Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:21])=[C:16]([NH2:20])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[C:14]3[C:15]([CH3:21])=[C:16]([NH2:20])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc2c(c(C)c1N)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCO
Product: Cc1cc2c(c(C)c1N)[C@@H](c1ccc(C(C)C)cc1)CO2
Temperature: 85 °C
Yield: 34 %

Procedure:
A suspension of 3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 32 (22.5 g, 80 mmol) and (2S, 3S)-(4′-methyl)-tartranilic acid (19.14 g, 80 mmol) in ethanol (480 mL) was heated at 85° C. for dissolution. The solution was cooled to 0° C. for 2 hours, and the precipitated crystals were taken. The crystals were washed with cold ethanol, and then were dried under reduced pressure. The obtained crystals were suspended in a 2 N aqueous sodium hydroxide solution (400 mL), which was extracted with diethyl ether. The extract was washed with a saturated sodium hydrogen carbonate solution and a saturated brine, and then was dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 9.44 g (yield 34%) of the title compound as an oily matter. The obtained oily matter was, if necessary, crystallized with cold hexane. Melting point: 53-55° C. [α]D20=+64.0° (c=0.44, chloroform).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH2:14]CCCC)[CH:6]=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21].Br[CH2:24]CCCCCCC>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH:12]=[C:13]([CH3:14])[CH3:24])[CH:6]=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: CCCCCCCCn1cc(CC(N)=O)c2cc(F)ccc21
Reactant: CCCCCCCCBr
Product: CC(C)=CCn1cc(CC(N)=O)c2cc(F)ccc21

Procedure:
2-(5-Fluoro-1-octyl-1H-indol-3-yl)acetamide) (1-8). The reaction between Amide A-2 and bromooctane can be carried out as described by Na, Y. M.; Le Borgne, M.; Pagniez, F.; Le Baut, G.; Le Pape, P. Synthesis and antifungal activity of new 1-halogenobenzyl-3-imidazolylmethylindole derivatives. Eur J Med Chem 2003, 38, 75-87. Yield: 70%; 1H NMR (300 MHz, CDCl3): δ7.26-7.18 (m, 2 H), 7.09 (s, 1 H), 6.97 (dt, J1=9 Hz, J2=2.4 Hz, 1 H), 5.73 (br. s, 2 H), 4.06 (t, J=7.2 Hz, 2 H), 3.65 (s, 2 H), 1.83 (t, J=6.3 Hz, 2 H), 1.29-1.25 (m, 10 H), 0.86 (t, J=6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.10, 159.39, 156.27, 139.66, 133.03, 128.67, 127.68, 127.55, 110.66, 117.23, 103.88, 46.63, 32.81, 31.70, 30.17, 29.09 (2C), 26.94, 22.55, 14.02; MS (APCI): m/z 305.5 [M+H]+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)[CH3:14]>>[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:17][CH:16]=1)[CH3:14]
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: CCc1ccc(N)cc1
Product: CCc1ccc(Nc2nc(C)nc3ccccc23)cc1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (100 mg, 0.56 mmol), 4-ethyl-phenylamine (0.07 ml, 0.56 mmol) by a procedure similar to Example 78. 1H NMR (CDCl3): 7.85-7.78 (m, 2H), 7.76-7.71 (m, 3H)), 7.49 (t, J=7.5 Hz, 1H), 7.36 (brs, 1H), 7.24 (s, 2H), 2.70-2.69 (m, 5H), 1.26 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:12]([O-])=O)=[C:5]([NH2:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.ClC1C=CC(OC)=C(N)C=1N>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([NH2:11])[C:4]=1[NH2:12]
Reactant: COc1cc(N)c([N+](=O)[O-])c(OC)c1
Agent: COc1ccc(Cl)c(N)c1N
Product: COc1cc(N)c(N)c(OC)c1

