Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([O:9][C@@H:10]2[O:27][C@H:26]([CH2:28][O:29]C(=O)C)[C@@H:21]([O:22]C(=O)C)[C@H:16]([O:17]C(=O)C)[C@H:11]2[O:12]C(=O)C)[C:5]=1[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:3])[CH3:2].C[O-].[Na+]>O1CCCC1.CO>[CH2:41]([O:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][C:5]1[C:6]([O:9][C@@H:10]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:21]([OH:22])[C@H:16]([OH:17])[C@H:11]2[OH:12])=[N:7][NH:8][C:4]=1[CH:1]([CH3:3])[CH3:2])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccccc2OCc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(2-benzyloxybenzyl)-5-isopropyl-1,2-dihydropyrazol-3-one (114 mg) and acetobromo-α-D-glucose (173 mg) in acetonitrile (2 mL) was added silver carbonate (127 mg), and the mixture was stirred under shading the light at room temperature for 3 days. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate/hexane=1/1) to give 5-isopropyl-4-(2-benzyloxybenzyl)-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole. To a solution of 5-isopropyl-4-(2-benzyloxybenzyl)-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole in tetrahydrofuran (1 mL) and methanol (0.5 mL) was added sodium methoxide (28% methanol solution, 50 μL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (22 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23]>C(#N)C>[CH2:23]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:22][CH2:21][CH2:20][CH:19]=[CH2:18]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C=CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCCCCOc1ccc([N+](=O)[O-])cc1

Procedure:
To an acetonitrile (40 mL) solution of 4-nitrophenol (2.79 g; 20.0 mmol) and potassium carbonate (4.15 g; 30.1 mmol), 6-bromo-1-hexene (4.01 g; 24.6 mmol) was added, and the mixture was refluxed and then reacted for 12 hours. After completion of the reaction, the solution was filtrated by Celite, and then the filtrate was concentrated under a reduced pressure. The residue was purified by flash column chromatography using methylene chloride, and then the effluent was concentrated to obtain 4-(5-hexenyloxy)nitrobenzene (1b) (4.11 g, 93% of yield, a light yellow oil) represented by the following formula.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=2[OH:28])[CH2:12][N:13]([CH3:24])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:6]=[CH:7][CH:8]=1.C([O:35][C:36](=[O:41])[C:37](Br)([CH3:39])[CH3:38])(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH2:12][N:13]([CH3:24])[S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:25]=[CH:26][C:27]=2[O:28][C:37]([CH3:39])([CH3:38])[C:36]([OH:41])=[O:35])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CN(Cc1ccc(O)c(-c2cccc(C(F)(F)F)c2)c1)S(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(OC(C)(C)C(=O)O)c(-c2cccc(C(F)(F)F)c2)c1)S(=O)(=O)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 4.7 %

