Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6]([Cl:17])[N:5]=[C:4]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[N:3]=1.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26].[Cl-].[Na+]>CN(C)C=O>[Cl:17][C:6]1[N:5]=[C:4]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[N:3]=[C:2]([NH:26][CH2:25][C:24]([F:28])([F:27])[F:23])[C:7]=1[C:8]1[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=1[F:16]
Reactant: Fc1cc(F)c(-c2c(Cl)nc(-n3ccnc3)nc2Cl)c(F)c1
Reactant: NCC(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(F)c(-c2c(Cl)nc(-n3ccnc3)nc2NCC(F)(F)F)c(F)c1
Yield: 88.3 %

Procedure:
A solution of 4,6-dichloro-2-(1H-imidazol-1-yl)-5-(2,4,6-trifluorophenyl)pyrimidine (35 mg, 0.10 mmol) and 2,2,2-trifluoroethylamine (50 mg, 0.5 mmol) in 2 mL of N,N-dimethylformamide is stirred at room temperature for 1 h. A saturated sodium chloride solution is added, and the product is extracted with ehtyl acetate. The organic solution is washed with saturated sodium chloride (×4), dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of 20% ethyl acetate in hexanes to 50% ethyl acetate in hexanes. Concentration provides 6-chloro-2-(1H-imidazol-1-yl)-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine as a light tan solid (36 mg, mp 168-170° C.). MS: m/z 408.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[N:18][OH:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Li])CCC.[C:25](OC(=O)C)(=[O:27])[CH3:26].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:25]([OH:27])([CH3:26])[O:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(Cc2ccccc2)=NO)cc1F
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2=NOC(C)(O)C2c2ccccc2)cc1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
1-(3-Fluoro-4-methoxyphenyl)-2-phenyl-ethan-1-one oxime (from Example 2, Step 2) (2.50 g, 9.64 mmol) and anhydrous THF (100 mL) under a nitrogen blanket, was cooled to -20° C., and n-butyllithium (1.6N, 15.0 mL) was added, via syringe, over 20 minutes, keeping the reaction temperature <-10° C. The deep red suspension was stirred at -20° C. for 1 hour, warmed to room temperature, and stirred at room temperature for 1 hour. Acetic anhydride (1.1 mL, 11.6 mmol) was added in one portion, and the yellow reaction was stirred for 2 hours without temperature control. The reaction was poured into aqueous hydrochloric acid (1N, 100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic solution was washed once each with aqueous hydrochloric acid (1N, 100 mL) and brine (100 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure to yield a crude oil. The oil was applied to a column of silica gel (250 mL) and eluted with ethyl acetate/hexane (10-40% ethyl acetate) to yield, upon concentration of the appropriate fractions 3-(3-fluoro-4-methoxyphenyl)-4-hydrido-5-hydroxy-4-phenyl-5-methylisoxazole (986 mg). This intermediate was dissolved in tetrahydrofuran (40 mL). Sulfuric acid (conc., 0.9 mL) was added, and the reaction was warmed to reflux. After one hour, the solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (2×50 mL) . The combined organic solution was washed with aqueous hydrochloric acid (1N, 50 mL), saturated aqueous sodium bicarbonate (2×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure to yield a crude, dark oil. Washing the oil with 50% dichloromethane in hexane dissolved the compound but did not dissolve the dark impurities. The resulting solution was evaporated under reduced pressure to yield 3-(3-fluoro-4-methoxyphenyl)-5-methyl-4-phenylisoxazole (797 mg, 29%) as a foam. Mass Spectrum: MH+=284. Anal. Calc'd. for C17H14NO2F: C, 72.07; H, 4.98; N, 4.94. Found: C, 72.13; H, 4.98; N, 4.92.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([PH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[BrH:16].C1C[O:20][CH2:19][CH2:18]1>>[BrH:16].[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([P:7]([CH2:18][CH:19]=[O:20])[C:4]2[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=2)=[CH:9][CH:10]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(Pc2ccc(C)cc2)cc1
Agent: Br
Product: Cc1ccc(P(CC=O)c2ccc(C)cc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A Schlenk flask was charged with KH (0.524 g, 13.1 mmol), and dry THF (13 mL). Di(p-tolyl)phosphine (2.331 g, 10.9 mmol) was added, and the solution turned red in colour. The solution was stirred for 30 min, and then cooled to −78° C. Bromoacetadehyde diethyl acetate (1.68 mL, 10.9 mmol) was added over 20 min, and the solution turned yellow. The solution was warmed to room temperature and 48% HBr (2.5 g, 14.8 mmol) was added. A white precipitate formed, and the solution turned colourless. The mixture was heated at 45° C. for 2 hours, and then left in the freezer overnight. The precipitate was filtered off and washed with 15 mL cold H2O, as well as 15 mL of a 1:1 mixture of cyclohexanol:ethyl acetate. The precipitate was then recrystallized in MeOH and ether, and dried under high vacuum. Yield: 2.698 g, 87.8%. Diastereomer 1: 1H NMR (CD3OD, 400 MHz, δ): 8.06 (dd, J=8.2, 12.3, aromatic CH, 4H), 7.63-7.58 (m, aromatic CH, 8H), 7.48 (dd, J=2.5, 8.2, aromatic CH, 4H), 6.19 (dd, J=6.8, 21.5, PCH(OH), 2H), 4.37-4.15 (m, H1 of PCH(OH)CH2, 2H), 3.99-3.81 (m, H2 of PCH(OH)CH2, 2H), 2.53 (s, CH3, 6H), 2.44 (s, CH3, 6H). 