Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N)(=O)C.Br[C:6]1[CH:11]=[N:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][N:7]=1.[CH3:15][S:16]([NH2:19])(=[O:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].Cl.C>O>[N+:12]([C:9]1[N:10]=[CH:11][C:6]([NH:19][S:16]([CH3:15])(=[O:18])=[O:17])=[N:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc(Br)cn1
Reactant: CS(N)(=O)=O
Agent: CC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: CS(=O)(=O)Nc1cnc([N+](=O)[O-])cn1
Temperature: 145 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
A solution of molten acetamide (1.58 g, 26.7 mmol) heated to 90° C. was treated with a mixture of 2-bromo-5-nitropyrazine (1.34 g, 6.58 mmol), methanesulfonamide (1.88 g, 19.7 mmol), and potassium carbonate (2.30 g, 16.6 mmol). The resulting mixture was quickly brought to 145° C. The resulting solution was stirred at 145° C. for 30 min. At this time, the reaction was cooled to 25° C. and then was treated with water (4 mL). This solution was cooled to 0° C. and then was treated with a 1N aqueous hydrochloric acid solution until the pH of the solution was adjusted to pH=8. This solution was treated with charcoal and was filtered through a pad of celite (9/1 methylene chloride/methanol wash). The filtrate was partitioned, and the aqueous layer was extracted with a solution of 9/1 methylene chloride/methanol. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, ethyl acetate) afforded N-(5-nitro-pyrazin-2-yl)-methanesulfonamide (583.9 mg, 40.6%) as a yellow solid: mp 204–207° C.; EI-HRMS m/e calcd for C5H6N4O4S (M+H)+ 219.0183, found 219.0185.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[H-].[Na+].F[C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29].Cl>CN(C=O)C.O>[C:11]([O:10][C:8]([NH:1][C@@H:2]([CH2:3][O:4][C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29])[C:5]([OH:7])=[O:6])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](COc1c([N+](=O)[O-])cccc1C(F)(F)F)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A solution of BOC-Ser-OH (981 mg, 4.78 mmol) in DMF (5.00 mL) was added to a suspension of NaH (60% in mineral oil, 402 mg, 10.0 mmol) in DMF (5 mL). The mixture was stirred at 0° C. for 1 h and a solution of 2-fluoro-1-nitro-3-(trifluoromethyl)benzene (1 g, 4.78 mmol) in DMF (5 mL) was added. After 2 h the mixture was diluted with H2O and acidified to pH 3 with 1 N HCl. The mixture was extracted with EtOAc, the combined extracts dried over MgSO4, filtered and the filtrate concentrated to give a residue that was purified by silica gel chromatography to afford (S)-2-(tert-butoxycarbonylamino)-3-(2-nitro-6-(trifluoromethyl)phenoxy)propanoic acid (1.53 g, 81%) as a light yellow solid. MS m/z 417 (M+Na)′
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:15])[CH:4]=1)[CH3:2].[Cl:16]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:16][C:4]1[C:5](=[O:15])[NH:6][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(=O)[nH]c(-c2ccccc2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CCc1nc(-c2ccccc2)[nH]c(=O)c1Cl
Temperature: 0 °C
Yield: 87.1 %

Procedure:
A stirred solution of 7.81 g (39.1 mmol) of 6-ethyl-2-phenyl-4(3H)-pyrimidinone and 5.80 g (43.4 mmol) of N-chlorosuccinimide in 100 mL of glacial acetic acid was heated at 90° C. for 4 h. The mixture was cooled, poured onto crushed ice and allowed to stand until the ice had melted. The mixture was filtered and the solid collected was washed with water and a little ether. The solid was dried in a vacuum oven at 50° C. to afford 7.99 g of 5-chloro-6-ethyl-2-phenyl-4(3H)-pyrimidinone (an intermediate for compound 172) as a white solid. 1H-NMR (d6-DMSO) 1.30(3H,t), 2.8(2H,q), 7.6(3H,m), 8.2(2H.m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+].CCCCCC.C(OCC)(=O)C>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a solution of 4-methylbenzotrifluoride (18.6 g, 116 mmol) in concentrated sulfuric acid (120 ml) was added dropwise a solution of potassium nitrate (12.9 g, 128 mmol) in concentrated sulfuric acid (60 ml) at room temperature over 15 minutes. After stirring for 2 hours at the same temperature, the reaction mixture was poured into ice water, which was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and solvent was distilled off. The residue obtained was submitted to silica gel column chromatography [hexane-ethyl acetate=8:1] to obtain 22.8 g of title compound as pale yellow liquid. Yield 96%.
