Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][CH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].CCCCCC>O.C(#N)C.C(Cl)(Cl)(Cl)Cl.CCOC(C)=O.[Ru](Cl)(Cl)Cl>[C:19]([O:18][C:16]([N:10]1[C@H:9]([C:8]([OH:2])=[O:7])[CH2:15][CH2:14][C@@H:13]2[C@H:11]1[CH2:12]2)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)CC[C@H]2C[C@H]21
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 32.5 %

Procedure:
To a solution of sodium periodate (15.5 g, 72.6 mmol) in water (80 mL) was added a solution of (1R,3S,6S)-tert-butyl 3-(hydroxymethyl)-2-azabicyclo[4.1.0]heptane-2-carboxylate (5.5 g, 24.2 mmol) in ACN (60 mL) and carbon tetrachloride (60 mL). Ruthenium (III)chloride (246 mg, 1.21 mmol) was added immediately and the reaction mixture was stirred vigorously for 75 min at RT, diluted with water (80 mL), filtered, and extracted with DCM (3×100 mL). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under vacuum to provide crude product (4.75 g) as a light charcoal-color solid. The crude product was dissolved in EtOAc (20 mL) with heating and allowed to stand at RT with seeding. After about 15 min, rapid crystal formation was observed. About 1 h later, hexane (10 mL) was added and the mixture was refrigerated overnight, filtered, washed with 2:1 ice-water-cooled hexanes:EtOAc (50 mL) and dried under high vacuum to provide the title intermediate (1.9 g) ([a]D=−135.2) The mother liquid was re-crystallized to provide additional product (300 mg) ([a]D=−142.6). 1H NMR: (DMSO-d6, 400 MHz) δ (ppm) 4.1 (m, 1H), 2.60 (m, 1H), 1.70 (m, 1H), 1.30 (m, 3H), 1.17 (m, 9H), 0.96 (m, 1H), 0.50 (m, 1H), 0.0 (m, 1H)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=3)=[CH:29][CH:28]=2)([CH2:14][O:15][C:16]2[NH:20][C:19]3[CH:21]=[C:22]([Cl:26])[C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.C1(C)C=CC=CC=1>[Cl:26][C:22]1[C:23]([Cl:25])=[CH:24][C:18]2[NH:17][C:16]([O:15][CH2:14][C:11]3([C:27]4[CH:28]=[CH:29][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=5)=[CH:31][CH:32]=4)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:20][C:19]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2nc3cc(Cl)c(Cl)cc3[nH]2)(c2ccc(-c3cccc(C#N)c3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N#Cc1cccc(-c2ccc(C3(COc4nc5cc(Cl)c(Cl)cc5[nH]4)CCNCC3)cc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 0.015 g of 4-(3′-cyano-biphenyl-4-yl)-4-(5,6-dichloro-1H-benzoimidazol-2-yloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester 53 (0.026 mmol) in 3 mL of dichloromethane at 0° C. was added 1 mL of trifluoroacetic acid. The mixture was stirred at 0° C. for 2 h then diluted with 10 mL of toluene and concentrated by rotary evaporation. The resulting residue was dissolved in 25 m) of ethyl acetate and washed with 10% aqueous NaHCO3 and saturated brine. The organic extracts were dried over Na2SO4, filtered and concentrated by rotary evaporation to give the crude product which was purified by reverse phase preparative HPLC to give 0.0113 g of the desired product 4′-[4-(5,6-dichloro-1H-benzoimidazol-2-yloxymethyl)-piperidin-4-yl]-biphenyl-3-carbonitrile 54 as a pale foam. 1H NMR (300 MHz, CDCl3/CD3OD): δ 7.85-7.75 (t, 1H), 7.72-7.70 (dt, 1H), 7.57-7.41 (m, 6H), 7.30(s, 2H), 5.19 (s, 2H), 4.31 (s, 2H), 3.33-3.25 (m, 2H), 2.90-2.82 (d, 2H), 2.47-2.34 (m, 2H), MS (ESI): Calcd m/z for C26H22Cl2N4O.H+=477.1. Found m/z=476.7/478.7 [(M+1)+/(M+3)+].
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[C:7]([Cl:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.CS([Cl:30])(=O)=O>C(Cl)Cl>[Cl:30][CH:2]1[C:11]2[C:6](=[C:7]([Cl:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(O)CCS2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(Cl)c2c(c1C)C(Cl)CCS2
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.1 %

