Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[N:7]=[C:8]([S:10]([CH2:12][C:13]3[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=3)=[O:11])[NH:9][C:5]=2[C:4]=1[S:25]([C:28]1[C:39]([CH3:40])=[CH:38][C:31]([O:32][CH2:33][C:34]([O:36]C)=[O:35])=[CH:30][C:29]=1[CH3:41])(=[O:27])=[O:26].[OH-].[Na+:43]>C(COC)OC>[Na+:43].[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[N:7]=[C:8]([S:10]([CH2:12][C:13]3[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=3)=[O:11])[NH:9][C:5]=2[C:4]=1[S:25]([C:28]1[C:29]([CH3:41])=[CH:30][C:31]([O:32][CH2:33][C:34]([O-:36])=[O:35])=[CH:38][C:39]=1[CH3:40])(=[O:26])=[O:27]
Reactant: COC(=O)COc1cc(C)c(S(=O)(=O)c2c(OC)ccc3nc(S(=O)Cc4ncc(C)c(OC)c4C)[nH]c23)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1S(=O)(=O)c1c(C)cc(OCC(=O)[O-])cc1C

Procedure:
A solution of methyl {4-[(5-methoxy-2{[4-methoxy,3,5-dimethyl(2-pyridyl)methyl]sulfinyl}benzimidazolyl)sulfonyl]-3,5-dimethylphenoxy}acetate (Intermediate A6, 2.96 g, 0.493 mol) in 250 mL of dimethoxyethane was stirred rapidly as 49 mL of 0.100 N aqueous sodium hydroxide was added. The mixture was concentrated at aspirator pressure (bath temperature<22° C.). The residue was reconcentrated from 200 mL of dimethoxyethane, left briefly at high vacuum, and partitioned between ethyl acetate and water. The aqueous layer was washed with several portions of ethyl acetate and was then concentrated at high vacuum. The residue was partitioned between ethyl acetate and water at pH 3. The aqueous layer was extracted with an additional portion of ethyl acetate, and the combined organic layers were reduced in volume and diluted with hexanes. The resulting solid was collected and combined with a second crop recovered from the filtrate. This material was washed with 10:1 diethyl ether:tetrahydrofuran, dissolved in dimethoxyethane, neutralized with 0.0100 N sodium hydroxide, and washed with ethyl acetate. The product, title compound weighed 0.925 g (31%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])NN)[CH3:2].[C:12](=[N:25][NH:26][C:27]([NH2:29])=[O:28])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[K+].C(Br)C=C>C1COCC1.CCOCC>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])[CH2:27][NH:26][NH:25][CH:12]=[CH2:13])[CH3:2].[C:12](=[N:25][NH:26][C:27]([NH2:29])=[O:28])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CNC(=O)NN
Agent: CC(C)(C)[O-]
Agent: NC(=O)NN=C(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: CCOCC
Product: C=CNNCC(=O)NCC(=O)OCC
Reaction time: 1 h

