Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:31])[C@@H:17]3[C@H:21]([O:23][Si](C(C)(C)C)(C)C)[CH3:22])[C:14]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:9][C@H:8]1[CH2:38][O:39][CH2:40][CH2:41][Cl:42])=[O:6])[CH:2]=[CH2:3].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:31])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:9][C@H:8]1[CH2:38][O:39][CH2:40][CH2:41][Cl:42])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCCl)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCCl)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 50.7 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-chloroethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.72 g) in tetrahydrofuran (7.2 ml) were added glacial acetic acid (0.65 ml) and a 1M solution (5.6 ml) of tetrabutylammonium fluoride in tetrahydrofuran in a stream of nitrogen, and the mixture was stirred at room temperature for 10 hours. To the mixture was added ethyl acetate (50 ml). The solution was washed with water (50 ml×3), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was chromatographed on silica gel (10 g) and eluted with a mixture of hexane and ethyl acetate (80:20 V/V) to give allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-chloroethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.30 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Li]CCCC.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:39]=[C:38]3[C:34]([C:35](I)=[N:36][N:37]3[S:40]([C:43]3[C:48]([CH3:49])=[CH:47][C:46]([CH3:50])=[CH:45][C:44]=3[CH3:51])(=[O:42])=[O:41])=[CH:33][CH:32]=2)=[CH:27][C:26]=1[O:53][CH3:54])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:39]=[C:38]3[C:34]([C:35]([C:2]4[CH:11]=[CH:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH:3]=4)=[N:36][N:37]3[S:40]([C:43]3[C:48]([CH3:49])=[CH:47][C:46]([CH3:50])=[CH:45][C:44]=3[CH3:51])(=[O:42])=[O:41])=[CH:33][CH:32]=2)=[CH:27][C:26]=1[O:53][CH3:54])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: COc1cc(-c2ccc3c(I)nn(S(=O)(=O)c4c(C)cc(C)cc4C)c3c2)ccc1OCc1ccccc1
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: [Cl-]
Solvent: C1CCOC1
Product: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)nn(S(=O)(=O)c4c(C)cc(C)cc4C)c3c2)ccc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
2-Bromonaphthalene (117 mg, 0.564 mmol, 6.0 equiv) was dissolved in THF (0.75 mL) and cooled to −78° C. The mixture was treated with n-BuLi (226 μL, 2.5 M, 6.0 equiv) and was allowed to stir at −78° C. for 30 min. The mixture was then added to freshly dried ZnCl2 solid (139 mg, 0.80 mmol, 8.5 equiv) via cannula and the resulting mix was allowed to warm to 23° C. (during the addition the yellow color disappears). After 30 min at 23° C. the mixture is added to a mixture of 6-(4-benzyloxy-3-methoxy-phenyl)-3-iodo-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole (60 mg, 0.094 mmol, 1 equiv) and Pd(PPh3)4 (6 mg, 0.005 mmol, 0.05 equiv) via cannula. The resulting solution was allowed to stir for 16 h. Saturated sodium bicarbonate was added and the mixture was partitioned between saturated sodium bicarbonate (15 mL) and ethyl acetate (15 mL). The organic material was dried over sodium sulfate, decanted and concentrated. Purification by silica gel chromatography (1:9–2:8 ethyl acetate-hexane) gave 6-(4-benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole as a solid (42 mg, 70%): Rf sm 0.4, p 0.4 (ethyl acetate-hexane 3:7); 1H NMR (CDCl3) δ 8.44 (s, 1H), 8.41 (s, 1H), 8.12 (d, 1H, J=8 Hz), 8.05–7.00 (m, 17H), 5.30 (s, 2H), 4.02 (s, 3H), 2.80 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[CH3:13][CH:14]1[CH2:16][O:15]1.O>O1CCCC1.CCOCC>[CH3:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:13][CH:14]([OH:15])[CH3:16])=[CH:6][CH:5]=1
Reactant: CC1CO1
Reactant: Cc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc2ccn(CC(C)O)c2c1
Reaction time: 1 h
Yield: 35 %

