Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10](C1CCCCO1)[N:9]=[CH:8]2.FC(F)(F)C(O)=O.CC(C)=O>C(Cl)Cl>[F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:10][N:9]=[CH:8]2
Reactant: CCOC(=O)c1cc2c(cnn2C2CCCCO2)cc1Oc1ccc([N+](=O)[O-])cc1F
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2[nH]ncc2cc1Oc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a solution of ethyl 5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carboxylate (15 g, 35 mmol) in DCM (300 mL) is added trifluoroacetic acid (TFA) (30 mL), and stirred at RT overnight. DCM is evaporated. The residue is partitioned between EtOAc (800 mL) and 5% aqueous NaHCO3 (400 mL). The organic layer is washed with saturated aqueous sodium chloride, dried over MgSO4, and concentrated. The residue is purified by silica gel column chromatography eluting with PE:acetone (5:1) to afford the product (10.4 g, 86% yield). MS (m/z): 346.1 (M+H).
Reaction SMILES: C([O:5]O)(C)(C)C.[CH3:7][O:8][C:9]([C:11]1[C@H:12]2[CH2:24][CH:23]=[C:22]([CH2:25][OH:26])[C@@H:13]2[C@H:14]([O:17][C:18](=[O:21])[NH:19][CH3:20])[O:15][CH:16]=1)=[O:10].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.[V]>[CH3:7][O:8][C:9]([C:11]1[C@H:12]2[CH2:24][C@@H:23]3[O:5][C@@:22]3([CH2:25][OH:26])[C@@H:13]2[C@H:14]([O:17][C:18](=[O:21])[NH:19][CH3:20])[O:15][CH:16]=1)=[O:10]
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(CO)[C@H]12
Reactant: CC(C)(C)OO
Agent: [V]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2C[C@@H]3O[C@@]3(CO)[C@H]12
Reaction time: 0.33 h
Yield: 89 %

Procedure:
85 mg of vanadium oxyacetylacetonate were dissolved in dichloromethane followed by dropping 7.1 ml of t-butylhydroperoxide (3.0 M, 2,2,4-trimethylpentane solution) and stirring for 20 minutes. Next, a dichloromethan solution of 3.0 g of (1S,4aS,7aR)-7-(hydroxymethyl)-1-(methylcarbamoyloxy)-1,4a,5,7a-tetrahydrocyclopenta [c] pyrane-4-carboxylic acid methylester was dropped thereinto followed by stirring for 17 hours at room temperature. The reaction mixture was poured into saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate. After washing the organic phase with brine, it was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain colorless needles from the hexane-ether eluate in the form of (1S,4aS,6S,7R,7aR )-6,7-epoxy-7-(hydroxymethyl)-1-(methylcarbamoyloxy)-1,4a,5,6,7,7a-hexahydrocyclopenta [c] pyrane-4-carboxylic acid methylester (2.9 g, yield: 89%). The physicochemical properties of this compound are described in Table 9, Compound No. 45.
Reaction SMILES: [O:1]([CH2:8][CH2:9]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>>[O:1]([CH2:8][CH2:9][N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:21][CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCOc1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NC1CCN(CCOc2ccccc2)CC1)c1ccccc1

Procedure:
2-Phenoxyethylbromide (2.01 g.), 4-benzamidopiperidine (2.04 g.) and anhydrous potassium carbonate (1.38 g.) were reacted together according to the procedure of Example 51. The title compound as its hydrochloride (2.06 g.) had m.p. 207° C. (Found: C, 67.0; H, 7.1; N, 7.7. C20H24N2O2.HCl requires C, 67.3; H, 7.1; N, 7.85%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[C:8]([CH2:11][CH2:12][NH2:13])=[CH:9][NH:10][C:3]=2[CH:2]=1.Cl.[OH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[C:17]=1[C:18](O)=[O:19].C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[OH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[C:17]=1[C:18]([NH:13][CH2:12][CH2:11][C:8]1[C:4]2[C:3](=[CH:2][CH:1]=[C:6]([OH:7])[CH:5]=2)[NH:10][CH:9]=1)=[O:19]
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: O=C(O)c1c(O)cccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(O)cc12)c1c(O)cccc1O
Temperature: 0 °C
Reaction time: 16 h
Yield: 14.9 %

