Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3](OC)=[O:4].Cl.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][NH2:20].C(N(CC)CC)C>CO>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:3]([OH:4])=[CH:2][C:1]([C:7]([O:9][CH3:10])=[O:8])=[N:20]1
Reactant: NNc1ccccc1F
Reactant: COC(=O)C#CC(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(O)n(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dimethyl acetylenedicarboxylate (87.4 g, 757 mmol) was added to a solution of 2-fluoro-phenylhydrazine hydrochloride (100 g, 615 mmol) in methanol (1 l) at 0° C. Then triethylamine (125 g, 1.23 mol) was added slowly during 60 min. The solution was stirred for 16 h at room temperature, the solvent then removed under reduced pressure and the residue dissolved in EA (500 ml). After washing with aqueous hydrochloric acid (500 ml), the solvent was removed under reduced pressure. The title compound was obtained as an almost white solid in quantitative yield.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[CH3:8][C:9](=O)[CH2:10][CH2:11][C:12](=O)[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:13][C:12]1[N:7]([C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[C:9]([CH3:8])=[CH:10][CH:11]=1
Reactant: Cn1ccc(N)n1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1ccc(C)n1-c1ccn(C)n1
Temperature: 115 °C
Yield: 94.3 %

Procedure:
A solution of 1-methyl-1H-pyrazol-3-ylamine (0.92 g, 9.5 mmol) in benzene (4.8 mL) was treated with hexane-2,5-dione (1.34 mL, 11.4 mmol) and para-toluenesulfonic acid (182 mg, 0.95 mmol) and was heated to 115° C. under Dean-Stark conditions for 4 h. After this time, the reaction was cooled to 25° C., concentrated in vacuo and dried under high vacuum overnight. The resulting residue was dissolved in methylene chloride (100 mL) and was washed with water (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO, 80 g, 1:4 ethyl acetate/hexanes) afforded 3-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (1.57 g, 94%) as a green oil; ES+-HRMS m/e calcd for C10H13N3 [M+H+] 176.1182, found 176.1182.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH:34]([CH3:36])[CH3:35]>CN(C)C=O>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH:34]([CH3:36])[CH3:35])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)Br
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3C(C)C)CC1
Yield: 42 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a light brown foam (42%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=O)=[CH:7][CH:6]=[CH:5]2.S(Cl)(Cl)=O.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:22]=1[NH2:23].C(N(CC)CC)C.Cl>O.C1COCC1>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:22]=1[NH:23][C:12]([C:8]1[C:9]2[C:4](=[CH:3][C:2]([OH:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:14]
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: COc1ccc(OC)c(N)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(OC)c(NC(=O)c2cccc3cc(O)ccc23)c1
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
A mixture of 6-hydroxy-1-naphthoic acid (5.0 g, 26.6 mmol) and thionyl chloride (20 mL) was refluxed for 1 h. The volatiles were then removed under vacuum. The residue was dissolved in THF (20 mL) and added into a cold (0° C.) solution of 2,5-dimethoxyaniline (4.06 g, 26.6 mmol), triethylamine (10 mL, 71.8 mmol) and THF (100 mL). The mixture was stirred for 30 min, poured into water, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/EtOAc 1/1) gave a tan solid (8.2 g, 95% yield, m.p. 165-166° C.); MS m/e 324 (M+H)+.
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:8]([NH:10][NH2:11])=[O:9])C(C)C.[CH2:16]([N:18](CC)[C:19]1[CH:20]=C(C=C(C)N=1)C(O)=O)[CH3:17]>>[CH2:16]([N:18]([CH2:19][CH3:20])[C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:8]([NH:10][NH2:11])=[O:9])[CH3:17]
Reactant: Cc1cc(C(=O)NN)cc(CC(C)C)n1
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Product: CCN(CC)c1cc(C(=O)NN)cc(C)n1

Procedure:
The title compound is prepared in analogy to 2-isobutyl-6-methyl-isonicotinic acid hydrazide from 2-diethylamino-6-methyl-isonicotinic acid; LC-MS: tR=0.47 min, [M+1]+=223.14.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9](B(O)O)=[CH:10][CH:11]=2)[N:6]([CH3:16])[C:5]1=[O:17].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[C:29]1[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:30]=1[C:31]#[N:32].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:29]3[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:30]=3[C:31]#[N:32])=[CH:10][CH:11]=2)[N:6]([CH3:16])[C:5]1=[O:17]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(B(O)O)nc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cc(O)ccc3C#N)nc21

