Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[O:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40](B4OC(C)(C)C(C)(C)O4)[CH:41]=3)[C:36]2=[O:53])[CH2:31][CH2:30]1>>[F:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:40]3[CH:41]=[C:42]4[C:37](=[CH:38][CH:39]=3)[C:36](=[O:53])[N:35]([CH:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)[CH2:43]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CCOCC2)C3=O)OC1(C)C
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(C4CCOCC4)C5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=507.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][C:10]1[CH:11]=[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:13]=[C:14]2[C:18]=1[NH:17][CH:16]=[C:15]2[CH2:19][CH3:20])(=[O:8])=[O:7].CCN(CC)CC>CCO>[O:7]=[S:6]1(=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][N:9]1[C:10]1[CH:11]=[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:13]=[C:14]2[C:18]=1[NH:17][CH:16]=[C:15]2[CH2:19][CH3:20]
Reactant: CCOC(=O)c1cc(NS(=O)(=O)CCCCCl)c2[nH]cc(CC)c2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(N2CCCCS2(=O)=O)c2[nH]cc(CC)c2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a solution of ethyl 7-{[(4-chlorobutyl)sulfonyl]amino}-3-ethyl-1H-indole-5-carboxylate (D242) (230 mg, 0.59 mmol, 1 equiv) in EtOH (10 ml) was added NEt3 (249 μl, 1.78 mmol, 3 equiv) and the resulting solution was stirred at 70° C. for 3 h. NEt3 (1 ml, excess) was added and the solution was stirred at the same temperature for 15 h then cooled to room temperature and concentrated in vacuo. The residue was dissolved in AcOEt and the organic phase was washed with a 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (AcOEt/iso-hexane: 3/7) gave ethyl 7-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-3-ethyl-1H-indole-5-carboxylate (B148) (150 mg, 72%) as a colorless oil. [M−H]−=349.3, RT=3.10 min.
Reaction SMILES: [CH3:1][C:2](=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=O)[C:3](O)=[O:4].C([O-])([O-])=O.[K+].[K+].Cl.O.[NH2:30][NH2:31]>CO>[CH3:1][C:2]1[C:3](=[O:4])[NH:30][N:31]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH:6]=1
Reactant: CC(=CC(=O)c1ccc(-c2ccc(F)cc2)cc1)C(=O)O
Reactant: NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc(-c2ccc(-c3ccc(F)cc3)cc2)n[nH]c1=O
Reaction time: 6 h

Procedure:
28.4 g of 2-methyl-4-(4'-fluoro-4-biphenylyl)-4-oxo-2-butenoic acid is dissolved in 100 ml of methanol; 15.4 g of K2CO3 is added and the mixture is stirred for 6 hours at 20°. It is then acidified with hydrochloric acid, 5.4 ml of hydrazine hydrate is added and the batch is boiled for 2 hours. Thereafter, it is again acidified; the solution is concentrated and cooled; and the 4-methyl-6-(4'-fluoro-4-biphenylyl)-2,3-dihydropyridazin-3-one obtained is filtered off and washed with water. m.p. 247°-248°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9](=N)([C:16]1C=CC=CC=1)[C:10]1C=CC=C[CH:11]=1>>[CH2:16]1[C@@H:2]([C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[NH:1][CH2:11][CH:10]=[CH:9]1
Reactant: NCc1cccnc1
Reactant: N=C(c1ccccc1)c1ccccc1
Product: C1=CC[C@@H](c2cccnc2)NC1
Reaction time: 6 h

Procedure:
3-aminomethylpyridine was added to neat benzophenoneimine (1 eq). The reaction was allowed to proceed for 6 hours at 50° C. providing Formula I as the product.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.O=S(Cl)Cl.C(Cl)Cl.C[N:22](C=O)C>>[F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH2:22])=[O:10])[CH2:5][CH2:4]1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reaction time: 0.08 h

Procedure:
A mixture of trans-4-trifluoromethyl-cyclohexane-carboxylic acid (10.4 g, 53.1 mmol), SOCl2 (10 mL, 137 mmol), DCM (100 mL) and DMF (200 μl) is heated to reflux for 1.5 h and concentrated. The crude acid chloride is diluted with 100 mL THF and conc. NH3 (350 mL) is slowly added. It is stirred for 5 min and the mixture is concentrated and dried at 40°.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][N:30]=1)[C:25](Cl)=[O:26].CCN(C(C)C)C(C)C>C1COCC1>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][N:30]=1)[C:25]([NH:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1)=[O:26]
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.2 %

