Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]2([CH3:38])[CH3:37].I/[C:40](/[CH3:44])=[CH:41]\[CH2:42][OH:43].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:35][C:31]1([CH3:36])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]2[CH:26]=[C:25](/[C:40](/[CH3:44])=[CH:41]\[CH2:42][OH:43])[CH:34]=[CH:33][C:32]1=2
Reactant: C/C(I)=C/CO
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: C/C(=C/CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 80 °C
Reaction time: 24 h
Yield: 77.4 %

Procedure:
Bis(pinacolato)diboron (5.8 g, 22.5 mmol), potassium acetate (4.5 g, 45 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (PdCl2(dppf)2) (500 mg, 0.6 mmol) were added to a solution of Intermediate 1 (4 g, 15 mmol) in 50 mL of DMF under argon. The mixture was then stirred at 80° C. for 24 h. After cooling to room temperature, 3-iodo-but-2Z-en-1-ol (6 g, 30 mmol), 2M Na2CO3 (30 ml), and PdCl2(dppf)2 (500 mg, 0.6 mmol) were added to the mixture, which was then stirred at 80° C. for another 24 h. The reaction was finally quenched with water (20 mL) and extracted with ether (3×10 mL). The organic layer was washed with brine (2×10 mL), dried (MgSO4) and concentrated to give a crude brown oil. The crude product was purified by flash chromatography using 20% EtOAc in hexane to give the title compound (3 g, 77% yield) as a colorless oil:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][C@H:30]([OH:40])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[OH:40][C@H:30]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[CH2:29][NH:28][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)cc4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and (2S)-1-amino-3-(4-hydroxy-phenoxy)-propan-2-ol (which was obtained in Example 5) according to the procedure of Example 255 as a grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.65 (m, 2H), 1.95-2.15 (m, 2H), 2.06 (s, 3H), 2.50-3.20 (m, 5H), 3.55-3.70 (m, 2H), 3.80-3.90 (m, 1H), 4.05-4.20 (m, 1H), 5.70 (brs, 1H), 6.67 (d, J=9.0 Hz, 2H), 6.76 (d, J=9.0 Hz, 2H), 6.78 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 7.58 (d, J=9.0 Hz, 2H), 7.69 (d, J=9.0 Hz, 2H), 8.97 (s, 1H), 10.37 (s, 1H); MS (ES) m/z: 555.1 (MH+); HRMS Calcd. for C28H35N4O6S(MH+): 555.2277. Found: 555.2267.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:32]=[CH:31][C:18]4/[C:19](=[CH:28]/[C:29]#[N:30])/[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH2:22][CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[C:4]([C:33]([NH:35][NH2:36])=[O:34])[CH:3]=1.[C:37](OCC)(OCC)(OCC)[CH3:38]>>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:32]=[CH:31][C:18]4/[C:19](=[CH:28]/[C:29]#[N:30])/[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH2:22][CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[C:4]([C:33]2[O:34][C:37]([CH3:38])=[N:36][N:35]=2)[CH:3]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CCCc1nc2c(C)cc(C(=O)NN)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Product: CCCc1nc2c(C)cc(-c3nnc(C)o3)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Yield: 62 %

Procedure:
[step 1] Using (E)-{2-[4-methyl-6-(hydrazinocarbonyl)-2-propylbenzimidazol-1-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (150 mg, 0.32 mmol) obtained in Example 70, step 1, and triethyl orthoacetate (10.5 mL) instead of triethyl orthoformate, and in the same manner as in Example 70, step 2, (E)-{2-[4-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-2-propylbenzimidazol-1-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (100 mg, 62%) was obtained.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].C([O-])(=O)C.[Na+].[F:13][C:14]1[C:19]([C:20](=O)[CH3:21])=[CH:18][CH:17]=[C:16]([F:23])[N:15]=1.O>C1COCC1.C(OCC)(=O)C>[F:13][C:14]1[C:19]([C:20](=[N:6][OH:7])[CH3:21])=[CH:18][CH:17]=[C:16]([F:23])[N:15]=1
Reactant: CC(=O)c1ccc(F)nc1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=NO)c1ccc(F)nc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
Hydroxylamine sulfate (13.1 g) and sodium acetate (10.9 g) were added to a solution of 1-(2,6-difluoropyridin-3-yl)ethanone (4.18 g) in aqueous THF (50%, 200 mL), and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate) to obtain 2.44 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)[CH3:2].[C:22]1([CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([S:16][CH2:29][CH:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:13][C:12]=12)[CH3:2]
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: ICC(c1ccccc1)c1ccccc1
Product: CCOC(=O)COc1cccc2c1CCc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 68 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate and 2,2-diphenylethyl iodide, the procedure of Example 48 was otherwise repeated to synthesize the title compound. Yield 68%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][C:3]=1[C:19]#N.C(O)=[O:22]>[Ni]>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][C:3]=1[CH:19]=[O:22]
Reactant: O=CO
Reactant: N#Cc1cnn(-c2ccc(OC(F)(F)F)cc2Cl)c1N
Agent: [Ni]
Product: Nc1c(C=O)cnn1-c1ccc(OC(F)(F)F)cc1Cl
Yield: 62 %