Procedure:
1.0 Gram (3.5 mmol) of 4-hydroxy-5-methyl-6-ethoxycarbonyl-8-chlorothiochroman was dissolved in 5 ml of methylene chloride, and 0.72 ml (5.2 mmol) of triethylamine and 0.4 ml (5.2 mmol) of methanesulfonyl chloride were added with an ice bath cooling. The mixture was stirred at room temperature for 1 hour. After the completion of the reaction, an organic layer was washed with 2N hydrochloric acid and with a saturated sodium hydrogencarbonate aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 1.24 g (yield 100%) of 4,8-dichloro-5-methyl-6-ethoxycarbonylthiochroman.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[N-].[BrH:11]>C(Cl)Cl>[Br:11][CH2:3][C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)CC(=O)C=[N+]=[N-]
Reactant: Br
Solvent: ClCCl
Product: CC(C)(C)CC(=O)CBr
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred, −10° solution of the crude product from Step A (1.233 grams) in methylene chloride (12 mL) was added 48% HBr dropwise (1.14 mL). After gas evolution ceased, the reaction was stirred for 15 minutes at room temperature. The reaction was partitioned between isopropyl acetate and water. The organic was washed once with water, dried over magnesium sulfate and filtered. Evaporation afforded an oil containing the title compound which was used without further processing.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([Cl:11])[N:3]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].O>C(OCC)C>[Cl:11][C:4]1[C:5]([C:9]#[N:10])=[C:6]([Cl:8])[N:7]=[C:2]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])[N:3]=1
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CCNCC
Solvent: O
Solvent: CCOCC
Product: CCN(CC)c1nc(Cl)c(C#N)c(Cl)n1
Reaction time: 1 h
Yield: 51.3 %

Procedure:
A stirred solution of 6.3 grams of 2,4,6-trichloro-5-pyrimidinecarbonitrile in 150 ml of diethyl ether was cooled to -10°, and a solution of 4.4 grams of diethylamine in 75 ml of diethyl ether was added dropwise. Upon complete addition, the reaction mixture was stirred at -10° for 1 hour. Water was added to the reaction mixture. The diethyl ether layer was separated and dried over magnesium sulfate. The mixture was filtered, and the filtrate was evaporated under reduced pressure to a residue. The residue was recrystallized from methylcyclohexane to give 3.8 grams of 4,6-dichloro-2-diethylamino-5-pyrimidinecarbonitrile; mp, 125°-126°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:9][C:10]1([Cl:17])[CH2:12][C:11]1(C)[C:13](O)=O.S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[OH-].[NH4+]>[N+]([O-])([O-])=O.[Ag+].O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[C:11]1([CH3:13])[CH2:12][C:10]1([Cl:17])[Cl:9]
Reactant: Clc1ccc(Cl)nn1
Reactant: CC1(C(=O)O)CC1(Cl)Cl
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: CC1(c2cc(Cl)nnc2Cl)CC1(Cl)Cl
Reaction time: 0.25 h

Procedure:
A 3.5 g. portion of 3,6-dichloropyridazine was slurried with 4.0 g. of 2,2-dichloro-1-methylcyclopropanecarboxylic acid, 15 ml. of water, 3.4 g. of concentrated sulfuric acid in 20 ml. of water, and 4.0 g. of silver nitrate, and the mixture was heated to 65° with rapid stirring. To it was added 11.9 g. of ammonium persulfate in 20 ml. of water, over 20 minutes, while the temperature was held at 70°-76°. The mixture was stirred 15 minutes after the addition and cooled to 10°. Its pH was adjusted to 8.0 with ammonium hydroxide, and the water layer was then decanted off. The remaining solids were washed twice with 100 ml. portions of diethyl ether, and that ether was then used to extract the water layer. The organic layer was washed with 1N sodium hydroxide and with brine, and dried. The solvent was removed under vacuum, and the residue was purified by chromatography, eluting with 3:1 heptane:ethyl acetate. The product-containing fractions were combined and evaporated, and the residue was recrystallized from heptane, to obtain 0.52 g. of the desired product, m.p. 78°-79°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]([F:31])([F:30])[S:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:26]\[C:25]3[CH:28]=[CH:29][C:22]([S:21][C:20]([F:31])([F:19])[F:30])=[CH:23][CH:24]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (1.2 g, 4.858 mmol) in toluene 40 mL was added 4-((trifluoromethyl)thio)benzaldehyde 72 (1 g, 4.858 mmol). PTSA (1.84 g, 9.716 mmol) was added and the reaction mixture was stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 73, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-6-methoxy-5-morpholino-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one 73 was eluted at 37% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@@H:5]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:17](=O)(OC1C=CC([N+]([O-])=O)=CC=1)[O:18]C1C=CC([N+]([O-])=O)=CC=1>ClCCCl>[CH3:16][C@@H:13]([CH2:14][CH3:15])[C@H:5]([N:4]1[CH2:3][CH2:2][NH:1][C:17]1=[O:18])[C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: CC[C@H](C)[C@H](NCCN)C(=O)OC(C)(C)C
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCNC1=O
Temperature: 70 °C
Yield: 91.9 %

