Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]([CH2:9][C-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH3:8].[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20].[CH2:21]=[O:22]>C(OCC)C>[OH:22][CH2:21][C-:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[CH2:9][N:7]([CH3:8])[CH3:6].[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20]
Reactant: CN(C)C[c-]1cccc1
Reactant: C=O
Agent: [Fe+2]
Agent: [Li]CCCC
Agent: c1cc[cH-]c1
Solvent: CCOCC
Product: CN(C)Cc1ccc[c-]1CO
Reaction time: 3 h

Procedure:
n-Butyl lithium (Aldrich, 1.6 molar in diethyl ether, 5.14 ml, 8.24 mmol) is added to a solution of 1-dimethylaminomethyl ferrocene (Aldrich, 1.0 g, 4.12 mmol) in diethyl ether (20 mL) under argon. The reaction is stirred for 3 hours and developes a reddish colour. The solution is then cooled in a dry ice/acetone bath, calcined paraformaldehyde (0.247 g, 2 times excess) added and the resultant mixture stirred overnight at room temperature. The reaction is then quenched with water, extracted with diethyl ether, dried over MgSO4, and filtered over celite. The solvent is removed in vacuo to yield crude title compound. The crude product is applied to a neutral alumina column, which is eluted with petrol/diethyl ether (9:1 ratio) to remove the starting material, 1-dimethylaminomethyl ferrocene. The column is then eluted with substantially pure ethyl acetate to elute the title compound. The ethyl acetate is removed in vacuo, to yield the title compound as an orange oil/crystalline mass.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[CH3:27][C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1>>[CH2:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:3](=[O:4])[CH2:2][NH:1][C:35]([NH:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH3:27])[CH:29]=1)=[O:36])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1Cc1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2Cc2ccccc2)c1
Yield: 60.1 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(2-benzylphenyl)acetamido]acetate (8.1 g) and 3-methylphenyl isocyanate (3 g), and after recrystallisation in ethyl acetate, tert-butyl 2-{N-(2-benzylphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (6.6 g), m.p 183° C., is obtained
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH:9]=[CH:8]1.[CH2:14]([OH:17])[CH2:15][CH3:16]>>[C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[C:10]([O:17][CH2:14][CH2:15][CH3:16])(=[O:11])/[CH:9]=[CH:8]\[C:7]([O-:12])=[O:13]
Reactant: CCCO
Reactant: O=C1C=CC(=O)O1
Solvent: C=COC(C)=O
Product: CCCOC(=O)/C=C\C(=O)[O-]
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To 160 g of vinyl acetate/maleic anhydride copolymer, prepared as described in Example 1A, was added 264.52 g of 1-propanol in a 500 ml kettle. This mixture was heated to 90° C. in a nitrogen atmosphere for 5 hours to effect esterification. After 5 hours, the alternating vinyl acetate/propyl maleate copolymer was obtained in a 50% solids solution. The solution was then cooled to 40° C. and product recovered. Analysis showed 46.86% solid in solution; a relative viscosity of 1.25 and a specific viscosity of 0.25, this product has a K value of 30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=2[NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[N:6][CH:7]=1.[B-][N+](C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=2[NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(CO)ccc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: [B-][N+](C)(C)C
Product: O=C(Nc1ccc(Cl)cn1)c1ccc(CO)cc1NCC1CCNCC1
Yield: 78.2 %

Procedure:
Using a similar procedure to that described in Example 47-D, N-(5-chloropyridin-2-yl)-4-hydroxymethyl-2-[(1-Boc-piperidin-4-ylmethyl)amino]benzamide (1.45 g, 3.07 mmol) and borane trimethylamine complex (672 mg, 9.22 mmol) afforded 900 mg (79%) of the title compound; which was used without, further purification.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Br[CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOCC>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCCc1c(OCc2ccc(C(=O)OC)cc2)ccc(C(C)=O)c1O
Yield: 68.7 %