31P NMR (CD3OD, 400 MHz, δ): 11.12. 13C NMR (CD3OD, 400 MHz, δ): 146.8 (aromatic C—P), 146.7 (aromatic C—P), 133.7 (aromatic CH), 133.1 (aromatic CH), 130.6 (aromatic CH), 130.4 (aromatic CH), 113.9 (CH3C), 113.0 (CH3C), 61.1 (PCHOH), 22.1 (PCH2), 20.5 (CH3), 20.3 (CH3). Diastereomer 2: 1H NMR (CD3OD, 400 MHz, δ): 7.96 (dd, J=8.3, 12.5, aromatic CH, 4H), 7.86 (dd, J=8.3, 12.0, aromatic CH, 4H), 7.63-7.58 (m, aromatic CH, 4H), 7.56 (dd, J=3.2, 8.3, aromatic CH, 4H), 5.80 (ddd, J=2.5, 9.4, 16.3, PCH(OH), 2H), 4.37-4.15 (m, H1 of PCH(OH)CH2, 2H), 3.99-3.81 (m, H2 of PCH(OH)CH2, 2H), 2.50 (s, CH3, 6H), 2.49 (s, CH3, 6H). 31P NMR (CD3OD, 400 MHz, δ): 16.06. 13C NMR (CD3OD, 400 MHz, δ): 147.5 (aromatic C—P), 146.9 (aromatic C—P), 133.3 (aromatic CH), 132.9 (aromatic CH), 131.3 (aromatic CH), 130.5 (aromatic CH), 112.5 (CH3C), 111.7 (CH3C), 62.2 (PCHOH), 23.6 (PCH2), 20.4 (CH3). Anal. Calcd for [C32H36P2O2][Br]2[CH3OH][H2O]: C, 54.71; H, 5.84. Found: C, 54.65; H, 6.04. MS (ESI, methanol/water; m/z+): 257.1 [C32H36O2P2]2+. The diastereomeric excess was found to be 13%, as determined by 1H NMR, and 31P NMR.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH:19]1([C:22]2[O:23][C:24]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:25]([C:27](O)=[O:28])[N:26]=2)[CH2:21][CH2:20]1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH:19]4[CH2:20][CH2:21]4)[O:23][C:24]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:28])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1nc(C2CC2)oc1-c1ccccc1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C4CC4)oc3-c3ccccc3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-cyclopropyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3].S(Cl)([Cl:29])(=O)=O>C(Cl)Cl>[Cl:29][C:9]1[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[N:6][N:7]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[C:8]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)Cc1cc(-c2ccccc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Solvent: ClCCl
Product: CC(C)Cc1nn(-c2ccc(S(N)(=O)=O)cc2)c(-c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the pyrazole prepared in Example 175 (0.15 g, 0.42 mmol) in CH2Cl2 (10 mL) was added an excess of sulfuryl chloride slowly at room temperature. The mixture was stirred at room temperature for 2 hours, quenched with water and the aqueous layer extracted three time with methylene chloride. The combined organic layers were dried over MgSO4 and concentrated to give an oil which was purified by flash chromatography on silica gel using 70:30 hexane/ethyl acetate as eluent to give the desired compound: HRMS m/z 389.0970 (calc'd for C19H20ClN3SO2, 389.0965).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]2([CH2:22][S:21][CH2:20][S:19][CH2:18]2)OC1=S)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:12](=[C:11]1[CH2:22][S:21][CH2:20][S:19][CH2:18]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1N(C(=O)OC(C)(C)C)C(=S)OC12CSCSC2
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)=C1CSCSC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of potassium tert.-butylate (5.35 g) in tetrahydrofurane (40 cc) is cooled to -70° C. A solution of 3-tert.-butoxycarbonyl-4-ethoxycarbonyl-2-thioxo-1-oxa-7,9-dithia-3-azaspiro[4.5]decane (9 g) in tetrahydrofurane (40 cc) is added dropwise. The mixture is stirred for a further 3 hours, acetic acid (2.9 g) is then added and the reaction mixture is allowed to warm up to 20° C. The tetrahydrofurane is evaporated off under reduced pressure (20 mm Hg) at 30° C. The residue is dissolved in ethyl acetate (25 cc). The solution is washed with water (25 cc) and then dried over sodium sulphate. The solution is filtered and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg). A solid residue is obtained and treated with petroleum ether (100 cc). The precipitate is filtered off and dried under reduced pressure. Ethyl α-tert.-butoxycarbonylamino-(4,5-dihydro-1,3-dithiin-5-ylidene)-acetate (5.3 g) is thus obtained in the form of a beige solid which melts at 154° C. (Kofler instantaneous m.p.).
Reaction SMILES: C([C:3]1([C:21]([O-:23])=[O:22])[CH:9](O)[CH2:8][CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:5][CH2:4]1)C.CS(Cl)(=O)=O.[CH2:29]1CCN2C(=NCCC2)C[CH2:30]1>C1COCC1>[N:6]1([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7][CH2:8][CH:9]=[C:3]([C:21]([O:23][CH2:29][CH3:30])=[O:22])[CH2:4][CH2:5]1
Reactant: CCC1(C(=O)[O-])CCN(C(=O)OCc2ccccc2)CCC1O
Reactant: C1CCC2=NCCCN2CC1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1=CCCN(C(=O)OCc2ccccc2)CC1
Temperature: 80 °C
Yield: 50.5 %