Procedure:
To a solution of N-(3-(3-trifluoromethylphenyl)-4-hydroxybenzyl)-4-fluoro-N-methylbenzenesulfonamide (36) (50.0 mg, 0.114 mmol, 1 eq) in DMF (3 mL) under argon, was added t-butyl-2-bromo-2-methylpropanoate (66.0 mg, 0.296 mmol, 2.6 eq) and potassium carbonate (31 mg, 0.224 mmol, 2 eq). The mixture was stirred at 80° C. for 16 h, cooled to room temperature and partitioned with saturated sodium bicarbonate and EtOAc. The organic layer was separated, dried (Na2SO4), and concentrated in vacuo. The crude residue was dissolved in TFA/DCM (1 mL/1 mL) and stirred at room temperature for 1 h. Solvent was removed in vacuo and the residue was purified via reversed phase semi-preparative HPLC to afford 2.8 mg of 2-(2-(3-trifluoromethylphenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)-2-methylpropanoic acid (Example 34). 1HNMR (CD3OD, 400 MHz): δ 7.91 (m, 3H), 7.88 (m, 1H), 7.61 (m, 2H), 7.35 (t, 2H), 7.27 (d, 2H), 6.90 (d, 1H), 4.20 (s, 2H), 2.67 (s, 3H), 1.46 (s, 6H). MS (ESI): MH+=526.1. HPLC (Method B) tR=2.53 min.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>C1(C)C=CC=CC=1>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:10][C:22]([NH:21][CH2:19][CH3:20])=[O:23])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Product: CCNC(=O)NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 42 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide (prepared in Example 13, 103 mg, 0.36 mmol) in toluene (10 mL) was treated with ethyl isocyanate (40 μL, 0.54 mmol). The resulting reaction mixture was heated under reflux for 24 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-ethyl-urea (54 mg, 42%) as a white foam: [α]23589=−41.9° (c=0.031, chloroform); FAB-HRMS m/e calcd for C17H22Cl2N2O2 (M+H)+357.1136, found 357.1137.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=O)[N:6]=[CH:5]2.[N:15]1[CH:16]=[CH:17][N:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]3)[C:19]=12.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[N:15]1[CH:16]=[CH:17][N:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:28][CH2:27][C@H:26]([NH:29][C:12]([C:7]4[N:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=5)[N:8]=4)=[O:14])[CH2:25]3)[C:19]=12
Reactant: N[C@H]1CCN(c2nccn3ccnc23)C1
Reactant: Cc1ccc2nc(C(=O)O)ncc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc2nc(C(=O)N[C@H]3CCN(c4nccn5ccnc45)C3)ncc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of 6-methylquinazoline-2-carboxylic acid (0.040 g, 0.21 mmol, 1.2 eq) and (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine (0.49 g, 0.18 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.10 mL, 0.7 mmol, 4 eq) and HATU (0.075 g, 0.20 mmol, 1.1 eq). After stirring for 1 h at room temperature, the mixture was concentrated and purified by HPLC to afford (S)—N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)-6-methylquinazoline-2-carboxamide (0.057 g, 0.15 mmol, 86%). 1H NMR (400 MHz, CD3OD) δ 9.48 (s, 1 H), 8.02 (d, J=1.6 Hz, 2 H), 7.98-7.88 (m, 3 H), 7.78 (s, 1 H), 7.17 (d, J=5.8 Hz, 1 H), 5.00-3.80 (br, 4 H), 2.60 (s, 3H), 2.65-2.40 (br, 2 H); MS: (ES) m/z calculated for C20H19N7O [M+H]+ 374.2, found 374.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[N:5]2[CH:15]=[CH:16][N:17]=[C:4]2[CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN(C=O)C>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=3)[N:5]3[CH:15]=[CH:16][N:17]=[C:4]3[CH:3]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: Cc1cc(Nc2nc(Cl)cc3nccn23)n[nH]1
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(N3CCN(C)CC3)cc3nccn23)n[nH]1
Temperature: 175 °C

Procedure:
Referring to Scheme 6, (7-Chloro-imidazo[1,2-c]pyrimidin-5-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (0.12 mol) and 1-methyl-piperazine (1.2 mol) were dissolved in DMF (0.3 mL). This solution was heated at between 150-200° C. for 1-25 minutes using a microwave reactor. Purification by preparative HPLC afforded the product as a solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.27 (s, 3H) 2.84 (s, 3H) 3.13 (bs, 2H) 3.32-3.49 (m, 4H) 4.41 (bs, 2H) 6.31 (s, 1H) 6.38 (s, 1H) 7.78 (d, J=2.53 Hz, 1H) 8.29 (d, J=2.27 Hz, 1H) 10.83 (s, 1H) 12.41 (s, 1H); ESI-MS: m/z 313.3 (M+H)+
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:7][C:8]#[N:9])C.[CH2:17](N)[CH2:18][NH2:19]>>[C:10]1([C:6]2[CH:7]=[C:8]3[NH:9][CH2:17][CH2:18][N:19]3[C:4](=[O:16])[CH:5]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NCCN
Reactant: CCOC(=O)CC(=CC#N)c1ccccc1
Product: O=c1cc(-c2ccccc2)cc2n1CCN2
Temperature: 160 °C

Procedure:
4-Cyano-3-phenyl-but-3-enoic acid ethyl ester (crude, 9.37 g, 0.043 mol), ethylenediamine (3 mL, 0.043 mol) were mixed in dichlorobenze (20 mL) and heated at 160° C. overnight. The resulting suspension was cooled to room temperature, filtered, and the filtrated cake was washed with EtOAc and finally dried to provide the title compound as a brownish yellow solid. MS m/e 213 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>O>[C:16]([N:1]1[CH2:9][CH:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:18])[CH3:17]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N1CC(O)C[C@H]1C(=O)O
Reaction time: 0.75 h
Yield: 64.4 %