Procedure:
To a solution containing the product from Example 3G (0.50 g, 2.08 mmol) in 1,2-dichloroethane (90.0 mL) was added bis(4nitrophenyl) carbonate (0.80 g, 2.63 mmol), and the mixture was heated to 70° C. for 12 hours. The reaction mixture was cooled and concentrated. The residue was dissolved in ethyl acetate, and washed with 10% Na2CO3 (3×), brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending ethyl acetate to give the product (0.49 g, 88% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[S:14][N:13]=[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:11]=2)[C:6]([CH3:24])=[CH:5][C:3]=1[NH2:4].CO.O([CH:29](OC)[N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[S:14][N:13]=[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:11]=2)[C:6]([CH3:24])=[CH:5][C:3]=1/[N:4]=[CH:29]\[N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: Cc1cc(N)c(Cl)cc1Oc1nc(CCc2ccc(Cl)cc2)ns1
Reactant: COC(OC)N1CCCCC1
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(/N=C\N2CCCCC2)c(Cl)cc1Oc1nc(CCc2ccc(Cl)cc2)ns1
Yield: 34.6 %

Procedure:
0.30 g (0.79 mmol) of 2-chloro-4-({3-[2-(4-chlorophenyl)ethyl]-1,2,4-thiadiazol-5-yl}oxy)-5-methylaniline is dissolved in 3 ml of toluene and 0.75 ml of methanol and treated with 0.37 g (2.37 mmol) of 1-(dimethoxylmethyl)piperidine. The reaction mixture is refluxed for 18 h, subsequently cooled, freed from the solvent under vacuum and purified by column chromatography. 0.13 g of product is obtained (84.2% purity, 29.3% yield, log P (pH 2.3)=2.64).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:13][C:14]([OH:16])=[O:15]>CN(C)C=O>[C:3]1([CH2:2][CH2:1][O:9][CH2:13][C:14]([OH:16])=[O:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CCl
Reactant: OCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)COCCc1ccccc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
6.1 g of phenethyl alcohol in 100 ml of dimethylformamide were treated with 4.8 g of a 50% sodium hydride dispersion in mineral oil and the mixture was stirred for 10 minutes at 60° C. 4.73 g of chloroacetic acid were added and the mixture was heated at 60° C. for 0.5 hour with stirring. The mixture was evaporated to dryness and the residue was partitioned between water and diethyl ether. The aqueous phase was acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue was recrystallized from ethyl acetate/hexane to give 7.65 g (85%) of 2-phenylethoxyacetic acid of melting point 46°-48° C.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:3]=1[O:4]/[C:5](=[CH:11]\[C:12]([O:14]CC)=[O:13])/[C:6]([O:8]CC)=[O:7].[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:3]=1[O:4]/[C:5](=[CH:11]\[C:12]([OH:14])=[O:13])/[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)/C=C(\Oc1ccc(OC)cc1Br)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(O/C(=C\C(=O)O)C(=O)O)c(Br)c1
Yield: 88.5 %

