Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[CH2:11][C@H:10]2[N:5]([C:6](=[O:12])[CH2:7][CH2:8][CH2:9]2)[C@H:4]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=2)[CH2:3]1.C(N(CC)CC)C.CS(Cl)(=O)=O.CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C.O>[F:19][C:17]1[CH:18]=[C:13]([C:4]2[N:5]3[C@H:10]([CH2:11][CH2:2][CH:3]=2)[CH2:9][CH2:8][CH2:7][C:6]3=[O:12])[CH:14]=[C:15]([F:21])[C:16]=1[F:20]
Reactant: O=C1CCC[C@H]2CC(O)C[C@@H](c3cc(F)c(F)c(F)c3)N12
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCC[C@H]2CCC=C(c3cc(F)c(F)c(F)c3)N12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (6S*,9aS*)-8-hydroxy-6-(3,4,5-trifluorophenyl)octahydroquinolizin-4-one obtained in Examples 13 and 14 (3.57 g) in THF (30 mL) was cooled to 0° C. Triethylamine (3.2 mL) and methanesulfonyl chloride (1.3 mL) were added to the reaction solution, which was then stirred at room temperature for 30 minutes. Potassium tert-butoxide (3.9 g) and THF (60 mL) were added to the reaction mixture, and the reaction mixture was heated under reflux for 80 minutes and left to cool. Then, water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.65 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C([NH:34][C@@H:35]([C:37](O)=[O:38])[CH3:36])(OCC1C=CC=CC=1)=O>>[NH2:34][C@H:35]([CH3:36])[C:37]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:38]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: Cl
Product: C[C@@H](N)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
The title compound was prepared substantially following the procedures as set forth in Step 4, Example 1, Method B and employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-D-alanine as the starting materials. Subsequent hydrogenation of the resulting product in accordance with the procedures of Step 5, Example 1, Method B, and RP-HPLC purification yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 4.04 (m, 1H), 3.89 (q, J=6.9 Hz, 1H,), 3.39 (dd, J=5.7, 13.5, 1H), 3.23 (dd, J=5.4, 13.5 Hz, 1H,), 1.85 (m, 2H), 1.77-1.62 (m, 6H), 1.57-1.53 (m, 2H), 1.48 (d, J=6.9 Hz, 3H), 1.37-1.15 (m, 3H), 1.08-0.97 (m, 2H). 31P NMR (CD3OD, 300 MHz): δ 43.74. LCMS m/z: [M+H]+=307.2.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[N:5]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:3]=1.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:31][C:32]1[CH:33]=[C:34]([C:2]2[C:7]([CH3:8])=[C:6]([N:9]3[CH2:14][CH2:13][N:12]([C:15]4[C:20]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:11][CH2:10]3)[N:5]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:3]=2)[CH:35]=[CH:36][C:37]=1[F:38]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Cc1c(Cl)nc(N2CCOCC2)nc1N1CCN(c2ncccc2C(F)(F)F)CC1
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: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(F)c(Cl)c2)nc(N2CCOCC2)nc1N1CCN(c2ncccc2C(F)(F)F)CC1
Temperature: 80 °C

