Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=[O:15])=O)=[CH:9][CH:8]=1.I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OC(=O)C)C.[Cu]I.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>[C:18]1([C:4]#[C:3][CH2:2][CH2:1][O:5][S:13]([C:10]2[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][CH:11]=2)(=[O:15])=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Ic1ccccc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: C#CCCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCC#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
A mixture containing 3-butyn-1-ol 4-methylbenzenesulfonate (0.45 g, 2 mmol), iodobenzene (0.45 g, 2.2 mmol), CuI (0.038 g, 0.2 mmol), triethylamine (1.01 g, 10 mmol) and tetrakis(triphenylphosphine)palladium (0.12 g, 0.1 mmol) in toluene (10 ml) was stirred 30 minutes at room temperature, and 2 hours at 65° C. The reaction mixture was cooled to room temperature, diluted with ethylacetate (10 ml), washed with H2O (10 ml), dried over Na2SO4, and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1 then 4:1) to provide toluene-4-sulfonic acid 4-phenyl-but-3-ynyl ester (0.35 g, 58%) as a brown oil, MS: m/e=300 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CN1C(=O)N(C)CC1.CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: CCCCCC=O
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN1CCN(C)C1=O
Product: CCCCCCNc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12

Procedure:
Analogously to Example 34, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6), 150 mg (1.5 mmol) of capronaidehyde and 180 mg of acetic acid are stirred in 39 ml of DMEU/methanol (1:2) and then reacted with 440 mg (7 mmol) of NaCNBH3. Stirring in DIPE yields 4-(3-chloro-phenyl-amino)-3-(n-hexyl-amino)-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100)=9.9; FAB-MS: (M+H)+=345.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH2:51]([O:58][P:59]([CH2:68][C@H:69]([OH:72])[CH2:70][NH2:71])([CH2:61][CH:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1)=[O:60])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:51]([O:58][P:59]([CH2:68][C@H:69]([OH:72])[CH2:70][NH:71][C:16](=[O:18])[C@@H:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:13]([CH3:14])[CH3:15])([CH2:61][CH:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1)=[O:60])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Yield: 48.8 %

Procedure:
The title compound can be synthesized in accordance with any one of the four procedures set forth below. Method A: A flask was charged with N-Cbz-L-valine (1.02 g, 4.04 mmol) and DMF (60 mL) and stirred under nitrogen. To this was added diisopropylethylamine (2.11 mL, 12.1 mmol) followed by TBTU (1.30 g, 4.04 mmol). After stirring for 5 minutes, a solution of ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride (8.08 mmol) dissolved in DMF (10 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction was diluted with ethyl acetate (300 mL) and the organic layer washed with 1N HCl (2×100 mL), water (100 mL), saturated sodium bicarbonate solution (2×100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product as an amber oil. The crude product was purified by gradient flash chromatography (methanol/methylene chloride) on a 120 g RediSep disposable column to give (1.10 g, 1.97 mmol) of [(R)-3-((S)-2-benzyloxycarbonylamino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester as a white foam. 1H NMR (CDCl3, 300 MHz): δ 7.40-7.25 (m, 10H), 6.70-6.51 (m, 1H), 5.48-5.35 (m, 1H), 5.18-5.01 (m, 4H), 4.20-3.98 (m, 2H), 3.62-3.42 (m, 1H), 3.38-3.18 (m, 1H), 2.30-2.05 (m, 1H), 2.03-1.60 (m, 10H, 1.38-1.02 (m, 5H), 0.98 (dd, 6H). LCMS m/z: [M+H]+=559.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][NH:5][C:6]([NH:8][CH3:9])=[S:7].[I:12][CH3:13]>CC(=O)C>[IH:12].[CH3:11][O:10][CH:3]([O:2][CH3:1])[CH2:4][NH:5][C:6]([S:7][CH3:13])=[N:8][CH3:9]
Reactant: CI
Reactant: CNC(=S)NCC(OC)OC
Solvent: CC(C)=O
Product: CN=C(NCC(OC)OC)SC
Product: I
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of 7.1 parts of N-(2,2-dimethoxyethyl)-N'-methylthiourea, 8.5 parts of iodomethane and 80 parts of 2-propanone was stirred overnight. The reaction mixture was evaporated, yielding 12.8 parts (99%) of methyl N-(2,2-dimethoxyethyl)-N'-methylcarbamimidothioate monohydroiodide (191).
Reaction SMILES: [CH3:1][C@H:2]1[C:6](=[O:7])[N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:4]([C:15](OC)=[O:16])[CH2:3]1.[BH4-].[Na+].CCO>C1COCC1.CCOC(C)=O>[OH:7][CH2:6][C@H:2]([CH3:1])[CH2:3][C@H:4]([NH:5][C:8](=[O:9])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:15][OH:16]
Reactant: COC(=O)[C@@H]1C[C@@H](C)C(=O)N1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](CO)C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butyl 2-methyl (2S,4R)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (0.47 g, 1.8 mmol) in THF (4.0 mL) at −10° C., NaBH4 (0.207 g, 5.48 mmol) was added followed by EtOH (1.0 mL). After stirring at −10° C. for 1 h, the mixture was allowed to warm to room temperature and stirred for 15 h. The reaction mixture was then diluted with EtOAc (50 mL), washed with water (25 mL) and brine (30 mL), then dried over Na2SO4 and concentrated under reduced pressure. The resulting crude product (0.39 g, 92%) was used directly in the next step without further purification. LCMS calc. for C11H24NO4 (M+H)+: m/z=234.2. found no ionization.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1.C(N(CC)CC)C.[C:20](Cl)(=[O:28])[CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24]>ClCCl>[CH3:1][CH:2]1[N:6]([C:20](=[O:28])[CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1
Reactant: CCCC(CCC)C(=O)Cl
Reactant: CC1NCC2(CCN(C)CC2)S1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(CCC)C(=O)N1CC2(CCN(C)CC2)SC1C
Temperature: 0 °C

