Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH:30][CH3:31])=[O:29])=[CH:24][CH:23]=2)=[C:16]([CH3:32])[CH:15]=1.C(N(CC)CC)C>ClCCCl.CC(O)(C)C.[Cl-].[Zn+2].[Cl-]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([NH:30][CH3:31])=[O:29])=[CH:24][CH:23]=3)=[C:16]([CH3:32])[CH:15]=2)[N:7]=1
Reactant: CNC(=O)c1ccc(-c2cc(OC)c(N)cc2C)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(-c2cc(OC)c(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2C)cc1
Reaction time: 0.5 h

Procedure:
To the mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (100 mg, 0.46 mmol) in 0.5 mL of DCE and 0.5 mL of t-BuOH is added zinc chloride (1.0 M in ether, 0.46 mL, 0.46 mmol), and stirred 30 min. 4′-amino-5′-methoxy-N,2′-dimethylbiphenyl-4-carboxamide (111 mg, 0.414 mmol) and triethylamine (46 mg, 0.46 mmol) are added sequentially, and the reaction is stirred at room temperature overnight. The precipitate is filtered, washed by MeOH, and dried in vacuo to afford 4′-(4-Chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)-5′-methoxy-N,2′-dimethylbiphenyl-4-carboxamide as a white solid; ESMS m/z 451.1 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:9](=[O:25])[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[S:24][CH:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)(C)(C)C.[ClH:35]>C(Cl)Cl.O1CCOCC1>[ClH:33].[ClH:35].[NH2:7][CH:8]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:9]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[S:24][CH:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)=[O:25]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3ccsc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3ccsc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of [1-(4-chlorobenzyl)-2-oxo-2-(4-thieno[3,2-d]pyrimidin-4-yl-piperazin-1-yl)-ethyl]-carbamic acid tert-butyl ester in DCM (2 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed to afford 2-amino-3-(4-chlorophenyl)-1-(4-thieno[3,2-d]pyrimidin-4-yl-piperazin-1-yl)-propan-1-one dihydrochloride quantitatively. MS (ESI+) [M+H]+ 402.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1.Br[CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(OC(=O)C)C>[CH3:1][C:2]1([CH3:12])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:14][CH2:15][Cl:16])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC1(C)Cc2cccc(OCCCl)c2O1

Procedure:
To 100 ml. ethylacetate 8.23 g. (0.05 mole) 2,3-dihydro-2,2-dimethyl-7-hydroxy-benzofuran, 14.3 g. (0.1 mole) 1-bromo-2-chloro-ethane, 6.9 g. (0.05 mole) anhydrous sodium carbonate and 8.3 (0.05 mole) potassium iodide are added. The reaction mixture is heated for 30 hours and the reaction is monitored by gas chromatographic analysis.
Reaction SMILES: [OH-].[K+].[C:3]([CH:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7]1)(=[O:5])[CH3:4].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.[CH2:40](Cl)[C:41](=[CH2:43])[CH3:42]>O.C1(C)C=CC=CC=1>[C:3]([CH:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7]1)(=[O:5])[CH3:4].[C:3]([C:6]1([CH2:42][C:41]([CH3:43])=[CH2:40])[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7]1)(=[O:5])[CH3:4]
Reactant: C=C(C)CCl
Agent: CC(=O)C1CCCC(C)(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)CC1(C(C)=O)CCCC(C)(C)C1
Temperature: 70 °C

Procedure:
A slurry of potassium hydroxide (84 grams, 1.5 moles), 1-acetyl-3,3-dimethylcyclohexane (156 grams, 1 mole), dibenzo-18-crown-6 (3 grams) having the structure: ##STR20## produced by the Aldrich Chemical Company of Metuchen, New Jersey, and toluene (150 ml) is heated to reflux whereupon the reaction mass thickens. The mass is cooled to 70° C, and methallyl chloride (135 grams, 1.5 moles) is added thereto rendering the reaction mixture more fluid. The reaction mixture is heated at reflux for an additional 9 hours whereupon the mass is cooled, and water is added. The aqueous layer is decanted and the organic layer is distilled to afford 1-acetyl-3,3-dimethylcyclohexane (62 gm) and 1-acetyl-3,3-dimethyl-1-(2-methyl-2-propenyl) cyclohexane (83 gm, NMR spectrum, FIG. 1; IR spectrum, FIG. 2).
Reaction SMILES: [Na:1].[F:2][C:3]([F:11])([S:7]([OH:10])(=[O:9])=[O:8])[C:4]([OH:6])=[O:5].[O:12]=[C:13]1[CH:20]2[CH2:21][C:16]3(O)[CH2:17][CH:18]([CH2:22][CH:14]1[CH2:15]3)[CH2:19]2.C(C1C=CC=CC=1)C.S(=O)(=O)(O)O>>[Na:1].[F:2][C:3]([F:11])([S:7]([OH:10])(=[O:9])=[O:8])[C:4]([O:6][C:18]12[CH2:22][CH:14]3[CH2:15][CH:16]([CH2:21][CH:20]([C:13]3=[O:12])[CH2:19]1)[CH2:17]2)=[O:5]
Reactant: O=C(O)C(F)(F)S(=O)(=O)O
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCc1ccccc1
Product: O=C1C2CC3CC1CC(OC(=O)C(F)(F)S(=O)(=O)O)(C3)C2