Procedure:
Prepared from 3,5-dimethoxy-2-nitro-phenylamine in analogy to the method described for 3-chloro-6-methoxy-benzene-1,2-diamine.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:5]1[N:10]2[CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[N:13]=[C:9]2[C:8]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:7][CH:6]=1)\[NH2:4].[C:32](N1C=CN=C1)(N1C=CN=C1)=[O:33].N12CCCN=C1CCCCC2>C(#N)C.CCOC(C)=O>[O:29]1[CH2:30][CH2:31][N:26]([C:8]2[C:9]3[N:10]([CH:11]=[C:12]([CH2:14][O:15][C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=4)[N:13]=3)[C:5]([C:3]3[N:4]=[C:32]([OH:33])[O:1][N:2]=3)=[CH:6][N:7]=2)[CH2:27][CH2:28]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N/C(=N\O)c1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Oc1nc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)no1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of compound 55b (70.0 mg, 0.170 mmol), 1,1′-carbonyldiimidazole (40.6 mg, 0.250 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.099 mL, 0.670 mmol) in acetonitrile (2 mL) was stirred at rt for 12 h. The residue was diluted with EtOAc (2×50 mL) and washed with 1N HCl (30 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with MeOH, collected by filtration, and dried to give the title compound 75 as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.79-3.96 (m, 4H), 4.49 (br. s., 4H), 5.66-5.76 (m, 2H), 6.99 (d, J=8.8 Hz, 1H), 7.36-7.47 (m, 1H), 7.66 (td, J=7.7, 1.2 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.81 (s, 1H), 7.91 (d, J=8.3 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 8.76 (s, 1H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C22H19N7O4: 446.2 [M+H]. found 446.2.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:25])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[C:20][Si](C)(C)C)[CH:14]=2)[CH:9]([CH3:26])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.ClCCl.O>[CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:25])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[CH:20])[CH:14]=2)[CH:9]([CH3:26])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CCC(C)(c2cccc(C#C[Si](C)(C)C)c2)C(C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#Cc1cccc(C2(C)CCN(CCCCCC)CC2C)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of 1-hexyl-3,4-dimethyl-4-{3-[2-(trimethylsilyl)ethynyl]-phenyl}piperidine (Preparation 4, 150 mg, 0.40 mmol) in tetrahydrofuran (2 mL) was cooled to -70° C. and tetrabutylammonium fluoride (1.0 M in THF, 0.41 mL, 0.41 mmol) was added slowly. The reaction mixture was allowed to warm to room temperature gradually before being diluted with dichloromethane (10 mL) and water (10 mL). The phases were separated and the aqueous layer was further extracted with dichloromethane (2×10 mL). The combined organics were dried (Na2SO4) and the solvent evaporated in vacuo. The oily yellow residue was purified by column chromatography on silica gel (10 g) eluted with ethyl acetate:hexane 0.880 ammonia (10:89:1) to give the title compound as an oil (100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13].[CH2:16](I)[CH3:17]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH2:11][N:10]=[C:9]1[S:15][CH2:16][CH3:17]
Reactant: NC(=O)CNC(=S)Nc1ccccc1Cl
Reactant: CCI
Solvent: CCO
Product: CCSC1=NCC(=O)N1c1ccccc1Cl
Yield: 65.9 %

Procedure:
A mixture of 2-[3-(2-chlorophenyl)-thioureido]-acetamide (12.2 g), ethyl iodide (15.6 g), and ethanol (200 mL) was heated at reflux for 5 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with water (2×300 mL). The organic phase was then extracted with 2N HCl (2×500 mL). The acid extract was neutralized with solid sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous MgSO4 then evaporated to dryness. The residue was dissolved in ethanol and the solution was saturated with hydrogen chloride. The solvent was evaporated and the residue was crystallized from ethyl acetate to give the hydrochloride salt of the title compound (8.4 g) as an off-white solid, m.p. 149°-150° C. (dec.). Anal. Calcd. for. C11H11Cl N2O S . HCl: C, 45.37; H, 4.15; N, 9.62. Found: C, 44.97; H, 4.06; N, 9.51. Mass spectrum (EI, M.+) m/z 254/256. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.69 (m, 1 H), 7.50-7.58 (m, 3 H), 4.45 (q, 2 H), 3.11-3.17 (m, 2 H), and 1.27 ppm (t, 3 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>COCCOC>[C:2]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccc(-c2ccccc2)cc1
Yield: 55.7 %

Procedure:
A solution of benzoic acid N′-[3-(4-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (100 mg, 0.26 mmol) in DME (5 ml)/2M Na2CO3 (450 μL, 0.90 mmol) was treated with phenylboronic acid (47 mg, 0.39 mmol) and Pd[PPh3]4 (30 mg, 0.026 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (56 mg, 56%). LC-MS m/e 387.17 (M+H+)
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.C(OCC)(=O)C(C)C.[CH2:29]([O:31][C:32](=[O:50])/[C:33](/[CH2:48]C)=[CH:34]/[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)=[CH:37][CH:36]=1)[CH3:30].[Cl-].[NH4+]>O1CCCC1.CCCCCC.CN(P(N(C)C)(N(C)C)=O)C>[CH2:29]([O:31][C:32](=[O:50])[C:33]([CH3:48])([CH3:1])[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)=[CH:39][CH:40]=1)[CH3:30]
Reactant: CCOC(=O)/C(=C/c1ccc(Cc2cccnc2)cc1)CC
Reactant: CC(C)[N-]C(C)C
Agent: CCOC(=O)C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(C)(C)Cc1ccc(Cc2cccnc2)cc1
Reaction time: 0.67 h