Procedure:
A suspension of 0.28 g of sodium hydride dispersion in 40 ml of tetrahydrofuran was treated with 0.98 g of 6-methylindole at 0° and stirred at this temperature for 1 hour. After the addition of 1 ml of (RS)-methyloxirane the reaction mixture was stirred at room temperature for 60 hours and subsequently treated with 7 ml of water. The mixture was diluted with 370 ml of ether, washed twice with 120 ml of water and with 60 ml of saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 35 g of silica gel with toluene-ethyl acetate (19:1). There was obtained 0.5 g (35%) of (RS)-1-(6-methyl-indol-1-yl)-propan-2-ol as light brown crystals with m.p. 65°-69°.
Reaction SMILES: [ClH:1].C([O:5][C:6]1[C:11]2[O:12][C:13]3[C:18]([C:19]4([CH2:24][CH2:23][N:22]([CH2:25][C:26]#[CH:27])[CH2:21][CH2:20]4)[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)(=O)C.Cl.C(=O)(O)[O-].[Na+]>CCOCC>[ClH:1].[OH:5][C:6]1[C:11]2[O:12][C:13]3[C:18]([C:19]4([CH2:24][CH2:23][N:22]([CH2:25][C:26]#[CH:27])[CH2:21][CH2:20]4)[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: C#CCN1CCC2(CC1)c1ccccc1Oc1c(OC(C)=O)cccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: C#CCN1CCC2(CC1)c1ccccc1Oc1c(O)cccc12

Procedure:
4-Acetoxy-1'-(prop-2-ynyl)xanthene-9-spiro-4'-piperidine hydrochloride (0.4 g.) is stirred with 3 N hydrochloric acid (20 ml.) at room temperature for 24 hours. The solution is basified using solid sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extract is dried over MgSO4 and evaporated to give a gummy residue which is dissolved in ether and treated with ethereal hydrochloric acid. The precipitate is recrystallised from ethanol-ether to give 4-hydroxy-1'-(prop-2-ynyl)xanthene-9-spiro-4'-piperidine hydrochloride, m.p. 246°-247° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:22]3[CH2:21][CH2:20][C:19]4[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=4[C:17]=3[N:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][C:13]2[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=23)=[CH:5][CH:4]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:22]3[CH:21]=[CH:20][C:19]4[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=4[C:17]=3[N:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]2[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=23)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2c3c(nc4c2CCc2ccccc2-4)-c2ccccc2CC3)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1ccc(-c2c3ccc4ccccc4c3nc3c2ccc2ccccc23)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
In an inert argon atmosphere 17 (4.93 g, 12.7 mmol, 1 eq) was dissolved in abs. 1,4-dioxane (300 mL, dried over sodium) under vigorously stirring at 80° C. 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ, 17.25 g, 76 mmol, 6 eq) was added in portions over a 5 minutes period and the DDQ-vessel was flushed with abs. dioxane (20 mL). The almost black mixture was stirred at 80° C. for two days maintaining the inert atmosphere. After cooling to room temperature the reaction mixture was carefully added to 500 mL of an aqueous saturated sodium carbonate solution and the reaction vessel was flushed with saturated Na2CO3 solution (250 mL) and water (200 mL). After stirring of the mixture at 65° C. for 75 minutes the precipitate was allowed to settle down and the product was isolated by filtration and purified by multiple slurry of the solid in water (overall ca. 1000 mL). After drying of the crude product in vacuo at 40° C. overnight the solid was suspended in methylene chloride (20 mL), stirred for 45 minutes, isolated by filtration and washed with DCM (2×20 mL) and dried overnight. 3.53 g of an ochre solid (72% yield) could be obtained in a 99.5% HPLC purity. Further purification of the material was possible by gradient sublimation (initial amount: 1.00 g, sublimation yield: 67%).
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([CH3:11])[N:3]=1.N([O-])=[O:13].[Na+]>S(=O)(=O)(O)O.O>[OH:13][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc(N)nc(C)c1C#N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(O)nc(C)c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.3 %

