Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1(CC)[C:7](=[O:8])[O:6][N:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH2:10])[C:4]1=[O:17])C.C(Cl)Cl.CCCCCC.O1C(=O)CC(=O)N1>C(Cl)(Cl)Cl.CCCCCC>[C:11]1([C:9]([N:5]2[C:4](=[O:17])[CH2:3][C:7](=[O:8])[O:6]2)=[CH2:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=C(c1ccccc1)N1OC(=O)C(CC)(CC)C1=O
Agent: O=C1CC(=O)ON1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C=C(c1ccccc1)N1OC(=O)CC1=O

Procedure:
Analysis of crude 4,4-diethyl-2-(1phenylethenyl) isoxazolidine 3,5-dione was performed by thin layer chromatography (TLC) on Bakerflex Silica Plates using methylene chloride:-hexane (98:2) as the mobile phase. Components appeared at Rf 0.80, 0.78, 0.72, 0.60, 0.52, and 0.0. A sample of the crude isoxazolidine-3,5-dione weighing 3.50 g (38.4% purity by HPLC) was dissolved in 5.0 ml of chloroform:hexane (98:2), and applied to a 37×2 cm (O. D.) chromatography column containing 60-200 mesh silica gel as the adsorbant. The eluting solvent was chloroform:hexane (98:2) and the elution rate was 1 ml/min. Twenty 50 ml fractions were collected and analyzed by TLC as described above Fractions 11, 12, 13 and 14 showed a single component, Rf 0.60. These fractions were combined and concentrated to give 1.0 g of pure 4,4-diethyl-2-(1-phenylethenyl-isoxazolidine-3,5-dione as a viscous oil: IR(neat) 2976(w), 2938(w), 2882(w), 1816(s), 1721(s) and 1626 (s)cm-1 ; UV max (CH3OH) 245 nm (ε6800); 1H NMR (CDCl3) δ 7.72 (s, overlapping a small m, 5, aromatic CH) 5.47 (s, 1, vinyl CH), 5.34 (s, 1, vinyl CH), 1.83 (q, 4, CH2) and 0.91 (t, 6, CH3); high resolution MS, calc'd for: C15H17NO3 : 259.1208. Found: 259.1209; MS m/z (rel. intensity) 259 (44), 215 (48), 199 (85), 108 (89) and 106 (100). Elemental Analysis: Calc'd for: C15H17NO3 :C, 69.48; H, 6.61; N, 5.40.Found: C,69,64; H, 6.91; N, 5.04
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:22][CH2:23][OH:24])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.ClS([N:29]=[C:30]=[O:31])(=O)=O.O.Cl>C(Cl)Cl.CO.CC(O)C>[ClH:21].[NH2:8][CH:9]([CH2:22][CH2:23][O:24][C:30](=[O:31])[NH2:29])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NC(CCO)COc1noc2ccc(Cl)cc12
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: NC(=O)OCCC(N)COc1noc2ccc(Cl)cc12
Reaction time: 0.5 h

Procedure:
To a solution of 0.67 g of 3-(2-tert-butoxycarbonylamino-4-hydroxybutoxy)-5-chloro-1,2-benzoisoxazole in 6 ml of methylene chloride is added 0.30 g of chlorosulfonyl isocyanate at -30° C., and the temperature is gradually elevated to 0° C., after which 5 ml of water is added and they are stirred for 30 minutes. The solvent is removed by distillation under reduced pressure, water and ethyl acetate are added to the residue obtained, and after shaking, the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The oily product obtained is dissolved in 8 ml of methanol, and thereto is added 1.5 ml of a 2-propanol solution (6.5M) of hydrogen chloride at room temperature, after which they are subjected to reaction at the same temperature for 18 hours. The crystals precipitated are collected by filtration, to obtain 0.29 g of colorless, crystalline 3-(2-amino-4-carbamoyloxybutoxy)-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 213.5°-215.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[O:20][C:21]([C:24]3[CH:29]=[C:28]([CH:30]=[CH2:31])[CH:27]=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=3)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[H][H]>CCO.CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[O:20][C:21]([C:24]3[CH:25]=[C:26]([C:32]([F:35])([F:33])[F:34])[CH:27]=[C:28]([CH2:30][CH3:31])[CH:29]=3)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:10])=[O:11]
Reactant: [H][H]
Reactant: C=Cc1cc(-c2ccc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)o2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1cc(-c2ccc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)o2)cc(C(F)(F)F)c1
Yield: 24 %

