Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@H:9]1[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCOc1ccc(F)cc1CCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(F)cc1CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
1490 mg of (2R,4R)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2-{2-[4-fluoro-2-(2-phenylethyl)phenoxy]ethyl}pyrrolidine [prepared as described in Example 5(a)] were dissolved in 15 ml of tetrahydrofuran, and then 0.79 ml of tetrabutylammonium fluoride were added to the resulting solution. The resulting mixture was then stirred at room temperature for 0.5 hours. At the end of this time, the reaction solution was concentrated by evaporation under reduced pressure, and the resulting concentrated oily substance was purified by silica gel column chromatography, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1115 mg (yield 95%) of the title compound as a colorless solid substance.
Reaction SMILES: Br[C:2]1[C:3]([N:9]([CH:16]([CH2:18][CH3:19])[CH3:17])[CH2:10][CH2:11][C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCCC(C)C>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][CH:16]([N:9]1[CH2:10][CH2:11][C:12](=[O:13])[N:14]([CH3:15])[C:2]2[C:3]1=[N:4][C:5]([Cl:8])=[N:6][CH:7]=2)[CH2:18][CH3:19]
Reactant: CCC(C)N(CCC(=O)NC)c1nc(Cl)ncc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: CCCC(C)C
Solvent: C1COCCO1
Product: CCC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 3-[(5-bromo-2-chloro-pyrimidin-4-yl)-butan-2-yl-amino]-N-methyl-propanamide (Intermediate 88; 559 mg, 1.60 mmol) in anhydrous 1,4-dioxane (15 mL) was added Caesium Carbonate (1.04 g, 3.19 mmol). Nitrogen was bubbled through the reaction mixture for 10 minutes, prior to addition of Tris(dibenzylideneacetone)dipalladium(0) (87 mg, 0.095 mmol) and XANTPHOS (88 mg, 0.152 mmol). The reaction was heated to 100° C. and stirred under nitrogen m for 18 hrs. The reaction mixture was cooled and diluted to ˜40 ml with DCM. The reaction mixture was filtered to remove insoluble material, washing filter cake through with DCM. The filtrate was evaporated to give a brown gum which was purified by flash chromatography on silica (40 g cartridge; ISCO companion) eluting with a 25-75% gradient of ethyl acetate in iso-hexane. Product containing fractions were combined and evaporated to give a waxy off white solid which was trituration with hot iso-hexane afforded, on cooling, and collection by suction filtration the title compound as a pale yellow solid (121 mg, 28%)
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>S(=O)(=O)(O)O>[O:14]=[C:3]1[C:2]2[N:1]=[C:18]([C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[CH3:15])[O:19][C:11]=2[C:10](=[O:13])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: Cc1ccccc1C(=O)Cl
Agent: O=S(=O)(O)O
Product: Cc1ccccc1-c1nc2c(o1)C(=O)c1ccccc1C2=O
Yield: 33.7 %

Procedure:
To a solution of 5.00 g (24 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 37 mL (280 mmol) of 2-methylbenzoic acid chloride, 8 drops of concentrated sulfuric acid are added with protection from light. After 7 h of reflux and complete cooling, the ocher precipitate that forms is filtered through fritted glass, washed with ether, and purified on a flash column (support: silica; conditioning: heptane; eluant: dichloromethane/heptane, 50/50). The yellow powder obtained after evaporation of the solvent is uncolored, and recrystallized in dichloromethane to produce 2.34 g of 4,9-dihydro-4,9-dioxo-2-(2-methylphenyl)-naphtho[2,3-d]oxazole in the form of yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:6](=[O:7])[N:5]([C:14]2[CH:15]=[CH:16][C:17]3[S:21][N:20]=[C:19]([CH:22]4[O:26][CH:25]([CH2:27][S:28][CH3:29])[CH2:24][O:23]4)[C:18]=3[CH:30]=2)[C:3]1=[O:4].ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl>[CH3:1][N:2]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:6](=[O:7])[N:5]([C:14]2[CH:15]=[CH:16][C:17]3[S:21][N:20]=[C:19]([CH:22]4[O:26][CH:25]([CH2:27][S:28]([CH3:29])=[O:39])[CH2:24][O:23]4)[C:18]=3[CH:30]=2)[C:3]1=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCC1COC(c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)O1
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C4OCC(CS(C)=O)O4)c3c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
