Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[C:13]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]([NH:29][NH2:30])=[O:28])[CH2:23][CH2:22]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[C:13]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]([NH:29][N:30]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:28])[CH2:23][CH2:22]1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NNC(=O)C1CCN(C(=O)c2ccccc2)CC1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 100 °C
Yield: 88 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added (±)-1-benzoyl-4-piperidinecarbohydrazide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 221 mg of the title compound (88%) as a yellow solid in 94.1% purity by HPLC (Rt: 3.93, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][O:20][CH3:21])([CH3:18])[CH2:13]1.[CH2:22](Br)[CH:23]=C>>[CH2:21]([O:20][CH2:19][C:14]1([CH3:18])[CH2:15][CH2:16][CH2:17][N:12]([CH2:11][CH:2]2[O:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3]2)[CH2:13]1)[CH:22]=[CH2:23]
Reactant: C=CCBr
Reactant: COCC1(C)CCCN(CC2COc3ccccc3O2)C1
Product: C=CCOCC1(C)CCCN(CC2COc3ccccc3O2)C1

Procedure:
The procedure described above for 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidine was repeated except that allyl bromide was used instead of methyl iodide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[OH-].[Na+]>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1cc(O)c(-c2ccccc2)c([N+](=O)[O-])c1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(OCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
A mixture of 3-hydroxy-5-nitro-4-phenylbenzoic acid (3.0 g), benzylbromide (1.5 ml) and 1 N sodium hydroxide (30 ml) is stirred at room temperature for 6-7 hours. After cooling, the precipitated sodium 3-benzyloxy-5-nitro-4-phenylbenzoate is collected by filtration and washed with a small amount of icecold water. After drying, the sodium salt is dissolved in hot water (100 ml), and the 3-benzyloxy-5-nitro-4-phenylbenzoic acid is precipitated by addition of 4 N hydrochloric acid (10 ml). After cooling, the acid is collected by filtration, washed with water and dried. After recrystallization twice from isopropanol, it is obtained with a melting point of 188.5°-189.5° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].O[CH2:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[C:17]([CH:18]2[CH:23]3[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]3)[CH2:19]2)=[N:16][S:15][N:14]=1.BrCCCC[OH:31]>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:11]([S:12][C:13]1[C:17]([CH:18]2[CH:23]3[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]3)[CH2:19]2)=[N:16][S:15][N:14]=1)[C:10](=[O:31])[CH2:9][CH3:8]
Reactant: OCCCCSc1nsnc1C1CN2CCC1CC2
Reactant: OCCCCBr
Agent: O=C(O)C(=O)O
Product: CCC(=O)CSc1nsnc1C1CN2CCC1CC2