Procedure:
To a stirred solution 1-benzyl 4-ethyl-5-hydroxyazepane-1,4-dicarboxylate (4.4 g, 13.7 mmol) in THF (100 ml) was added MsCl (2.58 ml, 33.6 mmol) and TEA (5.69 ml, 40.5 mmol) in three portions over 16 hours. The mixture was then concentrated, diluted with dichloromethane (100 ml), washed with saturated aqueous NaHCO3 (2×50 ml), dried (MgSO4), filtered and reconcentrated. The residue was dissolved in THF (100 ml) and DBU (3.1 ml, 20.6 mmol) was added and the resulting mixture was heated at 80° C. for 1 hour. The reaction was then concentrated, diluted with dichloromethane (100 ml), washed with saturated aqueous NaHCO3 (3×30 ml), dried (MgSO4), filtered and reconcentrated. The residue was purified via silica FCC (using a gradient of eluents; 9:1 to 7:3 Hexane/EtOAc) to give the title product as colourless oil (2.1 g, 51%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[NH4+:24].[NH4+].CCOC(C)=O>CN(C=O)C>[N+:17]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:7][C:2]=1[NH2:24])([O-:19])=[O:18]
Reactant: [NH4+]
Reactant: CCN(CC)CCCOc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)CCCOc1ccc([N+](=O)[O-])c(N)c1
Temperature: 80 °C

Procedure:
The nitro compound obtained as above (1.5 mmol) is dissolved in DMF (4 mL) and added with ammonium carbonate (500 mg). The reaction mixture is then heated at 80° C. for 48 h. EtOAc (2×10 mL). The combined organic layers are then washed with water and brine and dried over Na2SO4. Removal of the solvent in vacuo yielded the 2-nitro-5-(3-diethylamino-1-propoxy)aniline (300 mg) which is used for further transformation without any purification.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:7]=[C:6]([C:8](O)=[O:9])[N:5]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[N:4]=1.[NH2:23][C:24]1[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:25]=1[C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].C(N(CC)CC)C>C(#N)C>[CH3:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:25]([C:26]([NH:28][CH:29]([CH3:30])[CH3:31])=[O:27])[C:24]=1[NH:23][C:8]([C:6]1[N:5]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[N:4]=[C:3]([C:2]([F:21])([F:1])[F:22])[CH:7]=1)=[O:9]
Reactant: Cc1cccc(C(=O)NC(C)C)c1N
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1C(F)(F)F
Reaction time: 18 h
Yield: 78.3 %