Procedure:
A mixture of 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine (1.38 g, 5.07 mmol), 2-chloroisonicotinoyl chloride (1.34 g, 7.6 mmol), DIPEA (1.81 ml, 10.1 mmol) and THF (30 ml) is stirred at room temperature for 12 hours. The mixture is quenched with water (100 ml). The crude product is extracted with EtOAc (2×50 ml), the combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (3% MeOH in EtOAc) to afford 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide (1.07 g, 51%). 1H NMR (DMSO-d6) δ 10.61 (s, 1H), 8.62 (d, 1H), 8.21 (d, 1H), 8.10 (s, 1H), 7.95 (m, 2 H), 7.59 (d, 2 H), 7.49 (d, 1H), 7.09 (d, 1H), 4.33 (m, 2 H), 3.61 (m, 4 H), 2.92 (m, 2 H), 2.61 (m, 4 H). MS: 412 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][C:3]=1[N+:17]([O-])=O>C(O)C.C1COCC1.[Pd]>[NH2:17][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc(F)c(N)c1

Procedure:
535 mg (2.00 mmol) of tert-butyl (2E)-3-(4-fluoro-3-nitrophenyl)prop-2-enoate were dissolved in 1 ml of ethanol and 1 ml of THF, and 21.3 mg of palladium on carbon (10%) were added. At RT, the mixture was hydrogenated under an atmosphere of hydrogen at atmospheric pressure overnight. The reaction mixture was then filtered off with suction through kieselguhr, the residue was washed with THF and the filtrate was concentrated. This gave 479 mg (100% of theory) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:24](Br)[CH2:25][OH:26]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:24][CH2:25][OH:26])[CH2:11][CH2:12]1
Reactant: OCCBr
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1CCN(c2ccccn2)CC1

Procedure:
To a mixture of 1-(2-pyridyl)piperazine (5 g), potassium carbonate powder (9 g) and N,N-dimethylformamide (30 ml) was added dropwise ethylene bromohydrin (5.74 g) under stirring. The mixture was stirred at room temperature for 6 hours, diluted with water (100 ml) and extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel chromatography [eluent: dichloromethane-methanol (95:5)] to give 4-(2-pyridyl)-1-piperazineethanol as crystals, m.p. 82.5°-84° C. Yield 4.68 g (73.7%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12](CC3C=CC=CC=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[H][H]>[Pd].CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][NH:12][CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3ccccc3)CC2C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CNCC2C1

Procedure:
5-Benzyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (19.85 g, 65.6 mmol), MeOH (200 mL), HOAc (3 mL) and 10% Pd/C Degussa type (400 mg) were charged to a Parr shaker vial and shaken for 3 days at 70 psi hydrogen gas. The resulting material was filtered through Celite® and concentrated. The crude mixture was purified by flash column chromatography (FCC), DCM to 10% MeOH/DCM containing 1% NH4OH, to afford the product. MS (ESI) mass calcd. for C11H20N2O2, 212.29; m/z found, 213.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 3.60-3.55 (m, 2H), 3.38-3.25 (m, 4H), 2.95-2.86 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [S:1]([NH2:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].O[CH:13]=[C:14]1[C:23](=[S:24])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH3:25])[CH:21]=2)[O:16][CH:15]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[S:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:13]=[C:14]2[C:23](=[S:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH3:25])[CH:21]=3)[O:16][CH:15]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:7][CH:8]=1)(=[O:10])(=[O:2])[NH2:11]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccc2c(c1)C(=S)C(=CO)C(c1ccccc1)O2
Solvent: CCO
Product: Cc1ccc2c(c1)C(=S)C(=CNc1ccc(S(N)(=O)=O)cc1)C(c1ccccc1)O2

Procedure:
To a refluxing solution of 13 g sulfanilamide in 800 ml absolute ethanol is added 21 g 3-hydroxymethylidene-6-methyl-thioflavanone. After sixteen hours the reaction mixture is cooled and the crystals which separated are collected. After recrystallisation in a mixture of acetone and light petroleums, pure 3-(N-4-sulfamoylphenyl)aminomethylidene-6-methyl-thioflavanone is obtained as yellow crystals; m.p. 210°-213° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[C:5]([O:15][CH3:16])=[CH:4][CH:3]=1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([F:25])=[CH:20][N:19]=1.O>CO>[C:11]([C:9]([NH:8][C:6]1[C:5]([O:15][CH3:16])=[CH:4][CH:3]=[C:2]([NH:1][C:20]2[C:21]([F:25])=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=2)[N:7]=1)=[O:10])([CH3:13])([CH3:12])[CH3:14]
Reactant: COc1ccc(N)nc1NC(=O)C(C)(C)C
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: O
Solvent: CO
Product: COc1ccc(Nc2nc(Cl)ncc2F)nc1NC(=O)C(C)(C)C