Procedure:
Diethyl (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioate (29.9 g, 86.6 mmol) as prepared in Reference Example 2a was suspended in ethanol (55 ml) and a solution of sodium hydroxide (7.0 g, 0.175 mol) in water (55 ml) was added. The solution was refluxed for 1 h to give a clear orange solution. Most of the ethanol was removed in vacuo then 6 M HCl (50 ml) was added. The solid was filtered, washed with water and dried to give (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioic acid as a light orange solid (24.3 g, 88% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5](I)=[CH:4][N:3]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1cccs1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1I
Product: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Yield: 70 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-iodopyrimidine-4-ylamino)propan-1-ol (400 mg, 1.3 mmol) with thiophen-2-boronic acid (e. g.: Aldrich, Acros, Apin) (179 mg, 1.4 mmol) according to procedure 3, the desired product is obtained in 70% yield (240 mg) after chromatographic purification (silica gel, ethyl acetate/hexane (0%-100% ethyl acetate)).
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[O:15].C1(C)C=CC=CC=1>CN(C=O)C.O.Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[C:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[O:15])#[N:3]
Reactant: N#C[Cu]
Reactant: O=C1CCCc2c(Br)cccc21
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1cccc2c1CCCC2=O
Reaction time: 6 h

Procedure:
0.41 g (4.5 mmol) of copper(I) cyanide is added to a solution of 1.0 g (4.4 mmol) of 5-bromo-1-tetralone [see J. Org. Chem. 49, 4226 (1984)] in 1.3 ml of DMF, and the reaction mixture is stirred at 160° for 6 hours. The reaction mixture is then cooled to 80°, and a solution of 1.6 g of iron(III) chloride hexahydrate in 2.5 ml of water and 0.44 ml of concentrated hydrochloric acid is added. Stirring is continued for 45 minutes, the reaction mixture is cooled and diluted with water, and extraction is carried out with toluene. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated by evaporation. In that manner there is obtained the title compound in the form of yellow-orange crystals, IR (CH2Cl2): 2220, 1690 cm-1 ; 1H-NMR (CDCl3): δ=8.26 (q,1H); 7.81 (q,1H); 7.43 (t,1H); 3.21 (t,2H); 2.72 (t,2H); 2.23 (m,2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]2=[O:29])=[C:11]([OH:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]3([CH2:31][O:30][C:11]=2[CH:10]=1)[C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]([CH2:24][CH2:25][CH:26]([CH3:27])[CH3:28])[C:16]3=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: CC(C)CCN1C(=O)C(c2ccc(OCc3ccccc3)cc2O)c2ccccc21
Product: CC(C)CCN1C(=O)C2(COc3cc(OCc4ccccc4)ccc32)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(3-methylbutyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6-(benzyloxy)-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1H)-one was obtained (67%): 1H NMR (300 MHz, CDCl3) δ 7.41-7.28 (m, 7H), 7.14-7.12 (m, 1H), 7.04-6.99 (m, 1H), 6.90-6.87 (m, 1H), 6.59-6.55 (m, 1H), 6.44-6.30 (m, 1H), 5.00 (s, 2H), 4.79 (ABq, 2H), 3.87-3.64 (m, 2H), 1.71-1.56 (m, 3H), 0.98 (d, J=6.0 Hz, 6H); MS (ES+) m/z 414.3 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:1]([C:17]1[CH:18]=[CH:19][C:14]([Br:13])=[CH:15][CH:16]=1)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Brc1ccccc1
Reactant: CCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pentanoyl chloride (50 g) is added dropwise to a stirred, cooled 0° C.) mixture of bromobenzene (150 ml) and aluminum chloride (0.2 g). The mixture is stirred at 0° C. for 1 h, heated at 80° C. for 2 h, cooled and poured into 18% hydrochloric acid. The product is extracted into CHCl3 twice, the combined organic extracts are washed with water and steam distilled to remove chloroform and the excess of bromobenzene. The product is extracted into chloroform twice, the combined organic phases are washed with water and dried (MgSO4). The solvent is removed in vacuo and the residue is distilled (bp 180°-184° C. at 20 mm Hg) to yield a colourless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:26]#[C:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:18]=1)[CH2:7]2
Reactant: [H][H]
Reactant: Cc1cc(C#CCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(Oc3ccccc3)cc1)C2
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1cc(CCCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(Oc3ccccc3)cc1)C2
Yield: 108.4 %