A mixture of 1-methyl-3-[3-[4-[(methylthio)methyl]-1,3-dioxolan-2-yl]-1,2-benzisothiazol-5-yl]-6-(trifluoromethyl)uracil (0.970 g, 21.1 mmol), m-chloroperbenzoic acid (72%, 0.500 g, 21.1 mmol) and methylene chloride is stirred one hour at room temperature and concentrated in vacuo. The residue is taken up in ethyl acetate and washed twice with 5% aqueous sodium carbonate and once with brine. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to a white solid, which is chromatographed on silica gel with ethanol-ethyl acetate to afford the title compound as a white solid (0.700 g, 70.0%, mp 72-75° C.) which is identified by IR and NMR spectral analysis.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[C:4]([NH2:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][CH2:6]2.C(N(CC)C(C)C)(C)C.[CH3:26][O:27][C:28]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([S:41][CH3:42])[C:29]=1[C:30](Cl)=[O:31]>ClCCl>[CH3:26][O:27][C:28]1[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[C:33]([S:41][CH3:42])[C:29]=1[C:30]([NH:16][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:6][CH:7]2[N:2]([CH3:1])[CH:3]1[CH2:9][CH2:8]2)=[O:31]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Reactant: CN1C2CCC1C(N)(c1ccccc1)CC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(c2ccccc2)CCC2CCC1N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1RS,2RS,5SR)-8-methyl-2-phenyl-8-aza-bicyclo[3.2.1]oct-2-ylamine (intermediate A1) (670 mg, 3.1 mmol) in dichloromethane (10 ml) under nitrogen at room temperature, was added N,N-diisopropylethylamine (1.23 g, 1.61 ml, 9.29 mmol), followed drop-wise by a solution of 2-methoxy-6-(methylthio)-4-(trifluoromethyl)benzoyl chloride (intermediate B1) (970 mg, 3.41 mmol) in dichloromethane (7 ml). The reaction mixture was stirred at room temperature for 2 hours. The solution was washed once with a 2M sodium carbonate solution. The aqueous layer was extracted once with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude yellow oil (2.04 g), which crystallized in the fridge, was suspended in diethyl ether. The white precipitate was filtered and rinsed with diethyl ether to provide 1.16 g (y: 80.6%) of the title compound as a white solid. MS (m/e): 465.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:20])[C:17](F)=[CH:18][C:13]=2[NH:12][C:11](=[S:21])[CH2:10][N:9]=1.[CH2:22]([OH:24])[CH3:23].[H-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:20])[C:17]([O:24][CH2:22][CH3:23])=[CH:18][C:13]=2[NH:12][C:11](=[S:21])[CH2:10][N:9]=1
Reactant: CCO
Reactant: Fc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=S)N2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=S)N2

Procedure:
A mixture of 0.5 g (0.00155 mole) of 5-(2-chlorophenyl)-1,3-dihydro-7,8-difluoro-2H-1,4-benzodiazepin-2-thione (IImm), 10 mL of ethanol and 0.62 g of 60% sodium hydride was heated at reflux for 24 hours. The mixture was cooled, diluted with ethyl acetate and washed successively with water and then brine. The ethyl acetate extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.52 g of 5-(2-chlorophenyl)-1,3-dihydro-8-ethoxy-7-fluoro-2H-1,4-benzodiazepin-2-thione (IIg) as a yellow solid. MH+/Z=349.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][NH:10][S:9]2(=[O:15])=[O:14])=[CH:5][CH:4]=1.[H-].[Na+].[C:20]([C:24]1[CH:25]=[C:26]([NH:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=[O:39])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Cl)[CH:30]=2)[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[C:20]([C:24]1[CH:25]=[C:26]([NH:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=[O:39])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:10]3[CH2:11][C:12](=[O:13])[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=4)[S:9]3(=[O:15])=[O:14])[CH:30]=2)[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)cc1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(F)cc2)n(-c2cccc(CCl)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CN(Cc3cccc(-n4nc(C(C)(C)C)cc4NC(=O)Nc4ccc(F)cc4)c3)S2(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-methoxy-benzyl)-1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-3-one (64 mg, 0.25 mmol) in anhydrous DMF (2 mL) was added NaH (11 mg, 0.27 mmol) at 0° C. After stirred for 0.5 h at 0° C., a solution of 1-[5-t-butyl-2-(3-chloromethyl-phenyl)-2H-pyrazol-3-yl]-3-(4-fluoro-phenyl)-urea from the previous reaction (100 mg, 0.25 mmol) in anhydrous DMF (2 mL) was added to the reaction mixture, then was stirred overnight at RT. The crude was purified through prepared-HPLC to yield 1-(5-t-butyl-2-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1λ6-[1,2,5]thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-3-(4-fluoro-phenyl)-urea (45 mg). 