Procedure:
To a 3.0 M solution of lithium diisopropylamide in tetrahydrofuran [prepared from diisopropylamine (0.56 ml), tetrahydrofuran (5 ml) and a 1.4 M solution of butyllithium in hexane (2.2 ml)] was added dropwise 0.41 ml of ethyl isobutyrate at -70° C., and the mixture was stirred at that temperature for 40 minutes. To it was added dropwise a solution of 0.26 g of the benzyl chloride compound (prepared as described in Reference Example 2) in 2.8 ml of a mixture of HMPA and tetrahydrofuran (1:1) at -70° C., and the mixture was stirred at that temperature for 2 hours, and then at room temperature for one hour. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 0.27 g of the title compound having the following physical characteristics:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[C:7]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:23]#[N:24])=[CH:11][N:10]=1)=[O:8])[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:22][O:21][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][C:16]=1[O:19][CH3:20])[C:9]([C:7]([C:6]1[CH:25]=[CH:26][CH:27]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:8])=[N:10][CH:11]=[C:12]2[C:23]1[NH:30][N:29]=[N:28][N:24]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOc1cccc(C(=O)c2ncc(C#N)c3cc(OC)c(OC)cc23)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cccc(C(=O)c2ncc(-c3nnn[nH]3)c3cc(OC)c(OC)cc23)c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
The mixture of 1-(3-Ethoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carbonitrile (50 mg, 140 mmol), sodium azide (20 mg, 310 mmol) and ammonium chloride (16.2 mg, 310 mmol) in DMF (2 mL) was stirred at 120° C. for 24 h. After removal of solvent, the crude product was purified directly by HPLC (Reverse C18, 10%-90% acetonitrile in water in 10 min) afforded our desired product [6,7-Dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-(3-ethoxy-phenyl)-methanone with trifluoro-acetic (31 mg, 55%) as a light yellow solid. LC/MS m/e calcd for C21H19N5O4 (MH+) 406, found 406.
Reaction SMILES: C12(COC3C(I)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[CH:24]1([CH2:29][O:30][C:31]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:34]([C:35]([OH:37])=O)=[C:33]([F:43])[CH:32]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1.N1(S(N)(=O)=O)CCC1.[CH3:52][O:53][CH2:54][CH2:55][S:56]([NH2:59])(=[O:58])=[O:57]>>[CH:24]1([CH2:29][O:30][C:31]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:34]([C:35]([NH:59][S:56]([CH2:55][CH2:54][O:53][CH3:52])(=[O:58])=[O:57])=[O:37])=[C:33]([F:43])[CH:32]=2)[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COCCS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCCC2)cc1F
Agent: NS(=O)(=O)N1CCC1
Agent: O=C(O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CCCC2)cc1F

Procedure:
Following the procedure as described in Example 299 Step 2 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with 4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace azetidine-1-sulfonamide with 2-methoxyethanesulfonamide, the title compound was obtained as a colorless solid (0.039 g, 12%): 1H NMR (300 MHz, DMSO-d6) δ 11.88 (br s, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.93 (d, J=13.0 Hz, 1H), 3.96 (d, J=6.8 Hz, 2H), 3.71 (s, 4H), 3.21 (s, 3H), 2.42-2.26 (m, 1H), 2.07-1.96 (m, 1H), 1.86-1.73 (m, 2H), 1.68-1.47 (m, 4H), 1.44-1.30 (m, 2H), 0.92-0.84 (m, 2H), 0.70-0.62 (m, 2H); 19F NMR (282 MHz, DMSO-d6) δ −113.0 (s, 1F); MS (ES−) m/z 398.2 (M−1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]([C:10]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)=[C:8]=O.[OH-].[Na+].O>C1COCC1>[CH3:8][NH:7][C:10]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:11][CH2:12][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:18][CH2:19]1
Reactant: O=C=NC1(c2ccccc2)CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNC1(c2ccccc2)CCC2(CC1)OCCO2
Reaction time: 0.33 h