Procedure:
A mixture of 7-methyl-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.056 g, 0.11 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-Methyl-5-[3-(4-methyl-piperazin-1-yl)-propyl]-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.056 g, 100%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.79 (m, 2H), 2.23-2.66 (m, 18H), 4.18 (s, 2H), 4.72 (s, 2H), 6.88-7.38 (m, 11H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(OCC)(=O)C>[C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH:12][C:20](=[O:22])[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1CCC[C@H]1c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NC1CCCC1c1ccccc1
Reaction time: 1 h

Procedure:
4.45 g of trans-2-phenyl-cyclopentylamine and 4.2 ml of triethylamine were dissolved in 50 ml of ethyl acetate. 2.86 ml of acetic anhydride was added slowly and the mixture stirred for 1 hour and washed with 40 ml of water. After drying the organic layer with sodium sulfate, filtration and evaporation 4.7 g of a crude solid was obtained that was used without further purification.
Reaction SMILES: [Na+].[CH3:2][N:3]1[CH2:7][C@H:6]([S:8][C:9]2[C@H:10]([CH3:23])[C@@H:11]3[C@@H:18]([C@H:19]([OH:21])[CH3:20])[C:17](=[O:22])[N:12]3[C:13]=2[C:14]([O-:16])=[O:15])[CH2:5][C:4]1=[S:24].C(=O)([O-])[O-].[K+].[K+].[C:31]([O:34][CH2:35]I)(=[O:33])[CH3:32].P([O-])([O-])([O-])=O>CN(C)C=O>[C:31]([O:34][CH2:35][O:15][C:14]([C:13]1[N:12]2[C:17](=[O:22])[C@H:18]([C@H:19]([OH:21])[CH3:20])[C@H:11]2[C@@H:10]([CH3:23])[C:9]=1[S:8][C@H:6]1[CH2:7][N:3]([CH3:2])[C:4](=[S:24])[CH2:5]1)=[O:16])(=[O:33])[CH3:32]
Reactant: CC(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@@H]3CC(=S)N(C)C3)[C@H](C)[C@H]12
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=O)C1=C(S[C@@H]2CC(=S)N(C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 1 h
Yield: 55.2 %

Procedure:
(1R, 5S, 6S)-2-[(4R)-N-methylpyrrolidine-2-thion-4ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid sodium salt (400 mg) is suspended in N,N-dimethylformamide (5 ml), and thereto is added potassium carbonate (146 mg). To the mixture is added acetoxymethyl iodide (275 mg) at 5°-7° C., and the mixture is stirred at the same temperature for one hour. The reaction mixture is poured into phosphate buffer (pH 7.0) and extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated to dryness under reduced pressure. The residue is purified by silica gel column chromatography (eluent, chloroform - chloroform:ethanol=98:2), followed by crystallization from tetrahydrofuran and diethyl ether to give (1R, 5S, 6S)-2-[(4R)-N-methylpyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid acetoxymethyl ester (250 mg) as colorless needles.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:16]1CCOCC1>>[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:16]
Reactant: C1COCCO1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
0.05 mole of 1,4-dihydroxy-2-naphthoic acid was dissolved in 70 ml of DMF, and 10 ml of a 40% aqueous solution of sodium hydroxide was added dropwise to the solution while introducing nitrogen gas. Then, 0.05 mole of α-bromo-propionylethylamide dissolved in 15 ml of DMF was added dropwise and the reaction was conducted at 50° C. for 3 to 4 hours under agitation. After completion of the reaction, the reaction mixture was poured into ice-hydrochloric acid and crystals were recovered by filtration and recrystallized from acetonitrile to obtain a compound having a melting point of 192° C. Then, 0.01 mole of 1-hydroxy-4-[1-(ethylaminocarbonyl)ethoxy]-2-naphthoic acid so obtained was dissolved in 60 ml of dry dioxane, and 0.01 mole of dicyclohexylcarbodiimide was added to the solution. The reaction was conducted at 50° to 60° C. for 30 minutes under agitation. After completion of the reaction, the reaction mixture was filtered and dicyclohexylurea formed as a by-product was removed. The filtrate was concentrated under reduced pressure and n-hexane was added. Precipitated crystals were recovered by filtration and recrystallized from n-hexane to obtain a compound having a melting point of 95° C. (the yield being 65%). From the results of the elementary analysis, it was confirmed that the compound was the compound (2) illustrated above.