Procedure:
2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]decane (982 mg, 5.28 mmol) was dissolved in dry dichloromethane (5 ml) under argon atmosphere. Distilled triethylamine (1.10 ml, 7.92 mmol) was added and the resulting solution was cooled to 0° C. Valproyl chloride (910 mg, 5.60 mmol) was added dropwise with a syringe. The reaction flask was allowed to warm to room temperature with stirring, and white solid started to precipitate. After 4 h of stirring, dichloromethane (100 ml) was added and the resulting solution was washed with water (10 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic phase was dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 150/10/1) to give AF717 (521 mg, 99.2% chemical purity) as an off-white powder. 1H NMR (CDCl3, 300 MHz) δ 5.53, 5.26 (2q, J=6.12 and J=6.3 Hz, 1H, CHCH3), 4.67, 3.90 (2d, J=12.0 and J=11.35 Hz, 1H, CHHNCO), 3.48, 3.09 (2d, J=11.35 and J=12.0 Hz, 1H, CHHNCO), 2.78-2.59 (m, 2H, CH2N), 2.53-2.47 (m, 1H, CHCO), 2.30, 2.19 (2s, 3H, NCH3), 2.15-2.05 (m, 2H, CH2N), 2.02-1.84 (m, 2H, CH2CS), 1.74-1.61 (m, 4H, CH2CHCO), 1.55, 1.50 (2d, J=6.3 and J=6.12 Hz, 3H, CH3CH), 1.44-1.36 (m, 2H, CH2CS), 1.34-1.21 (m, 4H, CH2CH3), 0.93-0.87 (m, 6 h, CH3CH2) ppm; 13C NMR (CDCl3, 300 MHz) δ 174.35, 174.04 (C), 59.13 (C), 57.35, 57.19 (CH), 54.52, 54.06 (CH2), 53.13, 52.77 (CH2), 46.09 (CH3), 43.77, 42.55 (CH), 38.37, 37.58 (CH2), 37.04, 36.20 (CH2), 35.76, 35.35 (CH2), 35.08, 34.77 (CH2), 26.01, 23.01 (CH3), 21.08, 20.98 (CH2), 20.73, 20.56 (CH2), 14.27, 14.22 (CH3) ppm.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][N:13]=[C:7]2[N:6]=1)([F:4])[CH3:3].Br[C:28]1[C:29]([F:41])=[C:30]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:31]([F:34])=[CH:32][CH:33]=1>>[F:4][C:2]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:32]3[CH:33]=[CH:28][C:29]([F:41])=[C:30]([C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)[C:31]=3[F:34])=[CH:12][N:13]=[C:7]2[N:6]=1)([F:1])[CH3:3]
Reactant: Fc1ccc(Br)c(F)c1-c1cccnc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(C)(F)F)ccn12
Product: CC(F)(F)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3F)cnc2n1

