Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][OH:27])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:35](Cl)(=[O:39])[O:36][CH2:37][CH3:38]>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][O:27][C:35]([O:36][CH2:37][CH3:38])=[O:39])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)c1cc(-c2nn(CCO)c3ncccc23)cc(C(C)(C)C)c1O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)OCCn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a solution of 3.7 g of the compound of Example 43 in 20 ml of chloroform is added 1.5 g of triethylamine, and to the mixture with stirring at -10°--2° C. is added 1.4 g of ethyl chlorocarbonate dropwise. After completion of the addition, the whole mixture is stirred at 0° C. for 3 hours, and then at room temperature for 2 hours. The reaction solution is washed with water, dried and concentrated, and then the resulting residue is recrystallized from isopropyl ether to give 3.8 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1-(2-ethoxycarbonyloxyethyl)-1H-pyrazolo[3,4-b]-pyridine as white crystals, melting at 103°-105° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[C:6]=2[CH:5]=[CH:4]1.Br[CH2:15][C:16]([NH2:18])=[O:17].O>CN(C=O)C>[C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]2[CH2:15][C:16]([NH2:18])=[O:17])#[N:13]
Reactant: NC(=O)CBr
Reactant: N#Cc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc2c1ccn2CC(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of 60% NaH (12.38 g) in DMF (480 ml) was added a solution of 1H-indole-4-carbonitrile (40.0 g) in DMF (80 ml) at 0° C. After stirring at 0° C. for 30 min, it was stirred at room temperature for 0.5 hour. Thereafter, a solution of 2-bromoacetamide (40.76 g) in DMF (80 ml) was added dropwise thereto at 0° C. The solution was warmed from 0° C. to room temperature, and stirred for 12 hours. To the reaction solution was added water (1200 ml), and the precipitated white solid was collected by filtration. The solution was washed with hot water (300 ml) and diisopropyl ether (200 ml) to obtain 2-(4-cyano-1H-indol-1-yl)acetamide (52.1 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH:24]=O)=[CH:19][C:18]=3[CH3:26])[CH:13]=[CH:12][C:11]=2[O:27][CH3:28])=[CH:5][N:4]=1.[C:29]([NH:32][CH2:33][C:34]([OH:36])=[O:35])(=O)[CH3:30].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[CH3:30][C:29]1[O:36][C:34](=[O:35])[C:33](=[CH:24][C:20]2[CH:21]=[C:22]([CH3:23])[C:17]([O:16][C:14]3[CH:13]=[CH:12][C:11]([O:27][CH3:28])=[C:10]([CH2:9][C:6]4[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[CH:15]=3)=[C:18]([CH3:26])[CH:19]=2)[N:32]=1
Reactant: CC(=O)NCC(=O)O
Reactant: COc1ccc(Cc2cc(Oc3c(C)cc(C=O)cc3C)ccc2OC)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(Cc2cc(Oc3c(C)cc(C=C4N=C(C)OC4=O)cc3C)ccc2OC)cn1
Yield: 62.8 %

Procedure:
2-Methoxy-5-(2-methoxy-5-(2,6-dimethyl-4-formyl- phenoxy)benzyl)-pyridine (10.84 g), N-acetylglycine (5.38 g), sodium acetate (3.77 g) and acetic anhydride (70 ml) were stirred at 100°+5°, (oil bath temperature) for 24 hours. The solution was cooled and evaporated to leave a brown gum which was triturated with water, then with methanol to afford 2-methyl-4-(3,5-dimethyl-4-(4-methoxy3-(6-methoxy-3-pyridylmethyl)-phenoxy)-benzal)-5-oxazolone as a yellow solid (8.27 g, 64%), m.p. 164°-165°.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1C=O.ClC1C=CC=C([C:20]([O:22]O)=[O:21])C=1>C(Cl)Cl>[CH:20]([O:22][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[O:4][CH2:3][CH2:2][F:1])=[O:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1ccccc1OCCF
Solvent: ClCCl
Product: O=COc1ccccc1OCCF
Yield: 62 %