Procedure:
To a stirred solution of 6-amino-2,4-dimethylnicotinonitrile (Sato, K.; et al. Bull. Chem. Soc. Jpn., 1969, 42, 2319., 22.4 g, 152 mmol) in 5% aqueous sulfuric acid (600 mL) was added dropwise a solution of sodium nitrite (25.2 g, 365 mmol) in water (100 mL) at 0° C., and the mixture was stirred at room temperature for 16 h. The resulting precipitate was collected by filtration to afford 10.2 g (45%) of the title compound: 1H-NMR (DMSO-d6) δ 12.27 (1H, br.s), 6.17 (1H, s), 2.38 (3H, s), 2.20 (3H, s).
Reaction SMILES: CS(O[C@H:6]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:7]1[O:12][CH2:11][CH2:10][N:9]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:8]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[F:33][C:34]([F:43])([F:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[SH:41]>>[C:15]1([C@H:13]([N:9]2[CH2:10][CH2:11][O:12][C@H:7]([C@H:6]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:41][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[C:34]([F:33])([F:42])[F:43])[CH2:8]2)[CH3:14])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1ccccc1S
Reactant: C[C@H](c1ccccc1)N1CCO[C@H]([C@H](OS(C)(=O)=O)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@H](c1ccccc1)N1CCO[C@H]([C@@H](Sc2ccccc2C(F)(F)F)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.5 %

Procedure:
A mixture of 51 (0.035 g, 0.093 mmol), potassium carbonate (0.026 g, 0.19 mmol) and 2-trifluoromethylbenzenethiol (0.084 g, 0.47 mmol) in dry, degassed dimethylformamide (0.5 ml) was stirred under nitrogen at room temperature for 3 days. The reaction mixture was diluted with water and extracted with diethyl ether. The extracts was washed with water and brine, dried over magnesium sulphate, filtered and evaporated to give a colourless oil (0.03 g, 71%). Purification by flash column chromatography (eluent: ethyl acetate/heptane 20/80 [v/v]) gave 52 as a colourless oil (0.03 g, 71%); MW 457.56; C26H26F3NOS 1H NMR (CDCl3) 7.53 (1H, d), 7.10-7.28 (13H, m), 4.39 (1H, d), 3.85-4.04 (2H, m), 3.8 (1H, td), 3.35 (1H, q), 2.70 (1H, d), 2.40 (1H, d), 2.30 (1H, td), 2.10-2.20 (1H, m), 1.29 (3H, d). m/z [M+H]+ 458.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[CH3:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]([OH:42])[CH2:35][N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:28][C:26]=2[N:27]=1>CCO>[CH3:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C@H:34]([OH:42])[CH2:35][N:36]3[CH2:37][CH2:38][N:39]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH2:40][CH2:41]3)=[CH:28][C:26]=2[N:27]=1
Reactant: ClCCCCOc1ccccc1
Reactant: Cc1nc2cc(OCC(O)CN3CCNCC3)ccc2s1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCCCOc4ccccc4)CC3)ccc2s1
Temperature: 88 °C
Reaction time: 14 h

Procedure:
(4-Chlorobutoxy) benzene (320 mg, 1.39 mmol) in EtOH (17 Ml) was treated with DIEA (0.48 Ml, 2.78 mmol) and 1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol as prepared in Example 3A (427 mg, 1.39 mmol), then stirred 14 hours at 88° C. Upon cooling, concentrated in vacuo and purified on the Isco™ (10 g Redisep™ columns, 100% EtOAc hold 2 min., 8 min. gradient to 20% MeOH/EtOAc, hold 10 min) to provide (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-phenoxybutyl)piperazinyl]propan-2-ol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]2=[O:22])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:23](OC)(=[O:31])[C:24]1[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=1)[SH:26].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:22]=[C:10]1[N:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:1]3[S:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[C:23](=[O:31])[N:2]=3)[CH:8]=2)[CH2:13][CH2:12][N:11]1[CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)CN1CCN(c2ccnc(C#N)c2)C1=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN1CCN(c2ccnc(-c3nc(=O)c4ccccc4s3)c2)C1=O
Yield: 59.6 %

Procedure:
tert-Butyl [3-(2-cyano-4-pyridyl)-2-oxo-1-imidazolidinyl]acetate (0.80 g, 2.6 mmol) and methyl thiosalicylate (1.33 g, 7.8 mmol) were dissolved in toluene (6 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 8 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (3:1, v/v) were collected, concentrated and recrystallized from tetrahydrofuran-hexane to give the titled compound (0.68 g, 58%).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12]1([CH:17](OS(C)(=O)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][CH2:14][CH:13]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([S:1][CH:17]([C:12]2[CH2:16][CH2:15][CH2:14][CH:13]=2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:7]=1
Reactant: COc1cc(OC)nc(S)n1
Reactant: CCOC(=O)C(OS(C)(=O)=O)C1=CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Sc1nc(OC)cc(OC)n1)C1=CCCC1
Temperature: 25 °C
Yield: 49.5 %