Procedure:
3-(3-(4-Hydroxybutylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]octane oxalate (Compound 219) M.p. 160°-161° C., from 1-bromo-4-hydroxybutane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)[O:10][CH:11]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:12]2[CH2:16][CH:15]([OH:17])[CH2:14][N:13]2[C:18](=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:36](=[O:37])[C:35]3[C:30](=[N:31][C:32]([CH3:38])=[CH:33][CH:34]=3)[N:29]([CH2:39][CH3:40])[CH:28]=2)=[O:26])=[CH:5][CH:4]=1.[C:56]1(=[O:62])[O:61][C:59](=[O:60])[CH2:58][CH2:57]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:55][O:54][C:51]1[CH:50]=[CH:49][C:48]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:10][CH:11]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:12]2[N:13]([C:18](=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]3[C:36](=[O:37])[C:35]4[C:30](=[N:31][C:32]([CH3:38])=[CH:33][CH:34]=4)[N:29]([CH2:39][CH3:40])[CH:28]=3)=[O:26])[CH2:14][CH:15]([O:17][C:56](=[O:62])[CH2:57][CH2:58][C:59]([OH:61])=[O:60])[CH2:16]2)=[CH:53][CH:52]=1
Reactant: O=C1CCC(=O)O1
Reactant: CCn1cc(C(=O)NCCCCCC(=O)N2CC(O)CC2C(OC(c2ccc(OC)cc2)c2ccc(OC)cc2)c2ccccc2)c(=O)c2ccc(C)nc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1cc(C(=O)NCCCCCC(=O)N2CC(OC(=O)CCC(=O)O)CC2C(OC(c2ccc(OC)cc2)c2ccc(OC)cc2)c2ccccc2)c(=O)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Referring to scheme 27, Compound 99 (1.48 g, 2 mmol) is mixed with succinic anhydride (0.200 g, 2 mmol) and DMAP (0.244 g, 13 mmol) and dried in a vacuum at 40° C. overnight. The mixture is dissolved in anhydrous dichloromethane (5 mL), triethylamine (0.606 g, 0.96 mL, 6 mmol) is added and the solution stirred at room temperature under argon atmosphere for 16 h. It is then diluted with dichloromethane (100 mL) and washed with ice cold aqueous citric acid (5% wt., 100 mL) and water (2×100 mL). The organic phase is dried over anhydrous sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography to afford compound 101.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: OB(O)c1ccccc1
Product: CC1(C)CC(=O)c2ccc(-c3ccccc3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and phenyl boronic acid according to the procedure described in example 21. MS m/z 237; HRMS: calcd for C17H16O+H+, 237.12739; found (ESI, [M+H]+), 237.1271.
Reaction SMILES: C(OC(N1CC2C([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:24]=4[N:25]=3)[CH2:13]2)C1)=O)(C)(C)C.[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][C:42]2([CH2:49]CNC[CH2:45]2)[CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][C:42]2([CH2:49][CH2:13][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:24]=4[N:25]=3)[CH2:11][CH2:45]2)[CH2:41]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)CC2C1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)CC2)C1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a white solid (81 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:20]=[C:21](\[CH3:25])/[C:22]([OH:24])=[O:23])[C:6]2[C:11]([C:12]=1[O:13]COC)=[C:10]([CH2:17][CH2:18][CH3:19])[CH:9]=[CH:8][CH:7]=2.O.Cl>CC(C)=O>[OH:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:17][CH2:18][CH3:19])[C:5](/[CH:20]=[C:21](\[CH3:25])/[C:22]([OH:24])=[O:23])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(OCOC)c12
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
1.9 g of (E)-3-(3-methoxy-4-methoxymethoxy-5-propyl-1-naphthyl)-2-methylpropenoic acid was dissolved in 80 ml of acetone and 40 ml of water and 3 ml of concentrated hydrochloric acid was added, followed by stirring at 50° C. for 2 hours. After cooling to room temperature the reaction mixture was poured into water, and the resultant crystals were filtered and washed with hexane. 1.5 g of the titled compound was obtained as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][C:10](OC)=O)=[CH:4][C:3]=1[NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].[CH:26]1(Br)[CH2:30]C[CH2:28][CH2:27]1.Cl>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:28][CH2:27][CH2:26][CH2:30]2)=[CH:4][C:3]=1[NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18]
Reactant: CCOC(=O)Nc1cc(OC(=O)OC)c(Cl)cc1F
Reactant: BrC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Reaction time: 2 h
Yield: 94.4 %