Procedure:
7-(1,1-Difluoroethyl)-3-tributylstannylimidazo[1,2-α]pyrimidine was reacted with 3-(3-bromo-2,6-difluorophenyl)pyridine following the procedure described in Example 32 to give 7-(1,1-difluoroethyl)-3-[2,4-difluoro-3-(pyridin-3-yl)phenyl]imidazo[1,2-α]pyrimidine as a white solid: δH (360 MHz, CDCl3) 2.16 (1H, t, J 19), 7.22-7.78 (1H, m), 7.31 (1H, d, J 7), 7.59 (1H, ddd, J 8, 3 and 1), 7.52-7.59 (1H, m), 7.85 (1H, dd, J 8 and 1), 8.03 (1H, s), 8.39 (1H, dd, J 7 and 3), 8.69 (1H, d, J 5 and 3), 8.78 (1H, s); m/z (ES+) 373 (M++H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.[Br:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.C(OCC)(=O)C>[Br:13][CH2:14][CH2:15][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: O=c1ccc2cc(O)ccc2o1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: O=c1ccc2cc(OCCBr)ccc2o1
Yield: 26 %

Procedure:
A mixture of 6-hydroxy-chromene-2-one, which can be synthesized in accordance with the procedure set forth by T. Harayama, K. Katsuno, H. Nishioka, M. Fujii, Y. Nishita, H. Ishii, and Y. Kaneko, Heterocycles, 1994;39:613, (3.2 g, 19.7 mmol), 1,2-dibromoethane (6.7 mL, 14.6 g, 78 mmol), and potassium carbonate (5.4 g, 39 mmol) in 150 mL of acetone is stirred at reflux for 48 hours. The cooled reaction mixture is added to 1.0 L of water and 250 mL of ethyl acetate. The mixture is filtered, and the insoluble material is washed with a small amount of additional ethyl acetate. The combined filtrates are separated, and the aqueous layer is washed several times with fresh ethyl acetate. The combined organic layers are washed with 5% aqueous sodium carbonate solution and brine, then dried (sodium sulfate), and evaporated. The residue is purified by flash chromatography (1% methanol in dichloromethane elution) to give 1.4 g (26%) of product. A sample recrystallized from ethyl acetate-hexane had melting point (mp) 101-102° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.ClC(Cl)(Cl)C(=N)O[C:15]([CH3:18])([CH3:17])[CH3:16].[B-](F)(F)(F)[O+](C)C>O1CCCC1.C1CCCCC1.C(OCC)(=O)C>[C:15]([O:9][C:8]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: C[O+](C)[B-](F)(F)F
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
A solution of 5-chloro-pyrazine-2-carboxylic acid (10.00 g, 63.07 mmol) in tetrahydrofuran (126 mL) was treated with a solution of tert-butyl 2,2,2-trichloroacetimidate (23 mL, 126.14 mmol) in cyclohexane (126 mL). The reaction was stirred at 25° C. for 5 min and then was treated with boron trifluoride dimethyl etherate (3.2 mL, 25.23 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h and then was diluted with ethyl acetate (200 mL), washed with a saturated aqueous sodium bicarbonate solution (200 mL) and water (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 65M, Silica, 1/9 ethyl acetate/hexanes) afforded 5-chloro-pyrazine-2-carboxylic acid tert-butyl ester (12.73 g, 94%) as a colorless oil: EI-HRMS m/e calcd for C9H11ClN2O2 (M+) 214.0502, found 214.0510.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[O-:9][CH2:10][CH3:11].[Na+]>C(O)C>[CH2:10]([O:9][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1)[CH3:11]
Reactant: CC[O-]
Reactant: Clc1cc(I)ccn1
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(I)ccn1