Procedure:
A mixture of example 114 compound (20 mg, 0.04 mmol) and 10% Pd—C (10 mg) in EtOH was hydrogenated using hydrogen balloon for 2 hours. The mixture was diluted with EtOAc, filtered through silica gel pad and washed with EtOAc. The filtrate was concentrated under reduced pressure to give the title compound (5 mg, 24%) after recrystallization with EtOAc/Hex.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][NH:36][CH:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:36]([CH3:35])[CH:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CNC1CCN(C)CC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CN1CCC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[methyl-(1-methyl-piperidin-4-yl)-amino]-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Methyl-(1-methyl-piperidin-4-yl)-amine following General Procedure C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[CH3:12].B(O)O>>[CH3:12][CH:7]1[C:8]2[C:3](=[C:2]([C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][NH:6]1
Reactant: CC1NCCc2c(Br)cccc21
Agent: OBO
Product: CC1NCCc2c(-c3ccncc3)cccc21

Procedure:
In close analogy to the procedure described above, 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]#[N:23])=[CH:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C[Sn]([N:28]=[N+:29]=[N-:30])(C)C>C1(C)C=CC=CC=1>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3[NH:30][N:29]=[N:28][N:23]=3)=[CH:14]2)[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC2(C=C(C#N)c3ccccc32)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(C=C(c3nnn[nH]3)c3ccccc32)CC1
Yield: 62.5 %

Procedure:
To a solution of the title compound from Step A (298 mg, 0.96 mmol) in toluene was added trimethylstannyl azide (787 mg, 3.84 mmol). The mixture was refluxed for 18 hours and then cooled and 1N HCL was added. The aqueous layer was extracted with ethyl acetate (3×1 vol) and the organic layer was washed with water, brine, dried over magnesium sulfate and concentrated. Purification by MPLC (LH20 column methanol) provided the title compound (214 mg, 0.60 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(S)C=CC=1Cl.ClCCO.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][O:12][S:34]([CH3:33])(=[O:36])=[O:35])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCSc1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: OCCCl
Agent: Sc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CS(=O)(=O)OCCSc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
A solution of 2-[(3,4-dichlorophenyl)thio]ethanol (117.97 g, 0.53 mole) prepared from 3,4-dichlorothiophenol and 2-chloroethanol, in benzene (500 ml) with triethylamine (53.5 g, 0.53 mole) was prepared. To this solution was added dropwise a benzene solution of methanesulfonyl chloride (60.9 g, 0.53 mole) over 1 hr (in an ice bath). The reaction mixture was stirred at room temperature overnight and then filtered. Solvent was removed by evaporation to give an oil which crystallized. A 5 g portion was recrystallized from isopropyl ether to give 4.61 g (47.9% yield based on aliquot) of white crystalline solid, m.p. 53°-55° C.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[C:20]([NH:21][C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:37])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:12]=2)[NH:7][CH:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)CCc1c[nH]c2ccc(Nc3ncccc3N)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CCc1c[nH]c2ccc(Nc3ncccc3NC(=O)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.7 %

