Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[Mg]Cl.[O:11]=[C:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl-].[Mg+2].[Cl-]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:12]1([OH:11])[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18]
Reactant: Fc1ccc(F)c([Mg]Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1(O)c1cc(F)ccc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In step 6A-1, (2,5-difluorophenyl)magnesium chloride (6-1) was added drop-wise to a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (6-2) (9.6 g, 52 mmol) in THF under argon at −78° C. A maximum of 5 mL aliquots was used to minimize the temperature increase of the magnesium chloride reagent. The resulting solution was then stirred at −78° C. for one hour. The solution was then warmed to room temperature and quenched with concentrated HCl (4 mL). The solvent was then removed using a rotary evaporator resulting in a light yellow residue. The residue was then reconstituted in ethyl acetate and extracted with brine (3×150 mL). The organic layer was then dried using sodium sulfate. The ethyl acetate was removed yielding tert-butyl 2-(2,5-difluorophenyl)-2-hydroxypyrrolidine-1-carboxylate (6-3) as a light yellow oil. m/z=300 [M+1] The product was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:7]=1)=O)C.[NH3:24]>CO>[O:17]([C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH:9]=[CH:10][C:6]([C:4]([NH2:24])=[O:3])=[N:7]2)=[CH:12][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccn(-c2ccc(Oc3ccccc3)cc2)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccn(-c2ccc(Oc3ccccc3)cc2)n1
Temperature: 70 °C
Yield: 52 %

Procedure:
A solution of 3-ethoxycarbonyl-1-(4-phenoxyphenyl)-1H-pyrazole (120 mg, 0.39 mmol) in 5 mL of a 2N solution of ammonia in MeOH was stirred at rt for 4 d. TLC showed incomplete reaction and the solution was transferred to a sealed tube and heated at 70° C. overnight. The reaction was concentrated and purified by preparative TLC, eluting with 50% EtOAc/hexane, to yield 1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxamide (Rf=0.26, 56 mg, 52%), mp 165-167° C. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (d, J=2.7 Hz, 1H, pyrazole), 7.92 (d, J=9.0 Hz, 2H, Phenyl), 7.71 (br, 1H, NH2), 7.43 (m, 2H, Phenoxy), 7.39 (br, 1H, NH2), 7.18 (m, 1H, Phenoxy), 7.17 (d, J 9.0 Hz, 2H, Phenyl), 7.07 (m, 2H, Phenoxy), 6.87 (d, J=2.7 Hz, 1H, pyrazole).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](C=O)=[C:11]([O:17][CH:18]([CH3:20])[CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21]O>OS(O)(=O)=O.CO.O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([OH:21])=[C:11]([O:17][CH:18]([CH3:20])[CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Oc1cc(OCc2ccccc2)ccc1C=O
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CC(C)Oc1cc(OCc2ccccc2)ccc1O

Procedure:
A solution of 4-(benzyloxy)-2-isopropoxybenzaldehyde (2.76 g, 10.21 mmol) and 30 wt % hydrogen peroxide (1.35 mL, 13.07 mmol) in conc. H2SO4 (0.204 mL) and MeOH (20.4 mL) was stirred for 3 h at 25° C. under N2. After this time the mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3×30 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford 4-(benzyloxy)-2-isopropoxyphenol, as a colorless oil. LCMS calc.=281.1; found=281.0 (M+Na)+.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]1([CH3:22])[C@@H:9](/[CH:10]=[CH:11]\[C:12](O)=[O:13])[C@H:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:6][C:7]1([CH3:22])[C@@H:9](/[CH:10]=[CH:11]\[C:12]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:13])[C@H:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: OC1CCC1
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)OC2CCC2)C1(C)C