Procedure:
Ethyl N-(2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl)carbamate (1.45 g, 4.97 mmol) prepared by the process described in Reference Example 1 and a solution of potassium carbonate (1.03 g, 7.46 mmol) in ethanol (50 ml) were stirred for 1 hour while refluxing, and then cyclopentyl bromide (1.11 g, 7.46 mmol) was added thereto, followed by further stirring for 2 hours. After completion of the reaction, the mixture was poured into 1N hydrochloric acid (50 ml), and extracted with ethyl acetate (50 ml×3 times). The organic layer was dried, and concentrated under reduced pressure to obtain ethyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate as grey white crystals (1.41 g, 4.69 mmol, 94.4% yield). The spectral data and the like are as shown in Reference Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH2:11]Br)[C:4]=1[CH2:13]Br.[SH:15][CH2:16][C:17]([O:19][CH2:20]C)=[O:18].C[O-].[Na+].CC[O-].[Na+]>C(Cl)Cl.CO>[C:17]([CH:16]1[CH2:13][C:4]2[C:5](=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:11][S:15]1)([O:19][CH3:20])=[O:18]
Reactant: COc1ccc(OC)c(CBr)c1CBr
Reactant: CCOC(=O)CS
Agent: CC[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1Cc2c(OC)ccc(OC)c2CS1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
1,4-dimethoxy-2,3-dibromomethylbenzene (10.0 g, 30.88 mmol) was dissolved in CH2Cl2 and MeOH (750 ml, 6:4) followed by addition of ethyl 2-mercaptoacetate (4.02 ml, 37.06 mmol) with stirring under argon. The mixture was then cooled to 0° C. followed by dropwise addition of sodium methoxide (4.37M, 8.5 ml, 37.06 mmol) over a period of 2 h using an automatic syringe pump. After 5 minutes the solvent was evaporated and the crude was redissolved in THF (400 ml) and cooled to 0° C. again. NaOEt (2.10 g, 30.88 mmol) was then added. The ice bath was removed and the reaction was stirred for 2 more hours. The reaction mixture was then quenched with NH4Cl (sat.) and extracted with ether. The organic phases were combined, dried over MgSO4, filtered and concentrated. The crude residue was then treated with NaOME in MeOH and THF at 0° C. for 2 hours. The reaction mixture was extracted with ether (100 ml×2). The combined organic phases were washed with H2O, dried over MgSO4, filtered and concentrated to a residue that was purified by flash chromatography to give title compound in 45% yield. 1H NMR (300 MHz, CDCl3, ppm) d:2.97 (dd, 1H, J=16.51, 8.79 Hz, HCHaCHC=O), 3.36 (dd, 1H, J=16.7, 5.1 Hz, HCHeCHC=O), 3.73 (m, 2H, HCHa,e--O), 3.75 (s, 3H, OCH3), 3.78 (s, 6H, 2×OCH3), 3.85 (m, 1H, HC--S), 6.69 (m, 2H, ArH).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[CH:15][C:14]=3[OH:24])[C:11]=2[CH3:12])=[O:6])[CH2:3][CH2:2]1.Br[CH2:26][CH2:27][Cl:28]>C(OCC)(=O)C.CCCCCC>[Cl:28][CH2:27][CH2:26][O:24][C:14]1[CH:15]=[C:16]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])[CH:17]=[CH:18][C:13]=1[N:10]1[C:11]([CH3:12])=[C:7]([C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:6])[N:8]=[N:9]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C)c(O)c1
Reactant: ClCCBr
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C)c(OCCCl)c1

Procedure:
In the same manner as in Example 145, a product was obtained from N-cyclopropyl-1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-5-methyl-1H-1,2,3-triazole-4-carboxamide (0.17 g) obtained in Example 141 and 1-bromo-2-chloroethane (0.05 ml), and the title compound was obtained as a white powder (0.06 g, 31%) by recrystallization from ethyl acetate-hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[NH:19][C:18]2[NH:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=1)=[O:10].CCN(CC)CC.C1([O:33][C:34](=O)[NH:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)C=CC=CC=1>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[NH:19][C:14]2[CH2:15][CH2:16][N:17]([C:34]([NH:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[O:33])[CH2:18][C:13]=2[CH:12]=1)=[O:10]
Reactant: Nc1ccccc1NC(=O)c1cc2c([nH]1)NCCC2
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1cc2c([nH]1)CCN(C(=O)Nc1cccnc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-aminophenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2]pyridine-2-carboxamide (1.0 eq) in DMF was added Et3N (3.0 eq.) followed by Pyridin-3-yl-carbamic acid phenyl ester (1.0 eq). Reaction was stirred at room temperature for overnight. Reaction mixture was then quenched with water and extracted with ethyl acetate, dried over sodium sulphate and concentrated to dryness. Crude mass was then purified by silica gel column chromatography to afford N2-(2-aminophenyl)-N5-pyridin-3-yl-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-2,5-dicarboxamide.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:2]=1.Cl[C:17]1[C:18]2[S:25][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][C:19]=2[N:20]=[CH:21][N:22]=1>>[C:26]1([C:24]2[S:25][C:18]3[C:17]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([NH:7][C:3]5[CH:2]=[C:1]([CH3:15])[CH:6]=[CH:5][CH:4]=5)=[CH:9][CH:10]=4)=[N:22][CH:21]=[N:20][C:19]=3[CH:23]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccc(Nc2ccc(N)cc2)c1
Reactant: Clc1ncnc2cc(-c3ccccc3)sc12
Product: Cc1cccc(Nc2ccc(Nc3ncnc4cc(-c5ccccc5)sc34)cc2)c1
Yield: 21 %

