Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=1[O:17][CH2:18][CH:19]([OH:24])[CH2:20][N:21]([CH3:23])[CH3:22])#[N:4].Cl>C(O)C.C(Cl)Cl>[CH3:23][N:21]([CH3:22])[CH2:20][CH:19]([OH:24])[CH2:18][O:17][C:16]1[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([NH2:4])=[O:1]
Reactant: CN(C)CC(O)COc1ccccc1CCCCc1ccccc1C#N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CN(C)CC(O)COc1ccccc1CCCCc1ccccc1C(N)=O
Yield: 52.7 %

Procedure:
2 ml of an aqueous solution containing 1 g of sodium hydroxide were added to a solution of 430 mg of 1-{2-[4-(2-cyanophenyl)butyl]phenoxy}-3-dimethylamino-2-propanol [prepared as described in Example 9(b)] in 5 ml of ethanol, and the resulting mixture was heated under reflux for 15 hours. At the end of this time, the reaction mixture was neutralized by the addition of aqueous hydrochloric acid, after which it was concentrated by evaporation under reduced pressure. The resulting residue was mixed with ethanol, and insoluble materials were filtered off. The filtrate was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of methylene chloride and methanol as the eluent, to give a colorless oily material, which was dissolved in a small amount of methylene chloride and then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 238 mg (yield 62%) of the title compound as colorless crystals, melting at 149°-151° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][C:20]1=[C:28]([C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1)=[O:40])[C:29]([C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH:34]=O)=[O:30].C1(P(=O)(C2C=CC=CC=2)[CH2:55][C:56]([F:59])([F:58])[F:57])C=CC=CC=1>C1COCC1>[NH:21]1[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:19][C:20]1=[C:28]([C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[C:33](/[CH:34]=[CH:55]\[C:56]([F:59])([F:58])[F:57])[CH:32]=1)=[O:30])[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1)=[O:40]
Reactant: O=Cc1cccc(C(=O)C(C(=O)c2cccc(F)c2)=C2Nc3ccccc3N2)c1
Reactant: O=P(CC(F)(F)F)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(C(C(=O)c1cccc(/C=C\C(F)(F)F)c1)=C1Nc2ccccc2N1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.2 %

Procedure:
A 25 ml portion of THF solution containing 7.8 g of tetrabutylammonium fluoride and 24 g of Molecular Sieve 4A was stirred at room temperature for 12 hours in an atmosphere of argon. After cooling to 0° C., 20 ml of THF solution containing 300 mg of 3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]benzaldehyde and 1.7 g of diphenyl(2,2,2-trifluoroethyl)phosphine oxide was added dropwise thereto. This was stirred at room temperature for 5 hours. The reaction mixture was filtered, the filtrate was washed with water, dried with anhydrous sodium sulfate and concentrated, and then the thus formed residue was purified by a silica gel column chromatography to obtain 201 mg (57%) of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-{3-[(1Z)-3,3,3-trifluoroprop-1-en-1-yl]phenyl}propane-1,3-dione as a yellow powder from an ethyl acetate-hexane (1:3) eluate. FA: 463
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH:27]([CH3:28])[CH3:29])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)Oc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)Oc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-isopropoxy-1H-pyrrolo[2,3-b]pyridine (236 mg, 0.55 mmol) and 10% palladium on activated carbon (40 mg) in methanol (200 mL) was heated at 50° C. under 50 bar of hydrogen in a steel bomb pressure for 6 h. The mixture was cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-isopropoxy-1H-pyrrolo[2,3-b]pyridine (180 mg, 76%) as a white solid: LC/MS m/e calcd for C24H30N2O3S [M+H]+ 427.58, observed 427.2; 1H NMR (400 MHz, CD3OD) δ ppm 7.88-7.92 (m, J=8.3 Hz, 2H), 7.81 (d, J=2.3 Hz, 1H), 7.58-7.63 (m, J=8.3 Hz, 2H), 7.51 (d, J=2.5 Hz, 1H), 6.33 (s, 1H), 4.53 (dt, J=12.1, 6.1 Hz, 1H), 4.30 (t, J=7.8 Hz, 1H), 3.10 (s, 3H), 2.24-2.32 (m, 1H), 2.07-2.15 (m, 1H), 1.61-1.88 (m, 5H), 1.46-1.57 (m, 2H), 1.18-1.35 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:27]=[C:26]([CH3:28])[N:25]([CH3:29])[N:24]=1>>[CH3:29][N:25]1[C:26]([CH3:28])=[CH:27][C:23]([CH2:22][N:15]2[CH2:16][C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:20])[CH:12]=3)[C:14]2=[O:19])=[N:24]1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Cc1cc(CBr)nn1C
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cc(C)n(C)n3)C2=O)cn1
Yield: 22 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 3-(bromomethyl)-1,5-dimethyl-1H-pyrazole. Yield: 22%. MS M+H calculated 384.1. found 384.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.3 uM
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[CH:5]=[N:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.CS(O[CH2:35][CH2:36][CH:37]1[CH2:39][C:38]1([F:41])[F:40])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:40][C:38]1([F:41])[CH2:39][CH:37]1[CH2:36][CH2:35][O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:7]3[N:6]=[CH:5][C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])=[CH:3][C:2]=3[F:1])[O:9][C:10]=2[CH:16]=1
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(O)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCCC1CC1(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](COc1cnc(-c2nc3ccc(OCCC4CC4(F)F)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Triethylamine (14.1 mL) was added to a solution of hexachloroethane (7.46 g) and triphenylphosphine (9.91 g) in acetonitrile (50 mL) at room temperature, and the mixture was stirred at room temperature for 10 min. Then a mixture of tert-butyl [(1S)-2-({6-[(2,4-dihydroxyphenyl)carbamoyl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate (5.31 g) and acetonitrile (50 mL) was added, and the mixture was stirred at room temperature for 2 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give tert-butyl [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (10.7 g) as a mixture with impurities. A mixture of tert-butyl [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (4.28 g, a mixture with impurities), 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (0.531 g), potassium carbonate (0.367 g), and DMF (30 mL) was stirred at 60° C. for 1 hr. Then additional 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (0.531 g) and potassium carbonate (0.367 g) were added, and the mixture was stirred at 60° C. for 1 hr. Then additional 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (1.06 g) and potassium carbonate (0.733 g) were added, and the mixture was stirred at 60° C. for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.83 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:11]=2[F:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C([O-])([O-])=O.[Cs+].[Cs+]>CC(=O)CC.O>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:11]=2[F:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: Cc1cc(CNc2c(F)ccc(O)c2F)c(F)c(-c2cccc(F)c2)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(C)cc(-c3cccc(F)c3)c2F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]phenol (100 mg, 0.30 mmol, 1.0 eq) and Na2CO3 (58 mg, 0.60 mmol, 2.0 eq) in 2-butanone (10 mL) was added ethyl bromoacetate (75.1 mg, 0.45 mmol, 1.5 eq). The mixture was stirred at room temperature for 3 h. TLC showed the reaction to be incomplete so Cs2CO3 (50 mg, 0.15 mmol, 0.5 eq) was added and the reaction stirred a further 3 h. TLC showed the reaction was still not finished so ethyl bromoacetate (0.2 mL) was added and the