Procedure:
1.7 ml of cyclobutanol were added to a solution of 4 g of tert.-butyl(1R,cis)2,2-dimethyl-3-[Z-2-carboxyethenyl]-cyclopropane-carboxylate in 20 ml of methylene chloride and 3.45 g of dicyclohexylcarbodiimide and a solution of 28 mg of 4-dimethylamino-pyridine in 20 ml of methylene chloride were added thereto at 0° to 5° C. with stirring. The mixture was stirred for 2 hours at 5° C. and 2 hours at room temperature and was then filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 9-1 n-hexane-isopropyl ether mixture yielded 2.3 g of tert.-butyl(1R,cis)2,2-dimethyl-3-[Z-2-(cyclobutoxycarbonyl)-ethenyl]cyclopropane-carboxylate.
Reaction SMILES: [C:1]1([NH:7][C:8]([CH:10]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B>C1COCC1>[C:14]([N:12]1[CH2:13][CH:10]([CH2:8][NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11]1)([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)Nc2ccccc2)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CNc2ccccc2)C1
Yield: 84.3 %

Procedure:
1-Boc-Azetidine-3-carboxylic acid phenylamide 47 (650 mg, 2.35 mmol) in 5 mL of dry THF was added slowly to 5 mL of 1.0 M borane in THF while stirring in an ice bath. The mixture was refluxed for 3 hours, then cooled in ice bath and quenched with 5 mL of aqueous HCl (10%), then treated with NaOH (10%) to pH ˜10. The mixture was extracted with ethyl acetate (3×20 mL). The extracts were combined and washed with brine (2×10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was passed through a short column (silica gel, ethyl acetate) to afford N-(1-Boc-azetidine-3-ylmethyl)aniline 48 as a colorless oil (520 mg, 84%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][S:11]([C:14]3[CH:19]=[C:18]([CH2:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:16][C:15]=3[Cl:24])(=[O:13])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.C(O[CH:30](N(C)C)[N:31]([CH3:33])[CH3:32])(C)(C)C>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][S:11]([C:14]3[CH:19]=[C:18](/[C:20](=[CH:30]\[N:31]([CH3:33])[CH3:32])/[C:21](=[O:23])[CH3:22])[CH:17]=[CH:16][C:15]=3[Cl:24])(=[O:13])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Nc2ccc3c(c2)OCO3)c1
Product: CC(=O)/C(=C/N(C)C)c1ccc(Cl)c(S(=O)(=O)Nc2ccc3c(c2)OCO3)c1

Procedure:
This compound is prepared analogously to Example 1-39 by replacing 2-Chloro-N-(3-cyano-phenyl)-5-(2-oxo-propyl)-benzenesulfonamide with N-Benzo[1,3]dioxol-5-yl-2-chloro-5-(2-oxo-propyl)-benzenesulfonamide and by replacing N,N-dimethylformamide dimethyl acetyl with t-butoxy-bis(dimethylamino) methane to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=O)([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1>C1COCC1.[Zn].[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10]([C:15]([O:17][CH3:18])=[O:16])([C:11]([O:13][CH3:14])=[O:12])[CH2:19][C:20]=2[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(CC(=O)c1ccc(F)cc1)(CC(=O)c1ccc(S(C)(=O)=O)cc1)C(=O)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)OC)CC(c2ccc(F)cc2)=C(c2ccc(S(C)(=O)=O)cc2)C1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
To a vigorously stirred mixture of 50.4 g (771 mmol) of zinc dust in 640 mL of THF at -78° C. under an atmosphere of nitrogen was added dropwise 60.4 mL (551 mmol) of titanium(IV) chloride. The reaction was warmed to ambient temperature with a water bath and then stirred at reflux for 1 hour. To the resulting dark mixture under reflux was added a solution of 15 g (32.3 mmol) of dimethyl 2-[2-(4-fluorophenyl)-2-oxoethyl]-2-[2-[4-(methyl sulfonyl)phenyl]-2-oxoethyl]propanedioate (prepared above) in 20 mL of THF. The resulting mixture was stirred at ambient temperature for 16 hours, filtered through a pad of celite, rinsed with ethyl acetate, and concentrated in vacuo. The residue was partitioned between water and ethyl acetate; the organic phase was washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica gel to give 6.26 g (44%) of 1-[2-(4-fluorophenyl)-4,4-dicarbomethoxycyclopenten-1-yl]-4-(methylsulfonyl)benzene which was identical to the material prepared in Step 8, Method A.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14])(=[O:10])=[O:9].[NH2:16][C:17]1[C:18]([C:39]#[N:40])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:24]=2[F:38])=[CH:21][N:22]=1>>[NH2:16][C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:2]3[C:3]([S:8]([NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:25][C:24]=2[F:38])=[N:19][C:18]=1[C:39]#[N:40]
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)c(C#N)n3)c(F)c2)OC1(C)C
Reactant: C[C@@H](CO)NS(=O)(=O)c1ccccc1Br
Product: C[C@@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)c(C#N)n2)c(F)c1

