Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5]1=[O:12].[C:13](OC(=O)C)(=[O:15])[CH3:14]>S(=O)(=O)(O)O.C(O)(=O)C>[C:13]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5]1=[O:12])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=C(C)C(=O)N(CCO)C1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)OCCN1C(=O)C(C)=C(C)C1=O
Temperature: 160 °C
Yield: 95 %

Procedure:
126 g (1 mol) of 2,3-dimethylmaleic anhydride and 61 g (1 mol) of ethanolamine are reacted by heating at 180° C. for 1 hour to give 150 g of N-(2-hydroxyethyl)-2,3-dimethylmaleimide (boiling point 110° C. under 13.33 Pa; yield 89% of theory). After drying, the N-(2-hydroxyethyl)-2,3-dimethylmaleimide is mixed with 181.5 g (1.78 mols) of acetic anhydride and 3 drops of concentrated sulfuric acid and the mixture is refluxed for one hour in an oil bath heated to 160° C. The acetic acid formed and the acetic anhydride are then distilled off in vacuo. Fractionation of the residue under a high vacuum yields 179 g of N-(2-acetoxyethyl)-2,3-dimethylmaleimide (boiling point 104° C./6.66 Pa; yield 95% of theory). The N-(2-acetoxyethyl)-2,3-dimethylmaleimide is introduced dropwise, under nitrogen, in the course of 75 minutes into a glass column which is filled with Raschig rings and is heated to 550° C. The pyrolysis products are collected at the lower end of the glass column in a cooled receiver. The yellow oil obtained is taken up in diethyl ether and treated with aqueous sodium bicarbonate solution in order to remove the acetic acid. After drying the organic phase over sodium sulfate, the solvent is removed in vacuo and the product is distilled under a high vacuum. In addition to 39.3 g of unconverted starting material, 84.7 g of (N-vinyl)-2,3-dimethylmaleimide are obtained in the form of a yellowish oil; boiling point 58°-60° C./53.33 Pa; yield: 85% of theory, based on converted starting material.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[C:37]([Br:39])[CH:36]=[C:35]([Br:40])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:34]=[C:35]([Br:40])[CH:36]=[C:37]([Br:39])[CH:38]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc(Br)cc(Br)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(c1cc(Br)cc(Br)c1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
0.166 g (0.241 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dibromobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is reacted with 0.037 g (0.96 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR69## is obtained (0.094 g, 66%) as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.23, FD-MS: M+ =591, 593, 595.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[C:5]([C:23]#[N:24])=[C:4]([S:25][CH2:26][C:27]2[N:28]=[C:29]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[S:30][CH:31]=2)[N:3]=1.Cl>O1CCOCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[C:5]([C:23]#[N:24])=[C:4]([S:25][CH2:26][C:27]2[N:28]=[C:29]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[S:30][CH:31]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c(C#N)c(N)nc(SCc3csc(Nc4ccc(F)cc4)n3)c2C#N)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1c(N)nc(SCc2csc(Nc3ccc(F)cc3)n2)c(C#N)c1C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40 mg (0.07 mmol) of the compound from Example 18A are dissolved in 0.9 ml of dioxane, and 0.9 ml of a 4 M solution of hydrogen chloride in dioxane are added. The reaction mixture is stirred at RT for 2 h and then directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: Cl[CH:2]=[CH:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[I-:11].[Na+]>CC(C)=O>[I:11][CH:2]=[CH:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [I-]
Reactant: CCCCCC(=O)C=CCl
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCC(=O)C=CI
Reaction time: 18 h
Yield: 64.5 %

Procedure:
A mixture of 25 g (0.16 moles) of 1-chloro-1-octen-3-one (Example 187) and 35 g (0.23 moles) of sodium iodide in 200 ml of reagent acetone is stirred at the reflux temperature for 18 hours. The cooled mixture is filtered and the mother liquor taken to dryness. The residual oil is dissolved in benzene and the solution is washed with 5% sodium thiosulfate solution, saturated sodium chloride solution, dried and taken to dryness. The residual oil is crystallized from hexane to give 26 g of a white solid, mp 35°-37° C.; λ max 1670, 950 cm-1.
Reaction SMILES: C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29](C=O)[CH:30]=2)[CH:25]=1)=[O:23].[H][H]>O1CCCC1>[CH3:20][O:21][C:22]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[O:23]
Reactant: COC(=O)c1ccc2cc(C=O)ccc2c1
Reactant: [H][H]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ccccc2c1

Procedure:
For example, 4'-alkoxy-4-bromobiphenyl (17) is reacted with triphenylphosphin to obtain triphenylphosphonium salt of 4'-alkoxybiphenyl (21). The thus obtained triphenylphosphonium salt of 41 -alkoxybiphenyl (21) is reacted with 6-formyl-2-naphthalenecarboxylic acid methyl ester as a solution in such as methylene chrolide and then the resulting compound is reacted with hydrogen in the presence of the reducing catalyst such as paradium carbon in a solvent such as tetrahydrofuran (THF) to obtain 6-[4'-alkoxy-4-biphenyl)ethyl]-2-naphthalenecarboxylic acid methyl ester. The resulting 6-[4'-alkoxy-4-biphenyl)ethyl]-2-naphthalenecarboxylic acid methyl ester is hydrolysised to obtain 6-[4'-alkoxy-4-biphenyl)ethyl]-2-naphthalenecarboxylic acid (22).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-])=O)=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:10]([NH2:11])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1n[nH]cc1N
Reaction time: 20 h
Yield: 98.4 %

Procedure:
A mixture of 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester (6.40 g, 34.6 mmol) and 10% Pd/C (650 mg) in EtOH (150 ml) was stirred under an atmosphere of hydrogen for 20 h. The mixture was filtered through a plug of Celite, reduced in vacuo and dried through azeotrope with toluene to afford 4-amino-1H-pyrazole-3-carboxylic acid ethyl ester as a pink solid (5.28 g, 98%). (1H NMR (400 MHz, DMSO-d6) δ 12.7 (s, 1H), 7.1 (s, 1H), 4.8 (s, 2H), 4.3 (q, 2H), 1.3 (t, 3H)).
Reaction SMILES: [O:1]=[C:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.C(N(CC)CC)C.C(Cl)CCl.[NH2:23][C@@H:24]([CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[OH:26]>C(Cl)Cl.CO>[O:1]=[C:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([NH:23][C@@H:24]([CH2:33][N:34]1[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1)[C@H:25]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[OH:26])=[O:10]
Reactant: CC(=O)CCCCCC(=O)O
Reactant: N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Solvent: ClCCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)CCCCCC(=O)N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reaction time: 8 h
Yield: 59.1 %

Procedure:
A mixed solvent of methylene chloride:methanol=9:1 (20 ml), 7-oxooctanoic acid (700 mg, 4.4 mmol), triethylamine (1.40 ml, 10.0 mmol) and EDC (1.15 g, 6.0 mmol) were added to (1S,2S)-2-amino-3-morpholino-1-phenyl-1-propanol (944.0 mg, 4.0 mmol), followed by stirring overnight. Methylene chloride (100 ml) was added to the reaction solution. After washed with a saturated sodium hydrogen carbonate solution (50 ml), water (50 ml) and saturated brine (50 ml) successively, the organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform:ethanol=20:1) to obtain the title compound (890 mg, yield 59%) as colorless oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:19][CH2:18][NH:17][C:11]4([CH2:16][CH2:15][CH2:14][O:13][CH2:12]4)[C:9]=3[O:10][C:4]=2[CH:3]=1.CC1C=CC2C=CC3C=CC(C)=NC=3C=2N=1.CN(C=O)C.[F:41][C:42]1[CH:43]=[C:44]([SH:48])[CH:45]=[CH:46][CH:47]=1.CC(C)([O-])C.[Na+]>N#N.[Cu]I>[F:41][C:42]1[CH:43]=[C:44]([S:48][C:2]2[CH:7]=[CH:6][C:5]3[C:8]4[CH2:19][CH2:18][NH:17][C:11]5([CH2:16][CH2:15][CH2:14][O:13][CH2:12]5)[C:9]=4[O:10][C:4]=3[CH:3]=2)[CH:45]=[CH:46][CH:47]=1
Reactant: Ic1ccc2c3c(oc2c1)C1(CCCOC1)NCC3
Reactant: Fc1cccc(S)c1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: Cc1ccc2ccc3ccc(C)nc3c2n1
Solvent: CN(C)C=O
Product: Fc1cccc(Sc2ccc3c4c(oc3c2)C2(CCCOC2)NCC4)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
7-Iodo-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran] (0.20 g, 0.56 mmol), neocuproine (11.6 mg, 0.0558 mmol) and copper(I) iodide (53.1 mg, 0.279 mmol) were dissolved into the anhydrous DMF (4 mL, 50 mmol) in a 20 mL scintillation vial under N2. 3-Fluoro-benzenethiol (104 μL, 1.23 mmol) was added neat followed immediately by the addition of the sodium tert-butoxide (118 mg, 1.23 mmol). The reaction vial was capped with a teflon coated cap and the mixture was stirred at 100° C. overnight. After 15 h, the reaction was cooled to room temperature and concentrated under vacuum. The residual solid was partially dissolved into a 5% MeOH in DCM solution and flushed through a Celite plug. The concentrated filtrate was chromatographed on silica gel using DCM-MeOH—NH4OH to afford a brownish oil, used directly in the next step.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([OH:35])=[N:33][CH:34]=2)O1>>[OH:35][C:32]1[N:33]=[CH:34][C:29]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:30][CH:31]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2ccc(O)nc2)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(O)nc3)ccn2c1=O