Procedure:
To a solution of [1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]boronic acid (16-1, 500 mg, 1.90 mmol) in anhydrous THF (15 ml) was added a solution of Potassium phosphate tribasic (807 mg, 3.80 mmol, 2.0 equiv) dissolved in water (2 ml). This mixture was treated with 2-chloro-4-hydroxybenzonitrile (409 mg, 2.66 mmol, 1.40 equiv), deoxygenated, then charged with Pd(OAc)2 (21 mg, 0.10 mmol, 0.05 equiv) and S-Phos (78 mg, 0.19 mmol, 0.10 equiv). The resulting dark mixture was irradiated in a microwave at 125° C. for 15 min. The reaction was 75% complete by LC/MS, so more 2-chloro-4-hydroxybenzonitrile (405 mg, 2.66 mmol, 1.40 equiv), Pd(OAc)2 (21 mg, 0.10 mmol, 0.05 equiv) and S-Phos (78 mg, 0.19 mmol, 0.10 equiv) were introduced, and the reaction mixture was irradiated at 140° C. for 25 min. The completed reaction was partitioned between EtOAc (3×75 ml) and saturated aqueous NaHCO3 (80 ml) and the combined organic layers were dried over MgSO4 and concentrated. The crude oil was purified via flash column chromatography (SiO2: 100% Hex to 50/50 Hex/EtOAc) which afforded the title compound, 2-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-hydroxybenzonitrile (16-2), as a yellow solid-oil. LRMS m/z: Calc'd for C19H20N4O2 (M+H) 337.3. found 337.0.
Reaction SMILES: [OH:1][CH:2]1[CH:8]2[CH2:9][C:5]([C:10](O)=O)([CH2:6][CH2:7]2)[CH2:4][CH2:3]1.Cl.[NH2:14][C:15]1[C:16](=[O:29])[N:17]([CH2:26][CH2:27][CH3:28])[C:18](=[O:25])[N:19]([CH2:22][CH2:23][CH3:24])[C:20]=1[NH2:21]>>[OH:1][CH:2]1[CH:8]2[CH2:9][C:5]([C:10]3[NH:14][C:15]4[C:16](=[O:29])[N:17]([CH2:26][CH2:27][CH3:28])[C:18](=[O:25])[N:19]([CH2:22][CH2:23][CH3:24])[C:20]=4[N:21]=3)([CH2:6][CH2:7]2)[CH2:4][CH2:3]1
Reactant: O=C(O)C12CCC(O)C(CC1)C2
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: Cl
Product: CCCn1c(=O)c2[nH]c(C34CCC(O)C(CC3)C4)nc2n(CCC)c1=O
Yield: 44.9 %

Procedure:
Using the method described in Example 8, 4-hydroxy-bicyclo[3.2.1]octane-1-carboxylic acid (Kraus, W., et al. Liebigs Ann. Chem., 1981, 10, 1826) (0.50 mmol, 0.085 g) was reacted with 5,6-diamino-1,3-dipropyl-1H-pyrimidine-2,4-dione hydrochloride (0.50 mmol, 0.132 g) to provide the desired product (0.081 g, 44%).
Reaction SMILES: [CH3:1][C:2]12[CH2:9][CH2:8][N:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]2[C:10](Cl)=[O:11].[NH2:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15]1>>[C:21]1([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][CH:14]([NH:13][C:10]([C@H:3]3[C:2]4([CH3:1])[CH2:9][CH2:8][N:5]([CH2:6][CH2:7]4)[CH2:4]3)=[O:11])[CH2:15]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC12CCN(CC1)CC2C(=O)Cl
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Product: CC12CCN(CC1)C[C@H]2C(=O)NC1CCN(CCc2ccccc2)C1