Procedure:
12 g (0.042 mol) of 5-amino-4-cyano-1-(2-chloro-4-trifluoromethoxy-phenyl)-pyrazole are boiled under reflux with 5 g of Raney nickel in 50 ml of 75% strength aqueous formic acid for 1 hour; the still warm solution is filtered under suction, the residue is rinsed with water, the filtrate is extracted several times with ether, and the combined ether phases are washed with saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated down in vacuo. 8.0 g (62% of theory) of 5-amino-1-(2-chloro-4-trifluoromethoxy-phenyl)-4-formylpyrazole are obtained in the form of an oil.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[CH:7]=[N+:6]([O-])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]([O:19]C(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:19][CH:12]1[C:13]2[C:8](=[CH:7][N:6]=[C:5]3[C:14]=2[CH:1]=[CH:2][CH:3]=[CH:4]3)[CH2:9][CH2:10][CH2:11]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1cc2c(c3ccccc31)CCCC2
Product: CC(=O)OC1CCCc2cnc3ccccc3c21
Yield: 77 %

Procedure:
A solution of 7,8,9,10-tetrahydrophenanthridine N-oxide (Compound 4a) 1.23 g, 6.18 mmol) in acetic anhydride (50 mL) was heated to 100° C. for 20 hours, evaporated to dryness, dissolved in dichloromethane (50 mL) and washed with saturated sodium bicarbonate solution (50 mL). The aqueous layer was extracted with dichloromethane (2×50 mL), the combined organic layers were dried (Na2SO4), evaporated in vacuo, and the residue was purified by flash chromatography on silica eluting with Et2O to give pure Compound 5 (1.15 g, 77 percent ) as a white crystalline solid: Rf =0.33 (ether); mp=128°-129° c. (from ether); IR (CDCl3) νmax 2970, 1728, 1241 cm-1 ; 1H NMR (500 MHz, CDCl3): δ8.70 (s, 1 H, H-6), 8.08 (d, J=9.5 Hz, 1 H, H-4), 7.76 (d, J= 9.5 Hz, 1 H, H-1), 7.63 (t, J=7.2 Hz, 1 H, H-2 or H-3), 7.52 (t, J=7.2 Hz, 1 H, H-2 or H-3), 6.57 (bs, 1 H, CH--0Ac), 3.02 (bd, J=17.5 Hz, 1 H, H-7), 2.88-2.80 (m, 1 H, H-7), 2.27 (bd, J=13.8 Hz, 1 H, H-9), 2.05 (s, 3 H, 0Ac), 2.01-1.88 (m, 3 H); 13C NMR (125 MHz, CDCl3): δ1702.2, 152.3, 147.5, 137.8, 131.8, 130.1, 127.9, 127.0, 126.8, 122.2, 64.5, 29.1, 27.8, 21.7, 18.4; MS (FAB+) m/e (relative intensity) 242 (M+H, 100), 182 (23); HRMS calcd. for C15H16NO2 (M+H) 242.1181, found 242.1181; Anal. calcd. for C15H 15 NO2 ; C, 74.67; H, 6.27; N, 5.80. Found: C, 74.59; H, 6.31; N, 5.82.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][S:9][C:10]2[N:15]=[C:14]([OH:16])[CH:13]=[CH:12][N:11]=2)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][S:9][C:10]2[N:15]=[C:14]([O:16][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:13]=[CH:12][N:11]=2)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCCc1c(CSc2nccc(O)n2)ccc(C(C)=O)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCC(C)=O
Solvent: O
Product: CCCc1c(CSc2nccc(OCC(=O)OCC)n2)ccc(C(C)=O)c1O
Temperature: 60 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a mixture of 0.06 g of 2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-4-hydroxypyrimidine obtained in Example 14, 0.06 g of ethyl bromoacetate, 0.04 g of anhydrous potassium carbonate and 3 ml of methyl ethyl ketone was added a catalytic amount of tetra-n-butylammonium bromide. The mixture was stirred at 60° C. for 1 hour. Water was added to the reaction mixture The resultant mixture was extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was applied to silica gel column chromatography. Elution with a mixture of hexane-ethyl acetate (6:1) gave 0.06 g of ethyl [[2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-pyrimidin-4-yl]oxy]acetate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl.[CH3:25][O:26][C:27](=[O:33])[C@H:28]([CH:30]([CH3:32])[CH3:31])[NH2:29]>C(OCC)(=O)C>[CH3:25][O:26][C:27](=[O:33])[C@H:28]([CH:30]([CH3:32])[CH3:31])[NH:29][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C
Temperature: 45 °C
Reaction time: 25 h

