Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7](C2SC(=S)N(C)C2=O)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].N.C=O.[S:27]1[CH:31]=C[CH:29]=[C:28]1[C:32]([NH2:34])=[O:33]>C(O)(=O)C.O.CO>[CH3:14][C:12]([C:9]1[CH:8]=[C:7]([CH2:29][CH:28]2[S:27][CH2:31][NH:34][C:32]2=[O:33])[CH:6]=[C:5]([C:2]([CH3:3])([CH3:4])[CH3:1])[C:10]=1[OH:11])([CH3:15])[CH3:13]
Reactant: CN1C(=O)C(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)SC1=S
Reactant: NC(=O)c1cccs1
Agent: C=O
Agent: N
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(CC2SCNC2=O)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To 3.22 g (9.2 mmol) of 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]}-methyl-2-thioxo-4-thiazolidinone, in a 25 mL pressure tube equipped with magnetic stir bar, 13 mL of methanol was added. The resulting reaction mixture was cooled to 0° C. and ammonia gas (1.6 g, 91 mmol) was slowly added. Formalin (0.76 mL, 0.8 g, 10 mmol) was then added. The pressure tube was sealed and heated to 80° C. for approximately 17 hours with stirring. Reaction was deemed complete when the amount of thiolamide was below 4%, as determined by HPLC. Deionized water (12 mL) was then added in a drop-wise manner, followed by acetic acid (6 mL). After 30 min, the reaction mixture was cooled to 0° C. for 1 hour. The reaction mixture was filtered and the resulting crystalline product was dissolved in ethyl acetate (5 vol). Dissolution was facilitated by heating to 66° C. The resulting solution was filtered and seeded with a small amount of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl-4-thiazolidinone as the solution was slowly cooled to ambient temperature. Crystallization ensued and the resultant slurry was stirred for approximately 4 hours. The slurry was concentrated under reduced pressure (1 vol ethyl acetate) and stirred for an additional 16 hours. The slurry was filtered and the wet cake was washed with water (2×10 mL) and 1/4 ethyl acetate/hexane (2×10 mL). The product was dried in an oven at 50° C. to obtain 2.07 g (70% yield) of title compound.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].C1(N=C=NC2CCCCC2)CCCCC1.[Cl:21][C:22]1[C:27](O)=[CH:26][C:25]([N:29]2[C:34](=[O:35])[CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[N:31]([CH3:40])[C:30]2=[O:41])=[C:24]([F:42])[CH:23]=1>C(Cl)Cl>[C:1]([O:5][C:27]1[CH:26]=[C:25]([N:29]2[C:34](=[O:35])[CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[N:31]([CH3:40])[C:30]2=[O:41])[C:24]([F:42])=[CH:23][C:22]=1[Cl:21])(=[O:4])[C:2]#[CH:3]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: C#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C#CC(=O)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.68 g of propiolic acid in 5 ml of methylene chloride is added dropwise at 0° C. while stirring during 5 minutes to a solution of 2.18 g of N,N'-dicyclohexylcarbodiimide in 10 ml of methylene chloride and the mixture is stirred at 0° C. for 15 minutes. solution of 1.5 g of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 10 ml of methylene chloride is added dropwise while stirring during 20 minutes and the mixture is stirred at 0° C. for 2 hours. Insoluble constituents are filtered off under suction and the filtrate is evaporated to dryness under reduced pressure. The residue is purified by chromatography on a silica gel column using ethyl acetate/n-hexane (1:7) as the eluent. There is obtained 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl -4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorophenyl propiolate. 1H-NMR (CDCl3. 400 MHz: 7.40 ppm (d,1H), 7.21 ppm 1(d,1H), 6.36 ppm (s,1H), 3.56 ppm (d,3H). 3.15 ppm (s,1H),