Procedure:
To a stirred solution of 3-(2-dimethylaminoethyl)-5-(3-aminopyrid-2-ylamino)-1H-indole (0.157 g, 0.53 mmol) and triethylamine (74 μL, 0.54 mmol, 1.0 eq) in anhydrous tetrahydrofuran (3 mL) was added dropwise benzoyl chloride (62 μL, 0.54 mmol, 1.0 eq). The resulting reaction mixture was stirred at room temperature under nitrogen for 15 minutes. A saturated solution of sodium hydrogen carbonate (10 mL) was added, and this aqueous mixture was extracted with ethyl acetate (3×10 mL). The organic extracts were combined, dried (MgSO4), and evaporated under reduced pressure. The residue was triturated in diethyl ether to afford the title compound (0.082 g, 39%) as an amorphous solid: 13C NMR (DMSO-d6) δ166.5, 151.9, 144.5, 134.5; 132.7, 132.5, 131.6, 128.3, 128.0, 127.2, 122.8, 119.6, 117.3, 113.3, 112.1, 110.8, 110.4, 59.9, 45.0, 23.1; LRMS (m/z, relative intensity) 399 (M+, 100), 354 (33), 249 (10), 235 (18), 204 (40), 160 (86); HRMS calculated for C24H25N5O 399.2062, found 399.2080.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)c(Br)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Br
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a slurry of 2-bromo-1,4-dimethylbenzene (10.13 g, 54.7 mmol) in acetic acid (44 mL) at 8° C. (inner temperature) was added a solution of nitric acid (6 mL, 134 mmol) in sulfuric acid (22 mL, 413 mmol) over 45 min; temperature rose to 10° C. After 1 hr, the reaction mixture was poured into ice and stirred, filtered and washed with water to give a light yellow solid. This was triturated with EtOH (10 mL) to give the desired product (4.550 g, 19.78 mmol, 36.1% yield) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]=[CH:15][C:14](=O)[C:13](=[CH:18][N:19](C)C)[CH:12]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(=O)C.O.[NH2:32]N>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:16]=[CH:15][C:14]3[NH:32][N:19]=[CH:18][C:13]=3[CH:12]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)C1C(=CN(C)C)C(=O)C=CN1S(=O)(=O)c1ccc(Cl)cc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1c2cn[nH]c2C=CN1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
A flask was charged with compound 104 (5.8 g, 14.6 mmol), acetic acid (10 mL) and EtOH (10 mL). Hydrazine hydrate (1.4 mL, 30 mmol) was added and the reaction stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue was taken up in EtOAc. The organic layer was washed with sat. aq. NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield crude material that was purified by flash chromatography (50% EtOAc/hexanes) to yield 1.63 g (30%) of compound 105 as a yellow foam. 1H NMR (CDCl3) δ 7.76 (d, J=6.3 Hz, 2H), 7.48-7.41 (m, 3H), 6.90-6.87 (m, 1H), 5.96-5.93 (m, 1H), 5.80 (s, 1H), 4.13-4.11 (m, 2H), 1.24-1.18 (m, 3H; MS (m/z) 368.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21]([NH:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5])(=[O:23])=[O:22]
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Product: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1c(F)cccc1F