Procedure:
The title compound was prepared in manner similar to that described in Example 88 using (S)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide and 3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile. MS (ESI): mass calcd. for C20H18FN5O3S, 427.11; m/z found, 428.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.78 (d, J=1.6, 1H), 8.18 (dd, J=7.9, 1.4, 1H), 8.01 (m, 1H), 7.63 (m, 1H), 7.56 (m, 1H), 7.40-7.32 (m, 3H), 5.43 (s, 2H), 4.46-4.36 (m, 1H), 3.55-3.46 (m, 1H), 3.43-3.28 (m, 2H), 1.76 (t, J=5.7, 1H), 0.99 (d, J=6.6, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[CH2:9][OH:10].C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:8]=1[CH2:9][O:10][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: OCc1ccc(C(F)(F)F)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(C(F)(F)F)cc1Cl
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (1.1 ml) was added dropwise to a solution of 2-chloro-4-(trifluoromethyl)benzyl alcohol (2.64 g) and anhydrous triethylamine (2.3 ml) in anhydrous dichloromethane (30 ml) in a nitrogen stream under ice-cooling and the mixture was stirred for 30 minutes under the same conditions. The reaction mixture was successively washed with water, aqueous sodium hydrogencarbonate, and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate. The filtrate was concentrated to give 2-chloro-1-((methanesulfonyloxy)methyl)-4-(trifluoromethyl)benzene as white crystals (3.62 g).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[CH2:12]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20](Cl)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1.[I-].[Na+].C(N(CC)CC)C>O1CCOCC1>[CH:15]1[C:14]2[CH2:13][CH2:12][C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:20]([N:2]3[CH2:7][CH2:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C1=CCCNC1
Reactant: ClC1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)C1=CCCN(C2c3ccccc3CCc3ccccc32)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A mixture of methyl 1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (crude, 150 mmol), 5-chlorodibenzosuberane (41 g, 180 mmol, 1.2 eq), sodium iodide (2.2 g, 15 mmol, 0.1 eq) and triethylamine (63 mL, 450 mmol, 3.0 eq) in dioxane (300 mL) was stirred at 90° C. overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4, and concentrated. The crude product was passed through a silica gel plug, eluting with CH2Cl2. After concentration, the resulting solid was triturated with ether to yield 27 g (55%) of methyl 1-(10,11-dihydro5H-dibenzo[a,d][7]annulen-5-yl)-1,2,5,6-tetrahydropyridine-3-carboxylate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[F:31])[N:24]=[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:22]=1[CH3:38].Cl.O1CCOCC1.CN1C(=O)CCC1>>[N:4]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][C:29]=4[F:31])[N:24]=[C:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[C:22]=3[CH3:38])=[CH:11][C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure K, method 2 using 2,5-dimorpholinopyridin-3-amine (157 mg, 0.594 mmol; described herein), 4-chloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (162 mg, 0.59 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (150 μL, 0.59 mmol), and NMP (590 μL, 7.1 mmol), and heating in a microwave at 160° for 3 h. Purification afforded N-(2,5-di-4-morpholinyl-3-pyridinyl)-5-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.70 (1H, d, J=4.7 Hz), 7.98 (1H, d, J=8.2 Hz), 7.87-7.93 (2H, m), 7.83 (1H, d, J=11.7 Hz), 7.55-7.65 (2H, m), 7.38 (1H, m), 7.13-7.24 (1H, m), 6.46 (1H, d, J=2.7 Hz), 3.88-4.03 (4H, m), 3.77-3.88 (4H, m), 3.01-3.28 (4H, br. s.), 3.04-3.14 (4H, m), 2.23 (3H, s). Mass Spectrum (ESI) m/e=501.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:20][C:21]([CH3:23])=[O:22]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1/[CH:4]=[CH:20]/[C:21](=[O:22])[CH3:23]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)/C=C/c1c(Cl)cccc1Cl
Reaction time: 2 h