Procedure:
A solution of 100 g (0.76 mol) of L-hydroxyproline and 540 ml of water is cooled to 10° and 297 ml (3.7 mol) of pyridine is added. The temperature is lowered to 5° and 151.2 ml (1.6 mol) of acetic anhydride is slowly added. The reaction is stirred at 0°-5° for 45 min and 81 ml (0.97 mol) of pyridine is added followed by 42.7 ml (0.45 mol) of acetic anhydride. The reaction is stirred overnight in an ice bath allowing the bath to come to room temperature. The reaction is evaporated and the residue is dissolved in ethanol and evaporated to an oily residue. This step is repeated a number of times, and the residue is dissolved in acetone, seeded, and cooled. The white crystals are filtered and recrystallized from ethanol-ether and dried under vacuum at 40° to give 84.8 g of N-acetyl-4-hydroxy-L-proline; [α]D23 -117° (cl, water).
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].C[O-].[Na+].[C:10]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O)([OH:12])=[O:11].CS(O)(=O)=O>CO>[CH3:3][O:2][P:1]([CH:15]1[C:14]2[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10](=[O:12])[O:11]1)(=[O:6])[O:4][CH3:5]
Reactant: COP([O-])OC
Reactant: O=Cc1ccccc1C(=O)O
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COP(=O)(OC)C1OC(=O)c2ccccc21
Temperature: 20 °C

Procedure:
Dimethyl phosphite (22.0 g, 0.2 mol) was added drop-wise to a solution of sodium methoxide (43.0 g) in methanol (100 ml) at 0° C. 2-Carboxybenzaldehyde (21.0 g, 0.1 mol) was then added portion-wise to the reaction mixture as a slurry in methanol (40 ml), with the temperature kept below 5° C. The resulting pale yellow solution was warmed to 20° C. over 1 hour. Methanesulphonic acid (21.2 g, 0.22 mol) was added to the reaction drop-wise and the resulting white suspension was evaporated in vacuo. The white residue was quenched with water and extracted into chloroform (3×100 ml). The combined organic extracts were washed with water (2×100 ml), dried over MgSO4, and evaporated in vacuo to yield (3-oxo-1,3-dihydro-isobenzofuran-1-yl)phosphonic acid dimethyl ester as a white solid (32.0 g, 95%, 95% purity). This was then used without further purification in the next stage.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3cncn3)nc3sc4c(c23)CCCC4)c1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O.[CH3:12][C:13]([CH3:15])=[O:14]>O.CCO>[Cl:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1/[CH:6]=[CH:12]/[C:13](=[O:14])/[CH:15]=[CH:6]/[C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[Cl:3]
Reactant: CC(C)=O
Reactant: O=Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(/C=C/c1ccccc1Cl)/C=C/c1ccccc1Cl
Yield: 67.8 %

Procedure:
A solution of NaOH (1.4 g, 142 mmol) in H2O (60 mL) and EtOH (60 mL) was added to a mixture of 2-chlorobenzaldehyde (8 mL, 72 mmol) in acetone (2.6 mL, 36 mmol). The reaction mixture was stirred for 1d at room temperature and the resulting precipitate was filtered, washed with H2O, recrystallized from EtOAc and dried in vacuo to obtain NW268 as a bright yellow solid (7.4 g, 69%). mp: 107-109° C. 1H NMR (250 MHz, CDCl3) δ (ppm): 8.15 (d, 3J=16.0 Hz, 2H, Hvin), 7.79-7.66 (m, 2H, HAr), 7.51-7.29 (m, 6H, HAr), 7.08 (d, 3J=16.0 Hz, 2H, Hvin). 13C NMR (75 MHz, CDCl3) δ (ppm): 188.7 (C), 139.3 (CH), 135.4 (C), 133.0 (C), 131.2 (CH), 130.2 (CH), 127.7 (CH), 127.5 (CH), 127.1 (CH). MS (FAB) m/z: 303.1 (M+). Anal. calcd for C17H12Cl2O: C, 67.35; H, 3.99; Cl, 23.39. Found: C, 67.09; H, 4.06; Cl, 22.65%.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:16][C@@H:15]([CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:29].[Na+]>CC(C)=O.OP(O)=O.O[Mo](O)(=O)=O>[CH2:1]([O:8][C@@H:9]1[CH2:16][C@@H:15]([CH2:17][I:29])[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CO[C@@H]1C[C@H](OCc2ccccc2)C[C@@H](COS(=O)(=O)c2ccc(C)cc2)O1
Agent: O=[Mo](=O)(O)O
Agent: O=[PH](O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: CO[C@@H]1C[C@H](OCc2ccccc2)C[C@@H](CI)O1
Reaction time: 24 h
Yield: 75.2 %