Procedure:
A mixture of the title compound of Example 3, Step B (0.54 g, 1.1 mmol), the title compound from Example 1, Step B (0.44 g, 2.4 mmol) and BOP chloride (bis(2-oxo-oxazolidinyl)phosphinyl chloride, 0.54 g, 2.1 mmol) in acetonitrile (1.3 mL) was treated with triethylamine (0.9 mL). The mixture was shaken in a closed scintillation vial for 18 h. The reaction was partitioned between ethyl acetate (100 mL) and 1N hydrochloric acid. The ethyl acetate layer was washed successively with 1N hydrochloric acid (50 mL), 1N sodium hydroxide (50 mL) and saturated sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel with hexanes/ethyl acetate (5:1 to 3:1) as eluent. The title compound (0.43 g) a compound of the present invention, was isolated as a white solid. m.p. 227-230° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O.C(COC)OC>C(O)C>[Cl:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]2[N:3]([CH:14]=[C:12]([CH2:11][Cl:10])[N:1]=2)[CH:4]=1
Reactant: O=C(CCl)CCl
Reactant: Nc1ncc(Cl)cc1Cl
Solvent: COCCOC
Solvent: CCO
Product: ClCc1cn2cc(Cl)cc(Cl)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 2-amino-3,5-dichloropyridine (Aldrich; 5.12 g), 1,3-dichloroacetone (Aldrich; 4.68 g), and dimethoxyethane (28 mL) is stirred overnight at room temperature. Ethanol (28 mL) is then added and the mixture is refluxed for 7.5 h and then stirred overnight at room temperature. The mixture is then refluxed for an additional 24 h and is then concentrated under reduced pressure and partitioned between saturated aq. sodium bicarbonate and dichloromethane. The combined organic layers are washed with brine, dried with MgSO4, and concentrated under reduced pressure. The residue is adsorbed to silica gel and chromatographed on silica gel using ethyl acetate/chloroform (10/90), followed by a second chromatography of the combined product fractions using methanol/dichlormethane (2/98), to give 2.22 g of 6,8-dichloro-2-(chloromethyl)imidazo[1,2-α]pyridine in three crops after crystallization from methanol/dichloromethane; mp 162-163° C.; MS m/z 234, 236, 238; IR (mineral oil) 994, 808, 861, 1522, 3056 cm-1 ; 1H NMR (CDCl3) δ4.79, 7.69, 8.10.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].Cl.I[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)=[C:27]([CH3:39])[CH:26]=1.C(NC(C)C)(C)C>C1COCC1.[Cu](I)I>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[C:10][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)=[C:27]([CH3:39])[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(I)cc34)cc2C)cn1
Agent: I[Cu]I
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(C#CCNC(=O)OC(C)(C)C)cc34)cc2C)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.9 %

Procedure:
A mixture of prop-2-ynyl-carbamic acid tert-butyl ester (2.65 g, 17.08 mmol) and (6-Iodo-quinazolin-4-yl)-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine hydrochloride (8.2 g, 16.27 mmol), dichlorobis(triphenylphosphine) palladium (II) (570 mg, 0.81 mmol), copper iodide (154 mg, 0.81 mmol), and diisopropylamine (4.78 mL, 34.16 mmol) in anhydrous THF (80 mL) was stirred at room temperature for 5 hours. After concentration, the residue was dissolved in CH2Cl2 (100 mL), washed with aqueous NH4Cl and brine, dried over sodium sulfate, and concentrated to give the crude product (7.89 g, 98%) as a light yellow solid which was then used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[NH:4][N:5]=[C:6]([N+:22]([O-:24])=[O:23])[C:7]=1[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:20][CH3:21])=[CH:12][CH:11]=1.[CH2:26](I)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:26]([N:4]1[C:3](=[O:25])[C:2]([Cl:1])=[C:7]([NH:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([O:20][CH3:21])=[CH:12][CH:11]=2)[C:6]([N+:22]([O-:24])=[O:23])=[N:5]1)[CH3:27]
Reactant: COc1ccc(CNc2c([N+](=O)[O-])n[nH]c(=O)c2Cl)c2ccccc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCn1nc([N+](=O)[O-])c(NCc2ccc(OC)c3ccccc23)c(Cl)c1=O
Reaction time: 1.5 h