reaction stirred for a further 1 h. The solution was then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as a solid (100 mg, 81%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[F:52][B-](F)(F)F>ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[F:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: FC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of 2,3,4,6-tetra-O-benzyl-D-glucopyranose (100 mg, 0.18 mmol) and DBU (44 μL, 0.28 mmol) in dichloromethane (0.5 mL) is added diethylaminodifluorosulfinium tetrafluoroborate (68 mg, 0.28 mmol) at room temperature and under nitrogen. After 90 min of stirring, the reaction mixture is quenched at room temperature with a 5% aqueous sodium bicarbonate solution, stirred for 15 min, and the resulting mixture is extracted twice using dichloromethane. The organic phases are combined, dried over magnesium sulfate and filtered through a pad of silica gel. Solvents are evaporated to provide 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl fluoride (96 mg, 96%, β:α anomers in a 1.1:1 ratio respectively) as a foam. 1H NMR (CDCl3, 300 MHz) δ 7.47-7.15 (m, 20H), 5.61 (dd, 2JH-F=53.2 Hz, 3JH-H=2.3 Hz, 0.48H, α-anomer), 5.31 (dd, 2JH-F=51.8 Hz, 3JH-H=6.4 Hz, 0.52H, β-anomer), 5.07-4.48 (m, 8H), 4.11-3.54 (m, 6H); 19F NMR (CDCl3, 282 MHz) δ −138.0 (dd, 1JF-H=53.4 Hz, 2JF-H=10.6 Hz, β-F), −149.44 (dd, 1JF-H=54.4 Hz, 2JF-H=25.8 Hz, α-F); 13C NMR (CDCl3, 75 MHz) δ 138.5, 138.3, 138.1, 137.9, 137.5, 128.6, 128.5, 128.2, 128.1, 128.0, 127.9, 127.8, 112.8 (d, 1JC-F=215.2 Hz, β-anomer), 108.6 (d, 1JC-F=228.7 Hz, α-anomer), 83.6, 83.4, 81.7, 81.5, 81.4, 79.5, 79.2, 77.5, 77.1, 77.0, 77.7, 75.9, 75.5, 75.2, 75.0, 74.9, 74.8, 74.5, 73.6, 73.5, 72.7, 68.4, 67.8.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10](O)=[O:11])[C:6]=1[CH3:7].[CH3:44][C:45]1([CH3:55])[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:48][NH:47][CH2:46]1>>[CH2:39]([N:34]([CH2:35][CH2:36][CH2:37][CH3:38])[C:33]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:20])=[O:21])=[CH:13][C:9]=2[C:10]([N:47]2[CH2:46][C:45]([CH3:55])([CH3:44])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH2:48]2)=[O:11])[N:4]=1)=[O:43])[CH2:40][CH2:41][CH3:42]
Reactant: CC1(C)CNCc2ccccc21
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C(C)(C)C2)c(C)c1Cl
Yield: 35.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 93B, 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 91F, 32 mg, 0.051 mmol) and 4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline (Milestone Pharmtech, 9 mg, 0.056 mmol) were converted to the title compound (14 mg, 34%) following purification by preparative HPLC. 1H NMR (DMSO-d6, 1:1 mixture of amide rotamers) δ 8.64 (s, 1H), 8.20 (d, J=7.7 Hz, 1H), 8.14-7.90 (m, 5H), 7.78-7.59 (m, 3H), 7.36 (t, J=7.7 Hz, 1H), 7.26-7.13 (m, 2H), 7.11-7.02 (m, 0.5H), 6.99-6.89 (m, 0.5H), 4.85-4.20 (m, 2H), 3.58 (br s, 0.5H), 3.51-2.98 (m, 5H), 2.57-2.52 (m, 0.5H), 2.24 (s, 1.5H), 2.18 (s, 1.5H), 1.43-0.94 (m, 14H), 0.82 (t, J=7.3 Hz, 1H), 0.74 (t, J=7.3 Hz, 2H), 0.69 (t, J=7.4 Hz, 1.5H), 0.64 (t, J=7.4 Hz, 1.5H); MS(ESI+) m/z 768.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=12.[CH2:21]([NH:25][C:26]([C:28]1[C:32]2[CH:33]=[CH:34][C:35]([OH:37])=[CH:36][C:31]=2[O:30][C:29]=1[CH3:38])=[O:27])[CH:22]([CH3:24])[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:21]([NH:25][C:26]([C:28]1[C:32]2[CH:33]=[CH:34][C:35]([O:37][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][CH:14]5[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=34)=[CH:36][C:31]=2[O:30][C:29]=1[CH3:38])=[O:27])[CH:22]([CH3:24])[CH3:23]
Reactant: Cc1oc2cc(O)ccc2c1C(=O)NCC(C)C
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COCC1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)NCC(C)C)c(C)oc4c3)c2s1