Procedure:
Methyl 2-amino-4-chlorobenzoate was sulfonylated with 2,6-difluorobenzenesulfonyl chloride and hydrolyzed as in EXAMPLE 1, Parts A and B.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:35])[O:14][CH2:15][C@@H:16]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:5]2.[C:36]([O:40][C:41]([NH:43][CH2:44][C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:36]([O:40][C:41]([NH:43][CH2:44][C:45]([NH:20][CH2:19][CH2:18][CH2:17][C@H:16]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:15][O:14][C:13](=[O:35])[NH:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN)COC(=O)Nc1cc2cc(F)ccc2cn1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCNC(=O)CNC(=O)OC(C)(C)C)COC(=O)Nc1cc2cc(F)ccc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a solution of (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentyl 6-fluoroisoquinolin-3-ylcarbamate (96 mg, 0.19 mmol), 2-(tert-butoxycarbonylamino)acetic acid (51 mg, 0.29 mmol) and HBTU (110 mg, 0.29 mmol) in DMF (1.0 mL) was added DIEA (63 □L, 0.38 mmol). The mixture was stirred at RT for 30 min. The mixture was filtered and the filtrate was purified by RP-HPLC using a mixture of acetonitrile and water to give (6-Fluoro-isoquinolin-3-yl)-carbamic acid (S)-5-(2-tert-butoxycarbonylamino-acetylamino)-2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentyl ester (105 mg, 83%). LRMS (M+Na+) m/z 663.2.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[CH2:15]([NH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Product: CCCCNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
Using the general method of Example 41, 4-hydroxy-3-nitroquinoline (38.4 g, 0.2 moles) was chlorinated then reacted with n-butylamine (24.7 mL, 0.4 mole) to provide the desired product as a yellow sold.
Reaction SMILES: C([O:8][C:9]([CH:11]([CH2:25][CH2:26][C:27]([O:29]CC1C=CC=CC=1)=[O:28])[CH2:12][P:13]([CH2:16][CH2:17][CH2:18][C:19]1C=CC=CC=1)(=[O:15])[OH:14])=[O:10])C1C=CC=CC=1.[H-].[Na+].C=C(CCC(OCC1C=CC=CC=1)=O)C(OCC1C=CC=CC=1)=O.Cl>C1COCC1.CCOC(C)=O>[CH2:16]([P:13]([CH2:12][CH:11]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:9]([OH:10])=[O:8])([OH:15])=[O:14])[CH2:17][CH2:18][CH3:19]
Reactant: O=C(CCC(CP(=O)(O)CCCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCP(=O)(O)CC(CCC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 154.3 %

Procedure:
To a solution of 4-methylbenzyl-O-benzylphosphinic acid (2, R=4-methylbenzyl)(2.16 g, 8.3 mmol) in THF (15 mL) was added sodium hydride (0.10 g, 60% dispersion in oil) followed by dibenzyl 2-methylenepentanedioate at 0 C, and the mixture was stirred at rt for 4 h. The reaction mixture was then diluted with EtOAc (50 mL) and poured into 1N HCl (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated. This material was purified by silica gel chromatography (hexanes: EtOAc, 4:1 to 1:1) to give 3.41 g of 2,4-di(benzyloxycarbonyl)butyl(4-methylbenzyl)-o-benzylphosphinic acid (4, R=4-methylbenzyl) as colorless oil (70% yield): Rf 0.61 (EtOAc); 1H NMR (CDCl3) delta 1.6-1.8 (m, 1 H), 1.9-2.0 (m, 2 H), 2.1-2.4 (m, 6 H), 2.7-2.9 (m, 1 H), 3.05 (dd, J=9.0, 16.8 Hz, 2 H), 4.8-5.1 (m, 6 H), 7.0-7.1 (m, 4 H), 7.2-7.4 (m, 15 H).
Reaction SMILES: [CH:1]1([CH:7]([CH3:12])[C:8]([O:10]C)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].S(=O)(=O)(O)O>>[CH:1]1([CH:7]([CH3:12])[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(C)C1CCCCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
Into a 500 ml round bottom flask 50 g of methyl 2-cyclohexylpropionate and 70 g of 25% sodium hydroxide were charged. The mixture was stirred at 80° C. for 8 hours. To the reaction mixture 120 g of 20% sulfuric acid was gradually added under ice-cooling to separate a carboxylic acid. The carboxylic acid was extracted with hexane. The mixture obtained was distilled to obtain 42.3 g of 2-cyclohexylpropionic acid having a civet- and animal-like odor (yield: 92%, purity: 99.9%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2.[CH3:15]OS(OC)(=O)=O>C1(C)C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:15])[C:9](=[O:14])[CH2:8]2
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CC(=O)N2C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A dry round-bottom flask was charged with NaH (60% wt) (64 mg, 1.61 mmol) and toluene (2.0 mL). The suspension was heated to 100° C. and then 5-methoxyindolin-2-one (250 mg, 1.53 mmol) was added. After 30 min at 100° C., Me2SO4 (0.16 mL, 1.68 mmol) was added and the temperature maintained at 100° C. for 2.5 h. The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, hexanes/EtOAc, 3:1 to 2:1) to give the product as a beige solid (144 mg, 53%); MS ESI 164.1 [M+H]+, calcd for [C9H9NO2+H]+ 164.07.
Reaction SMILES: [C:1]([O:17]C)(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15])=[O:7].Cl[Si](C)(C)C.[I-].[Na+]>C(#N)C.C(OCC)(=O)C>[C:10]1(=[O:15])[N:9]([O:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:17])=[O:16])[C:13](=[O:14])[CH2:12][CH2:11]1
Reactant: COC(=O)CCCCC(=O)ON1C(=O)CCC1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)CCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Yield: 0 %