Procedure:
4-Methylquinuclidine-3-carbonyl chloride and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-4-methylquinuclidine-3-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[S:5][CH:6]=1.CO.[Br:22]N1C(=O)CCC1=O>[Pd].C(OCC)(=O)C>[Br:22][C:6]1[S:5][C:4]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)sc1Br
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To Compound 1062 (1.67 g, 5.98 mmol) in a solution of methanol and ethyl acetate (40 mL, 1:1) was added palladium on carbon (1 g, 10%, Degussa type). The reaction was shaken under hydrogen atmosphere at 45 psi on a Parr apparatus for 1 hour, filtered through diatomaceous earth, and concentrated under reduced pressure. The resulting material was dissolved in acetonitrile (30 mL) and treated with N-bromosuccinimide (1.14 g, 6.4 mmol). The reaction mixture was stirred for 30 minutes at room temperature and quenched with a saturated solution of sodium sulfite. The crude product was extracted with EtOAc (2×30 mL) and the combined organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified via silica gel chromatography to provide 1.26 g of tert-butyl 4-(5-bromo-4-methylthiophen-2-yl)piperidine-1-carboxylate Compound 1063) as a pale yellow solid; 1H NMR (300 MHz, CDCl3): δ 6.42 (s, H), 4.20-4.01 (m, 2H), 2.77-2.68 (m, 3H), 2.05 (s, 3H), 1.84 (d, J=12.3 Hz, 2H) and 1.50-1.39 (m, 11H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[O:28])=[CH:25][CH:24]=1
Reactant: Cc1cccnc1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccnc1N(C(=O)c1ccc(Br)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
To a solution of Preparation 2 (R)-tert-butyl 3-((3-methylpyridin-2-yl)amino)piperidine-1-carboxylate (33.3 g, 114 mmol) and 4-bromobenzoyl chloride (26.3 g, 120 mmol) in dry THF (300 mL) was added 1 M lithium bis(trimethylsilyl)amide (137 mL, 137 mmol) dropwise at 0° C. The reaction mixture was warmed and stirred at room temperature for 16 h. The reaction was quenched with water and extracted with EtOAc (3×1000 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to afford the title compound as a yellow solid (27 g, 50%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][N:15]=2)[C@H:10]([CH3:23])[CH2:9]1)=O)(C)(C)C.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:31]O>>[CH3:31][O:22][C:20](=[O:21])[C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]2[CH3:23])=[N:15][CH:16]=1
Reactant: CO
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)O)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1ccc(N2CCNC[C@H]2C)nc1
Temperature: 64 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-4-(5-carboxy-pyridin-2-yl)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (50 g, 0.156 mol) and methanol (500 mL) was slowly added concentrated sulfuric acid (37 mL). The reaction mixture was warmed to 64° C., stirred at 64° C. overnight, cooled to RT and then ice water (800 mL) was added followed by 50% aqueous sodium hydroxide (60 mL). The reaction mixture was extracted with ethyl acetate (3×800 mL). Combined organic layers were dried over sodium sulfate and evaporated to give the title intermediate as an oil. HPLC Method A: Retention time 3.50 and 3.72 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N+:31]([O-])=O)=[C:18]([S:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=2)[CH:19]=1>C(O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH:31][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[C:18]([S:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=2)[CH:19]=1
Reactant: CC(=O)Nc1ccc(Sc2cc(Cl)ccc2[N+](=O)[O-])cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2cc(Cl)ccc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (48 mg, 0.27 mmol) was reacted in ethanol (2 ml) with the product from Example 231b (78 mg, 0.27 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt. (12 mg, 28%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.06 (s, 3H) 2.77 (s, 3H), 6.39 (d, J=7.35 Hz, 1H), 6.96 (d, J=1.84 Hz, 1H), 7.38 (d, J=8.82 Hz, 2H) 7.51 (s, 2H), 7.62 (d, J=8.82 Hz, 2H), 7.81 (d, J=8.82 Hz, 1H), 8.47 (d, J=7.35 Hz, 1H) 8.97 (d, J=8.82 Hz, 1H), 10.15 (s, 1H), 11.01 (s, 1H), 14.48 (s, 1H); MS (DCI/NH3) m/z 435 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Reactant: C1CNCCN1
Product: Cc1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1
Yield: 29 %

Procedure:
2-chloro-1-(4-methylphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(4-methylphenyl)-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde (29% yield). ESI/MS 320 (M+H); RT=2.64 min; NMR (CDCl3) 10.27 (1H, s); 8.27 (1H, d, J=9 Hz); 7.38-7.15 (6H, m); 6.96 (1H, d, J=6 Hz); 3.26 (4H, m); 2.81 (4H, m); 2.47 (3H, s).
Reaction SMILES: [CH3:1][C@:2]12[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][C@H:15]([OH:22])[C:13](=[O:14])[C@@H:12]1[C@:11]1([CH3:23])[C@H:5]([C:6]([O:8][C@@H:9]([C:24]3[CH:25]=[CH:26][O:27][CH:28]=3)[CH2:10]1)=[O:7])[CH2:4][CH2:3]2.[Na+].[I-].C(N(C(C)C)CC)(C)C.Cl[CH2:41][O:42][CH2:43][CH3:44]>CC(N(C)C)=O.CCOC(C)=O>[CH3:44][CH2:43][O:42][CH2:41][O:7][CH2:6][O:8][CH2:9][CH3:24].[CH3:1][C@:2]12[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][C@H:15]([OH:22])[C:13](=[O:14])[C@@H:12]1[C@:11]1([CH3:23])[C@H:5]([C:6]([O:8][C@@H:9]([C:24]3[CH:25]=[CH:26][O:27][CH:28]=3)[CH2:10]1)=[O:7])[CH2:4][CH2:3]2
Reactant: CCOCCl
Agent: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@@H](c3ccoc3)C[C@]21C
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCOCOCC
Temperature: 80 °C
Reaction time: 18 h