Procedure:
A mixture of 4-(4-chloro-5-methyl-6-{4-[3-(trifluoromethyl)(2-pyridyl)]piperazinyl}pyrimidin-2-yl)morpholine (66 mg, 0.15 mmol), 3-chloro-4-fluorophenylboronic acid (35 mg, 0.2 mmol), Pd(PPh3)4 (10 mg) and 2M potassium carbonate (0.2 mL) in toluene (3 mL) is heated, under a nitrogen atmosphere, at 80° C. for 4 hours. The reaction mixture is cooled and the layers separated. The aqueous layer is extracted with EtOAc (3×10 mL) and the combined organics washed with 4M NaOH (10 mL), water (10 mL), brine (10 mL), dried (MgSO4) and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (70% hexane/30% ether) to give the title compound. MS 537 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Br)[CH:6]=[CH:5]2.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH:6]=[CH:5]2
Reactant: C1CCNC1
Reactant: BrCc1ccc2cc(Br)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc2nc(CN3CCCC3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.60 g (15.28 mmol) 6-bromo-2-bromomethyl-quinoline are added to a solution of 1.40 mL (16.8 mmol) pyrrolidine and 6.34 g (45.9 mmol) K2CO3 in 50 mL acetonitrile. The reaction is stirred overnight at RT and then the inorganic salts are filtered off. The organic phase is washed with water and the aqueous phase is extracted with EtOAc. The combined organic extracts are dried over MgSO4 and the solvent is eliminated i.vac.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([F:31])[C:16]([C:19]#[C:20][C:21]3[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][OH:28])=[CH:23][CH:22]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:28][CH2:27][CH2:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([C:20]#[C:19][C:16]2[C:15]([F:31])=[CH:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=3)=[CH:18][N:17]=2)=[CH:30][CH:29]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., 63 μL (0.816 mmol) of methanesulfonyl chloride was added dropwise to a solution of 0.20 g (0.544 mmol) of 2-{4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]phenoxy}ethanol and 0.11 mL (0.816 mmol) of triethylamine in 10 mL of DCM and the mixture was stirred for 16 hours at RT. A further 0.11 mL (0.816 mmol) of triethylamine and 63 μL (0.816 mmol) of methanesulfonyl chloride were added and the mixture was stirred for 8 hours. The reaction mixture was diluted with DCM, and the organic phase was washed with water and dilute aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 0.24 g (99% of theoretical); C22H17ClFNO4S (M=445.892); calc.: molpeak (M+H)+: 446/448 (Cl); found: molpeak (M+H)+: 446/448 (Cl); HPLC-MS: 6.19 minutes (method B).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][C@@H:6]1[C@H:9]([NH:10][C:11](=[O:38])/[C:12](=[N:26]\[O:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])/[C:13]2[N:14]=[C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:16][CH:17]=2)[C:8](=[O:39])[NH:7]1.C1N=CN([C:45](N2C=NC=C2)=[O:46])C=1>C(Cl)(Cl)Cl.CCOC(C)=O>[C:22]([O:21][C:19]([NH:18][C:15]1[S:16][CH:17]=[C:13](/[C:12](=[N:26]/[O:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])/[C:11](=[O:38])[NH:10][C@H:9]2[C@@H:6]([CH2:5][N:4]3[CH2:3][CH2:2][NH:1][C:45]3=[O:46])[NH:7][C:8]2=[O:39])[N:14]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCN)cs1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CN2CCNC2=O)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of tert-Butyl 2-(((Z)-(2-(((2R,3S)-2-(((2-aminoethyl)amino)methyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (100 mg, 0.151 mmol) in chloroform (756 μl) was added CDI (98 mg, 0.604 mmol) followed by TEA (105 μl, 0.756 mmol). After stirring at rt for 1 h it was diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (73 mg, 81%) as a white solid. It was used as crude in step 4. LCMS: Rt=0.70 min, m/z=596.2 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9].[N+]([O-])([O-])=O.[Ga+3:14].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C([O-])([O-])=O.[Na+].[Na+]>O>[Ga:14].[CH3:1][C:2]1[O:8][CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9]
Reactant: [Ga+3]
Agent: Cc1occc(=O)c1O
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: [Ga]
Temperature: 23 °C
Reaction time: 0.08 h