Procedure:
LiAlH4 (535 mg, 14.08 mmole) was suspended in dry THF (4 ml) with the exclusion of atmospheric moisture. 8-isocyanato-8-phenyl-1,4-dioxaspiro[4.5]decane (2.29 g, 8.8 mmole, dissolved in 40 ml of dry THF) was then added dropwise within 20 minutes. After the end of the addition the reaction mixture was boiled under reflux for 4 hours. After cooling the reaction mixture, aqueous THF (1 ml H2O in 3 ml) was first of all carefully added, followed by 1.7 ml of 15% sodium hydroxide solution and finally 5 ml of H2O. The reaction mixture was stirred for 20 minutes and then filtered through diatomaceous earth. The solvent mixture obtained by washing the filter cake several times with ethyl acetate was concentrated by evaporation to dryness on a rotary evaporator. The desired product was obtained in a yield of 2.1 g (97%) as a viscous oil.
Reaction SMILES: O[CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[O:8]=[C:6]1[NH:7][C@H:3]([CH2:2][N:13]2[C:9](=[O:19])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:14])[CH2:4][CH2:5]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1CC[C@@H](CO)N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1CC[C@@H](CN2C(=O)c3ccccc3C2=O)N1
Temperature: -30 °C
Reaction time: 16 h

Procedure:
To (S)-5-(hydroxymethyl)pyrrolidin-2-one (2.00 g, 17.39 mmol) dissolve in 25 mL THF was added phthalimide (2.81 g, 19.13 mmol), triphenylphosphine (5.01 g, 19.13 mmol) and diisopropylazodi-carboxylate (3.33 g, 19.13 mmol). This mixture was stirred for about 16 hr, and then diluted with 200 mL of hexanes and 2 mL of DCM, and then cool at −30° C. The product precipitated and was filtered and dried (4.11 g, 96%, white solid).
Reaction SMILES: C(OC([N:8]1[CH2:21][CH2:20][CH2:19][C@H:9]1[C:10]([S:12][CH2:13][CH:14]([CH3:18])[C:15](O)=[O:16])=[O:11])=O)(C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[CH3:18][CH:14]1[CH2:13][S:12][C:10](=[O:11])[C@@H:9]2[CH2:19][CH2:20][CH2:21][N:8]2[C:15]1=[O:16]
Reactant: CC(CSC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1CSC(=O)[C@@H]2CCCN2C1=O
Reaction time: 72 h