Procedure:
To a mixture of 5.0 parts of sodium salt of difluorosulfoacetic acid (purity: 62.6%), 2.6 parts of 4-oxo-1-adamantanol and 100 parts of ethylbenzene, 0.6 part of concentrated sulfuric acid was added and the resultant solution was refluxed for 30 hours. The mixture was cooled and filtrated. The obtained solid was washed with tert-butyl methyl ether to obtain 5.5 parts of sodium salt of 4-oxo-1-adamantyl difluorosulfoacetate. The purity thereof was 35.6% according to 1H-NMR analysis.
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[NH:4][CH2:3]1.FC(F)(F)S(O[C:26]1[CH2:27][O:28][C:29](=[O:32])[C:30]=1[CH3:31])(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].N#N>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[OH:1][CH:2]1[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][CH2:11]2)[C:5](=[O:19])[N:4]([C:26]2[CH2:27][O:28][C:29](=[O:32])[C:30]=2[CH3:31])[CH2:3]1
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)COC1=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCC2O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#N
Solvent: C1COCCO1
Product: CC1=C(N2CC(O)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Temperature: 90 °C

Procedure:
To a round bottom flask was charged tert-butyl 4-hydroxy-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (400 mg, 1.48 mmol), 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (546 mg, 2.22 mmol), Pd2(dba)3 (33.9 mg, 0.037 mmol), Xantphos (64.2 mg, 0.111 mmol), and cesium carbonate (964 mg, 2.96 mmol). The flask was equipped with a condenser, vacuumed and back filled with N2 and filled with dioxane (6 mL). The reaction mixture was heated at 90° C. overnight, and filtered through CELITE®. The filtrate was evaporated to give the crude product, which was purified by column chromatography (0-10% MeOH/DCM) to give the title compound as a racemate. LC/MS: [(M+1)]+=367. The racemic mixture was separated by SFC-HPLC, using the following conditions: chiralcel OJ, 21×250 mm, 10% MeOH+0.2 DEA, 50 mL/min to afford Isomer A (faster eluting enantiomer) LC/MS: [(M+1)]+=367, and Isomer B (slower eluting enantiomer) LC/MS: [(M+1)]+=367.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][C:6]=2[N:7]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2oc(-c3ccccc3)cc2n1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2oc(-c3ccccc3)cc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
2,4-Dichloro-6-phenylfuro[3,2-d]pyrimidine 43 (165 mg, 1.0 eq) was suspended in methanol (4.2 ml) and treated with morpholine (0.22 ml, 4.0 eq). Reaction mixture was stirred at room temperature for 4 h. Solid was filtered to yield pure 2-chloro-4-morpholino-6-phenylfuro[3,2-d]pyrimidine 44 (163 mg, 83% yield) as a beige solid: 1H NMR (CDCl3, 400 MHz) δ 7.80 (m, 2H), 7.51 (m, 3H), 6.99 (m, 1H), 4.10 (m, 4H), 3.89 (m, 1H); MS (Q1) 316 (M)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]([C:31]([CH3:34])([CH3:33])[CH3:32])[N:29]=[C:28]([CH:35]=O)[CH:27]=2)=[CH:22][CH:21]=1>>[C:31]([N:30]1[C:26]([C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=2)=[CH:27][C:28]([CH2:35][NH:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)=[N:29]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)n1nc(C=O)cc1-c1ccc(Cl)cc1
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Product: CC(C)(C)n1nc(CNCCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1-c1ccc(Cl)cc1
Yield: 50.4 %

Procedure:
Compound 57 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 5-(4-chlorophenyl)-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[Br:9][C:10]1[S:11][CH:12]=[CH:13][C:14]=1[CH3:15]>ClCCl>[Br:9][C:10]1[S:11][C:12]([C:1](=[O:3])[CH3:2])=[CH:13][C:14]=1[CH3:15]
Reactant: CC(=O)Cl
Reactant: Cc1ccsc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C)c(Br)s1
Reaction time: 0.75 h
Yield: 56.6 %