Procedure:
To 2.00 g (8.35 mmol) 2-chloro-4-iodopyridine in 15 mL ethanol are added 3.4 mL (9.2 mmol) sodium ethoxide and stirred at reflux for 12 h. The solvent is evaporated in vacuo and the residue is partitioned between water and DCM. The organic layer is dried over sodium sulphate and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel; DCM/MeOH gradient 100/0→96/4).
Reaction SMILES: [O:1]1[CH2:26][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:23])[N:10]([CH2:15][O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:24][CH3:25].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[OH:1][CH:2]([CH2:26][N:31]1[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:23])[N:10]([CH2:15][O:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:24][CH3:25]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CO1
Reactant: CN1CCNCC1
Solvent: ClC(Cl)Cl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC(O)CN1CCN(C)CC1
Yield: 75 %

Procedure:
A solution of 7-(2,3-epoxypropoxy)-6-methoxy-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-4-one (5 g, 13.8 mmol) and N-methylpiperazine (1.7 ml) in chloroform (70 ml) was refluxed for 21 hours. After cooling the mixture was poured onto a column of silica and eluted with methanol/methylene chloride/ethylacetate (5/45/50) followed by (8/42/50) followed by methanol (saturated with ammonia)/ methylene chloride/methanol (5/45/50) followed by (8/42/50). The fractions containing the expected product were combined and the volatiles were removed under vacuum. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 7-[2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy]-6-methoxy-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-4-one (4.8 g, 75%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@H:44]([C:60]([N:62]2[CH2:66][CH2:65][C@@H:64]([CH:67]([C:72]([O:74][CH2:75][C:76]3[CH:81]=[CH:80][C:79]([N+:82]([O-:84])=[O:83])=[CH:78][CH:77]=3)=[O:73])[NH:68][C:69]([NH2:71])=[NH:70])[CH2:63]2)=[O:61])[CH2:43]1.C(OCC)(=O)C>C(#N)C.C(N(CC)C(C)C)(C)C>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:41][C@@H:42]3[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=4)=[O:48])[C@H:44]([C:60]([N:62]4[CH2:66][CH2:65][C@@H:64]([CH:67]([C:72]([O:74][CH2:75][C:76]5[CH:77]=[CH:78][C:79]([N+:82]([O-:84])=[O:83])=[CH:80][CH:81]=5)=[O:73])[NH:68][C:69]([NH2:71])=[NH:70])[CH2:63]4)=[O:61])[CH2:43]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: N=C(N)NC(C(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@@H](C(NC(=N)N)C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 80 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (0.70 g) in anhydrous acetonitrile (10 ml), N,N-diisopropylethylamine (0.21 ml) and a solution of (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3R)-3-(4-nitrobenzyloxycarbonylguanidinomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine (1.28 g) in anhydrous acetonitrile (10 ml) were added while stirring in an ice bath. The resulting mixture was allowed to react overnight at 0° C. To the reaction mixture, ethyl acetate was added. The resulting mixture was washed with water and saturated saline solution, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate/methanol=95/5-9/1-6/4), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3R)-3-(4-nitrobenzyloxycarbonylguanidinomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (0.97 g) was obtained.
Reaction SMILES: C([O:4][C:5]([C:7]1[N:8]2[C@H:11]([S:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C@@H:10]([C@H:20]([OH:22])[CH3:21])[C:9]2=[O:23])=[O:6])C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[K+:53].C(OCC)C>C(Cl)Cl.O1CCCC1>[OH:22][C@@H:20]([C@H:10]1[C:9](=[O:23])[N:8]2[C@@H:11]1[S:12][C:13]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[C:7]2[C:5]([O-:6])=[O:4])[CH3:21].[K+:53]
Reactant: C=CCOC(=O)C1=C(c2cccnc2)S[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cccnc3)S[C@H]12
Reaction time: 0.25 h