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][NH:12]C(=O)OC(C)(C)C)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:20].C([Cl:24])(=O)C>CO>[ClH:24].[ClH:24].[F:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][NH2:12])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:20]
Reactant: CC(C)(C)OC(=O)NCc1nc2c(F)c(F)ccc2[nH]1
Reactant: CC(=O)Cl
Solvent: CO
Product: Cl
Product: NCc1nc2c(F)c(F)ccc2[nH]1
Temperature: 55 °C
Yield: 99.8 %

Procedure:
To a MeOH 144 mL solution of the product obtained in Step B (13.9 g, 48.9 mmol) was added acetyl chloride (16.6 g, 212 mmol) at room temperature. The reaction mixture (solution) was heated to 55° C. in an oil bath for 1 hr and then cooled to room temperature. Resulting suspension was cooled in an ice-water bath and the precipitate was collected by suction filtration and dried to give the title compound (12.5 g). LC/MS; m/z 184(M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[N+:19]([O-])([OH:21])=[O:20]>O>[CH3:1][O:2][C:3]1[C:13]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:12][C:11]([N+:19]([O-:21])=[O:20])=[C:5]([CH:4]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(OCCOC)c(OC)c1
Solvent: O
Product: CCOC(=O)c1cc(OC)c(OCCOC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
Ethyl 3-methoxy-4-(2-methoxyethoxy)benzoate (9.5 g, 37 mmol) was added in portions to stirred concentrated nitric acid (75 ml) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for a further 90 minutes. The mixture was diluted with water and extracted with methylene chloride, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with hexane to give ethyl 5-methoxy-4-(2-methoxyethoxy)-2-nitrobenzoate (10.6 g, 95%) as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]([C:13]([O:15]CC)=[O:14])[C:8]([O:10]CC)=[O:9])=[CH:4][CH:3]=1.[OH-].[K+]>OC(C)=O.O.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([C:8]([OH:10])=[O:9])[C:13]([OH:15])=[O:14])=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C(Cc1ccc(Br)cc1)C(=O)O
Yield: 873.2 %

Procedure:
Diethyl 2-(4-bromobenzyl)malonate (40 g, 13 mmol) and KOH (42.8 g, 76 mmol) was dissolved in a mixture of HOAc-H2O-THF (1:2:3, 200 mL), the mixture was refluxed for 12 hours. The solvent was removed in vacuo, the residue was added HCl aqueous, then extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated to give 2-(4-bromobenzyl)malonic acid (31 g, 95%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([Br:12])=[N:10][C:9]([Br:13])=[CH:8][N:7]=1)=[O:4].[I-:14].[Na+]>CC(C)=O.C(OCC)(=O)C>[Br:12][C:11]1[C:6]([NH:5][C:3](=[O:4])[CH2:2][I:14])=[N:7][CH:8]=[C:9]([Br:13])[N:10]=1
Reactant: [I-]
Reactant: O=C(CCl)Nc1ncc(Br)nc1Br
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(CI)Nc1ncc(Br)nc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
To a solution of 2-chloro-N-(3,5-dibromopyrazin-2-yl)acetamide (3.0 g, 9.11 mmol) in acetone (40 mL) was added sodium iodide (13.65 g, 91 mmol) dissolved in acetone (20 mL). Solution was allowed to stir at ambient temperature for 16 h. Solution was condensed under reduced pressure and diluted with ethyl acetate (500 mL) and washed consecutively with water (5×) to remove the blue color. Organics were dried over magnesium sulfate, filtered and solvent removed under reduced pressure to afford the crude product. The solid was diluted with 10% ethyl acetate in hexanes (40 mL) and sonicated while scraping the sides of the flask. The solution was then heated under a heat gun for 5 min, then cooled while sonicating at ambient temperature. The resulting solid was filtered and washed with additional hexanes and dried under vacuum to afford the title compound (3.0 g, 7.13 mmol, 78% yield). MS (ESI) m/z 420.3 [M−1]+, 422.0 [M+1]+, 424.0 [M+3]+.