Procedure:
Acetyl chloride (7.09 g) is added to a suspension of AlCl3 (11.53 g) in dichloromethane (310 ml) at 0° C. After 45 minutes at 0° C., 2-bromo-3-methylthiophene (5.0 g) is added dropwise. After 1 hour at 0° C., the reaction is quenched by added water (100 ml). The mixture is extracted three times with dichloromethane. The organic phases are combined, dried over MgSO4 and concentrated in vacuo. The crude product is purified by chromatography on silica gel (180 g) eluting with a mixture of ethyl acetate and heptane (1:6) to yield 1-(5-bromo-4-methyl-thiophen-2-yl)-ethanone (3.5 g) as a brown solid.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])=[O:9])C.Cl>O>[O:32]=[C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:33])[N:23]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)cc1

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-4-(4-methoxyphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 20, Part C). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:11][C:12]1([CH3:45])[C@H:16]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:15]2[C:24]([CH3:44])=[C:25]([N:30]3[C:35](=O)[CH2:34][CH:33]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:32][C:31]3=O)[C:26]([CH3:29])=[C:27]([CH3:28])[C:14]=2[O:13]1.O>C1COCC1>[CH3:11][C:12]1([CH3:45])[C@H:16]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[C:15]2[C:24]([CH3:44])=[C:25]([N:30]3[CH2:35][CH2:34][CH:33]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:32][CH2:31]3)[C:26]([CH3:29])=[C:27]([CH3:28])[C:14]=2[O:13]1
Reactant: Cc1ccc([C@@H]2c3c(C)c(N4C(=O)CC(c5ccccc5)CC4=O)c(C)c(C)c3OC2(C)C)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc([C@@H]2c3c(C)c(N4CCC(c5ccccc5)CC4)c(C)c(C)c3OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
Aluminum chloride (913 mg, 6.9 mmol) was added to THF (10 mL) under ice cooling, and allowed to warm to room temperature so as to dissolve the aluminum chloride. The mixture was cooled with ice cooling and then lithium aluminium hydride (260 mg, 6.9 mmol) was added. After stirring for 15 minutes, A solution of (3R)-1-(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-4-phenylpiperidine-2,6-dione obtained in Example 23 (640 mg, 1.4 mmol) in THF (5 ml) was added to the mixture under ice cooling. After the mixture was refluxed for 2 hours, the resulting mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=25/1) to obtain 350 mg (yield 58%) of the title compound via recrystallization (hexane). mp. 137–140° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[CH:21][C:22]2([CH2:28][CH3:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:15]3=[O:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH:14]([CH2:21][C:22]2([CH2:28][CH3:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:15]3=[O:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCC1(C=C2Cc3c(cccc3-c3ccc(C(C)(C)C)cc3)C2=O)CCCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC1(CC2Cc3c(cccc3-c3ccc(C(C)(C)C)cc3)C2=O)CCCCC1
Yield: 97.1 %

Procedure:
25.0 g of crude 4-(4-tert-butyl-phenyl)-2-(1-ethylcyclo-hexylmethylene)-indan-1-one (GC: ˜83% purity) are dissolved in 250 ml of ethyl acetate in a flask with gas inlet and stirrer. 1.75 g of palladium on activated carbon (10 wt-% palladium) are added. The system is evacuated and refilled with argon three times to remove oxygen and then evacuated and refilled with hydrogen three times. The stirrer is started and the reaction mixture is vigorously stirred to help the diffusion of hydrogen gas into the liquid reaction mixture. The hydrogen uptake is monitored and stirring is continued until the hydrogen uptake ceases. Filtering the crude reaction mixture over a paper filter and removing the solvent in a vacuum leaves crude 4-(4-tert-butyl-phenyl)-2-(1-ethyl-cyclohexylmethyl)-indan-1-one (yield 24.4 g, GC: ˜82% purity). The obtained crude product was used without further purification for the subsequent reduction/elimination-sequence.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH2:25][CH2:24][CH2:23][CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:2]1=[O:1]
Reactant: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 2-[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dione (1.25 g, 2.70 mmol) in ethanol (25 mL) was added hydrazine monohydrate (0.70 mL, 8.2 mmol). The reaction mixture was stirred at ambient temperature for 3 days, over which time a precipitate was deposited. The solid was collected by filtration and purified by column chromatography and eluted with ethyl acetate/methanol/7 N methanolic ammonia (10/1/0.2) to afford 1′-(3-aminopropyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one as a yellow oil: MS (ES+) m/z 336.9 (M+1).
Reaction SMILES: N#N.[C:3]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br.Br[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.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:3]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ccncc1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Br
Agent: N#N
Solvent: CC#N
Product: c1ccc(COc2ccc(-c3ccncc3)cc2)cc1
Temperature: 85 °C
Yield: 94.5 %