Procedure:
Methyl 3-O-benzyl-6-O-tosyl-2,4-dideoxy-α-D-erythro-hexopyranoside (3.0 g; 7.34 mmoles) and sodium iodide (13 g; 86.7 mmoles) are dissolved in acetone (130 ml). The resulting solution is refluxed under nitrogen and protected from the light for 24 hours. When tlc shows the reaction is complete (fluorosilica-methylene chloride, visualization with phosphomolybdic acid and heat), the acetone is evaporated in vacuo. The residue is partitioned between ether and water. The ether layer is washed with dilute aqueous sodium thiosulfate, then twice with water, dried (MgSO4), filtered, and the solvent is evaporated in vacuo to give crude product which is purified by flash chromatography on silica gel on a 60 mm×150 mm column. Elution with methylene chloride gives 2.0 g of methyl 3-O-benzyl-6-iodo-2,4,6-trideoxy-α-D-erythro-hexopyranoside. [α]D24 +53.45 (c, 0.66 CHCl3). Pmr (300 MHz) (DCCl3) δ1.52 (1H, m); 1.75 (1H, m); 1.95 (1H, m) 2.02 (1H, m); 3.21 (2H, m); 3.47 (3H, s); 3.78 (1H, m) 4.10 (1H, m); 4.56 (2H, q); 4.81 (1H, d); 7.24-7.42 (5H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[CH3:19][O:20][C:21](=[O:26])[CH2:22][C:23](Cl)=[O:24]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]([C:23](=[O:24])[CH2:22][C:21]([O:20][CH3:19])=[O:26])[CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)CC(=O)Cl
Reactant: COC(=O)c1cc(Cl)cn1NCc1cccnc1
Product: COC(=O)CC(=O)N(Cc1cccnc1)n1cc(Cl)cc1C(=O)OC

Procedure:
Prepared according to the acylation condition used in Example 2 step f) from 4-chloro-1-[(pyridin-3-ylmethyl)-amino]-1H-pyrrole-2-carboxylic acid methyl ester and chlorocarbonyl-acetic acid methyl ester (1.5 eq.). 1H NMR (CDCl3, δ in ppm): 8.55 (dd, 1H, J=1.8 Hz, 4.8 Hz), 8.34 (1H, J=2.2 Hz), 7.57 (m, 1H), 6.84 (d, 1H, J=2.2 Hz), 6.50 (d, 1.8 Hz), 5.29 (d, 1H, J=14.6 Hz), 4.45 (d, J=14.6 Hz), 3.76 (s, 3H), 3.69 (s, 3H), 3.19 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:11][C:12]1[CH:13]=[C:14]([C:27]2[C:28]([S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:15]=[CH:16][C:17]=1B1OC(C)(C)C(C)(C)O1>>[F:11][C:12]1[CH:13]=[C:14]([C:27]2[C:28]([S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:34])=[O:35])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:15]=[CH:16][C:17]=1[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3S(=O)(=O)NCCO)cc2F)OC1(C)C
Product: O=S(=O)(NCCO)c1ccccc1-c1ccc(-c2cnc3[nH]ccc3c2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 5-bromo-1H-pyrrolo[2,3-b]pyridine and 3′-fluoro-N-(2-hydroxyethyl)-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide. MS (ESI): mass calcd. for C21H18FN3O3S, 411.11; m/z found, 412.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.44-8.41 (m, 1H), 8.24-8.21 (m, 1H), 8.14-8.05 (dd, J=8.0, 1.3, 1H), 7.71-7.64 (m, 1H), 7.63-7.55 (m, 2H), 7.46-7.44 (d, J=3.5, 1H), 7.44-7.41 (dd, J=7.6, 1.2, 1H), 7.36-7.34 (dd, J=3.8, 1.7, 1H), 7.34-7.31 (dd, J=7.3, 1.4, 1H), 6.59-6.55 (d, J=3.5, 1H), 3.52-3.47 (t, J=5.9, 2H), 2.92-2.87 (t, J=5.9, 2H).
Reaction SMILES: C(=O)(O[CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)N.Cl>[OH-].[Na+]>[OH:22][C:7]1[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=[C:11]2[C:6]=1[C:5](=[CH2:4])[C:17]1([OH:19])[O:18][N:12]2[CH2:13][CH:14]2[CH:16]1[NH:15]2
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=C1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Temperature: 50 °C
Yield: 71 %

Procedure:
4-Formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (40 mg) was dissolved in 1N aqueous sodium hydroxide (4 ml) and the solution was heated at 50° C. for 100 minutes under argon atmosphere. The reaction mixture was cooled and neutralized with 1N aqueous hydrochloric acid (4 ml) and the resultant aqueous solution was lyophilized. The residue was subjected to a silica gel column chromatography and elution was carried out with a mixture of methanol and chloroform (1:4, v/v). The desired fractions were combined and then evaporated to dryness in vacuo to give 6,9-dihydroxy-8-methylene-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carbaldehyde (23 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:25][CH2:24][CH:23]([CH:26](OC)[O:27]C)[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[N:7]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([S:17]([N:20]3[CH2:25][CH2:24][CH:23]([CH:26]=[O:27])[CH2:22][CH2:21]3)(=[O:18])=[O:19])=[CH:15][CH:16]=2)[N:7]=1
Reactant: COC(=O)CCc1nc(-c2ccc(S(=O)(=O)N3CCC(C(OC)OC)CC3)cc2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCc1nc(-c2ccc(S(=O)(=O)N3CCC(C=O)CC3)cc2)no1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 223.1 %