Procedure:
In a manner similar to that disclosed by Godfrey et al., (J. Chem. Soc. Perkin I, 1353-1354 (1974), the reaction of 10.0 grams (0.06 mole) of 2-(2-fluoroethoxy)benzaldehyde with 3-chloroperbenzoic acid (15.5 grams of 80-85% assay, 0.075 mole) in 250 ml of methylene chloride yielded 6.85 grams of 2-(2-fluoroethoxy)phenyl formate as an oil.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[C:23]([F:24])=[CH:22][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=2)=[O:13])=[C:10](F)[CH:9]=1.[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[OH:34]>CN(C=O)C>[Cl:7][C:8]1[C:23]([F:24])=[CH:22][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=2)=[O:13])=[C:10]([O:34][C:28]2[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=2[Cl:26])[CH:9]=1
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1cc(F)c(Cl)cc1F
Reactant: Oc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1cc[nH]c(=O)c1)c1cc(F)c(Cl)cc1Oc1ccc(F)cc1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
Cs2CO3 (244.4 mg, 0.75 mmol) was added to a solution of 4-chloro-2,5-difluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (71.2 mg, 0.25 mmol) and 2-chloro-4-fluorophenol (109.9 mg, 0.75 mmol) in DMF (2 mL) and the reaction was stirred at 100° C. for 1 hours. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield 4-chloro-2-(2-chloro-4-fluorophenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (109) (22.8 mg, 27%). ESI-MS m/z calc. 410.00. found 411.2 (M+1)+; Retention time: 1.76 minutes (3 minutes run).
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([CH2:10][CH2:11][CH3:12])=[N:7][C:6]=1[CH2:13][CH3:14])([O:3][CH3:4])=[O:2].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[C:18]([F:24])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:9]2[C:5]([C:1]([O:3][CH3:4])=[O:2])=[C:6]([CH2:13][CH3:14])[N:7]=[C:8]2[CH2:10][CH2:11][CH3:12])=[C:18]([F:24])[CH:17]=1
Reactant: CCCc1nc(CC)c(C(=O)OC)[nH]1
Reactant: Fc1cc(Br)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(CC)c(C(=O)OC)n1Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Carbomethoxy-4-ethyl-2-n-propylimidazole (U.S. Pat. No. 5,137,902) (10.62 g, 54 mmol, 1 eq), 1-bromo-4-bromomethyl-3-fluorobenzene (19.58 g, 54 mmol, 1 eq), potassium carbonate (7.48 g, 54 mmol, 1 eq), and DMF (200 mL) were mixed and stirred overnight at room temperature. Ethyl acetate was added (500 mL) and the mixture was washed with water (3×300 mL). The ethyl acetate layer was dried (MgSO4), and the solvent removed in vacuo to yield 25.42 g of an oil. Flash chromatography in 75:25 to 65:35 hexanes/ethyl acetate yielded 13.65 g of product as an amber oil. NMR (CDCl3) δ 7.35-7.22 (m, 1H); 7.22-7.10 (m, 1H); 6.45 (t, 1H, J=7Hz); 5.49 (s, 2H); 3.78 (s, 3H); 2.90 (q, 2H, J=7Hz); 2.59 (t, 2H, J=7Hz); 1.70 (t of q, 2H, J=7,7Hz); 1.35-1.15 (m, 3H); 0.95 (t, 3H, J=7Hz). ##STR48##
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH2:17]O)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH2:17][N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2CO)CC1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CN1CCN(Cc2cc([N+](=O)[O-])ccc2N2CCN(C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To [2-(4-methylpiperazin-1-yl)-5-nitrophenyl]methanol (0.150 g, 0.60 mmol) in 5 mL of THF at 0° C. was added thionyl chloride (0.22 mL, 5 eq). The reaction mixture was refluxed for 45 minutes and then the solvent and the excess of thionyl chloride were evaporated. The residue was suspended in 5 mL of acetonitrile and 1-methylpiperazine (0.33 mL, 5 eq) was added at 0° C. The solution was stirred overnight at room temperature, evaporated and the residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of Na2CO3. The aqueous layer was extracted with ethyl acetate and then the combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was thoroughly washed with pentane and filtered off to yield expected compound as an orange powder (0.185 g, 92% yield).
Reaction SMILES: Cl.[NH2:2][OH:3].O.C(=O)([O-])O.[Na+].[CH3:10][C:11]([S:16][C:17]#[N:18])([CH3:15])[C:12](=O)[CH3:13]>C(O)C>[N:2](=[C:17]1[N:18]=[C:12]([CH3:13])[C:11]([CH3:15])([CH3:10])[S:16]1)[OH:3]
Reactant: CC(=O)C(C)(C)SC#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1=NC(=NO)SC1(C)C
Temperature: 25 °C