1H NMR (DMSO-d6): 8.95 (s, 1H), 8.37 (s, 1H), 7.50-7.54 (m, 3H), 7.36-7.41 (m, 3H), 7.25 (d, J=8.8 Hz, 2H), 7.07 (t, J=8.8 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 6.35 (s, 1H), 4.64 (s, 2H), 4.47 (s, 2H), 4.19 (s, 2H), 3.75 (s, 3H), 1.26 (s, 9H). MS (ESI) m/z: 515 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:28])=[C:4]([CH:10]2[N:15]([CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[C:14](=[O:27])[CH2:13][CH2:12][CH2:11]2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH3:29][C:30]1C=CC(S(O)(=O)=O)=CC=1.C(OCC)(OCC)(OCC)C>CCOC(C)=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:29]([CH3:30])[O:28][C:3]=2[C:4]=1[CH:10]1[N:15]([CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:14](=[O:27])[CH2:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(N)c(O)c1C1CCCC(=O)N1Cc1ccc2ccccc2n1
Agent: CCOC(C)(OCC)OCC
Solvent: CCOC(C)=O
Product: COc1ccc2nc(C)oc2c1C1CCCC(=O)N1Cc1ccc2ccccc2n1
Temperature: 100 °C

Procedure:
A mixture of 6-(3-amino-2-hydroxy-6-methoxyphenyl)-1-(quinolin-2-ylmethyl)piperidin-2-one (100 mg; 0.26 mmol), commercially available p-TsOH (2 mg; 0.01 mmol), and commercially available triethyl orthoacetate (290 mg; 1.69 mmol) was refluxed (100° C.) for 25 min. After cooling to rt, AcOEt was added, and the obtained mixture was filtered over a pad of celite. The filtrate was then washed with water and brine, and the mixed aq. layers were further extracted with AcOEt. The mixed organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by FC (DCM/MeOH=20/1) afforded the target compound. LC-MS (conditions A): tR=0.54 min.; [M+H]+: 401.73 g/mol.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[CH3:8][C:9](Br)([CH3:11])[CH3:10]>C(Cl)Cl>[CH3:8][C:9]([C:5]1[S:1][CH:2]=[C:3]([CH:6]=[O:7])[CH:4]=1)([CH3:11])[CH3:10]
Reactant: O=Cc1ccsc1
Reactant: CC(C)(C)Br
Solvent: ClCCl
Product: CC(C)(C)c1cc(C=O)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3.63 g (32.4 mmol) of 3-thiophenecarboxaldehyde (Aldrich Chemical Co.) in 60 mL of methylene chloride cooled to 0° C. was added 9.17 g (80.9 mmol) of AICl3 and 2-methyl-2-bromopropane. The solution was stirred under N2 at room temperature for 16 hours and at reflux for 4 hours. The solution was then cooled to room temperature, and the reaction was quenched by pouring the solution into water. The mixture was made basic with aqueous NaHCO3 and extracted with ether. The ether extract was washed with water, dried over MgSO4 and concentrated. The residue was chromatographed on silica gel, eluting with 15:1 hexane:ethyl acetate, to afford 2.23 g of the title product as an oil, after removal of the solvent. NMR (CD3OD) δ:1.41 (s, 9H), 7.26 (d, 1 H, J=1 Hz), 8.2 (d, 1H, J=l Hz), 9.78 (s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5](=O)[C:6]2[CH:11]=[CH:10][S:9][C:7]=2[N:8]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:5]1[C:6]2[CH:11]=[CH:10][S:9][C:7]=2[N:8]=[C:3]([S:2][CH3:1])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc2sccc2c(=O)[nH]1
Product: CSc1nc(Cl)c2ccsc2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Methylsulfanyl-3H-thieno[2,3-d]pyrimidin-4-one (12 g, 60.5 mmol) was combined with POCl3 (56 mL), and the resulting mixture was heated to reflux for about 1 hour. The reaction mixture was concentrated under reduced pressure at 50° C. The residue was diluted with ethyl acetate (700 mL) at 0° C. Saturated sodium bicarbonate solution (600 mL) was added slowly. The resulting mixture was stirred vigorously at 0° C. for one hour and the layers were separated. Saturated sodium bicarbonate solution (600 ML) was added to the organic layer at 0° C., and the mixture was stirred vigorously for 20 minutes. The layers were separated. Brine (600 mL) was added to the organic layer and stirred vigorously for 5 minutes, and the layers were again separated. The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (10.7 g) as a dark tan powder (M+=216, M.P.=105.0-107.4° C.).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]2[N:10]=[C:11]([O:21][CH3:22])[C:12]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:8]2[CH:7]=[CH:6][CH:5]=1.Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(OCC)(=O)C>CN(C)C=O>[Br:3][C:4]1[N:9]2[N:10]=[C:11]([O:21][CH3:22])[C:12]([N:13]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[C:8]2[CH:7]=[CH:6][CH:5]=1