Procedure:
Utilizing a procedure analogous to that described in Example 61, the title compound was prepared in 21% yield from N-m-Tolyl-benzene-1,4-diamine (230 mg, 1.16 mmol) and 4-chloro-6-phenyl-thieno[3,2-d]pyrimidine 250 mg, 1.16 mmol). RP18-HPLC RT: 7.432 minutes; APl MS: 409.1 (M+1); MP: 170-171° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([OH:16])=[CH:11][CH:12]=2)[CH:7]=1.[H-].[Na+].[Br:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([O:16][CH2:28][CH2:27][O:26][CH2:25][CH2:24][Br:23])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: BrCCOCCBr
Reactant: COC(=O)COc1ccc2ccc(O)c(C(C)=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2ccc(OCCOCCBr)c(C(C)=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
Under an argon atmosphere, 2 g of [[8-acetyl-7-hydroxy-2-naphthalenyl]oxy]acetic acid methyl ester was added to a suspension of 0.32 g of 60% sodium hydride in 30 ml of anhydrous dimethylformamide. The mixture was stirred at room temperature for 30 minutes and then 8.5 g of bis-(2-bromoethyl)ether was added and the mixture was stirred at room temperature for 20 hours. The solvent was removed and residual oil was purified by high pressure liquid chromatography using 7% ethyl acetate-toluene to yield 2.4 g (77%) of [[8-acetyl-7-[2-(2-bromoethoxy)ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
Reaction SMILES: [CH3:1]I.[NH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[S:5]>O1CCCC1>[NH:3]=[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])[S:5][CH3:1]
Reactant: CI
Reactant: NC(=S)Nc1cccc(C(=O)O)c1
Solvent: C1CCOC1
Product: CSC(=N)Nc1cccc(C(=O)O)c1
Temperature: 75 °C

Procedure:
Methyl iodide (18 g; 127.4 mmol; 7.93 ml) is added at ambient temperature, under an argon atmosphere, to a solution of 3-[(aminocarbothioyl)amino]benzoic acid (25 g; 127.4 mmol) in 375 ml of anhydrous tetrahydrofuran, and then the reaction mixture is heated at 75° C. for 2 hours. After cooling and concentration, the residue is taken up in ether and the precipitate formed is filtered off to yield the expected product.
Reaction SMILES: [BH4-].[Li+].C(C1C=CC=CC=1O[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:24]([CH2:25][CH2:26][CH3:27])=[C:23]2[C:18]([C:19](=O)[CH2:20][CH:21]([C:28]([OH:30])=O)[O:22]2)=[CH:17][CH:16]=1)CC.[BH4-].Cl.[CH3:38][CH2:39]OCC>O>[OH:30][CH2:28][CH:21]1[CH2:20][CH2:19][C:18]2[C:23](=[C:24]([CH2:25][CH2:26][CH3:27])[C:15]([O:14][CH2:13][C:12]3[CH:11]=[CH:10][CH:9]=[CH:39][CH:38]=3)=[CH:16][CH:17]=2)[O:22]1
Reactant: CCCc1ccccc1OCCCCCOc1ccc2c(c1CCC)OC(C(=O)O)CC2=O
Reactant: CCOCC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Product: CCCc1c(OCc2ccccc2)ccc2c1OC(CO)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A 3 neck 250 ml round bottom flask fitted with a magnetic stirring bar, a dropping funnel, a gas inlet tube, and a glass stopper was flame dried and flushed with argon. 100 ml of dry ether was introduced and 331 mg (15.2 mmole) of lithium borohydride was added to the ether. A solution of 5.17 g (15.2 mmole) of the compound of Example 32 in 50 ml of ether was added dropwise to the stirred slurry of borohydride. After the addition was completed, the solution was stirred for 2 hours additional at room temperature. The flask was cooled in an ice bath and 20 ml of water added dropwise followed by the careful dropwise addition of dilute hydrochloric acid until the solution cleared. The aqueous layer was drained off in a separatory funnel and the ether washed once with saturated sodium bicarbonate solution and then with brine. Drying the ether with anhydrous magnesium sulfate, filtration to separate the drying agent and ether removal by rotary evaporation gave 4.34 g (91%) of the title compound as an oil. Calc: C, 76.89; H, 7.74; Found: C, 76.75; H, 7.66.
Reaction SMILES: [K].C([O:9][C:10]1[CH:15]=[C:14]([CH2:16][CH:17]([CH3:26])[C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][C:11]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]1)C1C=CC=CC=1>CCO.O.[Pd]>[OH:9][C:10]1[CH:15]=[C:14]([CH2:16][CH:17]([CH3:26])[CH:18]([OH:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=[CH:12][C:11]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]1
Reactant: CC(Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)c1ccccc1
Agent: [Pd]
Agent: [K]
Solvent: O
Solvent: CCO
Product: CC(Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1)C(O)c1ccccc1
Reaction time: 4 h