Procedure:
8.3 g. (0.12 mol) of hydroxylamine hydrochloride were dissolved in 50 ml. of water and treated with 10.1 g. (0.12 mol) of sodium hydrogen carbonate. This solution (pH 6-7) was added with stirring at room temperature to a solution of 14.3 g. (0.1 mol) of 3-methyl-3-thiocyanato-2-butanone in 100 ml. of ethanol. The temperature of the mixture rose rapidly to 37° C. The mixture was then stirred for 1 hour, 120 ml. of the solvent were then distilled off at 50° C. in vacuo. The residue was extracted three times with 100 ml. of ether each time. The organic phase was washed with a small amount of water, dried over sodium sulfate and concentrated until crystallization began. After cooling, the crystal sludge was treated with 10 ml. of hexane. The crystals were filtered off under suction, washed with ether/hexane (2:1) and dried to yield 2-oxo-4,5,5-trimethyl-3-thiazoline-oxime, m.p. 151°-153° C.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.[OH:29][C@@H:30]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43](O)[CH:42]=1)[CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>>[O:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[CH2:17][CH:13]1[CH2:12][O:11][C:43]1[CH:42]=[C:41]([C@H:30]([OH:29])[CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH:46]=[CH:45][CH:44]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccccc3O2)cc1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2Cc3ccccc3O2)c1

Procedure:
Reaction between ((2,3-dihydrobenzofuran-2-yl)methyl 4-methylbenzenesulfonate and phenol (7, Intermediate I) following the method used in Example 12 gave tert-butyl ((3R)-3-(3-((2,3-dihydrobenzofuran-2-yl)methoxy)phenyl)-3-hydroxypropyl)carbamate as a white solid. Yield (65%); 1H NMR (400 MHz, CDCl3): δ 7.24-7.18 (m, 2H), 7.12 (t, J=8 Hz, 1H), 6.94 (t, J=8.4 Hz, 2H), 6.88-6.81 (m, 3H), 5.16-5.13 (m, 1H), 4.87 (s, 1H), 4.71 (s, 1H), 4.20 (dd, J=10.0, 6.8 Hz m, 1H), 4.10 (dd, J=6.0, 4.8 Hz, 1H), 3.41 (s, 1H), 3.39-3.35 (m, 1H), 3.25 (s, 1H), 3.17-3.11 (m, 2H), 1.85-1.80 (m, 2H), 1.45 (s, 9H); MS: m/z 400 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][NH2:15])([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CN)(c2ccc(Cl)cc2)CC1
Yield: 71.7 %

Procedure:
To a solution of 4-(4-chlorophenyl)-4-cyanopiperidin-1-carboxylic acid tert-butyl ester (0.355 g, 1.107 mmol) in ethanol (20 ml) at room temperature was added Raney Nickel (Raney Nickel 2800, 1 ml) and the suspension stirred under 1 atmosphere of hydrogen for 20 hours. The suspension was filtered through celite and the filtrate concentrated to give the amine as an oil (0.258 g, 69%). LC/MS: (LCT) Rt 5.02 [M—But—NH2]+ 324.
Reaction SMILES: Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[NH2:25][C:26]([NH2:28])=[O:27]>CN(C=O)C>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:25]=[C:26]([NH2:28])[O:27][C:2]=1[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1
Reactant: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Reactant: NC(N)=O
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(-c3oc(N)nc3-c3ccc(F)cc3F)nn12
Temperature: 100 °C
Yield: 4 %

Procedure:
2-Bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.500 g, 1.26 mmol, Preparation #A.2) and urea (0.228 g, 3.80 mmol) were added to DMF (5 mL) then heated at about 100° C. for about 2 h. The mixture was cooled to ambient temperature then purified by RP-HPLC (Table 1, Method f). Concentration under reduced pressure of most of the organic solvent resulted in a precipitate which was collected by filtration and dried to give the title compound (0.018 g, 4%): LC/MS (Table 1, Method b) Rt=1.96 min; MS m/z: 357.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=4)[CH2:25][CH2:24]3)[N:21]=[CH:22][C:15]=12.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=4)[CH2:27][CH2:28]3)[N:21]=[CH:22][C:15]=12
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Reactant: CC(C)c1noc(N2CCC(n3ncc4c(Cl)ncnc43)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5F)ncnc43)CC2)n1
Temperature: 180 °C
Yield: 13.3 %

