Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:22])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]1[CH:11](CC1C=CC=CC=1)[CH2:12][NH:13][CH3:14].[ClH:23]>C(O)C.[Pd]>[ClH:23].[C:1]1(=[O:22])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]1[CH2:11][CH2:12][NH:13][CH3:14]
Reactant: CNCC(Cc1ccccc1)n1ncc2ccccc2c1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNCCn1ncc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-(2H-phthalazin-1-on-2-yl)-N-methyl-N-benzylethylamine (41.5 g) in ethanol (1000 ml) and concentrated hydrochloric acid (50 ml) containing 5% palladium on charcoal (4.1 g) was stirred under a hydrogen atmosphere (50 p.s.i.) at room temperature for 18 hours. The reaction mixture was filtered and evaporated to afford a solid which was recrystallised from isopropanol to afford the title compound, yield 22.5 g, m.p. 200°-201°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:27][CH3:28])=[C:4](/[C:17](/[CH2:25][CH3:26])=[C:18](/[F:24])\[C:19](OCC)=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].[H-].C([Al+]CC(C)C)C(C)C>>[Cl:1][C:2]1[C:3]([O:27][CH3:28])=[C:4](/[C:17](/[CH2:25][CH3:26])=[C:18](/[F:24])\[CH2:19][OH:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:15])[CH3:16]
Reactant: CCOC(=O)/C(F)=C(/CC)c1cc2c(c(Cl)c1OC)OC(C)(C)C=C2C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC/C(=C(\F)CO)c1cc2c(c(Cl)c1OC)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure L, ethyl 3-(8-chloro-4-isopropyl-7-methoxy-2,2-dimethyl-4-chromen-6-yl)-2-fluoro-pent-2-enoate (Compound 147, 242 mg, 0.59 mmol 1) and diisobutylaluminum hydride (1M in hexanes, 2.4 mL, 2.4 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 to 1:4 ethyl acetate/hexane).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.C(N(CC)CC)C.[C:18]([C:20]1(Cl)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)#[CH:19].C(C1(O)CCCCC1)#C>CCOCC.O.CCOCC.Cl[Cu]>[CH2:2]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:20]2([C:18]#[CH:19])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:6][CH:5]=1)[CH3:1]
Reactant: C#CC1(Cl)CCCCC1
Reactant: CCOc1ccc(N)cc1
Agent: Cl[Cu]
Agent: C#CC1(O)CCCCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: C#CC1(Nc2ccc(OCC)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution, cooled to 10° C., of 18.2 mmol (2.5 g) of p-phenetidine in a mixture of ether:water (4:1; 30 ml) containing 24.5 mmol (3.42 ml) of triethylamine there are added, in succession, 0.25 mmol (0.025 g) of CuCl, 0.39 mmol (0.025 g) of Cu and, dropwise, 28.0 mmol (4.0 g) of 1-ethynyl-1-chlorocyclohexane prepared according to the method described in J. Am. Chem. Soc., 83, 725, 1961, starting from 1-ethynylcyclohexanol. After stirring for 4 hours (allowing the temperature to increase towards ambient temperature) the reaction mixture is diluted with ether and then washed with 1N sulphuric acid solution. The ethereal phase is removed and the aqueous phase is neutralised (at 0° C.) using potassium hydroxide pellets and then re-extracted with ether. The organic phase is dried and then concentrated to yield the expected product.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[CH2:14])[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36])(OCC)=O>O>[O:31]=[C:30]1[C:29]2[C:28](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27](=[O:36])[N:1]1[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[CH2:14])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: C=Cc1ccccc1CC(N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=Cc1ccccc1CC(C(=O)O)N1C(=O)c2ccccc2C1=O
Reaction time: 2.5 h
Yield: 60.1 %

Procedure:
Dissolve 2-amino-3-(2-vinyl-phenyl)-propionic acid (3.40 g) in water (75 mL) and add sodium carbonate (1.97 g, 18.6 mmol) and N-carbethoxyphthalimide (2.81 g, 12.8 mmol). Stir for 2.5 hours, wash with methylene chloride (200 mL), acidify to pH 1 with cold concentrated hydrochloric acid and extract with ethyl acetate (3×200 mL), dry (Na2SO4), evaporate the solvent in vacuo and purify by silica gel chromatography (1:1:0.02 hexane/ethyl acetate/acetic acid) followed by recrystallization (isopropanol) to give 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-vinyl-phenyl)-propionic acid as a pale yellow solid (2.47 g).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=12.BrC1C=C(O)C=CC=1.[C:19]1([CH:25]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:35])[C:27]2=[O:36])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[C:37]1([CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([OH:35])([C:9]3[C:4]4[C:5](=[N:1][O:2][N:3]=4)[CH:6]=[CH:7][C:8]=3[OH:10])[C:27]2=[O:36])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1ccc2nonc2c1
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1c(O)ccc2nonc12