Reaction SMILES: Cl[CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C[Si]([C:21]#[N:22])(C)C.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl.CCCCCCC>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([CH:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:21]#[N:22])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(C(Cl)c2ccccc2)c1
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCCC
Product: COc1cccc(C(C#N)c2ccccc2)c1
Reaction time: 2 h
Yield: 41.7 %

Procedure:
A solution of 1-(chlorophenylmethyl)-3-methoxybenzene (5.5 g, 24 mmol) in DCM (100 mL) was cooled to 0° C. Trimethylsilyl cyanide (3.5 mL, 26 mmol) was added to the stirred solution. 1.0 M of tin tetrachloride in heptane (0.75 mL, 0.75 mmol) was then added. The solution was stirred for 2 hours, then quenched with MeOH (50 mL). The solvent was removed under reduced pressure. The crude material was then purified via silica gel chromatography to obtain the title compound (2.2 g, 10 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[C:5]([O:8]C)=[N:6][CH:7]=1.[Br:13]Br>Br>[Br:13][CH2:11][C:10]([C:4]1[C:5]([OH:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:12]
Reactant: BrBr
Reactant: COc1ncc(Br)cc1C(C)=O
Agent: Br
Product: O=C(CBr)c1cc(Br)cnc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
To a solution of 1-(5-bromo-2-methoxypyridin-3-yl)ethanone (2.0 g, 8.69 mmol) in HBr (20 mL, HOAc solution), Br2 (1.4 g, 8.76 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 5 hours. Then the reaction mixture was filtered to collect the HBr salt. The solid was suspended with Na2CO3 solution, extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 2-bromo-1-(5-bromo-2-hydroxypyridin-3-yl)ethanone (2.0 g, yield: 74%). 1H-NMR (DMSO, 400 MHz) δ 12.83 (br s, 1H), 8.11˜8.13 (m, 2H), 4.85 (s, 2H). MS (M+H)+: 295.
Reaction SMILES: C(OC([C:6]1[O:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])=[N:9][N:10]=1)=O)C.[Li+].[OH-].Cl>C1COCC1.O>[F:25][C:19]1[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:8]1[O:7][CH:6]=[N:10][N:9]=1
Reactant: CCOC(=O)c1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc(I)ccc1Nc1cnccc1-c1nnco1
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a solution of 5-[3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-[1,3,4]oxadiazole-2-carboxylic acid ethyl ester (200 mg, 0.44 mmol) in THF-H2O (1:1)(5 mL) LiOH (32 mg, 1.32 mmol) was added. The reaction mixture was stirred for 2 hrs and then the pH was adjusted to 5 with 1N HCl. Upon dilution with water a solid precipitated. Filtration afforded the desired product (89 mg). LC/MS (Method A) [0.48 min; 383(M+1)]
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:21]2([CH3:23])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[C@H:19]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:31]([O:33][CH3:34])=[O:32])[CH2:7][C@@H:6]1[OH:35])(=[O:3])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.[C:47](OC(=O)C)(=[O:49])[CH3:48]>C(Cl)(Cl)Cl.C(O)C.C(OCC)(=O)C>[CH:25]1([NH:24][C@@H:19]2[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C:31]([O:33][CH3:34])=[O:32])[C@H:11]3[C@H:20]2[C@:21]2([CH3:23])[C@@H:8]([CH2:9][CH2:10]3)[CH2:7][C@H:6]([O:35][C:47](=[O:49])[CH3:48])[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:22]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OC(C)=O)C[C@]4(C)[C@H]3[C@H](NC3CCCCC3)C[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(C)=O)[C@@H](OC(C)=O)C[C@]4(C)[C@H]3[C@H](NC3CCCCC3)C[C@]12C
Reaction time: 0.33 h

Procedure:
Methyl 2β-acetoxy-11α-cyclohexylamino-3α-hydroxy-5α-androstane-17β-carboxylate (1.156 g) in chloroform (12.5 ml) containing dry PTSA (1.0 g) was stirred for 20 min. then treated with acetic anhydride (2.9 ml) and the mixture left for 18 h. The mixture was diluted with ethanol and evaporated to give an oil. This was dissolved in ethyl acetate, and washed with dilute ammonia solution (1×) water (1×), dried and evaporated under reduced pressure to give a foam. This was purified by preparative t.l.c. in chloroform/methanol (9:1) to give the title compound (790 mg), [α]D +36.8°, νmax 1724 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]2[N:40]=[CH:39][CH:38]=[CH:37][C:26]=2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:17][C:10]=12.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:45](C)=O.[Na+].Cl.C([O-])([O-])=O.[Na+].[Na+]>O.C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]2[N:40]=[CH:39][CH:38]=[CH:37][C:26]=2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH:18]3[CH2:23][CH2:22][N:21]([CH3:45])[CH2:20][CH2:19]3)[S:17][C:10]=12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(Nc1ccc(F)cc1)c1cccnc1Nc1ccc(Oc2ccnc3cc(C4CCNCC4)sc23)c(F)c1