Procedure:
In a 250 ml single neck flask was charged 10 g (57 mmoles, 1.0 eq) of 2,6-dichlorobenzaldehyde dissolved in 100 ml of acetone. To this was added 2.28 g (5.7 mmoles, 0. 10eq.) of a 10% aqueous sodium hydroxide solution, dropwise and during the course of addition, temperature was kept no higher than 25°C., while the mixture was agitated continuously for 2 h. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to afford of (E)-4-(2,6-dichlorophenyl)-3-buten-2-one as a faintly yellow oil which was used directly in the following procedure.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:6]2[CH:7]=[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]([O:3][CH2:1][CH3:2])=[N:5]2)=[CH:30][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a mixture of ethyl 3-[3-ethoxy-1H-pyrazol-4-yl]propionate (1.50 g), 4-benzyloxybenzyl chloride (1.81 g), and N,N-dimethylformamide (30 ml), sodium hydride (60%, oily, 0.35 g) was added at 0° C., and then the mixture was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-(4-benzyloxybenzyl)-3-ethoxy-1H-pyrazol-4-yl]propionate (2.76 g, yield: 96%) was obtained as a colorless oily substance from the faction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH:30](C(C)(C)C)[O:31][SiH2]C)[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:30][OH:31])[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[SiH2]OC(c1nccc2oc(-c3nc(COC4CCN(C(=O)OC(C)(C)C)CC4)no3)cc12)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(OCc2noc(-c3cc4c(CO)nccc4o3)n2)CC1
Reaction time: 0.17 h

Procedure:
To solution of 4-{5-[4-(tert-butylmethylsilanyloxymethyl)furo[3,2-c]pyridine-2-yl]-[1,2,4]oxadiazole-3-ylmethoxy}piperidine-1-carboxylic acid tert-butyl ester (Preparation 8, 54 mg, 99 μmol) in THF was added TBAF (0.25 mL of a 1.0M solution in THF, 250 μmol). After 10 min, the mixture was diluted with EtOAc, washed with H2O and brine, before being dried and concentrated. Purification via column chromatography afforded the title compound: RT=2.92 min; m/z (ES+)=431.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=CC=CC=1.O=CCCC[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.O>[C:29]([O:28][C:27]([NH:26][CH2:7][CH2:2][CH2:1][N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:13]1)=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)CCCN1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)NCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCCN1CCN(CCCNC(=O)OC(C)(C)C)CC1
Reaction time: 20 h
Yield: 78.2 %

