Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([N:38](CC)CC)C.Cl.CN(C)CCCN=C=NCC.O>CN(C)C=O>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][C:33]([NH2:38])=[O:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: CCN(CC)CC
Reactant: O=C(O)Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of [6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]acetic acid (0.320 g) in N,N-dimethylformamide (6 mL) were added 1-hydroxybenzotriazole ammonia complex (234 mg), triethylamine (0.271 mL) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (186 mg), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated, under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=50:50-100:0, volume ratio) and recrystallized from hexane-acetone to give the title compound (0.240 g, yield 75%) as colorless crystals. MS: 494 (MH+). melting point 151-153° C.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]3[CH2:18][OH:19])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O-:29])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([C:26]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:29])[CH2:14][CH:13]3[CH2:18][OH:19])[CH2:11]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCC1CNCCN1C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)C(CO)C1
Temperature: 0 °C
Reaction time: 62 h

Procedure:
Compound 37c (1.03 mmol) was dissolved in CH2Cl2 (5 mL) and cooled in an ice water bath to 0° C. A 10% aqueous Na2CO3 solution (5 mL) was added and a solution of compound 37d (143 μL, 1.23 mmol) dissolved in CH2Cl2 (1 mL) was added dropwise. The resultant mixture was allowed to warm to 20° C. and then stirred rapidly for 62 h. CH2Cl2 (10 mL) was added to the reaction mixture and the aqueous phase was extracted with CH2Cl2 (2×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give compound 37e (465 mg) as an off white foam. Compound 37e was used in the following step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.39 (m, 9H), 7.22-7.32 (m, 4H), 7.14-7.23 (m, 2H), 4.35 (s, 1H), 4.07 (br. s, 1H), 3.30-3.71 (complex, 8H), 2.2-3.0 (complex, 6H); LCMS m/z (M+H+) 442.2.
Reaction SMILES: [CH:1]([Si:4](OS(C(F)(F)F)(=O)=O)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Br:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH3:39])([CH3:38])[CH2:34][NH:35]2)=[CH:31][C:30]=1[F:40]>C(Cl)Cl>[Br:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH3:38])([CH3:39])[CH2:34][N:35]2[Si:4]([CH:1]([CH3:2])[CH3:3])([CH:5]([CH3:6])[CH3:7])[CH:8]([CH3:9])[CH3:10])=[CH:31][C:30]=1[F:40]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CC1(C)CNc2cc(Br)c(F)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[Si](C(C)C)(C(C)C)N1CC(C)(C)c2cc(F)c(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
Triisopropylsilyltrifluoromethanesulfonate (3.5 mL, 13.0 mmol) and DIPEA (3.2 mL, 19.5 mmol) were added to a solution of 6-bromo-5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole (1.5 g, 6.5 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature overnight then quenched with saturated aqueous NaHCO3 and extracted with DCM (×3). The organic phase was dried (MgSO4), filtered and concentrated. The crude material was purified by SiO2 chromatography (10% EtOAc in petrol) to give the title compound (1.8 g) as a white solid. 1H NMR (DMSO-d6): 7.07 (1H, d), 6.65 (1H, d), 3.44 (2H, s), 1.64-1.33 (3H, m), 1.33-1.17 (6H, m), 1.10 (18H, d).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.C(N(CC)C1C=CC=CC=1)C.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>C(OCC)(=O)C>[CH:29]([O:28][C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1)=[O:27])([CH3:31])[CH3:30]
Reactant: CCOc1ccc(N)nc1OCC
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1ccc(NC(=O)OC(C)C)nc1OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 83.2 %