Procedure:
Serotonin hydrochloride (430 mg, 2 mmol) and 2,6-dihydroxybenzoic acid (312 mg, 2 mmol) were dissolved in N,N-dimethylformamide (25 ml), and the solution temperature was maintained at 0° C. To this solution were added triethylamine (310 μl, 2.1 mmol), 1-hydroxybenzotriazole hydrate (HOBt H2O, 346 mg, 2.1 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI HCl, 429 mg, 2.1 mmol), the solution temperature was gradually warmed from 0° C. to room temperature, and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, water (20 ml) was added to the residue, and the mixture was extracted twice with ethyl acetate (20 ml). The ethyl acetate layer was washed twice with 5% aqueous citric acid solution (5 ml), once with saturated brine (5 ml), twice with 5% aqueous sodium hydrogen carbonate solution (5 ml), and once with saturated brine (5 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure, purified by preparative thin-layer chromatography (PTLC, eluent: ethyl acetate:hexane=3:1) to give 2,6-dihydroxy-N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-benzamide (93 mg, yield 14.9%) as a powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4](C2CC3N(C(OC(C)(C)C)=O)C(CC3)C2)[C:3]=1[S:38]([CH3:41])(=[O:40])=[O:39].[ClH:42].O1[CH2:48][CH2:47]OCC1>CO>[CH:48]12[NH:13][CH:14]([CH2:17][CH2:47]1)[CH2:15][CH:16]([C:9]1[C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:15][CH:16]=3)=[C:6]3[N:5]=[CH:4][C:3]([S:38]([CH3:41])(=[O:40])=[O:39])=[C:2]([NH2:1])[N:7]3[N:8]=1)[CH2:11]2.[ClH:42]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N)c1S(C)(=O)=O)C2
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)c1cnc2c(-c3ccc(-c4ccccc4)nc3)c(C3CC4CCC(C3)N4)nn2c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the crude tert-butyl 3-(7-amino-6-(methylsulfonyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate in MeOH (5 mL) was added 4M HCl in 1,4-dioxane at r.t. It was stirred further at room temperature for 2 h, at which time LC/MS analysis confirmed full consumption of the starting material. The solvent was removed in vacuo to afford the desired product as an HCl salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:5]([NH2:16])[CH:4]=1.[CH3:17][CH:18]([CH3:24])/[CH:19]=[CH:20]/[C:21](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:48]([OH:53])(=[O:52])[C:49]([OH:51])=[O:50]>C(OCC)(=O)C>[C:48]([OH:53])(=[O:52])[C:49]([OH:51])=[O:50].[CH3:17][CH:18]([CH3:24])/[CH:19]=[CH:20]/[C:21]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:6]2[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N:16]=1
Reactant: CC(C)/C=C/C(=O)Cl
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(/C=C/C(C)C)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-amino-N-(2-pyridyl)aniline and (E)-4-methyl-2-pentenoyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound. MW: 383.41; mp: 140.0-141.0° C.; 1H-NMR (DMSO) δ: 8.71 (1H, d, J=3.7 Hz), 8.16-8.10 (1H, m), 7.64-7.56 (2H, m), 7.28 (1H, d, J=9.2 Hz), 7.19 (1H, d, J=2.2 Hz), 6.99-6.83 (2H, m), 6.37 (1H, d, J=15.8 Hz), 3.80 (3H, s), 2.52-2.42 (1H, m), 1.02 (6H, d, J=6.6 Hz).
Reaction SMILES: C[O-].[Na+].CO[C:6](=[O:21])[CH:7]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:8]([O:10]C)=O.[F:22][C:23]([F:28])([F:27])[C:24]([NH2:26])=[NH:25]>CO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH:7]1[C:6](=[O:21])[NH:26][C:24]([C:23]([F:28])([F:27])[F:22])=[N:25][C:8]1=[O:10]
Reactant: N=C(N)C(F)(F)F
Reactant: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1OC1C(=O)N=C(C(F)(F)F)NC1=O
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a stirred solution of 22.9 g sodium methylate in 250 ml methanol was added 37.5 g dimethyl-2-(o-methoxyphenoxy)malonate in portions within 15 min. Stirring was continued for 30 min. Then 15.8 g trifluoro-acetamidine was added followed by stirring for 20 h at room temperature. Work up was done according to the procedure described in Example 1d) to give 29.77 g 5-(o-methoxyphenoxy)-2-trifluoromethyl-pyrimidine-4,6-dione (or its tautomeric form). LC-MS: tR=3.41 min, [M+1]+=303.32.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15](=[O:17])[NH2:16])[CH:9]=2)=[O:5])C.Cl>O1CCOCC1.O.O>[C:15]([C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2)=[CH:12][CH:11]=1)(=[O:17])[NH2:16]
Reactant: CCOC(=O)c1cc2ccc(C(N)=O)cc2[nH]1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1ccc2cc(C(=O)O)[nH]c2c1
Yield: 70 %