Procedure:
3-[1-(tert-butyloxycarbonyl)-L-prolylthio]-2-methylpropanoic acid (2.3 g) is dissolved in a mixture of trifluoroacetic acid (15 ml) and anisole (1.1 g). After fifteen minutes at room temperature the mixture is concentrated to dryness in vacuo and the residue triturated with ether-hexane (1:1). The insoluble material is dried in vacuo, dissolved in dichloromethane (100 ml) and added dropwise to a stirred solution of 1-cyclohexyl-3-(2-morpholinoethyl) carbodiimide metho-p-toluene sulfonate (20 g) in 900 ml of dichloromethane under argon. The reaction mixture is stored at room temperature for three days and the dichloromethane is then removed in vacuo. The residue is dissolved in ethyl acetate and the solution is washed with 10% potassium biculfate, water, saturated sodium bicarbonate and water. The organic layer is dried and concentrated to give the title compound.
Reaction SMILES: [K].[CH3:2][O:3][CH2:4][C:5]([CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:8]1=[O:22])=O.Cl.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1CCCCC1.C1(C)C=CC=CC=1>[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:5](=[C:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:8]2=[O:22])[CH2:4][O:3][CH3:2])=[CH:27][CH:26]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COCC(=O)C1CCN(C(=O)OCc2ccccc2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [K]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCCCC1
Product: COCC(Nc1ccc(Cl)cc1)=C1CCN(C(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
Into a 200 mL four-mouthed flask were added benzyl 3-(2-methoxyacetyl)-2-oxopyrrolidine-1-carboxylate potassium salt (6.60 g) [mw. 329.39, 20.0 mmol], 1 mol/L aqueous hydrochloric acid solution (33 mL) and toluene (60 mL), and the mixture was stirred at room temperature for 30 min. After partitioning, the organic layer was washed with water (33 mL), and dried over magnesium sulfate. After filtration, p-chloroaniline (2.56 g) [mw. 127.57, 20.0 mmol], p-toluenesulfonic acid monohydrate (0.038 g) [mw. 190.22, 0.2 mmol] and cyclohexane (33 mL) were added. Dean-Stark trap was set, and distillation by thermal dehydration was performed for 90 min. After cooling to room temperature, 5 w/w % aqueous acetic acid solution (33 mL) was added to allow for partitioning. The organic layer was washed successively with 5 w/w % aqueous sodium bicarbonate solution (33 mL) and water (33 mL), further washed with water (33 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. To the concentrate were added methanol (q.s.) and activated carbon (1 g), and the mixture was stirred at room temperature for 30 min. After filtration, the mother liquor was concentrated under reduced pressure. The concentrate was purified by basic silica gel column (silica gel amount; 25 g, eluent:toluene, Rf=0.2), and the effective fraction was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate (3 mL) and diisopropyl ether (30 mL). The mixture was cooled in a freezer to produce crystal core. The mixture was suspended by stirring at room temperature for 1 hr. After filtration under reduced pressure, the crystals were washed with a mixed solvent of ethyl acetate/diisopropyl ether (1/10) (10 mL), and dried at 45° C. under reduced pressure to give the object compound. Pale-yellow white crystal, 2.50 g, yield 31.2%, 1H-NMR (500 MHz, CDCl3, TMS) δ 2.78 (t, J=7.5 Hz, 2H), 3.34 (s, 3H), 3.81 (t, J=8.0 Hz, 2H), 3.99 (s, 2H), 5.29 (s, 2H), 7.03-7.05 (m, 2H), 7.25-7.44 (m, 7H), 10.50 (s, 1H). 13C-NMR (125 MHz, CDCl3, CDCl3) δ 20.95, 43.61, 58.53, 67.71, 67.96, 99.68, 123.83, 128.11, 128.25, 128.57, 129.28, 129.67, 135.81, 138.06, 149.88, 152.23, 169.93.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]=1[OH:20])([CH3:6])([CH3:5])[CH3:4].[Cl-].[Cr+3:22].[Cl-].[Cl-]>O>[C:3]([C:7]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:9]([C:10]([O-:12])=[O:11])[C:8]=1[OH:20])([CH3:6])([CH3:5])[CH3:4].[Cr+3:22].[C:3]([C:7]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:9]([C:10]([O-:12])=[O:11])[C:8]=1[OH:20])([CH3:6])([CH3:5])[CH3:4].[C:3]([C:7]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:9]([C:10]([O-:12])=[O:11])[C:8]=1[OH:20])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1cc(C(=O)O)c(O)c(C(C)(C)C)c1
Agent: [Cr+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cc(C(=O)[O-])c(O)c(C(C)(C)C)c1
Reaction time: 1.75 h

Procedure:
450 g of water and 7.2 g of NaOH were placed in a 500-cc beaker, and the mixture was heated under stirring to completely dissolve NaOH. This NaOH aqueous solution was heated to 65° C., and 45 g of 3,5-di-tert-butylsalicylic acid was added thereto under stirring. The mixture was further stirred while keeping the temperature at 65° C. to dissolve 3,5-di-tert-butylsalicylic acid. When pH of the dissolved solution became 6.8, heating and stirring were discontinued, and the solution was filtered to remove insoluble 3,5-di-tert-butylsalicylic acid, thus a brown filtrate being obtained. Separately, 37.2 g of a 40% CrCl3 solution and 120 g of water were placed in a 500-cc beaker to prepare a chromium(III) chloride solution having a pH of 2.1. To this chromium(III) chloride solution was gradually added 120 g of 1% NaOH aqueous solution with spending enough time to obtain a solution of 3.95 in pH. Then, this solution was transferred into a 2-liter beaker, and diluted with water to make the total amount 350 g. This chromium(III) chloride solution was heated to 60° C. and, under stirring, the above-described solution of 3,5-di-tert-butylsalicylic acid kept at 60° C. was dropwise added thereto over a period of time of 1.5 to 2 hours. As the addition proceeded, the reaction solution gradually assumed a light green color. After completion of the dropwise addition, stirring was further continued for 1 hour at a temperature of 60 to 65° C., and the reaction solution was suction filtered and washed with water to obtain 170 g of a reaction product (wet). The pH of the filtrate was 4.00. The reaction product collected by filtration was dried at 50° C. for about 14 hours, and the dried product was pulverized to obtain 70 g of an end product. The reaction product is completely soluble in carbon tetrachloride.