Procedure:
The intermediate 3-[3-(4-{[4-(dimethoxymethyl)-1-piperidinyl]sulfonyl}-phenyl)-1,2,4-oxadiazol-5-yl]propanoic acid methyl ester(0.13 g, 0.22 mmol) was dissolved in 10 mL of CH2Cl2 containing 1 mL of TFA and stirred at ambient temperature for 45 minutes. The reaction mixture was concentrated in vacuo to an oil. The residue was partitioned with CH2Cl2 and sat'd NaHCO3. The organic base was dried (Na2SO4) and concentrated in vacuo to give the product (0.2 g) as a clear oil which was used as is.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[S:18][N:17]=[C:16]([CH3:19])[N:15]=1)=[O:12].F[C:29]1[CH:41]=[CH:40][C:32]2[C:33](=[O:39])[N:34]([CH3:38])[CH2:35][CH2:36][O:37][C:31]=2[CH:30]=1>CC(N(C)C)=O>[CH3:35][CH:36]1[N:34]([CH3:38])[C:33](=[O:39])[C:32]2[CH:40]=[CH:41][C:29]([O:7][C:8]3[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=3)[C:11]([NH:13][C:14]3[S:18][N:17]=[C:16]([CH3:19])[N:15]=3)=[O:12])=[CH:30][C:31]=2[O:37]1
Reactant: Cc1nsc(NC(=O)c2cc(O)cc(O[C@@H](C)CO)c2)n1
Reactant: CN1CCOc2cc(F)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1nsc(NC(=O)c2cc(Oc3ccc4c(c3)OC(C)N(C)C4=O)cc(O[C@@H](C)CO)c2)n1
Temperature: 160 °C
Yield: 64.4 %

Procedure:
Cesium carbonate (489 mg, 1.5 mmol) was added to a solution of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide (155 mg, 0.5 mmol) and 8-fluoro-4-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (117 mg, 0.6 mmol) in DMA (5 mL) and the stirred mixture heated at 160° C. in a microwave reactor for 8 hours. The mixture was cooled to RT and pressure, the DMA removed in vacuo, and the residue partitioned between water (25 mL) and ethyl acetate (30 mL). The mixture was adjusted to pH 2, the organic layer washed with brine, dried (MgSO4) and evaporated in vacuo to a residue which was chromatographed on silica, eluting with ethyl acetate, to give desired compound (156 mg). 1H NMR δ (CDCl3): 1.3 (d, 3H), 1.5 (d, 2H), 2.4 (s, 3H), 3.0 (s, 3H), 3.7 (d, 2H), 4.5 (m, 1H), 5.35 (q, 1H), 6.4 (s, 1H), 6.6 (d, 1H), 6.75 (s, 1H), 7.15 (s, 1H), 7.2 (s, 1H), 7.8 (d, 1H); m/z 485 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][CH:21]=[C:22]1[CH:26]=[CH:25][O:24][CH2:23]1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([N:20]=[CH:21][C:22]4[CH:26]=[CH:25][O:24][CH:23]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: NC=C1C=COC1
Product: Fc1cnc(N=Cc2ccoc2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-aminomethylenefurane were reacted to give N4-(3,4-ethylenedioxyphenyl)-N2-(3-furanylmethylene)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 19.99 min.; purity: 88.4%; MS (m/e): 343.07 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[CH:31]12[O:36][CH:35]1[CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]2>CCOC(C)=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:13]=[C:14]([O:16][CH:35]2[CH:31]([OH:36])[CH2:32][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]2)[CH:15]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cc(OC2CN(C(=O)OC(C)(C)C)CC2O)cc(-c2ccc(C)cc2C#N)c1
Temperature: 135 °C

Procedure:
A stirred mixture of methyl 2′-cyano-5-hydroxy-4′-methylbiphenyl-3-carboxylate (300 mg, 1.1 mol), potassium carbonate (320 mg, 2.4 mmol), DMSO (8 mL), and tert-butyl 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylate (2.4 mmol) (J. Am. Chem. Soc. 2008, 130, 3900) was heated at 135° C. overnight. After cooling, the reaction mixture was diluted with EtOAc. The organic phase was washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-50% EtOAc/hexane) to afford the title compound.