Procedure:
A homogeneous mixture of 6-amino-2-(tert-butylcarbonyl)amino-3-methoxypyridine (35) (1.5 g, 6.72 mmol) and 2,4-dichloro-5-fluoropyrimidine (53) (1.68 g, 10 mmol) in methanol:water (20 mL, each) was stirred at 60° C. for 48 hours. The reaction mixture upon dilution with water (100 mL) gave a solid, which was isolated by filtration to obtain N4-[2-(tert-butylcarbonyl)amino-3-methoxypyrid-6-yl]-2-chloro-5-fluoro-4-pyrimidineamine. LCMS: purity: 89%; MS (m/z): 354 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([CH:9]=[CH2:10])=[O:8].[CH:11]([C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][C:25]=1[OH:26])[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=O>O1CCOCC1>[CH:7]([C:9]1[CH2:10][O:26][C:25]2[CH:24]=[CH:23][C:15]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][C:13]=2[CH:11]=1)=[O:8]
Reactant: O=Cc1cc(Cc2cccnc2)ccc1O
Reactant: C=CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=CC1=Cc2cc(Cc3cccnc3)ccc2OC1
Temperature: 100 °C
Yield: 94.3 %

Procedure:
2.21 g of potassium carbonate and 2.20 ml of acrolein were added to a solution of 3.50 g (16.4 mmol) of 3-(3′-formyl-4′-hydroxybenzyl)pyridine in 1,4-dioxane (40 ml) and the mixture was heated at 100° C. for 30 minutes. Then, the resultant reaction mixture was filtered by using Celite (Trademark) and the filtrate was evaporated in vacuo. The residue was purified by a silica gel column chromatography (i.e., hexane: ethyl acetate=2:1 to 1:2) to obtain 3.88 g (yield=94.3%) of the desired compound as a yellow crystal.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:19]1[O:23][C:22](=[O:24])[CH2:21][CH2:20]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1.CN1C(=O)N(C)CCC1>[C:1]([NH:8][C@H:9]([C@H:19]1[O:23][C:22](=[O:24])[C@H:21]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:20]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CCC(=O)O2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](Cc3ccccc3)C(=O)O2)cc1

Procedure:
In analogy with Example 5d), 4.17 g (12.44 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-methoxyphenyl)ethyl]dihydrofuran-2-(3H)-one, dissolved in 22.4 ml of THF and 2.5 ml of DMPU, are deprotonated, at -70° C., with 24 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and alkylated (-75° C., 1 h) with 1.5 ml (12.44 mmol) of benzyl bromide. Protonation, at -75° C., with 4.6 ml of propionic acid and 4.6 ml of water, extraction and column chromatography (SiO2, methylene chloride/ether 25:1) yields the title compound: TLC Rf (C)=0,74; tRet (II)=16.6 min; FAB-MS (M+H)+ =426.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Br:11]Br>S(=O)(=O)(O)O.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[Br:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[CH:10]2
Reactant: BrBr
Reactant: Cc1cc2ccccc2[nH]1
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: Cc1cc2cc(Br)ccc2[nH]1
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
To a solution of 2-methyl-1H-indole (5.0 g, 38.12 mmol) in sulfuric acid (80 ml) was added Ag2SO4 (12.5 g, 40.06 mmol) with ice cooling, and the solution was stirred for 30 min. Then Br2 (6.4 g, 40.05 mmol) was added to the solution dropwise over 30 min. After the solution was stirred for 4 h at room temperature, the reaction was quenched by the addition of water/ice (300 ml). The reaction mixture was extracted with dichloromethane (3×200 ml) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 5-bromo-2-methyl-1H-indole as a light brown solid (4.7 g, 59%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH:8]=[O:9])[N:7]=1.[CH3:12][Mg]Br>CCCCCC.C(OCC)(=O)C>[F:11][C:2]([F:1])([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH:8]([OH:9])[CH3:12])[N:7]=1
Reactant: C[Mg]Br
Reactant: O=Cc1csc(C(F)(F)F)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(O)c1csc(C(F)(F)F)n1

Procedure:
Using the procedure of Example 1, 2-trifluoromethyl-4-thiazolecarboxaldehyde and methyl magnesium bromide were reacted to obtain the desired product with a Rf=0.17 [hexane-ethyl acetate (7-3)].
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31][NH2:32])[CH:24]=1>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:32][CH2:31][CH2:30][CH2:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[O:16])=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: NCCCc1cccnc1
Reactant: CCCc1c(OCCCCCC(=O)O)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCCCC(=O)NCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid was allowed to react with 3-pyridine propanamine according to procedure A and the product was purified by chromatography on silica gel to give 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[3-(3-pyridinyl)propyl]hexanamide the title compound, mp 83°14 85° (from methylene chloride-ether) in 87% yield.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:2]1=2.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:11][C:8]1[CH:9]=[CH:10][C:2]2[O:1][CH2:6][CH2:5][O:4][C:3]=2[CH:7]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccccc1Nc1ccc2c(c1)OCCO2
Temperature: 120 °C
Reaction time: 10 h
Yield: 67.2 %