Procedure:
A mixture of 2-fluoro-4-methanesulfonyl-phenol (Intermediate 1; 20 mg, 0.1 mmol), 4-chloro-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 22; 31 mg, 0.09 mmol) and potassium carbonate (14 mg, 0.1 mmol) in DMF (2 mL) was heated in a Biotage Optimizer microwave at 180° C. for 10 min. The mixture was cooled and filtered through Celite, concentrated and held under vacuum. The residue was purified on a silica column (ISCO 4 g) eluting with 0-3% methanol/dichloromethane to give 4-(2-fluoro-4-methanesulfonyl-phenoxy)-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (6 mg, 14%). Mass spectrum (ES) MH+=502.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][N:27]=[C:26]3[CH3:30])=[CH:21][CH:20]=2)[CH:5]=[C:6]([C:8]2([C:14]([NH2:16])=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32].C(=O)(O)[O-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][N:27]=[C:26]3[CH3:30])=[CH:21][CH:20]=2)[CH:5]=[C:6]([C:8]2([C:14](=[S:32])[NH2:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: Cc1nccn1-c1ccc(COc2cc(F)cc(C3(C(N)=O)CCOCC3)c2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nccn1-c1ccc(COc2cc(F)cc(C3(C(N)=S)CCOCC3)c2)cc1
Temperature: 40 °C

Procedure:
To a stirred solution of 4-[5-fluoro-3-[4-(2-methylimidazol-1-yl)benzyloxy]-phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (Example 5) in THF (10 ml) was added phosphorus pentasulfide (236 mg, 0.53 mmol) and sodium bicarbonate (176 mg, 2.1 mmol). The resulting mixture was heated at 40° C. for 4 hr. The mixture was concentrated in vacuo. To the residue was added water (100 ml) and the mixture was extracted with dichloromethane (2×100 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified on column chromatography (LiChropprep --NH2) and then by p-TLC eluting with dichloromethane-methanol (10:1) to afford 38 mg of the titled compound as white solids.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[B:18]1[O:19][C:20]([CH3:26])([CH3:25])[C:21]([CH3:24])([CH3:23])[O:22]1
Reactant: Cc1cccc(CBr)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1NCc1cccc(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 2.09 g (19.5 mmol) of 2-methylaniline, 4.00 g (13.0 mmol) of 2-[2-(bromomethyl)-6-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 1.97 g (14.3 mmol) of K2CO3 in 75 ml of DMF was stirred for 12 h at the 80° C. The resulting mixture was poured into 300 ml of water. The product was extracted with 3×50 ml of ethyl acetate. The combined extract was dried over Na2SO4 and then evaporated to dryness. An excess of 2-methylaniline was distilled off using Kugelrohr apparatus. The residue was re-crystallized from 20 ml of hexane. Yield 2.60 g (59%) of light-yellow powder. Anal. calc. for C21H28BNO2: C, 74.79; H, 8.37; N, 4.15. Found: C, 74.95; H, 8.52; N, 3.95. 1H NMR (CDCl3): δ 7.22 (m, 1H, 3-H in 6-MeC6H3CH2), 7.16 (m, 1H, 3-H in 6-MeC6H3CH2), 7.12 (m, 1H, 5-H in 2-MeC6H4), 7.09 (m, 1H, 5-H in 6-MeC6H3CH2), 7.04 (m, 1H, 3-H in 2-MeC6H4), 6.71 (m, 1H, 6-H in 2-MeC6H4), 6.66 (m, 1H, 4-H in 2-MeC6H4), 4.34 (d, J=25.3 Hz, 1H, CHH′NH), 4.27 (d, J=25.3 Hz, 1H, CHH′NH), 3.85 (br.s, 1H, NH), 2.46 (s, 3H, Me in 6-MeC6H3CH2), 2.11 (s, 3H, Me in 2-MeC6H4), 1.25 (s, 12H, Bpin).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:23]([OH:25])=[O:24])[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[C:26]([O:32][CH2:33]Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[NH2:22][S:19]([C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:23]([O:25][CH2:33][O:32][C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:31])=[O:24])(=[O:21])=[O:20]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNc1cc(C(=O)OCOC(=O)C(C)(C)C)cc(S(N)(=O)=O)c1Oc1ccccc1
Temperature: 50 °C
Yield: 41.5 %