Procedure:
A mixture comprising 100 mg of 4-chloro-5-(4-methoxy-1-naphthylmethylamino)-6-nitro-3(2H)pyridazinone (Compound No. 30) prepared in Preparation Example 4, 218 mg of ethyl iodide, 193 mg of potassium carbonate and 30 ml of methyl ethyl ketone, was refluxed under stirring for 1.5 hours. The reaction mixture was filtered, and the solvent of the filtrate was distilled off under reduced pressure. Water was poured to the residue thus obtained, and the mixture was extracted with benzene. The extract was washed with water and with a saturated sodium chloride aqueous solution and dried over sodium sulfate. Then, the solvent was distilled off to obtain 110 mg of the above identified compound as a slightly yellow brown caramel substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[F:8].[C:15](Cl)([N:17]=[C:18]=[O:19])=[O:16]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[O:14][C:18](=[O:19])[NH:17][C:15](=[O:16])[C:11]=3[CH2:12][CH2:13]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C=NC(=O)Cl
Reactant: O=C1CCCC1c1ccc(F)c(F)c1
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)c(F)c1)CC2
Temperature: 130 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A solution of 2-(3,4-difluorophenyl)cyclopentanone, (prepared in the manner of Intermediate P(1) and P(2)) (1.5 g, 7.65 mmol) and carbonisocyanatidic chloride (1.129 g, 10.70 mmol) was stirred at 58° C. in a high-pressure vessel for 1 h. The temperature was raised to 130° C. and the reaction mixture was stirred for an additional 2 h. After cooling to rt, the reaction mixture solidified. The solid residue was dissolved in ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuum and the oily residue was purified by column chromatography on silica gel to provide 7-(3,4-difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (1.05 g, 3.96 mmol, 51.8% yield) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[CH3:6][C:7]([C:10]1[CH:11]=[C:12]([CH:21]=[C:22]2[N:26]([CH3:27])[C:25](SC)=[N:24][C:23]2=[O:30])[CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])([CH3:9])[CH3:8].CC(C)([O-])C.[K+].O>C(O)C>[CH3:6][C:7]([C:10]1[CH:11]=[C:12]([CH:21]=[C:22]2[N:26]([CH3:27])[C:25]([NH:4][C:3]([NH2:5])=[NH:2])=[N:24][C:23]2=[O:30])[CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])([CH3:9])[CH3:8]
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)N1C
Reactant: N=C(N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN1C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)N=C1NC(=N)N
Reaction time: 24 h
Yield: 20.2 %

Procedure:
Guanidine hydrochloride (1.7 g, 18 mmoles) is added to a mixture of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene)-1,5-dihydro-1-methyl-2-(methylthio)-4-H-imidazole-4-one (3.0 g, 8 mmoles) and potassium tert-butoxide (1.5 g, 13 mmoles) in ethanol (50 mL), and stirred and heated to reflux under an inert atmosphere. After 24 hours the mixture is allowed to cool, and is poured into water (300 mL) and stirred. After half an hour the product is filtered off, rinsed three times with water and dried. Recrystallization from ethanol/DMF gave pure 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-methylene)-4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-yl-guanidine (0.6 g), mp 288°-290° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:16](Cl)([Cl:18])=[O:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]([Cl:18])=[O:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Clc1cc(Cl)cc(Nc2ccccc2)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)N(c1ccccc1)c1cc(Cl)cc(Cl)c1

Procedure:
According to the procedure of Example 10, Step C, 10g (27.9 mmole) of N-(3,5-dichlorophenyl)aniline, 42 mL of 1.93M phosgene in toluene and 25 mL of toluene at a bath temperature of 105° C. for 4.5 hr gave 10.98 g of a yellow oil, which by 1H NMR was 40 mol % (46 wt %) product, the remainder being starting material.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][CH:12]1[S:16](=[O:18])(=[O:17])[O:15][CH2:14][CH2:13]1>O1CCOCC1.O>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:14][CH2:13][CH:12]([S:16]([OH:18])(=[O:17])=[O:15])[CH3:11]
Reactant: CC1CCOS1(=O)=O
Reactant: Sc1nc2ccccc2[nH]1
Solvent: O
Solvent: C1COCCO1
Product: CC(CCSc1nc2ccccc2[nH]1)S(=O)(=O)O
Yield: 86 %

Procedure:
To a hot solution of 2-mercaptobenzimidazole (2.0 g, 13.3 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was added via syringe pump (1 hour addition) a solution of 2,4-butane sultone (1.80 g, 12.7 mmol in 1,4-dioxane (total of 3 mL)). The solution was stirred at reflux for an additional 3 hours. The solid was collected by filtration. It was washed with acetone (2×20 mL) and dried in vacuo. Yield: 86%. 1H NMR (DMSO, 500 MHz) δ ppm 7.64(m, 2H), 7.44 (m, 2H), 3.63 (t, 2H, J=7.3 Hz), 2.68 (m, 1H), 2.10 (m, 1H), 1.90 (m, 1H), 1.15 (d, 3H, J=6.8 Hz). 13C (DMSO, 125 MHz) δ ppm 152.64, 133.32, 125.66, 113.67, 53, 10, 39.72, 33.48, 30.14, 16.85. ES-MS 287 (M+1).