Procedure:
2-Amino-5,6-diethoxypyridine (1.83 g) and N,N-diethylaniline (1.49 g) were dissolved in ethyl acetate (30 ml). To the resultant solution, there was dropwise added isopropyl chloroformate (1.23 g) in 5 minutes under ice-cooling. The resulting mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic alumina chromatography using a mixture of toluene and ethyl acetate as an eluent to give 2-isopropyloxycarbonylamino-5,6,-diethoxypyridine (2.24 g) in a yield of 83.5%.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[C:10]1([NH:16][C:17]([NH2:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OC(=O)C)(=O)C>>[C:10]1([N:16]2[C:4](=[O:5])[CH:3]([C:2]([F:9])([F:8])[F:1])[CH2:7][NH:19][C:17]2=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: NC(=O)Nc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1NCC(C(F)(F)F)C(=O)N1c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (350 mg; 2.5 mmoles), phenylurea (353 mg; 2.6 mmoles) and acetic anhydride (2 ml) was heated at 100° C. with stirring for 1 hour. After cooling, the precipitated solid was collected by filtration to give 298 mg (yield: 46%) of 3-phenyl-5-trifluoromethyldihydrouracil. The solvent was evaporated from the filtrate, and the residue was recrystallized from chloroform/hexane to give additional 133 mg (yield: 21%) of the above product. The total yield was 67%. The physical and spectral properties of the resulting 3-phenyl-5-trifluoromethyldihydrouracil completely agreed with those of the product obtained in Example 11.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]([C:5]2[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)[C@@H:3]1[C:12]([OH:14])=O.[F:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20]>>[F:16][C:17]1[CH:18]=[C:19]([NH:20][C:12]([C@H:3]2[C@H:4]([C:5]3[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=3)[C:2]2([CH3:1])[CH3:15])=[O:14])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: Cc1cccc([C@H]2[C@H](C(=O)O)C2(C)C)c1
Reactant: Nc1ccc(F)c(F)c1
Product: Cc1cccc([C@H]2[C@H](C(=O)Nc3ccc(F)c(F)c3)C2(C)C)c1
Yield: 92 %

Procedure:
trans-2,2-Dimethyl-3-m-tolyl-cyclopropanecarboxylic acid (2.04 g, 10 mmol) and 3,4-difluoroaniline (1.29 g, 10 mmol) were reacted as described under General Procedure D to furnish the title compound (2.9 g, 92%) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 7.70-7.64 (m, 1H), 7.47 (s, 1H), 7.20-6.96 (m, 6H), 2.79 (d, J=5.6 Hz, 1H), 2.33 (s, 3H), 1.80 (d, J=5.6 Hz, 1H), 1.40 (s, 3H), 0.97 (s, 3H). mp 110-113° C. ESIMS m/z [M+H]+ 316.2.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl.O>[O:26]=[C:20]([NH:9][CH2:10][C:11](=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: NCC(=O)c1ccccc1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.7 %

Procedure:
Triethylamine (36 mL, 262.1 mmol) was added to a solution of 2-aminoacetophenone hydrochloride (15.0 g, 87.39 mmol) in dry CH2Cl2 (300 mL), followed by ethyl chlorooxoacetate (10 mL, 87.39 mmol) at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for 16 h. The mixture was then diluted with water and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 20-30% EtOAc in petroleum ether) to afford ethyl 2-oxo-2-((2-oxo-2-phenylethyl)amino)acetate (13.5 g, yield 66%). 1H NMR (400 MHz, CDCl3) δ 8.09 (br s, 1H), 8.02-8.00 (m, 2H), 7.68-7.64 (m, 1H), 7.55-7.51 (m, 2H), 4.85-4.84 (d, J=4.9 Hz, 2H), 4.44-4.39 (q, J=7.0 Hz, 2H), 1.44-1.41 (t, J=7.2 Hz, 3H). MS (ESI) m/z: Calculated for C12H13NO4: 235.08. found: 236.2 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH2:17][OH:18])[CH2:16][O:15][CH2:14]1.C(OCC)(=O)C>N1C=CC=CC=1.CCCCCC>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:18][CH2:17][C:13]2([CH3:12])[CH2:16][O:15][CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC1(CO)COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
p-Toluene sulfonyl chloride (5.6 g, 29.41 mmol) was added to a cooled solution of (3-methyloxetan-3-yl)methanol (2 g, 19.60 mmol) in pyridine (25 mL) at 0° C. and the resulting reaction mass was stirred at 0° C. for 2 hours. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mass was poured into ice-water, stirred for 30 minutes, the solid formed was collected by filtration, washed with water and dried under reduced pressure to afford 2.5 g of the product (50% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>>[CH2:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([N:1]2[C:13](=[O:14])[C:12]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]3[C:10]2=[O:15])[CH2:3]1)[CH3:9]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCN1CCCC(N)C1
Product: CCN1CCCC(N2C(=O)c3ccccc3C2=O)C1

Procedure:
6.4 Grams of 3-amino-1-ethyl-piperidine and 7.4 grams of phthalic anhydride were heated together in an oil bath at 150° C. for 20 minutes. On cooling, the resulting solid was recrystallized twice from methanol to give 4.2 grams of the title compound. Melting Point: 155° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2(O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23].N1C=CC=CC=1.O>C(Cl)Cl>[Cl:3][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([Cl:5])[CH:7]=2)[NH:11][C:10]1=[O:15]
Reactant: COc1ccccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reaction time: 0.5 h