Procedure:
10.4 g of 2-mercapto-4,6-dimethoxypyrimidine, 15.0 g of ethyl 2-(1-cyclopentenyl)-2-(methylsulfonyloxy)acetate, 100 ml of N,N-dimethylformamide and 9.2 g of anhydrous potassium carbonate were stirred at 90° C. for 5 hours. The reaction mixture was cooled to room temperature and then diluted with water. The aqueous mixture was extracted with ethyl ether. The ethyl ether extract was washed with water and dried. Then, ethyl ether was removed by distillation under reduced pressure to obtain an yellow oily substance. The yellow oily substance was purified by silica gel column chromatography (eluent: hexane/ethyl acetate =10/1) to obtain 9.7 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[F:12][C:13](I)([F:18])[C:14]([F:17])([F:16])[F:15]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6](=[O:7])[C:13]([F:18])([F:12])[C:14]([F:17])([F:16])[F:15])[CH:9]=[CH:10][CH:11]=1
Reactant: FC(F)(F)C(F)(F)I
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Product: COc1cccc(C(=O)C(F)(F)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 48.7 %

Procedure:
Under protective gas, 31.5 g (0.185 mol) of 3-methoxybenzoyl chloride in 150 ml of CH2Cl2 are initially introduced into a round-bottomed flask. 48.6 g (0.2 mol) of phosphorous acid trisdiethylamide are added at about -10° C. 50 g (0.2 mol) of pentafluoroethyl iodide are then introduced into the reaction mixture at 0° C. during the course of one hour. The mixture is stirred for a further 5 hours at 0° C. and then worked up analogously to Example 1. 22.9 g (61% yield) of 1-(3-methoxyphenyl)-2,2,3,3,3-pentafluoropropan-1-one of b.p. 95°-97° C./11 mbar are obtained.
Reaction SMILES: [CH:1]1([N:7]2[C:12]3=[N:13][O:14][CH:15]=[C:11]3[C:10](=[O:16])[NH:9][C:8]2=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH:1]1([N:7]2[C:12]3=[N:13][O:14][CH:15]=[C:11]3[C:10](=[O:16])[N:9]([CH3:18])[C:8]2=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c(=O)n(C2CCCCC2)c2nocc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)c2conc2n(C2CCCCC2)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.5 %

Procedure:
In 50 ml of dimethylformamide is dissolved 1 g of the 7-cyclohexyl-5H,7H-isoxazolo[3,4-d]pyrimidine-4,6-dione obtained in Example 18, followed by addition of 800 mg of potassium carbonate and 1 ml of methyl iodide. The mixture is stirred at room temperature for 20 hours, after which the insolubles are filtered off. The filtrate is concentrated to dryness and the concentrate is dissolved in chloroform. After the insolubles are filtered off, the chloroform is removed by distillation and the residue is recrystallized from water-ethanol. By the above procedure is obtained 0.8 g of the captioned compound as pale-white platelets. melting point: 194°-197° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[OH:17])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(=NO)C1C(=CC=CC=1)O>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[O:17][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1cc(Br)ccc1O)C(=O)OC(C)(C)C
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(Cc1cc(Br)ccc1Oc1ccccn1)C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 66.9 %