Procedure:
To a solution of methyl 4-(4-benzylpiperazin-1-yl)butanoate (500 mg, 2.68 mmoles) in dichloromethane (5 mL) was added tert-butyl 4-oxobutyl-carbamate (505 mg, 2.68 mmoles) and sodium triacetoxyborohydride (900 mg, 1.5 eq) and stirred 20 h. To the reaction mixture water was added followed by 1M aqueous sodium bicarbonate solution. The solution was extracted with ethyl acetate. The organics were evaporated to afford methyl 4-(4-{3-[(tert-butoxycarbonyl)amino]propyl}-piperazin-1-yl)butanoate (0.72 g, 75%). MS (ESI+) for m/z 358 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([O:16]C)=[O:15])[CH2:10][CH:11]1[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]1[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](CC1CC1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CC1CC1)C(=O)O
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a stirred solution of methyl N-(tert-butoxycarbonyl)-3-cyclopropyl-D-alaninate (1.0 g, 4.1 mmol) in MeOH (25 mL) at 0° C. was added 1M NaOH (5.0 mL, 5.0 mmol) dropwise. After 1 h, the cold bath was removed, and the reaction followed by HPLC. After 5.5 h, the methanol was removed at reduced pressure, and the residue diluted with 15 mL water and washed with ether. The aqueous layer was acidified with cold 2M HCl and extracted with three portions of EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated at reduced pressure to give the title compound as a colorless oil (929 mg): 1H NMR (300 MHz, CDCl3): δ 5.10–5.22 (br d, J=6.1 Hz, 1H), 4.35–4.46 (m, 1H), 1.72 (t, J=6.2 Hz, 2H), 1.39 (s, 9H), 0.70–0.85 (m, 1H), 0.42–0.60 (m, 2H), 0.03–0.21 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[N:6]=[C:2]([NH:1][C:20]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:27])[S:3][C:4]=1[CH2:12][N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: Nc1nc(-c2ccco2)c(CN2CCOCC2)s1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1nc(-c2ccco2)c(CN2CCOCC2)s1)c1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.2 %

Procedure:
2-Amino-4-(2-furyl)-5-(morpholinomethyl)thiazole (225 mg, 0.85 mmol) obtained in Step 1 was dissolved in DMF (4 mL), and nicotinoyl chloride hydrochloride (302 mg, 1.70 mmol) and triethylamine (0.24 mL, 1.70 mmol) were added thereto, followed by stirring at room temperature for 4 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the entitled Compound 94 (73.0 mg, 23%).
Reaction SMILES: COC[O:4][C:5]1[C:10]2[C:11]3([CH2:14][O:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:13][CH2:12]3.O>CO.Cl>[C:11]12([C:10]3=[C:5]([OH:4])[CH:6]=[CH:7][CH:8]=[C:9]3[O:15][CH2:14]1)[CH2:13][CH2:12]2
Reactant: COCOc1cccc2c1C1(CC1)CO2
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1cccc2c1C1(CC1)CO2
Temperature: 50 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of 4-{[(methyloxy)methyl]oxy}spiro[1-benzofuran-3,1′-cyclopropane] (Reference Intermediate 213, 118 mg) in methanol (5 ml), HCl 2N in water (0.286 mL, 0.572 mmol) was added and the reaction mixture was stirred overnight at 50° C. Combined solvents were removed under reduced pressure and the residue was re-dissolved in toluen (10 ml) and the solvent was removed. The residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluents affording the title compound as a white solid (70 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:30])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)=[CH:14][CH:15]=2)[O:10][C:9](=[O:29])[CH:8]=1.C(CN)O>CN(C=O)C>[OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:30])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[O:10][C:9](=[O:29])[CH:8]=1
Reactant: O=C(Cc1cc(=O)oc2cc(O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)ccc12)NCCO
Solvent: NCCO
Solvent: CN(C)C=O
Product: O=C(Cc1cc(=O)oc2cc(O)ccc12)NCCO
Yield: 71.5 %

Procedure:
200 mg (0.85 mmole) of 7-hydroxycoumarin-4-methyl ester 2 (prepared as described in Scheme 1) was dissolved in 5 ml of dry DMF and stirred with 0.5 g (8.5 mmoles) of ethanolamine at room temperature for 52 hrs. The DMF was then evaporated from the dark brown solution. The residue obtained after further evaporation with methanol was dissolved in water and purified on a C-8 RP-HPLC column using a gradient of 5/95 CH3CN/water (0.1% TFA) to 30170 CH3CN/water (0.1% TFA) in 25.5 min. The peak eluting at 21.6 min was collected and lyophilized to give 0.16 g of an off-white powder MS: Mol. Formula, C13H13NO5 ; Calculated: 263.26, found (M+H)+ 264.2.