Procedure:
A solution of 1.0 g (5.15 mmoles) of 2,4-dihydroxy-3-propylacetophenone, see R. A. Appleton et al. in J. Med. Chem. 1977, 20, pages 371-379, and 1.77 g (7.7 mmoles) of methyl 4-bromomethylbenzoate in 20 ml of acetone was treated with 784 mg (5.66 mmoles) of K2CO3 and stirred at reflux for 15 hours. The reaction mixture was diluted with ether, washed with water and saturated aqueous NaHCO3 solution and dried with MgSO4. Evaporation of the solvent gave an oil which crystallized. This material was purified by chromatography on silica gel with 30% hexane/dichloromethane as eluent to provide 1.212 g (69% yield) of the title compound as a white powder mp 99.5°-100.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH2:18])[CH:13]([OH:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]1([C:26]([NH:28][CH:29]([CH2:33][S:34]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:36])=[O:35])[C:30](O)=[O:31])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:30](=[O:31])[CH:29]([NH:28][C:26]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:27])[CH2:33][S:34]([CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)(=[O:35])=[O:36])[CH:13]([OH:19])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Reactant: NC1CCCN(C(=O)OCc2ccccc2)CC1O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NC1CCCN(C(=O)OCc2ccccc2)CC1O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
Crude 4-amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester (150 mg, 0.57 mmol) prepared as in Reference 2, 2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid (400 mg, 1.12 mmol), EDC (400 mg, 2.1 mmol), and HOBt (400 mg, 2.5 mmol) were combined. Dichloromethane (10 mL) was added followed by 4-methylmorpholine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (100 mL) the solution was washed with 1N HCl, saturated aqueous NaHCO3 and brine, dried with MgSO4 and evaporated under vacuum. The residue was purified by flash chromatography (ethyl acetate/methanol 9: 1) to yield 3-hydroxy-4-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionyl-amino}-azepane-1-carboxylic acid benzyl ester (320 mg).
Reaction SMILES: B.O1CCCC1.[OH:7][CH:8]([CH:15]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=O.Cl.O>[Na+].[Cl-].O1CCCC1>[CH3:14][CH:12]([NH:11][CH2:9][CH:8]([OH:7])[CH:15]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:13]
Reactant: CC(C)NC(=O)C(O)C(Oc1ccccc1)c1ccccc1
Agent: B
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)NCC(O)C(Oc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Borane-tetrahydrofuran complex (1 M solution in tetrahydrofuran, 20 ml.) was transferred by a syringe to a 100 ml. three-neck flask equipped with a reflux condenser, a nitrogen gas inlet and a rubber septum. The reaction flask was then chilled in a mixture of ice and table salt. α-Hydroxy-β-phenoxy-N-(1-methylethyl)benzenepropanamide (1.9 g.) suspended in tetrahydrofuran (25 ml.) was added slowly keeping the temperature at ca. 0°. The solution thus obtained was brought to reflux and maintained there for 2.5 hours. The reaction mixture was cooled to room temperature, dilute hydrochloric acid (6 N HCl 3 ml.) and water (5 ml.) was added carefully, and the mixture was heated under reflux for 20 minutes. It was then evaporated on a rotary evaporator under reduced pressure to give a solid residue. The residue was treated with water. The water insoluble material was separated by collecting on a filter and washed with water. The filtrate and washings were combined and made alkaline by addition of 50% aqueous sodium hydroxide solution, then extracted with chloroform 3 times. The combined extract was dried over magnesium sulfate, and evaporated under reduced pressure to give an oil which solidified on standing. The crude product was recrystallized from ether and petroleum ether, giving 1.0 g. of product, m.p. 95°-96°.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3([C:18]([O:20]C)=[O:19])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1.[OH-].[Na+]>O1CCCC1.CO>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3([C:18]([OH:20])=[O:19])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1
Reactant: COC(=O)C1(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of methyl 1-[4-(5-trifluoromethylpyridin-2-yl)-piperazin-1-yl]-cyclopropanecarboxylate (0.32 g, 0.96 mmol) from Example 16D in tetrahydrofuran (5 mL) and methanol (2 mL) was treated with 4 N sodium hydroxide (2.40 mL, 9.60 mmol) and stirred overnight at 60° C. Reaction mixture concentrated under reduced pressure and dissolved in water. Solution neutralized with 1 N phosphoric acid (pH 7) and extracted three times with chloroform. Extracts dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound without further purification. MS (ESI) m/z 316 (M+H)+.
Reaction SMILES: Cl.[C:2]1([C:8]2[S:12][C:11]([CH2:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][C@@H:20]4[CH2:24][CH2:23][CH2:22][NH:21]4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32]>>[C:2]1([C:8]2[S:12][C:11]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:18][CH2:19][C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:25][CH:26]=3)=[CH:10][CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCBr
Reactant: c1ccc(-c2ccc(Cc3ccc(OC[C@@H]4CCCN4)cc3)s2)cc1
Agent: Cl
Product: O=C(O)CCCN1CCC[C@H]1COc1ccc(Cc2ccc(-c3ccccc3)s2)cc1