Procedure:
4′-Bromomethyl-2-cyanobiphenyl (75 g, 0.2757 moles) was added to a mixture of potassium carbonate (95.12 g), DM water (225 ml), ethyl acetate (450 ml) and L-valine methyl ester hydrochloride (55.45 g, 0.330 moles) at 20-30° C. The reaction mixture was heated to 40-50° C. and stirred for 25 h. After completion of the reaction, the ethyl acetate layer was separated at 20-30° C., added DM water (375 ml) and adjusted the pH to 0.8-1.0 with dilute hydrochloric acid at 20-30° C. The aqueous layer was separated and extracted the product in to toluene (430 ml) by adjusting the pH to 8.0-8.5 with 20% w/w aqueous sodium carbonate solution. The toluene layer was washed with DM water (225 ml), concentrated under reduced pressure and dissolved in toluene (450 ml)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].C(O)(C)C.[Cl-].[Na+]>CCOCC>[CH3:17][C:16]1[C:8]([OH:7])=[C:9]([CH2:10][OH:11])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(C(=O)O)c1O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1cccc(CO)c1O
Reaction time: 10 h

Procedure:
4.9 mmol of lithium aluminum hydride are placed, under a nitrogen atmosphere, in 50 ml of ether. 3.3 mmol of 2-hydroxy-3-methylbenzoic acid, in solution in 40 ml of ether, are added dropwise while maintaining a reflux for 4 hours. The mixture is then cooled on ice and 12.5 ml of isopropanol and then 7.5 ml of a saturated sodium chloride solution are added. After 10 hours at room temperature, the mixture is filtered, rinsed with 1N hydrochloric acid and extracted with ether. The product is then obtained after silica column purification, using as eluent a pentane/ethyl acetate mixture (7/3).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[C:10]1=[O:30])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[C:10]1=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Yield: 64.7 %

Procedure:
A solution of (S)-benzyl 4-(3-(tert-butoxycarbonylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (7 g, 17 mmol) in 50% TFA/CH2Cl2 (50 mL) was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed with saturated sodium carbonate (200 mL) and brine. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to yield (S)-benzyl 4-(3-amino-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (3.4 g, 11 mmol, 64%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Yield: 95 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(4-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 95%). 1H NMR (300 MHz, CDCl3): δ 3.25 (s, 4H), 3.78 (s, 3H), 4.13 (s, 4H), 6.86 (d, J=8.4 Hz, 2H), 7.22-7.26 (m, 3H), 7.44 (m, 1H), 7.70 (m, 1H).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1>>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:28][C:25]3[CH:26]=[CH:27][N:23]([CH3:22])[N:24]=3)=[O:18])=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Reactant: Cn1ccc(N)n1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)Nc2ccn(C)n2)cn1
Yield: 55 %

Procedure:
As described for example 19b, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) was converted, using 1-methyl-1H-pyrazol-3-ylamine instead of L-2,2,2-trifluoro-1-(methyl)ethylamine, to the title compound (70 mg, 55%) which was obtained as a yellow oil after purification by chromatography (silica, heptane:ethyl acetate 9:1 to 1:1). MS: m/e=370.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([OH:31])=O)[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].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.Cl.[NH:68]1[C:72]([CH2:73][CH2:74][CH2:75][NH2:76])=[N:71][N:70]=[N:69]1.Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:76][CH2:75][CH2:74][CH2:73][C:72]4[N:68]=[N:69][NH:70][N:71]=4)=[O:31])[CH:25]=3)[CH:19]=2)=[CH:32][CH:33]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: NCCCc1nnn[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCc5nn[nH]n5)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (100 mg, 0.22 mmol) in 10 ml of anhydrous DMF were added HATU (91 mg, 0.24 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 3-(1H-tetrazol-5-yl)propan-1-amine hydrochloride (54 mg, 0.33 mmol). The mixture was stirred at room temperature for another 60 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[3-(2H-tetrazol-5-yl)propyl]-1H-pyrrole-3-carboxamide as light brown solid. Yield: 105 mg, 85%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1>CN(C=O)C.CCOC(C)=O>[CH2:24]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 92 %