Procedure:
To a solution of semicarbazone 5i, (50 mg, 0.15 mmol) in THF (0.5 mL), potassium t-butoxide (25 mg, 0.18 mmol) was added at 0° C. under argon. The reaction mixture was stirred for 1 h, treated drop-wise with allyl bromide (20 μL, 0.18 mmol), stirred for 3 h at room temperature (22° C.) under argon, diluted in Et2O (5 mL) and extracted with NaHCO3 (2×2 mL) and brine (2×2 mL). The organic phase was dried over MgSO4, concentrated in-vacuo and purified by flash chromatography using 2:1 Hexane:EtOAc [Rf (6i): 0.45] to yield a an oil (35 mg, 60%). 1H NMR (CDCl3) δ: 1.23 (t, J=7 Hz, 3H), 3.86 (dd, J=1.6 Hz, 3.8 Hz, 2H), 4.05 (d, J=5.7 Hz, 2H), 4.16 (q, J=7 Hz, 2H), 4.78 (dd, J=1 Hz, 10 Hz, 1H), 4.92 (dd, J=1 Hz, 10 Hz, 1H) 5.33-5.43 (m, 1H), 6.89 (t, J=5.5 Hz, 1H), 7.18-7.42 (m, 10H); 13C NMR (CDCl3) δ: 13.8, 42.2, 47.9, 60.8, 116.3, 127.8, 128.2, 128.3, 128.7, 129.3, 129.6, 132.4, 135.6, 138.4, 157.7, 158.4, 170.2; LCMS (ESI) Calcd. for C21H23N3O3, M+: 365.4. Found (M+H)+366.1.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CN(C)C=O.O>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:8][C:5]2[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][CH:4]=2)=[CH:21][CH:20]=1
Reactant: O=c1cc(CO)occ1O
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2coc(CO)cc2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a suspension of kojic acid (50 g: 0.32 Mol.) in dimethylformamide (300 ml) are added potassium carbonate (63 g: 1.42 Eq.) and p-methoxybenzyl bromide (92 g: 1.42 Eq.), and the mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with water (1liter) to give 5-p-methoxybenzyloxy-2-hydroxymethyl-4-pyrone (74.5 g). Yield: 81%. mp. 124°~130° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2.C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.[Cl-].[NH4+]>C1COCC1>[CH:3]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=[CH:11][C:2]=1[B:17]([OH:22])[OH:18]
Reactant: Brc1ccc2c(c1)CCCC2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)CCCC2
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To 6.60 g of 6-bromo-1,2,3,4-tetrahydronaphthalene in THF (60 ml) cooled on a dry ice-acetone bath, 25 ml of n-butyllithium (1.60 M/hexane solution) was added dropwise over 30 minutes in an argon stream, and after the dropwise addition, the reaction mixture was stirred for 1 hour under the same conditions. Then, 6.47 g of triisopropyl borate was added dropwise over 20 minutes, and after the dropwise addition, the reaction mixture was allowed to react for 3.5 hours. The reaction mixture was poured into ice-cold water and brought to almost neutral (pH 8) with ammonium chloride and then extracted with ethyl acetate (400 ml×1, 100 ml×2), and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methanol/chloroform=1/30), and the resulting solid was washed with a small amount of cold hexane to obtain 5.11 g of the desired product (yield 93%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[CH2:7][C:6]2=[C:8]([C:14](O)=[O:15])[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:5]2[O:4]1)[CH3:2].S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:17][CH3:18])[CH2:7][C:6]2=[C:8]([C:14]([Cl:21])=[O:15])[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:5]2[O:4]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCC1(CC)Cc2c(C(=O)O)ccc(OC)c2O1
Solvent: Cc1ccccc1
Product: CCC1(CC)Cc2c(C(=O)Cl)ccc(OC)c2O1

Procedure:
Analogously to Example A1, 1.2 g of 2,2-diethyl-2,3-dihydro-7-methoxybenzofuran-4-carboxylic acid are reacted in a mixture of 10 ml of toluene and 2 ml of thionyl chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:23])[CH2:3]1.S(=O)(=O)(O)[OH:26].N>>[CH3:1][C:2]1([CH3:24])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([NH2:22])=[O:26])=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:23])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(C#N)cc4)[nH]c3cc21
Reactant: O=S(=O)(O)O
Agent: N
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(C(N)=O)cc4)[nH]c3cc21

Procedure:
3.6 g. of the compound obtained in Example 26 were introduced into 70 ml. concentrated sulphuric acid and stirred for 24 hours at 25° C. Subsequently, the reaction mixture was poured on to ice, neutralized with a concentrated aqueous solution of ammonia, filtered off with suction and well washed with water to give 1.8 g. of the title compound which, after crystallization from ethanol/water, had a melting point of 317°-319° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH3:18])[C:3]=1[C:19]([NH2:21])=[O:20].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][C:33](OC)=O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].CC(C)([O-])C.[K+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:32][C:33]1[NH:21][C:19](=[O:20])[C:3]2[C:4]([CH2:17][CH3:18])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=2[N:1]=1
Reactant: CCCCCCC(CCC)n1nc(CC)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CC)c2c(=O)[nH]c(Cc3ccc(OC)c(OC)c3)nc21
Yield: 44 %

Procedure:
6 mg (0.02 mmol) of 5-amino-3-ethyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.095 mmol) of methyl 3,4-dimethoxyphenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic potassium tert-butoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate have been added, the phases are separated. Purification by chromatography gives 4 mg (42%) of a solid, Rf=0.47 (dichloromethane/methanol=15:1).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][C:2]1=[O:11].C(=O)([O-])[O-].[K+].[K+].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:18]1([S:24]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:1][C:2](=[O:11])[CH2:3]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CNc2ccccc2N1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CN(S(=O)(=O)c2ccccc2)c2ccccc2N1
Yield: 52 %