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-2-methoxymethylpyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 2a with 6-hydroxy-2-methyl-benzofuran-3-carboxylic acid isobutyl amide 84b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (CD3CN) δ 8.53 (1H,d, J=5.3 Hz), 7.87 (1H, s), 7.82 (1H, d, J=8.5 Hz), 7.41 (1H, d, J=1.9 Hz), 7.20 (1H, dd, J=8.5, 1.9 Hz), 6.70 (1H, d, J=5.5 Hz), 4.38 (1H, m), 3.85 (2H, m), 3.65–3.41 (2H, m), 3.32 (3H, s), 3.23 (2H, t, J=6.4 Hz), 2.65 (3H, s), 2.15–1.94 (4H,m, partially obscured by CD3CN), 1.73 (1H, m),
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:21]#[N:22])[N:5]([CH3:20])[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:23][Sn](C)(C)C.O>CN(P(N(C)C)(N(C)C)=O)C>[CH3:17][C:12]1([CH3:18])[C:11]2[CH:19]=[C:7]([C:6]3[N:5]([CH3:20])[C:4]([C:21]#[N:22])=[CH:3][C:2]=3[CH3:23])[CH:8]=[CH:9][C:10]=2[NH:15][C:14](=[O:16])[O:13]1
Reactant: C[Sn](C)(C)C
Reactant: Cn1c(C#N)cc(Br)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cc(C#N)n(C)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Yield: 60.9 %

Procedure:
A solution of 4-bromo-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile (70 mg, 0.2 mmol), PhCNPdCl(PPh3)2 (cat., 7 mg) and tetramethyltin (10 eq, 0.35 g, 2 mmol) in HMPA (3 mL) was heated to 110° C. for 5 days. The solution was allowed to cool, poured into water (20 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layer was washed with brine, dried over MgSO4 and purified by flash column chromatography on silica gel eluting with 30% ethyl acetate/hexane to give 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,4-dimethyl-1H-pyrrole-2-carbonitrile (36 mg, 63%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 1.64 (s, 6H), 1.97 (s, 3H), 3.56 (s, 3H), 6.87 (s, 1H), 7.00 (d, 2H, J=8.1 Hz), 7.28 (dd, 1H, J=8.1, 1.6 Hz), 7.32 (s, 1H), 10.40 (s, 1H) MS (ESI (−)) 294 (M−H)−. Anal. calcd for C17H17N3O2, C, 69.1, H, 5.8, N,14.2. Found, C, 69.1, H, 5.72, N, 14.0.
Reaction SMILES: O=[C:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:3][NH:4][C:5]([C:7]1[CH:29]=[CH:28][C:10]2[S:11][CH2:12][CH2:13][N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:9]=2[CH:8]=1)=O.C([O-])(=O)C.[NH4+:40]>CN(C=O)C.C(=O)(O)[O-].[Na+].CCOC(C)=O>[C:30]1([C:2]2[NH:40][C:5]([C:7]3[CH:29]=[CH:28][C:10]4[S:11][CH2:12][CH2:13][N:14]([S:15]([C:18]5[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=5)(=[O:17])=[O:16])[C:9]=4[CH:8]=3)=[N:4][CH:3]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(CNC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCS2)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCSc2ccc(-c3ncc(-c4ccccc4)[nH]3)cc21
Yield: 6.3 %

Procedure:
To a solution of N-(2-oxo-2-phenylethyl)-4-(4-(trifluoromethyl)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (20 mg, 38 μmol) in DMF (1 mL) was added ammonium acetate (30 mg, 380 μmol). The reaction mixture was subjected to microwave irradiation (150° C., 15 min). LCMS analysis of the reaction mixture indicated nearly complete conversion of the starting material. The reaction mixture diluted with saturated aqueous sodium bicarbonate (1 mL) and EtOAc (2 mL). The organic layer was removed and the aqueous layer extracted with EtOAc (2 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography using a gradient elution of hexanes with 10-60% EtOAc to provide 6-(5-phenyl-1H-imidazol-2-yl)-4-(4-(trifluoro-methyl)phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (1.2 mg, 2.4 μmol, 6% yield) as a yellow oil. LCMS (+ESI) m/z=502.5 [M+H]+; 1H-NMR (CDCl3) δ 8.10 (m, 2H), 7.90 (d, 2H), 7.80 (d, 2H), 7.4-7.5 (m, 4H), 7.25 (d, 1H), 7.00 (dd, 1H), 6.76 (d, 1H), 3.53 (t, 2H), 3.08 (t, 2H).