Reactant: BrCC1CC1
Reactant: COc1nn2c(Br)cccc2c1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nn2c(Br)cccc2c1N(CC1CC1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in oil; 24.6 mg) was added to a solution of tert-butyl N-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)carbamate (140 mg) in N,N-dimethylformamide (10 mL) at room temperature and the reaction mixture was stirred for 30 minutes. (Bromomethyl)cyclopropane (0.06 mL) was added thereto at the same temperature, and the reaction mixture was stirred for 1 hour at 60° C. After completion of the reaction, the reaction mixture was gradually added to ice, extraction was performed with ethyl acetate, the organic extract was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure to afford a crude product of tert-butyl N-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylcarbamate.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:16]2[NH:20][C:19](=[O:21])[C:18]3([CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][C:32]4[CH:40]=[CH:39][C:35]([C:36]([OH:38])=O)=[CH:34][C:33]=4[CH3:41])(=[O:29])=[O:28])[CH2:23][CH2:22]3)[N:17]=2)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH2:2][C:3]#[CH:4].Cl.[N:43]([CH2:46][CH2:47][CH2:48][NH:49][CH3:50])=[N+:44]=[N-:45].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[N:43]([CH2:46][CH2:47][CH2:48][N:49]([CH3:50])[C:36](=[O:38])[C:35]1[CH:39]=[CH:40][C:32]([CH2:31][CH2:30][S:27]([N:24]2[CH2:23][CH2:22][C:18]3([N:17]=[C:16]([C:8]4[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:6]([O:5][CH2:1][CH2:2][C:3]#[CH:4])[CH:7]=4)[NH:20][C:19]3=[O:21])[CH2:26][CH2:25]2)(=[O:28])=[O:29])=[C:33]([CH3:41])[CH:34]=1)=[N+:44]=[N-:45]
Reactant: CNCCCN=[N+]=[N-]
Reactant: C#CCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)O)cc4C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)N(C)CCCN=[N+]=[N-])cc4C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-{2-[2-(3-But-3-ynyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3-methyl-benzoic acid, (3-azido-propyl)-methyl-amine hydrochloride (15.3 mg, 0.101 mmol) and DIPEA (0.044 ml, 0.255 mmol) were dissolved in DMF (0.400 ml). HATU (0.038 mg, 0.101 mmol) was added and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with ethyl acetate, and the organic layer was then washed with a 1 M aqueous hydrochloric acid solution, an aqueous sodium bicarbonate solution and saline. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane-ethyl acetate) to give N-(3-azido-propyl)-4-{2-[2-(3-but-3-ynyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3,N-dimethyl-benzamide as a colorless oily substance.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[C:6]([OH:18])=[CH:5][CH:4]=1.Br[CH2:20][CH2:21][CH2:22][Cl:23]>C(O)(C)C.O>[Cl:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[C:6]([O:18][CH2:20][CH2:21][CH2:22][Cl:23])=[CH:5][CH:4]=1
Reactant: ClCCCBr
Reactant: O=c1c2ccccc2sc2c(O)ccc(Cl)c12
Agent: [Na]
Solvent: CC(C)O
Solvent: O
Product: O=c1c2ccccc2sc2c(OCCCCl)ccc(Cl)c12
Yield: 71.9 %

Procedure:
A 500 mL flask was charged with the sodium salt of 1-chloro-4-hydroxy-9H-thioxanthen-9-one (28.5 g; 0.100 mol), 1-bromo-3-chloropropane (17.4 g; 0.111 mol) and isopropyl alcohol (280 mL). The turbid reaction mixture was refluxed for 24 h. The hot solution was diluted with isopropyl alcohol (130 mL), drowned out in water (1400 mL) and the resulting suspension was extracted with dichloromethane (3×250 mL). The organic phase was separated, dried (MgSO4), filtered and solvent removed in vacuo to give 1-chloro-4-(3-chloropropoxy)-9H-thioxanthen-9-one (24.4 g; 72% yield).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([CH:15]=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[ClH:18]>>[ClH:18].[OH:8][C:9]1[C:10]2[N:11]([CH:15]=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc(COc2cccn3ccnc23)cc1