Procedure:
A solution of methyl succinimidyl adipate (4.5 g, 17.5 mmol), chlorotrimethylsilane (11.1 ml, 7.5 mmol) and sodium iodide (13.1 g, 87.5 mmol) in 10 ml of acetonitrile was heated at reflux for 12 hours. The mixture was then cooled to room temperature and diluted with ethyl acetate. The reaction mixture was washed repeatedly with 5 percent aqueous sodium bisulfite until the organic solution was colorless. Then it was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to provide 3.2 pg (71 percent yield by weight) of adipic acid monosuccinimidyl ester as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=O)[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:5][C:4]=2[N:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:8]1[CH2:7][CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1ccc2c(n1)CC(c1ccccc1)CC2=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(n1)CC(c1ccccc1)CC2=NNC(=N)N
Yield: 81.5 %

Procedure:
A mixture of 2-methyl-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.3 g), aminoguanidine hydrochloride (0.15 g), concentrated hydrochloric acid (0.063 ml), water (0.063 ml) and ethanol (30 ml) was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the solution was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 1N hydrochloric acid, and the solvent was evaporated. The residue was recrystallized from ethanol to give 5-guanidinoimino-2-methyl-7-phenyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 82) (0.34 g) as colorless crystals.
Reaction SMILES: [CH:1]1([CH:4]=[CH:5][CH:6]2[CH2:8][CH2:7]2)[CH2:3]C1.B.[O:10]1CCC[CH2:11]1.[OH-].[Na+].OO.[Cl-].[Na+]>O1CCCC1>[CH:6]1([CH:5]([CH:4]2[CH2:1][CH2:3]2)[CH2:11][OH:10])[CH2:7][CH2:8]1
Reactant: C(=CC1CC1)C1CC1
Reactant: C1CCOC1
Agent: B
Agent: OO
Agent: [Cl-]
Product: OCC(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dicyclopropyl ethylene (19 g, 0.176 mole) was dissolved in dry tetrahydrofuran (100 ml) in a three-neck flask under nitrogen and treated with borane-tetrahydrofuran in tetrahydrofuran (1M, 210 ml). The mixture was stirred at room temperature for 4 hours before adding cautiously (foaming occurs) 3N sodium hydroxide (60 ml). After addition was complete, aqueous hydrogen peroxide (30%, 60 ml) was added dropwise at a rate sufficient to maintain reflux. When addition was complete, the mixture was refluxed for a further 30 minutes, cooled and the aqueous layer saturated with sodium chloride. The layers were separated, the organic layer dried (MgSO4) and evaporated under reduced pressure to give a quantitative yield of 2,2-dicyclopropylethanol which was pure by GC. (The product could also be distilled, b.p. 99° C./25 mm.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].S(Cl)([Cl:19])(=O)=O>C(OCC)C>[Cl:19][CH:9]([C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)c1ccccc1Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1Cl
Yield: 76.6 %

Procedure:
Using ethyl 3-(2-chlorophenyl)-3-oxopropanoate (1.0 g, 5.0 mmol), sulfuryl chloride (810 mg, 6.0 mmol) and diethyl ether (50 mL) as starting materials and in the same manner as in Example 20(i), the title compound (1.0 g, 85%) was obtained as a colorless oil.