Procedure:
The title compound was prepared from the product of Example 161 (0.1 g, 0.26 mmol) and methyl 4-bromobutyrate (56 mg, 0.31 mmol) using the procedure of Example 147; 1HNMR (400 MHz, CDCl3) δ 7.50 (d, J=8.8 Hz, 2H), 7.32 (t J=6 Hz, 2H), 7.24 (m, 3H), 7.18 (d, J=3.6 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 6.77 (d, J=3.6 Hz, 1H), 4.36 (dd, J=7.2, 3.6 Hz, 1H), 4.20 (br, 1H), 4.10 (s, 2H), 3.71 (br, 1H), 3.05 (br, 2H), 2.44 (br, 2H), 2.19-1.98 (m, 9H); LC/MS (ESI+) m/z: 95%; 437 (M+1, 100).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7](=[O:21])[C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:33](=[O:34])[O:32]1>CC(C)=O>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7](=[O:21])[C:8]2[CH:9]=[CH:10][C:11]([N:14]([S:15]([N:18]([CH3:20])[CH3:19])(=[O:16])=[O:17])[CH:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:33](=[O:34])[O:32]3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CN(C)S(=O)(=O)Nc1ccc(C(=O)Nc2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)S(=O)(=O)N(c1ccc(C(=O)Nc2ccc(Br)cc2)cc1)C1OC(=O)c2ccccc21
Yield: 51.1 %

Procedure:
To a solution of 1.0 g of 4'-bromo-4-[(dimethylaminosulfonyl)amino]benzanilide 10 and 10 ml of dried acetone are added 416 mg of potassium carbonate powder and 642 mg of 3-bromophthalide 11, and the mixture is refluxed for 1 hour. The reaction mixture is concentrated; to the residue is added water, and the precipitating crystals are collected by filtration and recrystallized from acetonitrile to give 680 mg of 4'-bromo-4-[(dimethylaminosulfonyl)(3-phthalidyl)amino]benzanilide 12 as crystals, m.p. 244°-245.5° C.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].C[C:18](C)([O-:20])C.[K+].C(OCC)=O.O>CN(C)C=O>[C:1]([CH:3]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)[CH:18]=[O:20])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(C#N)C=O)CC1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
Under an argon atmosphere, tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate (2.24 g, 10 mmol) and potassium tert-butoxide (6.73 g, 60 mmol) were dissolved in anhydrous N,N-dimethyl formamide (15 mL), and a solution of ethyl formate (4.44 g, 60 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added dropwise under ice-cooling. The temperature was gradually raised to room temperature, and then the resultant mixture was stirred overnight. Water was added to the reaction liquid, followed by extraction with ethyl acetate. 1 N hydrochloric acid was added to the obtained aqueous layer until it reached a pH of 6, and then the resultant mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give tert-butyl 4-(1-cyano-2-oxoethyl)piperidine-1-carboxylate (2.35 g) as a crude product.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[C:3]=1[Cl:10].[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11](=[O:13])[CH3:12])=[C:4]([F:9])[C:3]=1[Cl:10]
Reactant: Nc1ccc(Br)c(Cl)c1F
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Br)c(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 4-bromo-3-chloro-2-fluoroaniline (15.0 g) in ethyl acetate (200 mL) was added dropwise acetic anhydride (7.57 mL) at 0° C. Then, pyridine (10.8 mL) was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained solid was washed with hexane to give the title compound as a colorless solid (yield: 17.1 g, 96%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N.S(=O)(=O)(O)[OH:17]>>[C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)(=[O:17])[NH2:2]
Reactant: N#Cc1cccc(N2CCNCC2)c1
Reactant: O=S(=O)(O)O
Agent: N
Product: NC(=O)c1cccc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
1-(3-Cyanophenyl)piperazine (1.6 g, 8.3 mmol) was dissolved in 90% sulfuric acid aqueous solution (17 ml) and stirred at a room temperature for 2 days. The reaction solution was slowly added drbpwise to a mixture consisting of ice (65 g) and 28% aqueous ammonia (65 ml), and the reaction product was extracted with chloroform. The resulting extract was washed with saturated brine and dried with sodium sulfate, and then the solvent was evaporated under a reduced pressure to obtain 990 mg of the title compound (4.9 mmol, 58% in yield).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[C:7](=[N:9]/[N:10]=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)/[CH3:8].[C:24]1([C:30](=[N:37][NH2:38])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:12]1([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10]/[N:9]=[C:7](/[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[NH:38][N:37]=[C:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)\[CH3:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C/C(=N\N=C(c1ccccc1)c1ccccc1)c1sccc1Br
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: C/C(=N\N=C(c1ccccc1)c1ccccc1)c1sccc1NN=C(c1ccccc1)c1ccccc1
Temperature: 80 °C
Yield: 76.9 %