Procedure:
Maltol is dissolved in chloroform to form a 0.75M solution, and gallium nitrate nonohydrate is dissolved in ethanol to form a 0.5M solution. To 20 mL of the 0.75M maltol solution is slowly added, with continuous stirring, 10 mL of the 0.5M gallium nitrate nonohydrate solution. The resulting solution is stirred for 5 minutes at 23° C. Approximately 5.5 g (a large excess) of powdered Na2CO3 is added with stirring to raise the pH to close to 7. When the sodium carbonate is added, a trace of water may sometimes need to be added to facilitate the reaction, which is evidenced by some effervescence. Stirring is then continued for an additional ten minutes. The mixture is filtered to remove all solids, and the filtrate is evaporated in a rotary evaporator. The remaining crystalline solid is the 3:1 maltol:gallium composition. This composition is analyzed using powder x-ray diffraction and found to consist of orthothrombic crystals with unit cell dimensions of about a=18.53(1)Å, b=16.96(1)Å, c=12.05(1)Å. Crystallization from other solvents or under other conditions may produce other crystal structures. It is contemplated that amorphous structures can also be used in the methods and compositions of this invention.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=3)[O:8][C:7](=[O:16])[C:6]=2[CH:17]=1.II>CC(C)=O.CN1CCCC1=O>[OH:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]1[C:6](=[C:17]3[C:2](=[CH:3][CH:4]=1)[NH:1][C:5]([CH3:14])([CH3:6])[CH:4]=[C:3]3[CH3:2])[C:7](=[O:16])[O:8]2
Reactant: Nc1ccc2c(c1)c(=O)oc1cc(O)ccc12
Agent: II
Solvent: CC(C)=O
Solvent: CN1CCCC1=O
Product: CC1=CC(C)(C)Nc2ccc3c(c21)c(=O)oc1cc(O)ccc13
Temperature: 110 °C
Reaction time: 72 h
Yield: 48 %

Procedure:
In a pressure tube, 8-amino-3-hydroxybenzo[c]chromen-6-one (Reference Compound No. 1-1-(3), 40.0 g, 176 mmol) was dissolved in acetone (440 mL)-N-methylpyrrolidone (240 mL), iodine (17.9 g, 70.5 mmol) was added thereto, the pressure tube was sealed, and then the reaction mixture was stirred at 110° C. for 3 days. After cooling down, acetone was removed under reduced pressure. To the obtained residue, ethyl acetate (700 mL), hexane (150 mL) and 1% aqueous sodium thiosulfate solution (700 mL) was added thereto and the mixture was separated. The water layer was extracted with a mixed solvent of ethyl acetate (250 mL)-hexane (50 mL) (3 times). The organic layer was combined and washed with water (500 mL, 3 times) and saturated brine (500 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. To the obtained residue, chloroform (150 mL) was added and the unsoluble materials were filtered. After the filtrate was concentrated, the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (26.0 g) as a yellow solid. (Yield 48%)
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH3:15]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:15][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CNc1ccccc1
Reactant: CI
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(C)c1ccccc1
Temperature: 70 °C

Procedure:
Ethyl N-Phenylglycinate (2 g, 11.1 mmol) was dissolved in toluene (4.5 mL) and iodomethane (0.35 mL, 5.6 mmol) added. After warming at 70° C. over 4 hours, the reaction mixture was cooled to ambient temperature and diluted with EtOAc. The organic layer was washed several times with brine, dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (10:1 hexanes/EtOAc) afforded a quantitative yield of the title compound as a light yellow oil. MS (ES+) m/z 194 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:17])=[CH:4][C:5]2[C:6](=[O:16])[CH:7]3[CH2:14][CH2:13][C:12](=O)[N:8]3[CH2:9][C:10]=2[CH:11]=1.Cl.[NH2:19][OH:20].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[Cl:1][C:2]1[C:3]([Cl:17])=[CH:4][C:5]2[C:6](=[O:16])[CH:7]3[CH2:14][CH2:13][C:12](=[N:19][OH:20])[N:8]3[CH2:9][C:10]=2[CH:11]=1
Reactant: O=C1c2cc(Cl)c(Cl)cc2CN2C(=O)CCC12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1c2cc(Cl)c(Cl)cc2CN2C(=NO)CCC12
Yield: 78.7 %