Procedure:
Treat a solution of 6-carbamoyl-1H-indole-2-carboxylic acid ethyl ester (54 mg, 0.23 mmol) in dioxane/water (5:1, 12 mL) with LiOH monohydrate (14 mg, 0.33 mmol). Stir the reaction at rt overnight. Concentrate the reaction to dryness and dissolve the residue in water (5 mL) to form a solution. Acidify with 1 M HCl solution to form a solid. Collect by filtration and dry to give the desired product 6-carbamoyl-1H-indole-2-carboxylic acid as a solid in 70% yield (33 mg, 0.16 mmol).
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[CH2:17][C:16](=[O:18])[CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])(=O)C.N>>[SH:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[CH2:17][C:16](=[O:18])[CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9]
Reactant: CC(=O)SCCCC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: N
Product: O=C1C[C@@H](C(=O)O)N(C(=O)CCCS)C1

Procedure:
The product form part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 2 to yield 1-(4-mercapto-1-oxobutyl)-4-oxo-L-proline.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15](O)=[O:16])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][O:20]1)[CH2:4][CH3:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[C:44]([O:48][C:49](=[O:56])[C@H:50]([CH2:52][CH:53]([CH3:55])[CH3:54])[NH2:51])([CH3:47])([CH3:46])[CH3:45].Cl>CN(C=O)C.O.C(Cl)CCl>[C:44]([O:48][C:49](=[O:56])[C@@H:50]([NH:51][C:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[C:7]([CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][O:20]3)=[N:8][C:9]=2[CH:14]=1)=[O:16])[CH2:52][CH:53]([CH3:54])[CH3:55])([CH3:46])([CH3:45])[CH3:47]
Reactant: CCC(CC)n1c(CC2CCCO2)nc2cc(C(=O)O)ccc21
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCC(CC)n1c(CC2CCCO2)nc2cc(C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
To a solution of 55 mg of 1-(1-Ethyl-propyl)-2-(tetrahydro-furan-2-ylmethyl)-1H-benzoimidazole-5-carboxylic acid in 1 ml of dry DMF 26 mg of HOBT, 37 mg of EDC and 0.05 ml of DIPEA were added at 0° C. After 15 min 100 mg of L-leucine tert-butyl ester-hydrochloride and 0.05 ml of DIPEA were added and the reaction was stirred at rt for 16 h. The reaction was then poured into water and the pH was adjusted to 3 by the addition of 2 M aqueous hydrochloric acid. The reaction was extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated. 75 mg (88%) of (S)-2-{[1-(1-Ethyl-propyl)-2-(tetrahydro-furan-2-ylmethyl)-1H-benzoimidazole-5-carbonyl]-amino}-4-methyl-pentanoic acid tert-butyl ester were obtained.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][CH2:14][NH:15]3)=[CH:11][C:10]=2[O:18][CH3:19])[CH2:3]1.C[Al](C)C.[C:24]([NH:27][C:28]1[N:33]=[C:32]([CH3:34])[C:31]([C:35]2[CH:44]=[CH:43][C:38]([C:39](OC)=[O:40])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>C1(C)C=CC=CC=1>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][CH2:14][N:15]3[C:39]([C:38]3[CH:37]=[CH:36][C:35]([C:31]4[CH:30]=[CH:29][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[N:33][C:32]=4[CH3:34])=[CH:44][CH:43]=3)=[O:40])=[CH:11][C:10]=2[O:18][CH3:19])[CH2:3]1
Reactant: COC(=O)c1ccc(-c2ccc(NC(C)=O)nc2C)cc1
Reactant: COc1cc2c(cc1N1C[C@@H](C)N[C@@H](C)C1)NCC2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1C[C@@H](C)N[C@@H](C)C1)N(C(=O)c1ccc(-c3ccc(NC(C)=O)nc3C)cc1)CC2
Temperature: 90 °C
Yield: 45.4 %