Procedure:
5.9 g (39 mmol) of 2,3-dihydrobenzo[b]1,4-dioxin-6-amine and 5.0 g (35 mmol) of 2-fluoronitrobenzene were dissolved in N-methylpyrrolidone (70 mL) and 20.8 g (150 mmol) of potassium carbonate was added thereto. The solvent was heated with stirring for 10 hours at 120° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The extracted organic layer was washed with water, 10% hydrochloric acid, water, and a saturated aqueous solution of sodium chloride in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (developing solvent: ethyl acetate:hexane=1:4), to obtain 6.4 g (yield: 66%) of N-(2-nitrophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-amine as a red liquid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[O:15]([C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=[C:2]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:23]=2)[CH:7]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: Nc1cccc(Oc2ccccc2)c1
Product: Cc1cc(Nc2cccc(Oc3ccccc3)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol) and 3-phenoxyaniline (74.0 mg, 0.4 mmol) similar to Example 173 and was isolated as a white solid. (96 mg, 68 %). 1H NMR (CDCl3): 8.62 (d, J 4.2 Hz, 1H), 8.25 (d, J=8.1 Hz, 1H), 7.65 (t, J=1.5 Hz, 1H), 7.21 (m, 5H), 6.94 (m, 5H), 6.64 (d, J=8.1 Hz, 1H), 6.49 (s, 1H), 2.33 (s, 3H),
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([C:15](=O)[N:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3].B#B.Cl>O1CCCC1.O>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CN(C)C(=O)c1ccc(-c2csc(NC(=N)N)n2)o1
Agent: B#B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(-c2csc(NC(=N)N)n2)o1
Reaction time: 5 h

Procedure:
To a stirred solution of 676 mg. (2.43 mmole) of 2-guanidino-4-(5-[N,N-dimethylcarbamoyl]-2-furyl)thiazole in 25 ml. of tetrahydrofuran was added dropwise, at room temperature, 24.9 ml. (24.3 mmole) of a 0.97M solution of diborane in tetrahydrofuran. Stirring was continued for 5 hours at room temperature and then 15 ml. of 6N hydrochloric acid was added slowly, keeping the temperature below 30° C. Stirring was continued for 30 minutes, and then the mixture was diluted with water and washed with ethyl acetate. The resulting aqueous phase was made alkaline with 1N sodium hydroxide solution and the solid which precipitated was recovered by filtration, to give 340 mg. of the title compound, mp greater than 200° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[OH:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1.0 g (7.41 mmol) of 3,4-dihydroxybenzonitrile was dissolved in 10 ml of N,N-dimethylformamide. 1.12 g (8.15 mmol) of potassium carbonate and 0.88 ml (7.41 mmol) of benzyl bromide were added to the obtained solution, and they were stirred at 50° C. for 2 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the solvent was evaporated, and the obtained residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:11][CH:10]=1)C1C=CC=CC=1.O1CCOCC1.[H][H]>[C].[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1
Reactant: CCOC(=O)CCCCCCCCCCOc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)CCCCCCCCCCOc1ccc(O)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
In a 1000 ml pressure resistant flask equipped with a stirrer were charged 100.0 g of ethyl 11-(p-benzyloxyphenoxy)undecanoate synthesized in Synthetic example 1, 3.0 g of a 10% palladium-carbon, 400 ml of 1,4-dioxane and 200 ml of ethanol, and the mixture was heated to 60° C. and under pressurized conditions of an inner vessel pressure at 2.5 kgf/cm2, a hydrogen gas was passed through and the mixture was vigorously stirred for 3 hours. Insolubles were removed by filtration, and the filtrate was concentrated to precipitate crystals. The resulting crystals were washed with cooled n-hexane to obtain 73.4 g of the title compound.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[CH:12]=[C:13]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH:14](O)[C:15]([O:17][CH3:18])=[O:16]>C(Cl)Cl>[F:7][CH:14]([C:13]1[CH:12]=[C:11]([F:10])[CH:22]=[C:21]([F:23])[CH:20]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C(O)c1cc(F)cc(F)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(F)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of diethylaminosulfur trifluoride (DAST) (1.1 eq) in methylene chloride was cooled to 0° C. and a pre-cooled solution of methyl 3,5-difluoromandelate (1 eq) in methylene chloride was added. The transfer flask was rinsed with a small portion of methylene chloride. After 15 minutes, the cooling bath was removed and the reaction mixture was stirred an additional 40 minutes at ambient temperature. The mixture was poured over ice and the layers separated. The organic phase was washed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified via HPLC eluting with 7% ethyl acetate/hexanes providing the title intermediate as a yellow oil.