Procedure:
Methyl 8-(6-hydroxypyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol (90.8 mg, 0.41 mmol). The precipitate was rinsed with DCM and dried in a vacuum stove to afford quantitatively the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:4]2[O:12][C:13]([CH3:17])([CH3:16])[O:14][CH2:15][C:3]=12.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:4]3[O:12][C:13]([CH3:17])([CH3:16])[O:14][CH2:15][C:3]=23)=[O:24])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ncc(N)c2c1OC(C)(C)OC2
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: COC(=O)c1ncc(NC(=O)c2ccc(F)cc2)c2c1OC(C)(C)OC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 5-amino-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate (23c) (70 mg, 0.25 mmol), 4-fluorobenzoyl chloride (35 μL, 0.27 mmol) and 4-dimethylaminopyridine in pyridine (1 mL) was stirred at room temperature overnight and a saturated solution of ammonium chloride was added. The reaction mixture was extracted with dichloromethane (3×25 mL) and the combined organic layers were dried (anh. Na2SO4), filtered and concentrated under reduced pressure to give methyl 5-(4-fluorobenzamido)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate (23d) as a white solid MS-ESI m/z 361 [MH]+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=[C:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH:18]1(I)[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:18]1([N:7]2[C:2](=[O:1])[C:3]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: IC1CCCC1
Reactant: COC(=O)c1c[nH]c(=O)c(-c2ccccn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccccn2)c(=O)n(C2CCCC2)c1
Yield: 21 %

Procedure:
Methyl 6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxylate (Step 2, 210 mg, 0.91 mmol), cyclopentyl iodide (196 mg, 1.0 mmol) and potassium carbonate (150 mg, 1.1 mmol) were stirred at room temperature in 2 mL of DMF for 24 h. The reaction mixture was quenched with H2O and extracted 3× with EtOAc. The combined organic extracts were washed 3× with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was taken up in CH2Cl2 and loaded on to a 5 g pre-packed silica gel column and purified. Elution with 0-30% EtOAc:hexanes gave the title compound as an off-white powder (57 mg, 21%). MS m/z: 299 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH:12]([C:14]1[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1)=O.[OH-].[K+]>CCO>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9](=[O:11])/[CH:10]=[CH:12]/[C:14]2[CH:15]=[CH:16][C:17](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:23][CH:24]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: CC(=O)c1cccc(CO)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(/C=C/C(=O)c2cccc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
A mixture of 1-(3-hydroxymethyl-phenyl)-ethanone (810 mg), 4-formylcinnamic acid (950 mg, 5.4 mmol) and 1.7 M KOH (6.4 ml) in EtOH (40 ml) was stirred at room temperature for 18 h. The resulting precipitate was filtered and washed with EtOH to give 1.25 g of (E)-3-{4-[(E)-3-(3-hydroxymethyl-phenyl)-3-oxo-propenyl]-phenyl}-acrylic acid as its potassium salt.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45](O)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1.Cl.[S:51]1[CH:55]=[CH:54][N:53]=[C:52]1[CH2:56][NH2:57]>>[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45]([NH:57][CH2:56][C:52]4[S:51][CH:55]=[CH:54][N:53]=4)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1
Reactant: NCc1nccs1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Agent: Cl
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1nccs1
Yield: 66 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with thiazol-2-ylmethanamine hydrochloride, the title compound was obtained as a white solid in 66% yield: mp 189-190° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), 7.74 (br s, 1H), 7.40-7.31 (m, 3H), 7.06-6.97 (m, 2H), 6.78 (t, J=5.4 Hz, 1H), 4.97 (s, 2H), 4.92 (d, J=5.4 Hz, 2H), 2.67 (s, 3H); MS (ES+) m/z 431.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:32])=[C:5]([C:28]([O:30][CH3:31])=[O:29])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:9].[C:33]1([O:39][CH2:40][CH:41]2[O:43][CH2:42]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CO>[CH3:1][C:2]1[NH:3][C:4]([CH3:32])=[C:5]([C:28]([O:30][CH3:31])=[O:29])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:42][CH:41]([OH:43])[CH2:40][O:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:9]
Reactant: c1ccc(OCC2CO2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCN)C1c1cccc(C(F)(F)F)c1
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCNCC(O)COc2ccccc2)C1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 45 h
Yield: 32.9 %