Procedure:
To a stirred solution of 6-hydroxy-2,3-dihydroinden-1-one (30 g, 0.203 mol) in 300 mL DMF was added K2CO3 (70 g, 0.507 mol), followed by addition of BnBr (38.2 g, 0.225 mol) dropwise at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 20 h. The mixture was diluted with EtOAc (500 mL), then filtered to remove the solid. The filtrate was washed with brine (200 mL×5), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulted solid was recrystallized in ether to give the title compound (44.5 g, 92%) as a white solid. 1H-NMR (600 MHz, CDCl3) δ 7.47-7.46 (m, 2H), 7.44-7.39 (m, 3H), 7.38-7.35 (m, 1H), 7.31-7.30 (m, 2H), 5.12 (s, 2H), 3.11-3.09 (m, 2H), 2.76-2.74 (m, 2H) ppm.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]=[C:21]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][N:22]1[CH2:38][C:39](O)=[O:40].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:39](=[O:40])[CH2:38][N:22]2[CH2:23][CH2:24][C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:21]2=[O:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzhydrylpiperazine (0.58 g, 2.30 mmol) in dichloromethane (20 mL) under nitrogen was added the product from Example 1C (0.68 g, 2.30 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.88 g, 4.60 mmol) and N,N-dimethylpyridin-4-amine (0.014 g, 0.12 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:3) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.42-7.46 (m, 4H), 7.19-7.33 (m, 16H), 4.31 (s, 1H), 4.15-4.16 (br s, 2H), 3.38-3.47 (m, 4H), 3.35 (t, J=6.3 Hz, 2H), 2.71 (t, J=6.5 Hz, 2H), 2.23-2.29 (m, 4H); MS (DCI+) m/z 530 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)(=O)=O.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[C:24]#[CH:25].C([O-])(=O)C.[Na+]>CN(C)C=O.CC([O-])=O.CC([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd+2]>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:19][CH3:20])[CH:8]=[C:7]([C:25]#[C:24][C:23]([O:27][CH2:28][CH3:29])=[O:26])[CH2:16][CH2:15]2
Reactant: C#CC(=O)OCC
Reactant: COc1cc2c(cc1OC)CCC(OS(=O)(=O)C(F)(F)F)=C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C#CC1=Cc2cc(OC)c(OC)cc2CC1

Procedure:
To a solution of 178 mg (0.53 mmol) of (3,4-dihydro-6,7-dimethoxy-2-naphthyl) trifluoromethane-sulfonate in dimethylformamide (2 ml) were added 0.39 ml (3.9 mmol) of ethyl 2-propynoate, 84.8 mg (1.0 mmol) of sodium acetate and 14.8 mg (0.020 mmol) of bis(triphenylphosphine)-palladium (II) acetate with stirring under nitrogen, and the mixture was stirred for 1 hour and 30 minutes at 60° C. A saturated saline solution was added to the reaction mixture to conduct extraction with benzene-hexane (1:2). An organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel to obtain 76.5 mg (yield: 51%) of crude crystals of the title compound. The crude crystals were recrystallized from diethyl ether-hexane, thereby obtaining a pale yellow crystalline powder.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([OH:14])[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH3:13].N1C=CC=CC=1.Cl>ClCCl.CN(C1C=CC=CN=1)C.CCOCC>[CH2:8]([O:14][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH2:9][CH:10]=[CH:11][CH2:12][CH3:13]
Reactant: O=C1CCC(=O)O1
Reactant: CC/C=C\CCO
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCC=CCCOC(=O)CCC(=O)O
Yield: 92.5 %

Procedure:
A mixture of 100 g succinic anhydride, 100 g cis-3-hexen-1-ol, 88.5 ml pyridine and 7.3 g dimethylaminopyridine in 500 ml dichloromethane was refluxed for 4 hours. Ether was added and the mixture was acidified with HCl 2N then washed with brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was distilled under vacuum to afford 185 g of product.