Procedure:
A suspension of 10 g. (0.068 mole) of 3,4-dihydro-2(1H)-quinoxalinone (3,4-dihydro-2-hydroxyquinoxaline) [prepared in 50% yield according to the procedure described by W. H. Perkin et al. in the Journal of the Chemical Society, Vol. 123, p.2399(1923)] and 9.6 g. (0.069 mole) of potassium carbonate in 250 ml. of acetone was stirred under a nitrogen atmosphere at 40° C., while 11.5 g. (0.07 mole) of benzenesulfonyl chloride was added during the course of a 30-minute period. The reaction mixture was next heated at reflux temperature for 14 hours and then poured onto 500 ml. of ice. The resulting brown solid was recrystallized from ethyl acetate to yield 10.2 g (52%) of pure 4-benzenesulfonyl-3,4-dihydro-2(1H)-quinoxalinone, m.p. 183°-185° C. The pure product was further characterized by means of nuclear magnetic resonance data and elemental analysis.
Reaction SMILES: C([O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][CH2:14][S:15]([O:18][CH2:19][CH3:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][CH2:14][S:15]([O:18][CH2:19][CH3:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CCOS(=O)(=O)CCc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOS(=O)(=O)CCc1ccc(O)cc1

Procedure:
To a solution of ethyl 4-benzyloxyphenethyl sulfonate (1.43 g) in ethyl acetate (25 ml) is added 10% palladium on carbon (0.25 g) and the mixture shaken under 30 psi of hydrogen for 3 hours. The mixture is filtered and concentrated in vacuo to give ethyl 4-hydroxyphenethyl sulfonate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[NH2:13][C:14]1[C:15]([CH:20]=O)=[N:16][CH:17]=[CH:18][CH:19]=1.C(OCC)(=O)C.N1CCCCC1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:10]#[N:11])=[CH:20][C:15]3[C:14](=[CH:19][CH:18]=[CH:17][N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCC(=O)c1cccc(F)c1
Reactant: Nc1cccnc1C=O
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: N#Cc1cc2ncccc2nc1-c1cccc(F)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(3-fluorophenyl)-3-oxopropanenitrile (0.8991 g, 5.511 mmol) and 3-amino-2-pyridinecarbaldehyde (0.6730 g, 5.511 mmol) in ethyl acetate (16.70 mL, 5.511 mmol) was added piperidine (0.04360 mL, 0.4409 mmol) and the mixture was heated under reflux (bath temp. 85° C.) with stirring. After 1 h, the mixture was cooled to room temperature and concentrated under reduced pressure to give a dark brown solid. The dark brown solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc in hexane for 25 min as eluent to give 2-(3-fluorophenyl)-1,5-naphthyridine-3-carbonitrile as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.27 (1H, d, J=0.8 Hz), 9.18 (1H, dd, J=4.1, 1.8 Hz), 8.56-8.62 (1H, m), 8.01 (1H, dd, J=8.6, 3.9 Hz), 7.76-7.85 (2H, m), 7.63-7.71 (1H, m), 7.44-7.52 (1H, m); LC-MS (ESI) m/z 249.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([CH:6]1[C:11](=[O:12])OC(C)(C)OC1=O)=[O:5].[CH2:20]([NH2:23])[CH2:21][CH3:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4](=[O:5])[CH2:6][C:11]([NH:23][CH2:20][CH2:21][CH3:22])=[O:12]
Reactant: CC1(C)OC(=O)C(C(=O)c2ccccc2Cl)C(=O)O1
Reactant: CCCN
Solvent: Cc1ccccc1
Product: CCCNC(=O)CC(=O)c1ccccc1Cl
Temperature: 85 °C
Yield: 53 %

Procedure:
A suspension of 5-(2-chlorobenzoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.06 g, 7.30 mmol) in 100 mL of toluene was treated with neat propylamine (550 μL, 395 mg, 6.70 mmol) added dropwise via syringe. The reaction was then heated at 80-90° C. for 4 h. Once at rt, the reaction was concentrated to dryness. The residue was adsorbed onto flash silica gel and added to 19 cm of flash silica gel in a 5 cm dia. column. Elution with 4:1 hexanes/EtOAc afforded 851 mg (53%) of the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([CH2:11][CH3:12])=[N:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC(N(C)C)=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][C:2]2[C:3]([CH2:11][CH3:12])=[N:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CCc1nc([N+](=O)[O-])ccc1Br
Reactant: Oc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 41.1 %