Procedure:
38 ml (0.518 mol) thionyl chloride were slowly added by drops to 100 g (0.345 mol) of the intermediate product 1a, 56 ml (0.695 mol) pyridine in 1 l methylene chloride at 0° C., and then stirred for approximately 30 minutes more. Then the reaction mixture was poured on to icy water and the organic phase was separated. This organic phase was then washed with water, dried and concentrated in a vacuum. The residue was treated with toluene a number of times and the organic solvent was removed in a vacuum each time. 79 g of the raw product were obtained and further reacted without further cleaning.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[S:20][C:21]1[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[Br:27][CH2:28][CH2:29]Br>>[Br:27][CH2:28][CH2:29][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:5][C:4]1[CH:17]=[CH:18][C:19]([S:20][C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:2]([F:1])[CH:3]=1
Reactant: BrCCBr
Reactant: Cn1ccnc1Sc1ccc(Nc2ncnc3ccc(O)cc23)cc1F
Product: Cn1ccnc1Sc1ccc(Nc2ncnc3ccc(OCCBr)cc23)cc1F
Yield: 45 %

Procedure:
Using an analogous procedure to that described in Example 22, a mixture of 4-[3-fluoro-4-(1-methylimidazol-2-ylthio)anilino]-6-hydroxyquinazoline was reacted with 1,2-dibromoethane to give 6-(2-bromoethoxy)-4-[3-fluoro-4-(1-methylimidazol-2-ylthio)anilino]quinazoline in 45% yield;
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][NH:10]2)([O-:5])=[O:4].[Cl:15][O-].[Na+].Cl>O>[Cl:15][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[N+:3]([O-:5])=[O:4])[NH:10][N:9]=1
Reactant: [O-]Cl
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cccc2[nH]nc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a solution of sodium hydroxide (2.94 g, 73.6 mmol) in 100 mL of water was added 4-nitro-1H-indazole (3.00 g, 18.39 mmol), followed by sodium hypochlorite (33.4 g, 6.15% aqueous solution). This mixture was allowed to stir at ambient temperature overnight. The mixture was acidified to pH 2 with 10% aqueous HCl and extracted with 25% IPA/DCM. The combined organic extracts were washed with water, dried over sodium sulfate and concentrated under reduced pressure. The resulting solids were triturated with ether to give 1.5 g (41%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.CCOC(C)=O>[Cl:1][C:2]1[C:3]([C:31]2[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: Cc1ccc(B(O)O)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: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(Cl)cnc3[nH]c(-c4ccc(OCCN5CCOCC5)cc4)nc23)cc1
Temperature: 100 °C
Yield: 32.6 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.050 g, 0.13 mmol), 4-methylphenylboronic acid (0.027 g, 0.19 mmol), K2CO3 (0.097 g, 0.70 mmol) and Pd(PPh3)4 (0.029 g, 0.025 mmol) were mixed in a vial. Dioxane (3 ml) was added and the reaction mixture was heated to 100° C. under argon for 4 h. EtOAc (50 ml) was added and the solution was washed with water. Drying (Na2SO4) and evaporation gave crude material which was purified by column chromatography (dichloromethane/methanol, 95:5), giving the title product (0.019 g, 33%).
Reaction SMILES: [C:1]1([CH:7]=[N:8][N:9]2[CH2:13][C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18]Cl)[C:10]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:21].[Na+]>CC(C)=O>[C:1]1([CH:7]=[N:8][N:9]2[CH2:13][C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][I:21])[C:10]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [I-]
Reactant: O=C1CN(N=Cc2ccccc2)C(=O)N1CCCCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CN(N=Cc2ccccc2)C(=O)N1CCCCI
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A mixture of 1-phenylmethyleneamino-3-(4-chlorobutyl)-2,4 imidazolidinedione (prepared as described in Part I above) (43.1 g, 0.1467 mole), acetone (1200 ml) and sodium iodide (48.4 g, 0.3227 mole) is heated to reflux. Reflux is maintained for 5 hours. The mixture is filtered, collecting the insoluble. The filtrate is recharged with sodium iodide (10 g) and reflux is resumed and is maintained for 15 hours. After cooling to ambient temperature, the mixture is filtered, removing the insoluble NaCl (total recovery, 9.5 g, 110%). The filtrate is poured into H2O (2000 ml) while stirring. After stirring for 30 minutes, the solid is collected and air-dried to yield 51.5 g (0.1337 mole) of 1-phenylmethyleneamino-3-(4-iodobutyl)-2,4-imidazolidinedione.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[CH:23]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)([CH3:25])[CH3:24]>C(O)(C)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][N:5]=[C:4]([NH:38][C:35]2[CH:34]=[CH:33][C:32]([N:29]3[CH2:28][CH2:27][N:26]([CH:23]([CH3:25])[CH3:24])[CH2:31][CH2:30]3)=[CH:37][CH:36]=2)[N:3]=1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2ccccc2OC)c(N)n1
Reactant: CC(C)N1CCN(c2ccc(N)cc2)CC1
Solvent: CC(C)O
Product: COc1ccccc1C(=O)c1cnc(Nc2ccc(N3CCN(C(C)C)CC3)cc2)nc1N
Temperature: 110 °C
Yield: 42.2 %