Procedure:
A mixture of (5-bromo-2-hydroxy-benzyl)-methyl-carbamic acid tert-butyl ester (581 mg, 1.22 mmol), 2-bromopyridine (238 μL, 2.44 mmol), Cs2CO3 (795 mg, 2.44 mmol), powdered 3 Å molecular sieves (366 mg), salicylaldoxime (33.5 mg, 0.244 mmol), Ca2O (9 mg, 0.06 mmol), and DMF (3 mL) was heated at 100° C. for 24 h. After cooling to rt, the mixture was diluted with DCM, filtered through diatomaceous earth, and concentrated. FCC purification (EtOAc/hexanes) gave the desired product (321 mg, 67%). 1H NMR (CDCl3, mixture of rotamers): 8.17-8.12 (m, 1H), 7.74-7.66 (m, 1H), 7.44-7.38 (m, 2H), 7.04-6.90 (m, 3H), 4.44-4.32 (m, 2H), 2.88-2.75 (m, 3H), 1.52-1.40 (m, 9H).
Reaction SMILES: [CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:42])[C@H:12]([CH3:41])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:40])[CH2:22][C@@H:23]([O:38][CH3:39])[C@@H:24]([N:29]([CH3:37])[C:30](=[O:36])[C@H:31]([CH:33]([CH3:35])[CH3:34])[NH2:32])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH2:53][CH2:52][C@@:51]1([CH3:59])[C:56](O)=[O:57])=[O:49])([CH3:46])([CH3:45])[CH3:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:42])[C@H:12]([CH3:41])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:40])[CH2:22][C@@H:23]([O:38][CH3:39])[C@@H:24]([N:29]([CH3:37])[C:30](=[O:36])[C@@H:31]([NH:32][C:56]([C@:51]2([CH3:59])[CH2:52][CH2:53][CH2:54][CH2:55][N:50]2[C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])=[O:57])[CH:33]([CH3:34])[CH3:35])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCCN1C(=O)OC(C)(C)C)C(C)C

Procedure:
According to the general procedure D, from #176 (100 mg, 0.170 mmol, 1 eq.), #156 (53.8 mg, 0.221 mmol, 1.3 eq.), dichloromethane (4.5 mL), HATU (84.9 mg, 0.221 mmol, 1.3 eq.) and N,N-diisopropylethylamine (0.123 mL, 0.697 mmol, 4.1 eq.), was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0 to 100% ethyl acetate in heptane) to afford #177 (145 mg, assume quantitative yield) as a white solid. LC-MS (Protocol Q1): m/z 814.7 [M+H+], retention time=1.14 minutes.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C@@H:17]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].N1C(C)=CC=CC=1C>C(Cl)Cl>[CH:28]1([C@H:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(OCc1ccccc1)[C@@H](O)C1CCCCC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H](OS(=O)(=O)C(F)(F)F)C1CCCCC1
Reaction time: 0.33 h

Procedure:
A solution of trifluoromethanesulfonic anhydride (12.7 g, 45.2 mmol) in 40 mL CH2Cl2 was cooled in an ice bath. A solution of 2-(S)-hydroxy-2-(cyclohexyl)acetic acid, benzyl ester (10.7 g, 43 mmol, from Step A) and 2,6-lutidine (4.6 g, 43 mmol) in 40 mL CH2Cl2 was added dropwise over 25 min and the mixture was stirred for an additional 20 min. The mixture was washed with water and sat'd NaCl then the organic layer was dried over sodium sulfate and concentrated. Flash chromatography (150 g silica, 0→15% EtOAc/hexanes) gave the desired product. 1H NMR (500 MHz, CDCl3) δ1.09-1.33 (m, 5H), 1.66-1.73 (m, 2H), 1.75-1.83 (m, 2H), 2.01-2.08 (m, 1H), 4.98 (d, 1H), 5.27 (d, 1H), 5.29 (d, 1H), 7.35-7.4 (m, 5H).
Reaction SMILES: C(OCC[C:7]1[CH:19]=[CH:18][C:10]2[S:11][C:12]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:13][C:9]=2[CH:8]=1)(=O)C.[OH-].[Na+].Cl.[CH2:23]([OH:25])[CH3:24]>>[OH:25][CH2:23][CH2:24][C:13]1[C:9]2[CH:8]=[CH:7][CH:19]=[CH:18][C:10]=2[S:11][C:12]=1[S:14](=[O:16])(=[O:17])[NH2:15]
Reactant: CCO
Reactant: CC(=O)OCCc1ccc2sc(S(N)(=O)=O)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1sc2ccccc2c1CCO
Reaction time: 4.5 h
Yield: 97 %

Procedure:
A solution of 5-(2-acetoxyethyl)-2-sulfamoyl benzo[b]thiophene (1.8 g, 0.006 mol), ethanol (50 ml) and 10% NaOH (50 ml) was heated at reflux. After 4.5 h, the mixture was poured into 3N HCl (150 ml) and extracted with ethyl acetate (3X). The organic extracts were washed with saturated Na2CO3, dried, filtered and concentrated to dryness to yield 1.5 g (97%) of product, m.p. 162°-164° C.