Procedure:
12-epi-Salvinorin B (15 mg, 0.038 mmol) was dissolved in DMA (500 μL) under argon. To this solution was added NaI (23 mg, 0.15 mmol), diisopropylethylamine (37 μL, 0.21 mmol), and chloromethylethyl ether (16 μL, 0.19 mmol). This solution was warmed to 80° C., and stirred for 18 hours. The mixture was then cooled to rt and diluted with EtOAc, washed with water and brine, and dried over MgSO4. After evaporation of the solvent, flash chromatography (0% to 70% EtOAc in hexanes) gave ethoxymethyl ether 37 as an off-white solid. (11.2 mg, 65% yield); Rf 0.28 (98:2, CH2Cl2/MeOH); 1H NMR (300 MHz, CDCl3) δ 7.43 (m, 1H), 7.40 (t, J=1.7 Hz, 1H), 6.41 (m, 1H), 5.29 (dd, J=6.0, 11.6, 1H), 4.76 (q, J=7.2, 2H), 4.16 (dd, J=7.4, 12.2, 1H), 3.72 (s, 3H), 3.69-3.51 (m, 2H), 2.72 (dd, J=3.3, 13.3, 1H), 2.46-2.27 (m, 4H), 2.20 (m, 1H), 2.05-1.68 (m, 4H), 1.57 (m, 1H), 1.38 (s, 3H), 1.18 (t, J=7.1, 2H), 1.06 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:32]1[N:37]=[C:36]([O:38][C:39]2[N:43]([CH3:44])[N:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=2)[CH:35]=[C:34]([CH3:49])[N:33]=1.[S:50]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51]1.C(=O)([O-])O.[Na+]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.O1CCOCC1.O.C1(C)C=CC=CC=1>[S:50]1[CH:54]=[CH:53][C:52]([C:32]2[N:37]=[C:36]([O:38][C:39]3[N:43]([CH3:44])[N:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=3)[CH:35]=[C:34]([CH3:49])[N:33]=2)=[CH:51]1
Reactant: OB(O)c1ccsc1
Reactant: Cc1cc(Oc2cc(C(F)(F)F)nn2C)nc(Cl)n1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Oc2cc(C(F)(F)F)nn2C)nc(-c2ccsc2)n1
Reaction time: 1 h
Yield: 86 %

Procedure:
0.145 g of 1,4-bis(diphenylphosphino)butane and 0.115 g bis(benzonitrile)palladium(II)chloride are refluxed in 10 m toluene under nitrogen for 2 hours. At room temperature 1 g 2-chloro-6-methyl-4-(1-methyl-3-trifluoromethyl-5-pyrazolyloxy)pyrimidine, 0.55 g thiophene-3-boronic acid, 0.8 g sodium hydrogen carbonate, 15 mL water and 20 mL dioxane are added, and the mixture is heated to reflux. After 2 hours another 0.2 g thiophene-3-boronic acid are added, and reflux continued for 1 hour. The organic phase is washed with with water and chromatographed to give 1 g of the title compound (m.p. 122° C.).
Reaction SMILES: C1(C)C=CC(S(CC[O:12][C:13](=[O:52])[CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([N:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=[C:28]3[S:36]([CH2:38][C:39]3[C:44]([CH3:45])=[C:43]([O:46][CH2:47][C:48]([F:51])([F:50])[F:49])[CH:42]=[CH:41][N:40]=3)=[O:37])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH2:15][CH3:16])(=O)=O)=CC=1.C([O-])(O)=O.[Na+:58]>CC#N.O>[Na+:58].[CH3:45][C:44]1[C:39]([CH2:38][S:36]([C:28]2[N:27]([S:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH:14]([CH2:15][CH3:16])[C:13]([O-:52])=[O:12])=[CH:19][CH:20]=3)(=[O:25])=[O:26])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]=2)=[O:37])=[N:40][CH:41]=[CH:42][C:43]=1[O:46][CH2:47][C:48]([F:50])([F:49])[F:51]
Reactant: CCC(Oc1ccc(S(=O)(=O)n2c(S(=O)Cc3nccc(OCC(F)(F)F)c3C)nc3ccccc32)cc1)C(=O)OCCS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC(Oc1ccc(S(=O)(=O)n2c(S(=O)Cc3nccc(OCC(F)(F)F)c3C)nc3ccccc32)cc1)C(=O)[O-]
Yield: 56.8 %