Agent: C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(c2cc3nccc(Oc4ccc(Nc5ncccc5C(=O)Nc5ccc(F)cc5)cc4F)c3s2)CC1
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
A round-bottomed flask was charged with 2-(3-fluoro-4-(2-(piperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylamino)-N-(4-fluorophenyl)nicotinamide (Example 177, Step D, 47 mg, 0.084 mmol), formaldehyde (7.7 mg, 0.084 mmol) 33% in water and THF (5 mL). The mixture was stirred for 30 minutes and then NaBH(OAc)3 (18 mg, 0.084 mmol) was added. The mixture was stirred for another 30 minutes and then HCl (1N, 1 mL) was added. The acid was neutralized with Na2CO3 and the mixture extracted with EtOAc. The organics were dried over sodium sulfate, filtered and concentrated to get product as a free base. The crude product was diluted in MeOH (2 mL) and HCl (0.1 mL, 4N Dioxane) added. The mixture was concentrated under high vacuum to get product (34 mg, 67%) as a yellow solid. LRMS (esi+) 572 m/z (M+1) detected. 1H NMR (CDCl3, 400 MHz) δ 10.65 (s, 1H), 10.55 (br s, 2H). 9.14 (s, 1H), 8.39 (d, J=6 Hz, 2H), 8.34 (m, 1H), 8.18 (d, J=8 Hz, 1H), 8.03 (d, J=13 Hz, 1H), 7.65 (m, 2H), 7.12 (m, 4H), 6.78 (m, 1H), 6.50 (d, J=5.5 Hz, 1H), 3.36 (m, 2H), 3.13 (m, 1H), 2.81 (m, 2H), 2.26 (m, 4H), 2.05 (s, 3H).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH:24]=[CH:25][C:26](=[O:28])[CH3:27]>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH:24]1[CH2:3][C:2](=[O:1])[CH2:27][C:26](=[O:28])[CH2:25]1
Reactant: CC(=O)C=Cc1cc(F)ccc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: O=C1CC(=O)CC(c2cc(F)ccc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (0.43 g) was added at room temperature diethyl malonate (0.2 g), and then added little by little 4-(2-chloro-5-fluorophenyl)-3-buten-2-one (0.24 g). The mixture was stirred at room temperature for 30 minutes, refluxed for 2 hours and cooled, and the solvent was evaporated. The residue was dissolved in water, and the aqueous layer was washed with ethyl acetate and concentrated. To the reside was added 2M sodium hydroxide (0.7 ml), and the mixture was refluxed for 2 hours cooled. To the mixture was added 2.5M sulfuric acid (0.7 ml), and the mixture was refluxed for 15 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 5-(2-chloro-5-fluorophenyl)cyclohexane-1,3-dione (0.17 g) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C=O)[CH:5]=[N:6][C:7]=1[I:8].[CH:11](OC)([O:14][CH3:15])[O:12][CH3:13].Cl.C(Cl)Cl>CO>[CH3:13][O:12][CH:11]([O:14][CH3:15])[C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([I:8])=[N:6][CH:5]=1
Reactant: COC(OC)OC
Reactant: O=Cc1cnc(I)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(OC)c1cnc(I)c(Cl)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
A mixture of 5-chloro-6-iodo-3-pyridinecarbaldehyde (260 mg, 0.972 mmol), trimethyl orthoformate (1.064 ml, 9.72 mmol), HCl (3M in MeOH) (0.778 ml, 2.333 mmol), DCM (1.5 ml) and MeOH (1.5 ml) was stirred at 50° C. for 3 h. TLC showed full conversion. The solution was cooled to room temperature and concentrated under vacuum. The residue was diluted with sat. NaHCO3 and EtOAc. Extraction, drying (MgSO4), filtration, and concentration afforded 271.5 mg of crude material. Purification by flash chromatography using Flashmaster II, a 5 g silica gel cartridge, and mixtures of hexane and EtOAc as eluent afforded 5-[bis(methyloxy)methyl]-3-chloro-2-iodopyridine (239.9 mg, 79%) as a yellow oil. It will be used in the next step without further purification.