Agent: Cl
Product: Oc1cccn2ccnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 80 ml of concentrated hydrochloric acid is dissolved 5 g of 8-benzyloxyimidazo[1,2-a]pyridine, and the solution is stirred at room temperature for 24 hours and then concentrated. After addition of 1-butanol, water is azeotropically removed by distillation, and the residue is crystallized from diethyl ether to give 3.8 g of the above-identified compound.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].C(O)C.C(=O)(OCC)OCC.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:30][CH3:31])=[C:23]([CH:25]([OH:29])[C:26]([NH2:28])=[O:27])[CH:24]=1.C(N)(=O)C.Cl>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:30][CH3:31])=[C:23]([CH:25]2[O:29][C:2](=[O:4])[NH:28][C:26]2=[O:27])[CH:24]=1
Reactant: COc1ccc(Cl)cc1C(O)C(N)=O
Reactant: CC(C)(C)[O-]
Agent: CC(N)=O
Agent: Cl
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CCOC(=O)OCC
Product: COc1ccc(Cl)cc1C1OC(=O)NC1=O
Temperature: 25 °C

Procedure:
Potassium tert.-butoxide (539 mg., 4.8 mmoles) was dissolved in ethanol (2.12 g., 2.65 ml., 4.6 moles). Diethyl carbonate (625 mg., 5.3 mmoles) and then 2-(5-chloro-2-methoxyphenyl)-2-hydroxyacetamide (1.0 g., 4.6 mmoles) were added and the mixture was stirred for a few minutes to achieve solution, and then heated to reflux for 16 hours, at which time tlc (1:1 ethyl acetate:chloroform) indicated some unreacted starting material. Addition of more diethyl carbonate (625 mg.) and potassium tert-butoxide (100 mg.) and a further 2.5 hours of reflux did not appear to significantly reduce the level of starting acetamide. The reaction mixture was cooled to room temperature, poured into excess, iced 1 N hydrochloric acid and extracted with three portions of chloroform. The combined chloroform extracts were extracted with excess 5% sodium bicarbonate in two portions. The combined bicarbonate extracts were poured slowly into excess 1 N hydrochloric acid to precipitate 5-(5-chloro-2-methoxyphenyl)oxazolidine-2,4-dione (430 mg. 39%; m.p. 179°-181° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[NH:13]([C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncnc2c(Cl)cccc12
Solvent: CCO
Product: Clc1cccc2c(Nc3ccccc3)ncnc12
Yield: 49.3 %

Procedure:
15 ml of ethanol were added to a mixture of 3.0 g of 4,8-dichloroquinazoline and 1.9 g of aniline, and then the mixture was heated. The reagents dissolved and immediately solidified. After cooling, the solidified product was collected, washed with ethanol and then recrystallized from ethanol to give 1.9 g (yield 48%) of the desired Compound No. 13 in the form of colourless crystals having a melting point of 206° C. (with decomposition).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.[C:15]([O:19][C:20](=[O:47])[CH:21]=[C:22](OS(C(F)(F)F)(=O)=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[CH2:35][CH2:34][CH2:33][NH:32][C:31]=2[N:30]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[C:15]([O:19][C:20](=[O:47])[CH:21]=[C:22]([C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[CH2:35][CH2:34][CH2:33][NH:32][C:31]=2[N:30]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)C=C(CCCCCCc1ccc2c(n1)NCCC2)OS(=O)(=O)C(F)(F)F
Reactant: c1ccc2scnc2c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=C(CCCCCCc1ccc2c(n1)NCCC2)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of benzthiazole (165 mg, 1.22 mmol) in anhydrous tetrahydrofuran (5 mL) at -78° C. was added a solution of n-butyllithium in hexanes (0.52 mL of a 2.5 M solution). After 5 minutes, a solution of zinc chloride in tetrahydrofuran (2.6 mL of a 0.50 M solution) was added and the reaction mixture was allowed to warm to ambient temperature. To the resulting solution was added 9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-3-(trifluoromethanesulfonyloxy)-non-2-enoic acid tert-butyl ester 29-6 (400 mg, 0.81 mmol) and palladium(tetrakis)-triphenylphosphine (94 mg, 0.081 mmol) and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was then poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography over silica gel with 4:1 ethyl acetate/hexanes to give 29-7c as a colorless oil.