Reaction SMILES: [Cl-].[OH:2][CH:3]1[CH2:6][NH2+:5][CH2:4]1.CCN(C(C)C)C(C)C.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1>C(#N)C>[N+:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:5]1[CH2:6][CH:3]([OH:2])[CH2:4]1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: OC1C[NH2+]C1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(CN2CC(O)C2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-hydroxyazetidinium chloride (0.68 g, 6.2 mmol) and Hunig's base (2.5 mL, 14.1 mmol) in acetonitrile (10 ml) was added 1-(bromomethyl)-3-nitrobenzene. After the reaction mixture was stirred at room temperature for 18 hours, it was partitioned between ethyl acetate and NaHCO3. The organic layer was washed with brine, dried and concentrated. The crude material was purified by silica gel column chromatography, eluting with 20% ethyl acetate/hexanes to give 0.54 g 1-(3-nitrobenzyl)azetidin-3-ol. MS (DCI(+)) m/e 209 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][O:15][C:14](=[O:26])[C@@H:13]([NH:27]C(=O)OCC2C=CC=CC=2)[CH2:12][O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOC(C)=O.N.C(O)C>CO.[Pd]>[NH2:27][C@H:13]1[CH2:12][O:11][CH2:10][C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][O:15][C:14]1=[O:26]
Reactant: O=C(N[C@H]1COC[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)COC1=O)OCc1ccccc1
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: N[C@H]1COC[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)COC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
Benzyl (3S,7S,8S)-7,8-bis(benzyloxy)-2-oxo-1,5-dioxonan-3-ylcarbamate (71 mg, 0.140 mmol) was dissolved in MeOH (1 mL) and EtOAc (1 mL) and 2.0 molar (M) ammonia in ethanol (EtOH) (35 μL, 0.070 mmol) and 5% Pd/C (10 mass wt. %) were added. The air was removed by two cycles of evacuating the flask under vacuum and backfilling with H2. The reaction mixture was placed under an atmosphere of H2 (balloon, ˜1 atmosphere) and stirred at room temperature for 2 h. The reaction mixture was filtered through Celite®, and the filtrate was concentrated to afford the title compound as an off-white solid (47 mg, 91%): 1H NMR (400 MHz, CDCl3) δ 7.79-6.92 (m, 10H), 4.79-4.53 (m, 6H), 4.14 (dd, J=11.4, 3.6 Hz, 1H), 3.97 (dd, J=11.4, 7.2 Hz, 1H), 3.87-3.74 (m, 3H), 3.73-3.56 (m, 2H), 3.45 (ddd, J=7.8, 6.0, 1.8 Hz, 1H), 3.25 (dd, J=11.5, 7.9 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 175.95, 138.09, 138.04, 128.46, 128.40, 128.00, 127.88, 127.85, 127.74, 81.49, 79.46, 75.01, 73.66, 72.75, 71.53, 63.47, 54.33; ESIMS m/z 372.9 ([M+H]+).
Reaction SMILES: [OH:1][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].C[N:14]([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[OH:40][CH:41]1[O:49][C@H:48]([CH2:50]O)[C@H:46](O)[C@H:44](O)[C@H:42]1[NH2:43]>CN(C=O)C.C(N(CC)CC)C>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:43][C@H:42]([C:41]([OH:49])=[O:40])[CH2:44][CH2:46][CH2:48][CH2:50][NH2:14]
Reactant: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NCCCC[C@H](N)C(=O)O
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
To a 250 ml round bottom flash, charged with 10.0 g (0.041 mole) of N ε-(tert-butoxy carbonyl) L-lysine 27, commercially available from BACHEM Bioscience Inc. (subsidiary of BACHEM Switzerland, 3700 Horizon Drive, Renaissance at Gulph Mills, King of Prussia, Pa., 19406, U.S.A.), and 100 ml of methanol is added 10.0 g (0.07 mole) of ethyl trifluoroacetate followed by 20.0 ml (0.144 mole) of triethylamine. The mixture is stirred at 20-30°0 C. for 20 hours and then concentrated via rotary evaporation. The residue is diluted with 50 ml of diethyl ether and then filtered. The filtrate is then washed with 3×30 ml aliquots of 1N aqueous HCL, 20 ml of deionized water, and finally with 20 ml of deionized water. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is distilled under vacuum to yield product 28 in good yield. N ε-(tert-butoxy carbonyl) N1 -α-trifluoroacetyl L-lysine is reacted with tri-o-acetyl tet-Gal-NAC 1-a-S-Pentylamine in the presence of a BOP reagent. The activated carboxylic acid reacts with the clustered galactosamine in DMF and Triethylamine to afford galactose cluster lysine adduct 29 in good yield. The N α-trifluoroacetyl protection of the lysine is removed to afford Primary α-amino lysine-galactose cluster 29a in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][C:13](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]=3[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]>C(O)(=O)C.O=[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]=3[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C=C1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)CC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Yield: 66.3 %

Procedure:
PtO2 (30 mg) is added to a solution of a E/Z isomers mixture of ethyl (1-(3,4-dichlorophenyl)-1,5,6,7-tetrahydro-4H-indazol-4-ylidene)acetate (1.5 g, 4.27 mmol) in acetic acid (25 mL); the mixture is maintained under stirring under a pressure of 1 H2 atm. A sample is next extracted and a 1H NRM is done. The mixture is then filtered, diluted with AcOEt, and washed with H2 O and with a saturated solution of NaHCO3. The solvent is next evaporated at reduced pressure, giving ethyl 2-(1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl)acetate (1.0 g, 2.83 mmol, purity 66%, oil).