Procedure:
A stirred suspension of 6.37 g of 7,8-dichloro-1,10a-dihydropyrrolo[1,2-b]isoquinoline-3,10[2H,5H]-dione in 95% ethanol (40 ml) was treated with a premixed solution of 3.28 g of hydroxylamine hydrochloride in water (25 ml) and 6.42 g of sodium acetate trihydrate in water (25 ml). The solution was heated at reflux for 2.5 hours. The solution was then cooled with an ice-water bath as a precipitate began to separate from the reaction mixture. The solid was collected by vacuum filtration and recrystallized from 95% ethanol (250 ml) to afford 5.29 g of crystals, m.p. 245°-246° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(CCCCCCO)c1cc(F)ccc1F
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCCCCC1
Yield: 58.1 %

Procedure:
In toluene (5 ml) was dissolved 7-[(4-chlorophenyl)sulfonyl]-7-(2,5-difluorophenyl)-1-heptanol (200 mg, 0.496 mmol), followed by the addition of cyanomethylenetri-n-butylphosphorane (400 mg, 1.66 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, the residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=10:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with hexane, whereby the title compound (111 mg, 0.288 mmol, 58%) was obtained as a white powder.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[N:11]=[C:10]([NH:12][CH3:13])[C:9]([NH2:14])=[CH:8][CH:7]=1.[OH-].[Na+]>Cl>[Cl:5][C:6]1[N:11]=[C:10]2[N:12]([CH3:13])[N:1]=[N:14][C:9]2=[CH:8][CH:7]=1
Reactant: CNc1nc(Cl)ccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1nnc2ccc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
NaNO2 (350 mg, 5.08 mmol) was added to a stirred solution of 6-chloro-N2-methylpyridine-2,3-diamine (Step 102.2) (800 mg, 5.08 mmol) in 2N HCl (8 mL) at 0° C. and the resulting mixture was stirred for 10 min at 0° C. The reaction was basified with 2N NaOH and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (50% EtOAc/hexane) to afford the title product (545 mg, 3.23 mmol, 64% yield) as beige solid. tR: 0.69 min (LC-MS 2); ESI-MS: 168/170 [M+H]+ (LC-MS 2); Rf=0.46 (50% EtOAc/hexane); 1H NMR (400 MHz, DMSO-d6) δ ppm 4.25 (s, 3H) 7.44-7.62 (m, 1H) 8.62 (d, J=8.6 Hz, 1H).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][N:9]1[C:13]([CH2:14][OH:15])=[CH:12][CH:11]=[N:10]1.F[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1>O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([O:15][CH2:14][C:13]2[N:9]([CH3:8])[N:10]=[CH:11][CH:12]=2)=[N:18][CH:19]=1
Reactant: Fc1ccc(F)nc1
Reactant: Cn1nccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nccc1COc1ccc(F)cn1
Reaction time: 2 h
Yield: 58.4 %

Procedure:
60% Sodium hydride (390 mg) was added to a dimethylformamide (9.0 mL) solution of (1-methyl-1H-pyrazol-5-yl)methanol (1.00 g) at a room temperature, and the obtained solution was then stirred for 2 hours. Thereafter, 2,5-difluoropyridine (1.17 g) was added to the reaction solution, and the mixed solution was then stirred for 16 hours. Subsequently, water was added to the reaction solution, and the obtained mixture was then extracted with hexane/ethyl acetate (1/2). The organic layer was concentrated under a reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=95:5 to 60:40), so as to obtain the title compound (1.08 g) in the form of a colorless solid.
Reaction SMILES: [C:1](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][CH2:26][CH3:27])[CH:22]=2)[CH:17]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[CH:16]1[C:37]([O:39]C)=[O:38])([O:3]C)=[O:2].[OH-].[Na+]>O1CCOCC1>[C:1](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][CH2:26][CH3:27])[CH:22]=2)[CH:17]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[CH:16]1[C:37]([OH:39])=[O:38])([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1/C=C/C(=O)OC)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1/C=C/C(=O)O)C(C(=O)O)C2c1ccc2c(c1)OCO2