Procedure:
To a solution of 5-[2-benzyloxy-4-(2-methyl-3-oxo-3-phenylpropyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium salt (Example 246, step C) in 5 mL of EtOH/water (1:1)) is added 15 mg of Degussa Pd/C and the resulting mixture is hydrogenated at 1 atm for 4 h. The catalyst is filtered through Celite and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC to give the title compound: (M−1)−=375.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@@H:44]1[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])[C@H:46]([CH:62]2[CH2:66][CH2:65][NH:64][C:63]2=[O:67])[CH2:45]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[CH:18][C@:19]([S:43][C@@H:44]3[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=4)=[O:50])[C@H:46]([CH:62]4[CH2:66][CH2:65][NH:64][C:63]4=[O:67])[CH2:45]3)([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: O=C1NCCC1[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C[C@@](C)(S[C@H]3C[C@@H](C4CCNC4=O)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H]12
Yield: 75.6 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (180 mg, 0.30 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-3-yl)pyrrolidine (110 mg, 0.30 mmol) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (161 mg, yield: 74.9%).
Reaction SMILES: C([S:4][CH2:5][CH2:6][C@@H:7]([C:19]([NH:21][C@H:22]([C:32]([O:34][CH3:35])=[O:33])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=[O:31])=[O:20])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(=O)C>CO.C(Cl)Cl>[CH:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][C@@H:22]([C:32]([O:34][CH3:35])=[O:33])[NH:21][C:19](=[O:20])[C@H:7]([CH2:6][CH2:5][SH:4])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])=[O:31]
Reactant: COC(=O)[C@H](Cc1ccccc1C=O)NC(=O)[C@H](CCSC(C)=O)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1C=O)NC(=O)[C@H](CCS)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 104.2 %

Procedure:
A solution of the title compound of step (J) (0.77 g, 1.54 mmol) in MeOH (16 mL) and CH2Cl2 (3 mL) cooled at 0° C. was purged with argon for 20 minutes. To this solution 370 μL of NaOMe (25% w/w in MeOH) was added dropwise. After addition, the mixture was stirred at 0° C. for 15 minutes before being quenched with sat. aqueous NH4Cl (20 mL). The mixture was extracted with EtOAc (200 mL). The separated aqueous phase was back-extracted with EtOAc (50 mL). The combined EtOAc was washed with sat. aqueous NH4Cl, H2O, brine, dried (MgSO4), filtered, concentrated and dried in vacuo to give 0.736 g of the title compound of this step as a white foam which was used in the next reaction step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[N:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: COc1cccc(C=O)c1
Solvent: CCOCC
Product: COc1cccc(C=NCc2ccccc2)c1

Procedure:
A solution of 100 gm. of 3-methoxybenzaldehyde. 78.7 gm. of benzylamine, and 800 ml. of anhydrous ether was refluxed for 14 hours and then concentrated in vacuo to an oil. Distillation provided 144.3 gm. of clear oil, b.p. 152°-154° (1.2 Torr).