=O)(=O)c1ccc(C)cc1)C2
Yield: 80.9 %

Procedure:
(RS)-(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-methanol (939 mg, 4.88 mmol), p-toluenesulfonyl chloride (934 mg, 4.9 mmol), triethylamine (1.12 ml, 7.88 mmol) and N,N-dimethyl aminopyridine (10 mg) in CH2Cl2 (10 ml) was stirred together at ambient temperature for 24 hr. Acidification with 1N HCl (pH 1-2), extraction of the aqueous phase with CH2Cl2 (2×20 ml), drying (Na2SO4) filtration and evaporation afforded the crude product which wag chomatographed over SiO2 (Merck 230-400 mesh) eluting with EtOAc-n-Hexane (1:3) to afford the title compound as a colourless oil (1.37 g, 3.95 mmol, 81%), MS m/e=346.1 (M+).