Procedure:
To a solution of methyl(1RS,2SR,3SR)-3-[2-[(E)-2-carbomethoxyethen-1-yl]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (80 mg, 0.15 mmol) in dioxane (2 ml) was added 1N NaOH (0.5 ml, 0.5 mmol). The resulting mixture was heated to reflux for 3 h, then cooled and concentrated under reduced pressure. The residue was partitioned between dilute aqueous HCl and ethyl acetate. The ethyl acetate extract was washed with water and dried (MgSO4 anhydrous). The solvent was removed in vacuo and the title compound was obtained as a white solid (73 mg, 96%).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:99]=[C:100]([F:102])[CH:101]=1)[CH2:50][N:51]1[CH:55]=[CH:54][C:53]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([CH:71]5[CH2:76][CH2:75][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:73][CH2:72]5)=[C:67]([NH:84][S:85]([CH3:88])(=[O:87])=[O:86])[CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:99]=[C:100]([F:102])[CH:101]=1)[CH2:50][N:51]1[CH:55]=[CH:54][C:53]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([CH:71]5[CH2:72][CH2:73][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:75][CH2:76]5)=[C:67]([NH:84][S:85]([CH3:88])(=[O:87])=[O:86])[CH:66]=4)[CH:63]=3)[NH:58][CH:57]=2)=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(Cc4cc(F)cc(F)c4)n3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5ccn(Cc6cc(F)cc(F)c6)n5)c4c3)cc2NS(C)(=O)=O)CC1
Yield: 67.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(methylsulfonamido)phenyl)piperidine-1-carboxylate (200 mg, 0.245 mmol) was hydrolyzed by lithium hydroxide (52 mg, 1.225 mmol) in THF/methanol/water (3/5/2 mL) to yield 110 mg (66.6% yield) of the titled compound. MS: m/z=662.8 (M+1)
Reaction SMILES: C1CC1.[CH2:4]=[CH:5][C:6]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])([CH3:8])[OH:7].[C:15](Cl)(=[O:17])[CH3:16]>>[C:15]([O:7][C:6]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])([CH3:8])[CH:5]=[CH2:4])(=[O:17])[CH3:16]
Reactant: C=CC(C)(O)CCC=C(C)C
Reactant: CC(=O)Cl
Agent: C1CC1
Product: C=CC(C)(CCC=C(C)C)OC(C)=O

Procedure:
The cyclopropane derivative of linalool was then reacted with acetyl chloride to produce the cyclopropanated derivative of linalool acetate.
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[C:17]([C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]2[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=2[OH:20])=[O:19])=[CH:16][CH:15]=1)#[N:18]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(C#N)cc1)OC
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(C#N)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 46 %

Procedure:
3-[(4-Cyanobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 62-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (46% yield); mp 161° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.75 (3H, s, OCH3), 4.17 (2H, s, NCH2), 4.93 (2H, s, NCH2), 7.44 (2H, d, J=8.2 Hz, aromatics), 7.65 (2H, d, J=8.2 Hz, aromatics). Anal. calcd for C15H15N3O4: C, 59.79; H, 5.01; N, 13.94. Found: C, 59.51; H, 4.90; N, 13.69.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[F:13][C:14]([F:42])([F:41])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:40]=[CH:39][C:34]([C:35](OC)=[O:36])=[CH:33][CH:32]=1.Cl>O1CCCC1.COCCOC>[F:13][C:14]([F:41])([F:42])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:40]=[CH:39][C:34]([C:35](=[O:36])[CH2:3][S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:6])=[O:5])=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: CS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: O=C(CS(=O)(=O)c1ccccc1)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A solution of 864 mg. of sodium hydride and 5.3 g. of methylphenylsulfone in 20 ml. of 1,2-dimethoxyethane is stirred at 60° C. for one hour under an atmosphere of argon. To this solution is then added a solution of 5.0 g. of methyl 4-[15-(trifluoromethyl)pentadecylamino]benzoate and 50 ml. of tetrahydrofuran and the reaction mixture is stirred at 60° C. for 1.5 hours. The mixture is cooled, poured onto ice, acidified with dilute hydrochloric acid to pH 3 and then extracted with chloroform. The organic layer is separated, washed three times with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated to dryness. The crude solid is chromatographed on silica gel, eluting with methylene chloride to yield the product.