Procedure:
To a mixture of (E)-1-(1-(3-bromothiophen-2-yl)ethylidene)-2-(diphenylmethylene)hydrazine (12.5 g, 32.6 mmol, including its Z isomer) and (diphenylmethylene)hydrazine (7.68 g, 39.1 mmol) in toluene (25 mL) was added palladium(II) acetate (0.385 g, 6.52 mmol), 1,1′-bis(diphenylphosphino)ferrocene (1.808 g, 3.26 mmol) and Cs2CO3 (21.25 g, 65.2 mmol). The reaction mixture was heated at 80° C. for 14 hours. The mixture was subsequently diluted with toluene (25 mL) and filtered to remove solids. The filtrate was evaporated and chromatographed using a gradient of 0-100% hexane and EtOAc. The pure product fractions were combined and evaporated to give the title compound (12.5 g, 77%). ESI-MS m/z [M+H]+ calc'd for C32H26N4S, 499. found, 499.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:11]([O-])=O)=[CH:4][C:5]2[CH2:9][CH2:8][S:7][C:6]=2[CH:10]=1.[NH4+].[Cl-]>C(O)C.C1COCC1.[Fe]>[F:1][C:2]1[C:3]([NH2:11])=[CH:4][C:5]2[CH2:9][CH2:8][S:7][C:6]=2[CH:10]=1
Reactant: O=[N+]([O-])c1cc2c(cc1F)SCC2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc2c(cc1F)SCC2
Yield: 94.6 %

Procedure:
To a solution of 6-fluoro-5-nitro-2,3-dihydrobenzo[b]thiophene (2.1 g, 10.5 mmol) in ethanol (80 mL), THF (40 mL), and aqueous NH4Cl (20 mL) was added Fe (O) (3.53 g, 63.3 mmol). The mixture was refluxed for 2 hours, then filtered through celite and washed with ethyl acetate. The residue was purified using silica gel column chromatography with 50% ethyl acetate in hexanes to provide 6-fluoro-2,3-dihydrobenzo[b]thiophen-5-amine (1.68 g, 94.2% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:50])[C:19]([C:25]3[N:26]=[C:27]([NH:30]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:28][CH:29]=3)=[N:20][O:21][CH2:22][CH2:23][NH2:24])[C:15](=[O:51])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]>C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:50])[C:19]([C:25]3[N:26]=[C:27]([NH2:30])[S:28][CH:29]=3)=[N:20][O:21][CH2:22][CH2:23][NH2:24])[C:15](=[O:51])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: O=CO
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN)c3csc(N)n3)[C@H]2SC1
Temperature: 50 °C