Procedure:
A stirred solution of D3 (40 mg, 150 umole) in toluene (2 ml) at room temperature under argon was treated with 2M trimethylaluminium in toluene (0.15 ml, 300 umole) and maintained for 15 min, then a solution of D7 (57 mg, 200 umole) in toluene (3 ml) was added and the mixture heated at 90° C. for 1 h. The solution was allowed to cool, then added directly to a silica gel column (5 g) and eluted initially with 2% MeOH/DCM to remove high Rf impurities, then with 10% MeOH/DCM to afford the product. This was triturated with Et2O/DCM to afford the title compound as a beige solid (35 mg, 82%).
Reaction SMILES: [CH3:1][C:2]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][Cl:20])=[O:17]>ClCCl>[C:16](=[O:17])([O:8][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[O:18][CH2:19][Cl:20]
Reactant: O=C(Cl)OCCl
Reactant: CC1(O)CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(OC(=O)OCCl)CCCCC1
Reaction time: 2 h

Procedure:
1-Methylcyclohexanol (4.57 g) in dichloromethane (40 ml) was cooled in an ice-bath and treated with pyridine (3.24 ml). Chloromethyl chloroformate (3.65 ml) in dichloromethane (10 ml) was added dropwise through a pressure-equalising funnel. The mixture was stirred for 2 h and then washed with water (2×), dried (MgSO4) and then evaporated to leave a reddish-coloured oil, which was dissolved in dichloromethane and filtered through silica gel (230-400 mesh ASTM) to give (after evaporation) chloromethyl 1-methylcyclohexyl carbonate as a colourless oil (8.97 g), υmax(CH2Cl2) 2940, 2865, 1763, 1444, 1346, 1292, and 1237 cm−1; δ(CDCl3) 1.25-1.70 (11H, m), 2.12-2.18 (2H, m), 5.69 (2H,s) ppm.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)CC)C.[Cl:12][CH2:13][CH2:14][CH2:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:2][N:3]([CH3:4])[S:16]([CH2:15][CH2:14][CH2:13][Cl:12])(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)CCCCl

Procedure:
To a suspension of dimethylamine hydrochloride (1.38 g) in dichloromethane (20 mL) was added triethylamine (2.52 mL) and then 3-chloropropanesulfonyl chloride (0.69 mL) and the reaction was stirred at room temperature for 16 h. The reaction was quenched with water (20 mL) and extracted into dichloromethane (2×30 mL). The combined organics were washed with 1 M aqueous hydrochloric acid solution (40 mL) then saturated aqueous sodium hydrogen carbonate solution, dried (MgSO4) and reduced in vacuo to give 3-chloro-propane-1-sulfonic acid dimethylamide as a yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:24]([C:25]2[CH:26]=[CH:27][C:28]([O:43][CH3:44])=[C:29]([CH:42]=2)[C:30]([NH:32][C:33]2([C:36]3[N:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH2:35][CH2:34]2)=[O:31])=[CH:23][C:7]2[C:8]([C:18]3[NH:19][CH:20]=[CH:21][N:22]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=1)[CH3:2].[CH3:45][S:46](Cl)(=[O:48])=[O:47]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.O>[CH2:1]([N:3]([C:4]1[C:24]([C:25]2[CH:26]=[CH:27][C:28]([O:43][CH3:44])=[C:29]([CH:42]=2)[C:30]([NH:32][C:33]2([C:36]3[N:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH2:35][CH2:34]2)=[O:31])=[CH:23][C:7]2[C:8]([C:18]3[N:19]([S:46]([CH3:45])(=[O:48])=[O:47])[CH:20]=[CH:21][N:22]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=1)[S:46]([CH3:45])(=[O:48])=[O:47])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCNc1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1-c1ccc(OC)c(C(=O)NC2(c3ncccn3)CC2)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CCN(c1cc2oc(-c3ccc(F)cc3)c(-c3nccn3S(C)(=O)=O)c2cc1-c1ccc(OC)c(C(=O)NC2(c3ncccn3)CC2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(6-(ethylamino)-2-(4-fluorophenyl)-3-(1H-imidazol-2-yl)benzofuran-5-yl)-2-methoxy-N-(1-(pyrimidin-2-yl)cyclopropyl)benzamide (40 mg, 0.068 mmol) in pyridine (3.0 mL) at room temperature was added DMAP (16.60 mg, 0.136 mmol) followed by methanesulfonyl chloride (7.94 μl, 0.102 mmol). The reaction mixture was stirred at rt overnight, and then diluted with water. The mixture was extracted with EtOAc, and the organic extract washed with brine, dried over Na2SO4 and concentrated to obtain the title compound as an off white solid. Yield: 45 mg (89%). LCMS: (ES+) m/z=745.2 (M+H)+; Column—ACE Excel 2 C18 (50×3.0 mm-2 μm); M phase A: 2% MeCN-98% H2O-10 mM NH4COOH; M phase B: 98% MeCN-2% H2O-10 mM NH4COOH
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10](=[O:21])[CH2:9]1)=O)(C)(C)C>CCOC(C)=O>[Cl:20][C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]2=[O:21])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Cl)c2)C(=O)C1
Solvent: CCOC(C)=O
Product: O=C1CNCCN1c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Through a solution of Boc-protected piperazinone from Step D (17.19 g, 55.4 mmol) in 500 mL of EtOAc at −78° C. was bubbled anhydrous HC1 gas. The saturated solution was warmed to 0° C., and stirred for 12 hours. Nitrogen gas was bubbled through the reaction to remove excess HC1, and the mixture was warmed to room temperature. The solution was concentrated in vacuo to provide the hydrochloride as a white powder. This material was taken up in 300 mL of CH2Cl2 and treated with dilute aqueous NaHCO3 solution. The aqueous phase was extracted with CH2Cl2 (8×300 mL) until tlc analysis indicated complete extraction. The combined organic mixture was dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled free amine as a pale brown oil.
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:9]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:8](=[O:19])[CH2:7][CH2:6]1)=O.[NH3:20]>CO>[O:19]=[C:8]1[N:9]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]([C:3]([NH2:20])=[O:2])[CH2:6][CH2:7]1
Reactant: N
Reactant: COC(=O)C1CCC(=O)N1CC#CCN1CCCC1
Solvent: CO
Product: NC(=O)C1CCC(=O)N1CC#CCN1CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
An ice water chilled solution of 5-methoxycarbonyl-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone (5.52 g) in sieve dried methanol (175 ml) was treated with anhydrous ammonia for fifteen minutes and was allowed to stand at ambient temperature overnight. The solution was concentrated to a brown solid (3.33 g). The solid was recrystallized from toluene (100 ml) to give 2.03 g of slightly brown crystals, mp 146°-147.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8]Br)=[CH:5][CH:4]=1.[NH2:12][C:13]([CH3:30])([CH3:29])[CH2:14][O:15][CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][CH2:14][C:13]([NH:12][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([CH3:30])[CH3:29])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: CC(C)(N)COC(c1ccccc1)c1ccccc1
Product: COc1ccc(CCNC(C)(C)COC(c2ccccc2)c2ccccc2)cc1