Reaction SMILES: CN(C)C=O.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH2:17]([O:22][CH3:23])[CH2:18][CH2:19][C:20]#[CH:21]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:23][O:22][CH2:17][CH2:18][CH2:19][C:20]#[C:21][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: NS(=O)(=O)c1ccccc1I
Reactant: C#CCCCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCCC#Cc1ccccc1S(N)(=O)=O
Reaction time: 22 h

Procedure:
135 ml of N,N-dimethylformamide and 22 ml of triethylamine are taken and 7.5 g of 2-iodobenzenesulfonamide, 2.6 g of pent-4-yn-1-yl-methyl ether as well as 0.067 g of copper(I) iodide and 0.144 g of bis(triphenylphosphine)palladium(II) dichloride are added. The reaction mixture is heated to 65° and stirred for 22 hours at that temperature under argon. After that time, the N,N-dimethylformamide is distilled off at 0.1 torr and 40°. The crude product is purified on 500 g of silica gel (Merck Si 60, 40-63 μm) with hexane/ethyl acetate=2/1 as eluant. The fractions containing the product are concentrated by evaporation at 15 torr and 40° to yield white crystalline 2-(5-methoxy-pent-1-yn-1-yl)-benzenesulfonamide, melting point: 59°-61°.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:17])[N:10]([C@@H:18]3[O:35][C@H:34]([CH2:36][O:37]C(=O)C)[C@@H:29]([O:30]C(=O)C)[C@H:24]([O:25]C(=O)C)[C@H:19]3[O:20]C(=O)C)[CH:9]=2)=[CH:4][CH:3]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1>>[F:41][C:42]1[CH:47]=[CH:46][C:45]([C:2]2[S:6][C:5]([CH2:7][C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][C:15]=4[CH3:17])[N:10]([C@@H:18]4[O:35][C@H:34]([CH2:36][OH:37])[C@@H:29]([OH:30])[C@H:24]([OH:25])[C@H:19]4[OH:20])[CH:9]=3)=[CH:4][CH:3]=2)=[CH:44][CH:43]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(Br)s3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1cccc2c1c(Cc1ccc(-c3ccc(F)cc3)s1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
3-(5-Bromothiophen-2-yl-methyl)-4-methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 45-(3) and 4-fluorobenzeneboronic acid were treated in a manner similar to Example 45-(4) and 2-(7) to give the titled compound as a yellow powder. APCI-Mass m/Z 484 (M+H). 1H-NMR (DMSO-d6) δ 2.50 (s, 3H), 3.25 (td, J=8.8, 5.4 Hz, 1H), 3.40 (td, J=9.0, 5.4 Hz, 1H), 3.43-3.48 (m, 2H), 3.67-3.71 (m, 2H), 4.37 (s, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.09 (d, J=5.1 Hz, 1H), 5.15 (d, J=5.1 Hz, 1H), 5.17 (d, J=6.1 Hz, 1H), 5.36 (d, J=9.2 Hz, 1H), 6.75 (d, J=7.1 Hz, 1H), 6.80 (d, J=3.5 Hz, 1H), 7.00 (t, J=7.7 Hz, 1H), 7.19 (t, J=8.8 Hz, 2H), 7.30 (d, J=3.5 Hz, 1H), 7.32 (s, 1H), 7.36 (d, J=8.3 Hz, 1H), 7.59 (dd, J=8.7, 5.3 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([I:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([I:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: NC1CCc2ccc(I)cc2NC1=O
Product: CC(C)(CC(=O)NC1CCc2ccc(I)cc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step E by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.33 (s,6H), 1.42 (s,9H), 1.80 (m,1H), 2.24 (m,2H), 2.50 (d,2Hz,1H), 7.43 (dd;2,8 Hz;1H). FAB-MS: calculated for C20H28IN3O4 501; found 502 (M+H,20%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:4]=[CH:5][C:6]([NH:9][C@H:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:15]C(=O)OC(C)(C)C)=[N:7][CH:8]=1.BrN1C(=O)CCC1=O.[ClH:33].O1CCOCC1>C(Cl)Cl>[ClH:33].