Procedure:
3-Bromo-2-ethyl-6-nitropyridine (2.6 g, 11.3 mmol) and 2-chloro-4-hydroxypyridine (2.9 g, 22.5 mmol) were dissolved in DMA (20 mL). The solution was sonicated and sparged with Ar for 10 min. K2CO3 (4.7 g, 33.8 mmol) was added and the reaction mixture was stirred at 110° C. for 12 h. EtOAc (80 mL) was added and the suspension was washed with 10% K2CO3 (aq) (2×50 mL), 5% LiCl (aq) (2×50 mL), and brine (2×50 mL). The solution was dried (Na2SO4), concentrated in vacuo, and the resultant residue was purified by silica gel chromatography (EtOAc/hexanes) to afford 3-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-nitropyridine (1.3 g, 37.2%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J=5.7 Hz, 1H), 8.25 (d, J=8.7 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.16 (dd, J=5.7, 2.3 Hz, 1H), 2.79 (q, J=7.5 Hz, 2H), 1.21 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 280.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5]([CH3:32])=[CH:6][NH:7][C:8](=[O:31])[C:9]=2[CH:10]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[O:27][C:26]([CH3:29])=[CH:25][C:24]3=[O:30])[C:11]=1[C:12]([O:14][CH2:15][CH2:16][C:17]#[N:18])=[O:13].C(OCC)(OCC)O[CH2:35][CH3:36]>CN(C=O)C.S(=O)(=O)(O)O>[CH2:35]([O:31][C:8]1[N:7]=[CH:6][C:5]([CH3:32])=[C:4]2[C:9]=1[CH:10]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=1[O:27][C:26]([CH3:29])=[CH:25][C:24]3=[O:30])[C:11]([C:12]([O:14][CH2:15][CH2:16][C:17]#[N:18])=[O:13])=[C:2]([CH3:1])[NH:3]2)[CH3:36]
Reactant: CCOC(OCC)OCC
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc3c(=O)cc(C)oc23)c2c(c(C)c[nH]c2=O)N1
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: CCOc1ncc(C)c2c1C(c1cccc3c(=O)cc(C)oc13)C(C(=O)OCCC#N)=C(C)N2
Temperature: 130 °C
Reaction time: 2 h