Procedure:
Pd(PPh3)4 (10.0 mg, 0.01 mmol) was added to a degassed (N2) mixture of 4-(phenylmethoxy)phenylboronic acid (230 mg, 1.01 mmol), 4-bromopyridine hydrobromide (194 mg, 1.00 mmol), aqueous 1 M Na2CO3 solution (4.0 mL) in MeCN (4 mL). The reaction mixture was heated to 85° C. for 5 h. The cooled suspension was filtered and the resulting solid was washed with aqueous MeCN. The filtrate was extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc) and combined with the solid obtained by filtration to give the title compound (247 mg, 94% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Reactant: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3ccccc3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
A mixture of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole), pyridine (158 mg, 2 mmoles) in dimethylsulfoxide (DMSO) (1 ml) was stirred for 1 hour at room temperature. To the mixture was added ethyl acetate (20 ml) to precipitate a solid (620 mg), which was added to formic acid (6 ml) containing sodium bisulfite (60 mg). The mixture was stirred for 30 minutes at 40° C. and concentrated to dryness. The residue was dissolved in H2O (40 ml) and some insolubles were removed. The aqueous solution was charged on a column of reverse phase (PrepPAK-500/C18, 100 ml) eluting with H2O (300 ml) and 5% aqueous CH3OH (800 ml), and the eluate was monitored by uv (254 nm) and HPLC. The fractions (5% aqueous CH3OH) containing the desired product were combined, concentrated to a small volume and lyophilized to yield 40 mg (8%) of the title compound (I-1B), melting at >200° C. (dec.).
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:5](=[C:6]([C@H:14](O)[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[CH2:25]([N:27](CC)[CH2:28][CH3:29])[CH3:26].C(=O)=O.S(Cl)(C)(=O)=O.C(NCC)C>CC(C)=O.C(Cl)(Cl)Cl.C(OCC)C>[CH2:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:5](=[C:6]([C@@H:14]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2c([C@H](O)CO[Si](C)(C)C(C)(C)C)cccc2cc1C
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: O=C=O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: CCc1nc2c([C@H](CO[Si](C)(C)C(C)(C)C)N(CC)CC)cccc2cc1C
Temperature: 25 °C
Yield: 21 %

Procedure:
1.85 g (5.35 mmol) of (+)-2-ethyl-3-methyl-8-(1(S)-hydroxy-2-[tert-butyldimethylsilyloxy]ethyl)-quinoline, 65 ml of ethyl ether and 1.33 ml (9.6 mmol) of triethylamine are introduced into a 250 ml round-bottomed flask. The mixture is cooled to −30° C. on a bath of cardice in acetone and 0.67 g (8.53 mmol) of mesyl chloride is added. The cooling bath is removed and the reaction mixture is allowed to warm to room temperature over 30 minutes. 100 ml of water are added and the resulting mixture is extracted with ethyl ether (3×50 ml). The organic phases are combined, dried over magnesium sulphate and concentrated. A portion of the residue (0.8 g of the 2.5 g obtained) is transferred, without further purification, into a 50 ml three-necked flask fitted with a condenser. 2.5 ml (34.6 mmol) of diethylamine and 3 ml of chloroform are added and this mixture is refluxed for 16 hours. The reaction mixture is cooled to room temperature and concentrated under vacuum, 50 ml of water are added and the resulting mixture is extracted with ethyl ether (3×30 ml). The organic phases are combined, dried over magnesium sulphate and concentrated under vacuum. The residue is purified by chromatography on a column of silica (elution solvent: 10% methanol in dichloromethane). 0.45 g (yield: 60%) of (+)-2-ethyl-3-methyl-8-(1(R)-diethylamino-2-[tert-butyldimethylsilyloxy]-ethyl)quinoline is obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.B.[O:16]1CCCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH:13]2[OH:16])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CN1CC=C(c2ccc(Cl)cc2)CC1
Agent: B
Product: CN1CCC(c2ccc(Cl)cc2)C(O)C1

Procedure:
In an analogous manner to that described in Example 1(c), from 4-(4-chloro-phenyl)-1-methyl-1,2,3,6-tetrahydropyridine [U.S. Pat. No. 3,320,265] by hydroboration using borane in tetrahydrofuran there was obtained (3RS,4RS)-4-(4-chloro-phenyl)-1-methyl-piperidin-3-ol which, after recrystallization from a mixture of methylene chloride and hexane, formed colourless crystals of m.p.: 99-100° C.