Procedure:
In 45 ml of methanol were dissolved 2.51 g of 6-aminohexyl methyl 2,6-dimethyl-4-(m-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.83 g of glycidyl phenyl ether, and the mixture was stirred for 45 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The produce was eluted with chloroform-methanol (95:5 v/v), and 1.10 g of 6-(2-hydroxy-3-phenoxypropylamino)hexyl methyl 2,6-dimethyl-4-(m-trifluoromethylphenyl)-1,4-dihydropyridin-3,5-dicarboxylate was obtained. This product was treated with an ethanol solution of hydrogen chloride to obtain amorphous powder of 1.16 g of hydrochloric acid salt.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: Oc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1ccc(-c2ccc(O)cn2)cc1
Temperature: 80 °C
Yield: 69 %

Procedure:
A mixture of [4-(methylthio)phenyl]boronic acid (7.2 g, 43.1 mmol), 6-bromo-3-pyridinol (5 g, 28.7 mmol), 2M Na2CO3 (44 mL), Pd(PPh3)4 (1.7 g, 1.4 mmol) and DME (70 mL) was degassed with N2 for 30 min, and stirred and heated at 80° C. for 18 h. The mixture was charged with water and CH2Cl2 and the organic layer was washed with 1N NaOH (100 mL). The basic aqueous layer was washed with Et2O, cooled in an ice bath and the pH was adjusted to about 10 with 6N HCl. The resulting solid was collected, washed with water and air-dried to give 6-[4-(methylthio)phenyl]-3-pyridinol (4.3 g, 69%) as a yellow solid. The reaction was repeated on twice the scale (10 g of 6-bromo-3-pyridinol) to provide 9.1 g (72%) of product. The reaction was repeated on 10× the scale (101.5 g of 6-bromo-3-pyridinol) to provide 53.7 g of product. 1H NMR (400 MHz, DMSO-d6): δ 9.96 (s, 1H), 8.15 (d, 1H, J=2.6 Hz), 7.87 (d, 2H, J=8.6 Hz), 7.73 (d, 1H, J=8.7 Hz), 7.27 (d, 2H, J=8.6 Hz), 7.18 (dd, 1H, Ja=8.6 Hz, Jb=2.9 Hz), 2.46 (s, 3H); LRMS (ESI), m/z 218 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.C([O:22][C:23]1[C:24](=[O:39])[O:25][CH:26]([CH2:36][CH2:37]O)[C:27]=1[O:28]CC1C=CC=CC=1)C1C=CC=CC=1>>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[O:1][CH2:37][CH2:36][CH:26]1[O:25][C:24](=[O:39])[C:23]([OH:22])=[C:27]1[OH:28]
Reactant: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1
Reactant: Oc1ccc2oc3ccccc3c2c1
Product: O=C1OC(CCOc2ccc3oc4ccccc4c3c2)C(O)=C1O
Yield: 10.2 %