Procedure:
Bumetanide (1.2 g, 3.29 mmol) was dissolved in dimethylformamide (DMF, 10 mL) and chloromethyl pivalate (575 uL, 3.9 mmol) was added followed by triethylamine (0.70 mL) and sodium iodide (545 mg, 3.6 mmol). The reaction was heated to 50° C. for 10 hours, at which time TLC and LC/MS indicated the reaction was complete. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate, water and brine, and dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure and the product was purified via flash chromatography to yield 653 mg (60%) of pure t-butylcarbonyloxymethyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzoate.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH2:9][CH2:8][C:7]3[S:10][C:11]([NH:13][C:14]([CH:16]4[C:18]([CH3:20])([CH3:19])[C:17]4([CH3:22])[CH3:21])=[O:15])=[N:12][C:6]=3[C:5]=12.CC(C)([O-])C.[K+].[CH3:29][O:30][CH2:31][CH2:32]Br>COCCOC.CCOC(C)=O>[CH3:29][O:30][CH2:31][CH2:32][N:12]1[C:6]2[C:5]3=[N:1][O:2][N:3]=[C:4]3[CH2:9][CH2:8][C:7]=2[S:10]/[C:11]/1=[N:13]\[C:14]([CH:16]1[C:18]([CH3:20])([CH3:19])[C:17]1([CH3:22])[CH3:21])=[O:15]
Reactant: COCCBr
Reactant: CC1(C)C(C(=O)Nc2nc3c(s2)CCc2nonc2-3)C1(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COCCn1c2c(s/c1=N\C(=O)C1C(C)(C)C1(C)C)CCc1nonc1-2
Temperature: 250 °C

Procedure:
The product of Example 123B (1 equiv), potassium tert-butoxide (1.1 equiv) and 2-bromoethyl methyl ether (1 equiv) were combined in DME (0.1 M) and heated in a SmithSynthesizer™ microwave at 250° C. for 15 minutes. The mixture was diluted with EtOAc and washed with 1 M aqueous NaHCO3. The phases were separated and the aqueous phase was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography afforded the title compound and the product of Example 124. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (s, 6H), 1.26 (s, 6H), 1.57 (s, 1H), 3.10 (t, J=7.5 Hz, 2H), 3.23 (s, 3H), 3.26 (t, J=7.4 Hz, 2H), 3.71 (t, J=5.8 Hz, 2H), 4.67 (t, J=5.8 Hz, 2H); MS (ESI+) m/z 377 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)[OH:4].[H-].[Na+].[NH2:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[C:25]([Cl:30])[N:24]=1>C1COCC1>[Cl:30][C:25]1[CH:26]=[C:27]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[C:2]([F:18])([F:19])[F:1])[N:28]=[C:23]([NH2:22])[N:24]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1cccc(-c2ccccc2C(O)C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 72.2 %

Procedure:
2,2,2-Trifluoro-1-(3′-methylbiphenyl-2-yl)ethanol (0.15 g, 0.563 mmol) was treated with NaH (60% in mineral oil, 45 mg, 1.12 mmol) in dry THF (5 ml) for 30 minutes. 2-Amino-4,6-dichloropyrimidine (92 mg, 0.5633 mmol) was added and the mixture was stirred at 50° C. for 6 hours. The mixture was quenched with water and extracted with methylenechloride (2×). The organics were combined, washed with water, then brine, dried over MgSO4, and concentrated to give 0.16 g of 4-chloro-6-(2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethoxy)pyrimidin-2-amine.
Reaction SMILES: [CH3:1][N:2]([CH2:17][CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1)[CH2:19][CH2:20]S(C)(=O)=O)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1.I.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][N:43]1[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[N:45]=[C:44]1[C:52]([CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1)=[O:53]>>[CH3:1][N:2]([CH2:17][CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1)[CH2:19][CH2:20][N:57]1[CH2:58][CH2:59][CH:54]([C:52]([C:44]2[N:43]([CH2:42][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=3)[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=3[N:45]=2)=[O:53])[CH2:55][CH2:56]1)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1
Reactant: COc1cc(C(=O)N(C)CC(CCS(C)(=O)=O)c2cccc(C(F)(F)F)c2)cc(OC)c1OC
Reactant: O=C(c1nc2ccccc2n1Cc1ccccn1)C1CCNCC1
Agent: I
Product: COc1cc(C(=O)N(C)CC(CCN2CCC(C(=O)c3nc4ccccc4n3Cc3ccccn3)CC2)c2cccc(C(F)(F)F)c2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(3-trifluoromethylphenyl)-4-methanesulfonylbutyl)-3,4,5-trimethoxybenzamide and 4-(1-(pyrid-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine hydriodic acid salt to give the title compound.