Procedure:
The title compound was prepared as described in Example 1 using 4-methoxyphenethyl bromide and 2-amino-1-diphenylmethoxy-2-methylpropane (see Preparation 1). The title compound was obtained as a colourless oil (378 mg, 33%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[N:16]1([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2B(O)O)(=[O:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[F:15][C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[S:22]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:24])=[O:23])[CH:7]=[CH:6][C:5]=1[C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Reactant: O=S(=O)(c1ccccc1B(O)O)N1CCCCC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCCCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 42 using 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine and (2-(piperidin-1-ylsulfonyl)phenyl)boronic acid. MS (ESI): mass calcd. for C21H21FN4O2S, 412.14; m/z found, 413.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.40-8.30 (m, 2H), 8.10-8.06 (m, 1H), 7.98 (m, 1H), 7.79-7.73 (m, 1H), 7.71-7.64 (m, 1H), 7.62-7.56 (m, 1H), 7.43-7.39 (m, 1H), 7.34-7.28 (m, 1H), 2.86 (d, J=5.3, 4H), 1.50-1.38 (m, 6H).
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=4[F:51])[CH:34]=3)[O:32][C@@:10]1([C:52]([OH:55])([CH3:54])[CH3:53])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([C:52]([OH:55])([CH3:53])[CH3:54])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=1[F:51]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
To a solution of 2-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]propan-2-ol 24c (250 mg, 0.32 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL) were added o-dichlorobenzene (0.18 mL, 1.62 mmol) and 10% Pd/C (100 mg, 0.09 mmol) at room temperature. The mixture was stirred at room temperature under H2 for 4 hours and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/2 to give the title compound 24 as a white solid (160 mg, 98.7%, HPLC: 96.6%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 545 [M+HCOO]−; and 1H NMR (600 MHz, DMSO-d6) δ(ppm): 7.42 (d, 1H), 7.36 (m, 2H), 6.94 (t, 1H), 6.87 (t, 1H), 5.51 (s, 1H), 4.98 (s, 2H), 4.23 (d, 1H), 4.11 (q, 2H), 4.03 (m, 3H), 3.79 (d, 1H), 3.71 (d, 1H), 3.46 (t, 2H), 1.34 (t, 3H), 1.20 (s, 3H), 1.15 (s, 3H).