Procedure:
A mixture of 1.054 g of the product of Step A and 5 ml of 70% aqueous formic acid was heated at 50° C. for 15 minutes and the mixture was vacuum filtered to remove triphenylcarbinol. The filtrate was evaporated to dryness under reduced pressure and the residue was taken up in water. The mixture was filtered and the filtrate was evaporated to dryness and the residue was taken up in ethanol. After efflorescence, the mixture was vacuum filtered to obtain 0.125 g of the syn isomer of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(2-aminoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=[C:8]1[Sn](CCCC)(CCCC)CCCC.[CH:31]1([C:35]2[N:39]3[CH:40]=[CH:41][N:42]=[C:43]([NH2:44])[C:38]3=[C:37](I)[N:36]=2)[CH2:34][CH2:33][CH2:32]1>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:31]1([C:35]2[N:39]3[CH:40]=[CH:41][N:42]=[C:43]([NH2:44])[C:38]3=[C:37]([C:8]3[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:29])[CH3:30])[C:11]4=[N:12][CH:13]=[CH:14][CH:15]=[C:10]4[CH:9]=3)[N:36]=2)[CH2:32][CH2:33][CH2:34]1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2cccnc2n1COCC[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(-c2nc(C3CCC3)n3ccnc(N)c23)cc2cccnc21
Temperature: 25 °C
Yield: 24.9 %

Procedure:
A mixture of N-(2-trimethylsilyl-1-ethoxymethyl)-2-(tributylstannyl)-1H-pyrrolo[2,3-b]pyridine (110 mg, 0.20 mmol), 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine (50 mg, 0.1592 mmol) and bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.02 mmol) in ethanol (2 mL) was heated at reflux for 48 h. The mixture was then cooled to rt, filtered through a pad of Celite and concentrated in vacuo. The residue thus obtained was chromatographed over silica gel eluting with hex:EtOAc to afford 17.2 mg of the title compound. 1H NMR (400 MHz CDCl3) δ 0.22 (s, 9H), 0.70 (t, 2H), 1.87-2.19 (m, 2H), 2.49-2.64 (m, 4H), 3.37 (t, 2H), 3.81-3.86 (m, 1H), 5.51 (bs, 2H), 6.07 (s, 2H), 6.67 (s, 1H), 7.10-7.16 (m, 3H), 7.93 (dd, J=1.6, 8.0 Hz, 1H) and 8.41 (dd, J=1.6, 4.8 Hz, 1H). MS (ES+): m/z: 435.21 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)=[N:8][NH:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2].[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)=[N:8][N:9]([C:26]2[CH:25]=[CH:24][C:23]([O:22][C:21]([F:20])([F:32])[F:33])=[CH:28][CH:27]=2)[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1c(-c2cncnc2)n[nH]c1C1CC1
Product: CCOC(=O)c1c(-c2cncnc2)nn(-c2ccc(OC(F)(F)F)cc2)c1C1CC1
Yield: 29 %

Procedure:
In analogy to the procedure described in Example 162C], 5-cyclopropyl-3-pyrimidin-5-yl-1H-pyrazole-4-carboxylic acid ethyl ester (Example 177B]) and 4-(trifluoromethoxy)benzeneboronic acid gave the title compound as a yellow oil (29%). MS: 419.0 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][C:16]#[N:17])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].N.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>CCO.[Ni]>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][CH2:16][NH2:17])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2cc(CC#N)ccc2n1
Agent: [Ni]
Agent: N
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CCO
Product: CC(=O)Nc1ccc2cc(CCN)ccc2n1
Reaction time: 0.5 h

Procedure:
Compound 47 (0.060 g, 0.266 mmol) was diluted in absolute EtOH (7 mL) and methanolic ammonia (7 N, 7 mL) was added. Raney nickel (˜1.5 g, washed with H2O and MeOH) was added, and the mixture was degassed and hydrogenated with a balloon at room temperature for 30 min while stirring rapidly. The clear solution was decanted away from the nickel and was filtered through a Pall 0.2 μm syringe filter to remove fine particulate matter. The solution was concentrated and dried in vacuo to yield a colorless gum that became a white semisolid upon standing (0.050 g, 82%). Conversion to this amine was confirmed by 1H NMR spectrometry, TLC, MS, and ninhydrin staining, and it was used crude without any further characterization or purification.