Procedure:
A solution of 2-(4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzoimidazole-1-sulfonyl}phenoxy)butyric acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 11, 400 mg, 0.50 mmol) and NaHCO3 (47 mg, 0.55 mmol, 1.1 eq) in CH3CN-H2O (7 mL-3 mL) was heated to 70° C. for 3 h. Then volatile materials were removed by evaporation and the residual gummy oil was dissolved in CH3CN. The CH3CN solution was filtered to remove un-dissolved solids. The filtrate was dried and the residual yellow foam was treated with ether-EtOAc (5:1) to precipitate a solid. The solid was again treated with CH3CN, and the CH3CN solution was filtered to give 180 mg (58%) of 2-(4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}phenoxy)butyric acid sodium salt (Compound 4 sodium salt). The sodium salt was dissolved in water, and acidified to pH 3 by 1 N HCl solution, and extracted with dichloromethane. The dichloromethane layer was evaporated to give Compound 4 as a free acid, which was further purified on a short silica gel column to yield 125 mg of 2-(4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]benzimidazole-1-sulfonyl}phenoxy)butyric acid (Compound 4).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:4]([C:5](O)=O)[C:3]=1[C:12](O)=O.[ClH:15].[CH2:16]([O:18][C:19]([C:21]1([NH2:32])CC2C(=CC=C(F)C=2F)C1)=[O:20])[CH3:17]>>[ClH:15].[CH2:16]([O:18][C:19]([C:21]1([NH2:32])[CH2:5][C:4]2[C:3](=[C:2]([F:1])[CH:10]=[CH:9][C:8]=2[F:11])[CH2:12]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(N)Cc2ccc(F)c(F)c2C1
Reactant: O=C(O)c1c(F)ccc(F)c1C(=O)O
Agent: Cl
Product: CCOC(=O)C1(N)Cc2c(F)ccc(F)c2C1

Procedure:
2-Amino-4,7-difluoro-indan-2-carboxylic acid ethyl ester HCl salt was prepared from 3,6-difluoro-phthalic acid as indicated by the scheme above regarding A7-D7 utilizing the same procedures as for the synthesis of 2-amino-4,5-difluoro-indan-2-carboxylic acid ethyl ester HCl salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11](=[O:24])[CH:10]=[C:9]2[CH:25]=[O:26])[CH:5]=[CH:6][CH:7]=1.[F:27][C:28]([Si](C)(C)C)([F:30])[F:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11](=[O:24])[CH:10]=[C:9]2[CH:25]([OH:26])[C:28]([F:30])([F:29])[F:27])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(COc2cn(-c3cccc(Br)c3)c(C=O)cc2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(COc2cn(-c3cccc(Br)c3)c(C(O)C(F)(F)F)cc2=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a semi-suspension of 1-(3-bromophenyl)-5-[(4-methoxybenzyl)oxy]-4-oxo-1,4-dihydropyridine-2-carbaldehyde (500 mg, 1.21 mmol) in THF (5 mL) at 0° C. was added (trifluoromethyl)trimethylsilane solution (5.3 mL of 0.5 mL solution in THF) followed by tetrabutylammonium fluoride solution (0.1 mL of a 1 M solution in THF). The reaction mixture was stirred at 0° C. for 1 h and then quenched by adding water. The quenched reaction mixture was then diluted with dichloromethane, washed with brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (24 g silica gel, linear gradient of 0 to 5% methanol in dichloromethane) afforded 1-(3-bromophenyl)-5-[(4-methoxybenzyl)oxy]-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH:15]([CH2:14][N:13]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)[CH2:12]2)[CH2:16]1)=[O:8]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Reactant: Cc1cccc(Cl)n1
Product: Cc1cccc(N2CC3CN(C(=O)c4ccccc4-c4ccccc4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-6-methyl-pyridine. MS (ESI) mass calcd. for C25H25N43O, 383.5; m/z found, 384.3 [M+H]+.