Procedure:
Mitsunoble coupling of 0.22 g (1.2 mmol) of 2-hydroxydibenzofuran with 0.34 g (10 mmol) of 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone and subsequent benzyl group deprotection by hydrogenation were performed in a similar manner as described in the synthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone to provide 40 mg (10% yield) of 5-[2-(dibenzofuran-2-oxy)ethyl]-3,4-dihydroxy-2(5H)-furanone a white solid.: mp 191-192° C. (ether/hexanes), 1H NMR (acetone-d6) δ 8.23-8.18 (m, 1H), 7.83-7.44 (m, 5H), 7.28-7.23 (m, 1H), 5.12 (dd, J=5.3, 8.7 Hz, 1H), 4.42 (dd, J=2.6, 4.7 Hz, 2H), 2.69-2.59 (m, 1H), 2.21-2.08 (m, 1H). 13C NMR (acetone-d6) δ 169.68, 157.31, 155.75, 153.70, 151.31, 127.76, 125.05, 124.83, 123.07, 121.34, 118.46, 116.42, 112.39, 111.90, 105.40, 72.72, 64.57, 32.64. Anal Calcd for C18H14O6+0.25 H2O: C, 65.36; H, 4.57. Found: C, 65.52; H, 4.23.
Reaction SMILES: Br[CH:2]1[CH2:10][CH2:9][C:8]2[N:7](S(C3C=CC(C)=CC=3)(=O)=O)[N:6]=[CH:5][C:4]=2[C:3]1=O.[CH3:22][C:23]1[N:28]=[C:27]([NH:29][C:30]([NH2:32])=[S:31])[CH:26]=[CH:25][CH:24]=1>CCO.Cl>[CH3:22][C:23]1[N:28]=[C:27]([NH:29][C:30]2[S:31][C:2]3[CH2:10][CH2:9][C:8]4[NH:7][N:6]=[CH:5][C:4]=4[C:3]=3[N:32]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c2CCC(Br)C3=O)cc1
Reactant: Cc1cccc(NC(N)=S)n1
Agent: Cl
Solvent: CCO
Product: Cc1cccc(Nc2nc3c(s2)CCc2[nH]ncc2-3)n1
Yield: 86.7 %

Procedure:
According to Scheme 3 Step 4: A solution of 5-bromo-1-tosyl-6,7-dihydro-1H-indazol-4(5H)-one (0.90 mmol, 331 mg) and of 1-(6-methylpyridin-2-yl)thiourea (0.90 mmol, 150 mg) in EtOH (10 mL) and HCl (35%, 1 mL) was stirred at 80° C. for 5 hours. The reaction was quenched with the addition of a saturated solution of NaHCO3 at room temperature until pH=8. The aqueous phase was extracted with DCM. The organic phase was dried over Na2SO4 and concentrated. The crude residue was washed with Et2O and dried to yield N-(6-methylpyridin-2-yl)-5,6-dihydro-4H-thiazolo[4,5-e]indazol-2-amine (0.78 mmol, 220 mg, 87%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([OH:12])[C:5]=1[CH2:13][CH:14]=[CH2:15]>[OH-].[K+]>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]2[O:12][CH:14]([CH3:15])[CH2:13][C:5]=12)=[O:16]
Reactant: C=CCc1c(O)cc(OC)cc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Product: COC(=O)c1cc(OC)cc2c1CC(C)O2
Yield: 45 %

Procedure:
2-allyl-3-hydroxy-5-methoxybenzoic acid methyl ester is heated under nitrogen atmosphere to 260° C. for about 3 hours. Upon cooling, the reaction mass is dissolved in a small amount of 20%KOH and the aqueous alkaline solution is then extracted with ethyl ether. The organic phase is evaporated and the crude residue affords the title compound in 45% yield. B.p./0.3 mmHg 136°-38° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](O)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)([Cl:31])=O>>[F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([Cl:31])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 59.2 %

Procedure:
A 500 ml round bottom flask equipped with nitrogen inlet and magnetic stirrer is charged with 40 g (0.132 mol) of product from Example 2 and 24.97 g (0.233 mol) of 2,6-lutidine. To this is slowly added (exothermic) 185 ml (1.98 mol) of phosphorous oxychloride. The flask is fitted with a condenser and the mixture is heated to reflux. After refluxing for 18 hours the material is cooled, concentrated, and the mixture was poured into 150 g of ice slowly. The ice mixture was then poured into 200 ml of 10% HCl (aqueous) and extracted twice with ether. The combined ether layers were washed with 10% NaOH (aqueous), dried (MgSO4), and concentrated in vacuo affording a black oil. The residue was kugelrohr distillcd at 67 Pa. The earlier fraction (pot temperature 50° C.) was discarded. The later fraction (pot temperature 85° C.) afforded 25.15 g (60%) of product, nD25 1.4185.