Procedure:
1.20 g (2.78 mmol) of the compound from Example 39A and 9.25 ml (55.6 mmol) of triethyl orthoformate are taken up in 30 ml of dry DMF and heated to 130° C., and 5 drops of concentrated sulfuric acid are added. After 2 h, an HPLC check shows complete conversion. After cooling, the volatile components are removed in a rotary evaporator, and the crude product is purified by MPLC (Biotage cartridge 40 M, eluent: isohexane/ethyl acetate 1:2). 640 mg (50% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[NH:17][CH:16]=[C:15]([C:18](O)=[O:19])[CH:14]=3)[CH:8]=2)=[CH:4][C:3]=1[NH:23][C:24]([C:26]1[O:27][CH:28]=[CH:29][C:30]=1[CH3:31])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:65][CH2:66][CH2:67][CH:68]([O:72][CH2:73][CH3:74])[O:69][CH2:70][CH3:71]>CN(C=O)C.O>[CH2:70]([O:69][CH:68]([O:72][CH2:73][CH3:74])[CH2:67][CH2:66][NH:65][C:18]([C:15]1[CH:14]=[C:13]([C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[C:3]([NH:23][C:24]([C:26]4[O:27][CH:28]=[CH:29][C:30]=4[CH3:31])=[O:25])[CH:4]=3)[CH:12]=[CH:11][N:10]=2)[NH:17][CH:16]=1)=[O:19])[CH3:71]
Reactant: Cc1ccoc1C(=O)Nc1cc(Oc2ccnc(-c3cc(C(=O)O)c[nH]3)c2)ccc1F
Reactant: CCOC(CCN)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(F)c(NC(=O)c4occc4C)c3)ccn2)c1)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (300 mg, 0.71 mmol) in 10 ml of anhydrous DMF were added HATU (324 mg, 0.85 mmol) and N,N-diisopropylethylamine (200 mg, 1.55 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 1-amino-3,3-diethoxypropane (157 mg, 1.06 mmol), and stirring was continued for another 10 minutes. The mixture was poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide as white solid. Yield: 380 mg, 97%.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Br:10][C:11]1[CH:12]=[CH:13][C:14](Cl)=[N:15][CH:16]=1>CN(C)C(=O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:15][CH:16]=1
Reactant: Clc1ccc(Br)cn1
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Brc1ccc(OC2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclohexanol (3.99 mL) was added to a mixture of NaH (60%, 1.50 g) in N,N-dimethylacetoamide (10 mL) at 0° C. The mixture was stirred at room temperature for 30 min. The solution of 5-bromo-2-chloropyridine (6.00 g) in N,N-dimethylacetoamide (10 mL) was added and the mixture was stirred at 100° C. for 1.5 hr. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (7.67 g) as colorless oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][O:6][C@@H:5]([CH3:19])[O:4]1.[H-].[Na+].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Cl>CN(C)C=O>[CH3:18][O:17][C:15]([CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][C@H:8]1[CH2:7][O:6][C@@H:5]([CH3:19])[O:4][C@H:3]1[CH2:2][O:1][CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1)=[O:16]
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CO
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1COCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of (2R,4R,5S)-4-hydroxymethyl-5-[(Z) -6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (272 mg) in N,N-dimethylformamide (10 ml) were added sodium hydride (80 mg, 60% in oil) and 2-picolyl chloride hydrochloride (110 mg) and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified with preparative thin layer chromatography with ethyl acetate as an eluent to give (2R,4R,5S)-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl -4-(2-pyridylmethoxymethyl)-1,3-dioxane (201 mg) as a pale yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]2[CH:10]=[CH:11][N:12]=[C:4]2[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:9][O:8][C:6]1[N:5]2[CH:10]=[CH:11][N:12]=[C:4]2[CH:3]=[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(I)cc2nccn12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2ccccc2)cc2nccn12
Temperature: 85 °C
Reaction time: 16 h

Procedure:
7-iodo-5-methoxyimidazo[1,2-a]pyridine (539 mg, 1.97 mmol), phenylboronic acid (719 mg, 5.90 mmol), tetrakis(triphenylphosphine)palladium (0) (227 mg, 0.197 mmol), and sodium carbonate (625 mg, 5.90 mmol) were added to a dry flask. Dioxane (18 ml) and water (2 ml) were added and the reaction mixture was sparged with argon for 5 minutes. The reaction mixture was heated to 85° C. After 16 h, the reaction mixture was cooled, diluted with ethyl acetate, washed with water, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane gradient) to give 5-methoxy-7-phenylimidazo[1,2-a]pyridine. LRMS (ESI) calculated for C14H13N2O [M+H]+, 225.1 found 225.0.
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:18][CH2:17]1)[CH3:3].[CH3:36][S:37]([C:39]1[CH:47]=[CH:46][C:45]([N:48]2[CH:52]=[N:51][N:50]=[N:49]2)=[CH:44][C:40]=1[C:41](O)=[O:42])=[O:38].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.CO.C(OCC)(=O)C.ClCCl>[CH3:36][S:37]([C:39]1[CH:47]=[CH:46][C:45]([N:48]2[CH:52]=[N:51][N:50]=[N:49]2)=[CH:44][C:40]=1[C:41]([N:27]1[CH2:28][CH2:29][C:25]([CH2:24][CH2:23][N:19]2[CH2:20][CH2:21][CH2:22][N:16]([C:8]3[N:7]([CH2:6][CH2:5][O:4][CH2:2][CH3:3])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH2:17][CH2:18]2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26]1)=[O:42])=[O:38]
Reactant: CS(=O)c1ccc(-n2cnnn2)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4S(C)=O)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (0.46 g, 1.0 mmol) and dichloromethane (20 mL). Add 2-methylsulfinyl-5-(1H-tetrazol-1-yl)benzoic acid (0.32 g, 1.3 mmol), 1-hydroxybenzotriazole hydrate (0.2 g, 1.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g, 1.5 mmol), and N,N-diisopropylethylamine (0.34 mL, 2 mmol). After 18 hours, dilute the reaction mixture with ethyl acetate and extract with brine, dry the organic layer over MgSO4, filter, and concentrate invacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with ethyl acetate and then 10% methanol/ethyl acetate give the title compound.