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(C[Br:25])=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1.[Br:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[N:41][N:40]([CH2:43][C:44]([C:46]3[CH:51]=[CH:50][C:49]([CH2:52]O)=[CH:48][C:47]=3[CH3:54])=[O:45])[C:39](=[O:55])[CH:38]=2)=[N:33][CH:34]=1.C(OC1C=CN(CC(C2C=CC(CO)=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1>>[Br:25][CH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:44](=[O:45])[CH2:43][N:40]2[C:39](=[O:55])[CH:38]=[C:37]([O:36][CH2:35][C:32]3[CH:31]=[CH:30][C:29]([Br:28])=[CH:34][N:33]=3)[CH:42]=[N:41]2)=[C:47]([CH3:54])[CH:48]=1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ncc(OCc2ccc(Br)cn2)cc1=O
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Agent: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CBr)ccc1C(=O)Cn1ncc(OCc2ccc(Br)cn2)cc1=O
Yield: 59 %

Procedure:
2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-bromo-pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 1d employing 5-(5-bromo-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 8a) instead of preparation 1c.
Reaction SMILES: N1(C2CCCCCCCCCC2)CCCCCCCCCN1.[C:23]1([CH2:33][NH:34][C:35]2[N:43]=[C:42]([C:44]#[N:45])[N:41]=[C:40]3[C:36]=2[N:37]=[CH:38][NH:39]3)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.[C:46]([O:54][C@H:55]1[C@@H:59]([O:60][C:61](=[O:68])[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C@@H:58](OC(=O)C)[O:57][C@@H:56]1[C:73]([NH:75][CH2:76][CH3:77])=[O:74])(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(O[C@H]1[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C)O[C@@H]1C(NCC)=O)(=O)C1C=CC=CC=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C.C(OCC)(=O)C>[C:61]([O:60][C@@H:59]1[C@H:55]([O:54][C:46](=[O:53])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:56]([C:73]([NH:75][CH2:76][CH3:77])=[O:74])[O:57][C@H:58]1[N:39]1[CH:38]=[N:37][C:36]2[C:40]1=[N:41][C:42]([C:44]#[N:45])=[N:43][C:35]=2[NH:34][CH2:33][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: N#Cc1nc(NCc2cccc3ccccc23)c2nc[nH]c2n1
Reactant: CCNC(=O)[C@H]1O[C@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Agent: CCNC(=O)[C@H]1O[C@@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
Diazabicycloundecane (0.18 ml, 1.2 mmol) was added to a solution of (6-[(1-naphthylmethyl)amino]-9H-purine-2-carbonitrile (200 mg, 0.67 mmol) (Preparation 10) and (2S,3S,4R,5R)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate and (2S,3S,4R,5S)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (309 mg, 0.70 mmol) (Preparation 18) in acetonitrile (5 ml). Trimethylsilyl trifluoromethanesulfonate (0.24 ml, 1.33 mmol) was added and the reaction mixture heated under reflux for 30 minutes. The reaction mixture was then allowed to cool to room temperature, diluted with ethyl acetate (20 ml) and washed twice with water (20 ml). The ethyl acetate layer was then washed with 10% w/w aqueous citric acid and saturated aqueous sodium chloride solution (20 ml). The organic phase was dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane increasing in polarity to dichloromethane:methanol (98:2 by volume). The solvent was removed under reduced pressure to give the title compound (235 mg) as a foam.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccc(-c2ccc(C(C)=O)cc2)cc1
Yield: 97 %

Procedure:
10.5 g of 4-hydroxy-4'-acetylbiphenyl (C) obtained in Example 1 was heated together with 20 ml of acetic anhydride in the presence of a small amount of concentrated sulfuric acid. Crude crystals thus obtained were recrystallized from carbon tetrachloride to obtain 12.5 g of 4-acetoxy-4'-acetylbiphenyl (1): ##STR51##