[Cl:33][C:5]1[C:6]([NH:9][C@H:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[NH2:15])=[N:7][CH:8]=[C:3]([C:2]([F:24])([F:23])[F:1])[N:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]carbamate (1.04 g, 3.00 mmol) in dry DCM (10 ml) at 0° C. under an atmosphere of nitrogen was added 1-bromopyrrolidine-2,5-dione (CAS number 128-08-5; 0.80 g, 4.50 mmol). The reaction was allowed to warm to room temperature and stirred for 17 hours and then was concentrated in vacuo. The resulting residue was purified by column chromatography (basic silica, 0-50% ethyl acetate/petrol). To this was then added HCl in 1,4-dioxane (4 M, 7.51 ml, 30.0 mmol) and stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo and azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH:5]2[CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.[NH4+].[Cl-]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8]([C:7]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)([OH:11])[CH2:6][CH:5]2[CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CN1CCC(C2CC(=O)c3ccc(F)cc32)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C2CC(O)(c3ccc(F)cc3)c3ccc(F)cc32)CC1
Temperature: 0 °C

Procedure:
5-Fluoro-3-(1-methyl-4-piperidyl)indanone (100 g) (prepared according to standard methods--J. Med. Chem., 11, (1968), 1064-66) in dry tetrahydrofuran (500 ml) was added dropwise to 4-fluorophenylmagnesium bromide (from 95 g of 4-bromofluorobenzene and 20 g of Mg-turnings in 500 ml of dry tetrahydrofuran). The reaction mixture was poured into NH4Cl (100 g) and crushed ice (3 L) and extracted with ether (2×300 ml). The combined organic phases were extracted with 0.5M CH3COOH (2×500 ml). The acid H2O-phase was made alkaline with 2M NaOH solution and extracted with ether (2×200 ml). The combined ether-phases were worked up as above and the starting material removed by washing with light petroleum. The title compound crystallized from isopropylether. Yield: 16.5 g (11.7%). MP: 148°-150° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.Cl[CH:19]([C:25]([CH3:27])=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].CC1C=CC=C(C)N=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:25]([CH3:27])[N:12]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Temperature: 130 °C
Reaction time: 24 h

Procedure:
Under a nitrogen atmosphere, a mixture of 5.0 g of 3-[(2,6-difluorobenzyl)oxy]pyridin-2-amine, 4.1 ml of ethyl 2-chloroacetoacetate, 3.5 ml of 2,6-dimethylpyridine, and 50 ml of toluene was stirred at 130° C. for 24 hours. After leaving to be cooled to room temperature, the reaction mixture was washed with water, a 1 M aqueous sodium hydroxide solution, a 10% aqueous citric acid solution, and a saturated aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure to obtain 5.47 g of ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=[O:13])=[N:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Si](C)(C)C)=[CH:17][C:16]=1[F:25].[I:27]Cl>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=[O:13])=[N:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:27])=[CH:17][C:16]=1[F:25]
Reactant: ClI
Reactant: COC(=O)c1ccc(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC=O)nc1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 2-(2-fluoro-4-trimethylsilanylphenylamino)-6-formylamino methyl-nicotinic acid methyl ester (10.3 g, 27.4 mmol) in DCM (275 mL) at 0° C. was added dropwise iodine monochloride as a solution in DCM (54.9 mL, 1M, 54.9 mmol). The reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was washed with aqueous sodium metabisulfite (100 mL, 0.5 M) and the aqueous layer extracted twice with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an orange gum (11.6 g, 100%). LCMS (Method B): RT=3.72 min, M+H+=430.