Procedure:
(+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid allyl ester (332.4 g) was dissolved in a mixture of methylene chloride (2.5 liters) and tetrahydrofuran (1.3 liters). To the solution were added triphenylphosphine (26.2 g) and tetrakis(tripheylphosphine)palladium (11.6 g), followed by further addition of the above solution of potassium 2-ethylhexanoate. The mixture was stirred for 15 minutes and ethyl ether was added dropwise thereto to deposit crystals. After stirring for 30 minutes, the crystals were corrected by filtration and washed with ethyl ether (2 liters). The crystals were dried under reduced pressure to obtain crude crystals of potassium (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]1[C@@H:9]([CH3:12])[CH2:10][OH:11].[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1.C(OCC)(=O)C>ClCCl.COC(OC)(C)C>[CH3:14][C:13]1([CH3:18])[O:11][CH2:10][C@H:9]([CH3:12])[C@H:4]2[C@@H:3]([C@@H:7]([CH3:8])[CH2:6][CH2:5]2)[CH2:2][O:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@@H](CO)[C@H]1CC[C@H](C)[C@H]1CO
Solvent: COC(C)(C)OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H]1COC(C)(C)OC[C@H]2[C@H]1CC[C@@H]2C
Temperature: 25 °C
Reaction time: 12 h
Yield: 162.2 %

Procedure:
(2R)-2-[(1R, 2R, 3S)-2-(hydroxymethyl)-3-methylcyclopent-1-yl]propan-1-ol (100 mg, 0.00058 mol) (obtained in Definite Example 45) was dissolved in 5 mι of dichloromethane, and 2 mι of 2, 2-dimethoxypropan and 5 mg of p-toluenesulfonic acid were added. After being stirred at room temperature for 12 hours, the reaction mixture was poured into 50 mι of ethyl acetate. After the organic layer was washed with an aqueous mixed solution of aqueous sodium bicarbonate (10 mι) and saturated sodium chloride solution (20 mι), it was dried by magnesium sulfate, filtered, and then concentrated under a reduced pressure. The residual substance was purified by a chromatography using silica gel. When the solvent of the fraction obtained from hexane:ether=8:2 eluent was distilled off, a colorless oily substance, i.e., (1R, 7R, 8S, 11S)-4, 4, 7, 11-tetramethyl-3, 5-dioxabicyclo[6. 3. 0]undecane (10 mg, yield=7.9%). This (1R, 7R, 8S, 11S)-4, 4, 7, 11-tetramethyl-3, 5-dioxabicyclo[6.3.0]undecane had the following physicochemical properties:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([OH:11])=[CH:3][C:2]=1[OH:12].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH:17]=O.[C:26](#[N:30])[CH2:27][C:28]#[N:29].C1N2CCN(CC2)C1>C(O)C.O>[NH2:30][C:26]1[O:11][C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[N:1]=[C:2]([OH:12])[C:3]=2[CH:17]([C:16]2[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:14]([Br:13])[CH:15]=2)[C:27]=1[C:28]#[N:29]
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: N#CCC#N
Reactant: Oc1cc(O)c2ccccc2n1
Agent: C1CN2CCN1CC2
Solvent: CCO
Solvent: O
Product: COc1cc(C2C(C#N)=C(N)Oc3c2c(O)nc2ccccc32)cc(Br)c1OC
Temperature: 80 °C
Reaction time: 21 h
Yield: 87 %

Procedure:
2,4-Quinolinediol (193 mg, 1.2 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (245 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 25 ml ethanol at room temperature, charged with DABCO (11 μl, 0.1 mmol) and then stirred at 80° C. under LC-MS control for 21 h whereby the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with water to about 100 ml and stirred for over night at room temperature. The solids were collected by filtration, washed well with 50% aqueous ethanol and dried under high vacuum yielding 395 mg (0.87 mmol, 87%) of the pure title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][C:31]([CH:36]=O)=[CH:30]3)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13](=[CH:36][C:31]4[NH:32][C:33]5[C:29]([CH:30]=4)=[CH:28][C:27]([O:26][CH2:25][CH2:24][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:35][CH:34]=5)[C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2cc3cc(OCCN4CCCC4)ccc3[nH]2)cc1

Procedure:
6-(4-Methoxy-phenyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.