Reaction SMILES: [O:1]=[S:2]1(=[O:12])[CH2:7][CH2:6][N:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1.Cl[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2[F:31])[N:15]=1>>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][S:22][C:16]1[N:15]=[C:14]([NH:11][S:8]([N:5]2[CH2:4][CH2:3][S:2](=[O:1])(=[O:12])[CH2:7][CH2:6]2)(=[O:9])=[O:10])[CH:19]=[C:18]([O:20][CH3:21])[N:17]=1
Reactant: NS(=O)(=O)N1CCS(=O)(=O)CC1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Product: COc1cc(NS(=O)(=O)N2CCS(=O)(=O)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared from 1,1-dioxothiomorpholine-4-sulfonamide (0.31 g, McManus, J. M. et al, J. Med. Chem (1965) 8 766-776) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.25 g) according to the procedure outlined in Example 1, step iv). The crude material was purified by column chromatography using EtOAc/isohexane (1:1) as eluent. Yield: 0.48 g
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:14]2[C:9]([CH:10]=[CH:11][N:12]=[N:13]2)=[C:8]([Cl:23])[CH:7]=1)[CH3:5])=[N+]=[N-].O.CP(C)C>O1CCCC1.C(OCC)(=O)C>[Cl:23][C:8]1[CH:7]=[C:6]([CH:4]([NH2:1])[CH3:5])[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[N:13]2
Reactant: CC(N=[N+]=[N-])c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(N)c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of peak 1 of 7-(1-azidoethyl)-5-chloro-8-(3-fluorophenyl)cinnoline (0.57 g, 1.7 mmol) from step N, in tetrahydrofuran (9.3 mL) and water (1.8 mL) was treated with 1 M of trimethylphosphine in tetrahydrofuran (2.1 mL, 2.1 mmol) and stirred at 20° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with brine, dried with sodium sulfate, filtered, and concentrated to give the desired product (quantitative). This material was used without further purification. LCMS for C16H14ClFN3 (M+H)+: m/z=302.1; Found: 301.9.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH:28]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]1.CN(C=O)C>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:28]2[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: OC1CCNC1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCC(O)C3)sc2Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (300 mg; 0.72 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The solution is put under nitrogen. Triethylamine (0.5 ml; 3.61 mmol; 5 eq) and 3-pyrrolidinol (0.3 ml; 3.61 mmol; 5 eq) are added successively. DMF (0.2 ml) is added and the reaction mixture is stirred for 1 hour at room temperature. It is then washed with water, NaHCO3 sat., brine and dried over MgSO4, affording the title compound (310 mg; 83%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:20]1[N:21]=[CH:22][N:23]=[C:24]2[C:31]=1[C:30]1[CH2:29][CH2:28][CH2:27][C:26]=1[S:25]2>C1COCC1>[CH3:16][N:8]([CH:5]1[CH2:6][CH2:7][CH:2]([O:1][C:20]2[N:21]=[CH:22][N:23]=[C:24]3[C:31]=2[C:30]2[CH2:29][CH2:28][CH2:27][C:26]=2[S:25]3)[CH2:3][CH2:4]1)[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: Clc1ncnc2sc3c(c12)CCC3
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.3 %

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl N-(4-hydroxycyclohexyl)-N-methylcarbamate (447 mg, 1.95 mmol, 1.30 equiv) in anhydrous THF (30 mL), then sodium hydride (300 mg, 7.50 mmol, 5.00 equiv, 60% dispersion in mineral oil) was added and stirring for 20 min at room temperature under nitrogen. Then 12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (316 mg, 1.50 mmol, 1.00 equiv) was added and stirred for 6 h at ambient temperature. The reaction mixture was quenched with NH4Cl (sat.) at 0° C., diluted with brine, extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by a silica gel column with EA/PE (1:10-1:4) to provide tert-butyl N-methyl-N-(4-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yloxy]cyclohexyl)carbamate (450 mg, 74%) as a white solid. MS: (ES, m/z): 404 [M+H]+.