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C@@H:27]2[NH:32][CH2:31][CH2:30][N:29]([C:33]3[C:42]4[N:41]=[C:40]([C:43]([F:46])([F:45])[F:44])[S:39][C:38]=4[NH:37][C:36]4[CH:47]=[CH:48][CH:49]=[CH:50][C:35]=4[N:34]=3)[CH2:28]2)[CH:22]=[CH:23][CH:24]=1>CO.ClC(Cl)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C@@H:27]2[N:32]([CH3:1])[CH2:31][CH2:30][N:29]([C:33]3[C:42]4[N:41]=[C:40]([C:43]([F:45])([F:46])[F:44])[S:39][C:38]=4[NH:37][C:36]4[CH:47]=[CH:48][CH:49]=[CH:50][C:35]=4[N:34]=3)[CH2:28]2)[CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C(F)(F)F)nc43)CCN2)c1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(Cl)Cl
Product: COc1cccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C(F)(F)F)nc43)CCN2C)c1
Reaction time: 1.5 h
Yield: 60.1 %

Procedure:
Add sodium triacetoxyborohydride (0.23 g, 1.1 mmol) and aqueous formaldehyde (37% w/w, 0.083 mL, 1.1 mmol) to a solution of (S)-10-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1 yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.36 g, 0.74 mmol) in methanol: dichloroethane (1:1) and stir. After 1.5 hours, concentrate the reaction under reduced pressure to remove methanol, and then dilute with a saturated aqueous solution of sodium bicarbonate and dichloromethane, and separate the layers. Extract the aqueous layer with dichloromethane (2×), combine organics, and dry (sodium sulfate), filter, and concentrate under reduced pressure to a residue. Purify the residue by flash chromatography, eluting with a gradient of a solution of ethyl acetate: hexane (1:1) with 1% 2M ammonia in methanol added (40–100% in hexane over 30 minutes, then 100% for 10 minutes) to give the title compound (0.223 g, 60%): mass spectrum (APCI+, m/e): 502 (M+1); 1H NMR (300 MHz, DMSO-d6), δ (ppm): 8.48 (s, 1H), 7.19–7.10 (m, 1H), 6.97–6.81 (m, 3H), 6.76–6.67 (m, 4H), 3.96–3.76 (br. m, 2H), 3.68 (s, 3H), 3.15–3.02 (m, 1H), 2.93–2.81 (m, 1H), 2.80–2.69 (m, 1H), 2.65–2.34 (m, 2H), 2.27–2.04 (m, 5H), 1.91–1.75 (m, 1H), 1.66–1.48 (m, 1H).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22].O>CC(C)=O>[Cl:22][CH2:21][CH2:20][CH2:19][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: ClCCCBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C=O)ccc1OCCCCl
Yield: 5.9 %

Procedure:
A mixture of vanillin (30.4 g, 200 mmol), K2CO3 (27.6 g) and acetone (150 ml) was stirred and refluxed for 0.5 hours. Heating was removed and 1-bromo-3-chloropropane (40.8 g, 260 mmol) in acetone was added dropwise. The reaction was stirred and refluxed for 16 hours, and then it was poured into water. The aqueous mixture was extracted with diethyl ether, the extract was dried (MgSO4), and the solution was concentrated to afford an oil, which upon evacuation solidified to a white solid (50.2 g). An 8.0 g sample was flash chromatographed on silica gel with 50% ethyl acetatehexane as eluent. Concentration of appropriate fractions gave 2.7 g (37%) of 4-(3chloropropoxy)-3-methoxybenzaldehyde as a white solid, m.p.=53°-55° C.