Procedure:
A suspension of (4-amino-2-ethanesulfonylpyrimidin-5-yl)-(2-methoxyphenyl)-methanone (26.6 mg, 0.0828 mmol, Example 6) and 4-(4-isopropylpiperazin-1-yl)phenylamine (19.5 mg, 0.0889 mmol) in isopropanol (2.5 mL) was placed in a sealed tube and heated at 110° C. under microwave conditions for 1 hour. The resulting mixture was concentrated and the crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give [4-amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone as a light yellow solid (15.6 mg, 42% yield). HRMS, observed: 447.2507; Calcd for (M+H)+: 447.2503.
Reaction SMILES: CS([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=O)=O.BrC1C=CC([S:26]([NH2:29])(=[O:28])=[O:27])=CC=1>>[OH:18][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:7]2[CH:6]=[CH:5][C:10]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:9][CH:8]=2)=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CO)cc2)c1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(-c2ccc(CO)cc2)cc1

Procedure:
This compound was prepared in a manner analogous to the preparation of (3′-methanesulfonyl-biphenyl-4-yl)-methanol (WO 01/70753, Example 27) using 4-bromo-benzenesulfonamide as the starting material. LCMS found for C13H13NO3SNa (M+Na)+: m/z=286.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[O:9]([C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][NH2:22])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>CO>[O:9]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][CH2:21][NH:22][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:23][CH:24]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cccnc1
Reactant: NCCc1ccc(Oc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(Oc2ccc(CCNCc3cccnc3)cc2)cc1
Temperature: 5 °C
Reaction time: 18 h
Yield: 94.5 %

Procedure:
A solution of pyridine-3-carboxaldehyde (322 mg, 3.0 mmol) and 4-phenoxyphenethylamine (747 mg, 3.5 mmol) in reagent grade methanol (5 mL) under nitrogen was refluxed for 2 h, then cooled to 5° C. (ice bath), and diluted with more methanol (5 mL). Sodium borohydride (0.23 g, 6 mmol) was added, and the mixture was slowly allowed to reach room temperature and stirred at room temperature overnight (18 h). The mixture was concentrated in vacuo, taken up in dichloromethane, and filtered. The filtrate was concentrated in vacuo and chromatographed on silica gel (eluted with 7% methanol/dichloromethane) to afford N-((4-phenoxy)phenylethyl)pyridine-3-methylamine (863 mg, 94%).
Reaction SMILES: [C:1]([C:3](=[C:6]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)SC)[C:4]#[N:5])#[N:2].O.[NH2:20][NH2:21]>CO>[NH2:2][C:1]1[NH:21][N:20]=[C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5]
Reactant: NN
Reactant: COc1ccc(CNC(SC)=C(C#N)C#N)cc1
Solvent: O
Solvent: CO
Product: COc1ccc(CNc2n[nH]c(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 15 g (57.8 mmol) of 2-cyano-3-(4-methoxy-benzylamino)-3-methylmercapto-acrylonitrile, 3.03 ml (61.1 mmol) of hydrazine hydrate and 40 ml of methanol is stirred for 1 hour at RT, heated under reflux for 2 hours and then concentrated by evaporation in vacuo. Recystallization of the residue from ethanol/hexane yields the title compound; m.p. 148-149° C.
Reaction SMILES: [C:1]1([S:7][C:8]([CH3:18])([CH3:17])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=[O:21])C.C(OC(=O)C)(=O)C.OO>C(OCC)C>[C:1]1([S:7]([C:8]([CH3:18])([CH3:17])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[O:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(Sc1ccccc1)C(=O)c1ccccc1
Reactant: CC(=O)O
Agent: OO
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C(=O)c1ccccc1)S(=O)c1ccccc1
Reaction time: 48 h

Procedure:
68 g of 2-phenylthio-2-methylpropiophenone (1a) are added at 0° C. to a solution prepared from 500 ml of glacial acetic acid, 47 g of acetic anhydride and 45.5 g of 33% hydrogen peroxide. After 48 hours of agitation at ambient temperature, it is taken up in ethyl ether, washed with water and neutralised with sodium bicarbonate.