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 2,1,3-benzoxadiazol-5-ol to replace 3-bromophenol, and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,1,3-benzoxadiazol-4-yl)-1,3-dihydro-2H-indol-2-one was obtained (71%) as a colorless solid: MS (ES+) m/z 472.0 (M+23).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:10]=2)[C:5](=[O:21])[N:4]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)[C:3]1=[O:32].CCN=C=NC[CH2:39][CH2:40][N:41]([CH3:43])[CH3:42].Cl.C1C=CC2N(O)N=NC=2C=1.C(CN)O>CN(C=O)C.O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:10]=2)[C:5](=[O:21])[N:4]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([O:29][CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])=[O:28])=[CH:25][CH:24]=2)[C:3]1=[O:32]
Reactant: Cn1c(=O)n(Cc2ccc(C(=O)O)cc2)c(=O)c2cc(C#CCc3ccccc3)ccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: NCCO
Solvent: CN(C)C=O
Product: CN(C)CCOC(=O)c1ccc(Cn2c(=O)c3cc(C#CCc4ccccc4)ccc3n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.72 g (1.7 mmol) 4-[1-Methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-quinazolin-3-ylmethyl]-benzoic acid, 0.43 g (2.2 mmol) EDAC-HCl, 0.29 g (2.2 mmol) HOBT in 10 ml DMF is treated with 0.19 g (2.2 mmol) ethanolamine. The resulting mixture is stirred overnight at room temperature before diluting with water and extracting with 1:1 EtOAc/Et2O (2×). The combined organic extracts are washed with saturated aqueous NaCl (3×), dried (MgSO4). The resulting oil is dissolved in EtOAc and treated with saturated methanolic HCl. Concentration provided a solid which is triturated in EtOAc and filtered.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13](Br)[C:12]=2[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36][CH:35]=1.[F-].[Cs+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.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]>[CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13]([C:38]3[CH:39]=[N:34][CH:35]=[N:36][CH:37]=3)[C:12]=2[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cncnc1
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(Br)c32)C1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(-c4cncnc4)c32)C1=O
Temperature: 80 °C

Procedure:
A mixture of 10-(benzyloxy)-4-bromo-2-(4-fluorobenzyl)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.10 g, 0.19 mmol; Example 160, step 1), pyrimidine-5-boronic acid (73 mg, 0.59 mmol), cesium fluoride (0.12 g, 0.78 mmol), bis(tri-t-butylphosphine)palladium(0) (10 mg, 0.02 mmol), and tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol) in dioxane (3 mL) was purged with nitrogen for 2 minutes and heated in a sealed tube at 80° C. overnight. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 0 to 20% methanol in chloroform gradient. Collection and concentration of appropriate fractions afforded the title material.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.C[O:28][B:29](OC)[O:30]C.[Cl-].[NH4+]>O1CCCC1.O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([B:29]([OH:30])[OH:28])=[CH:3][CH:4]=1
Reactant: Brc1ccc(COc2ccccn2)cc1
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1ccc(COc2ccccn2)cc1
Reaction time: 0.75 h
Yield: 25.7 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-[(4-bromobenzyl)oxy]pyridine (50 g, 190 mmol) in tetrahydrofuran (200 mL) was cooled to −78° C. and a 2.6 m n-butyllithium hexane solution (88 mL, 228 mmol) was added thereto dropwise. After stirring for 45 minutes, trimethoxy borane (29.6 g, 285 mmol) was added thereto dropwise at the same temperature. After 30 minutes, a saturated aqueous solution of ammonium chloride and water were added thereto for quenching, and the solution was extracted with ethyl acetate. After the organic layer was washed with a mixture of saturated aqueous solution of ammonium chloride and saturated sodium chloride water and dried over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure. To the residue was added acetonitrile (200 mL), followed by suspending and stirring at 70° C. for 30 minutes, then, cooled, and stirred overnight at 4° C. The precipitated solid was filtered to obtain the title compound (11.2 g) as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C@H:10]([N:19]([CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[C:20]#[N:21])[CH2:9][C@@H:8]1[CH2:37][CH3:38])=[O:6])([CH3:3])[CH3:2].[N-:39]=[N+:40]=[N-:41].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C@H:10]([N:19]([CH2:22][C:23]2[CH:24]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=2)[C:20]2[N:39]=[N:40][NH:41][N:21]=2)[CH2:9][C@@H:8]1[CH2:37][CH3:38])=[O:6])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[C@H]1C[C@@H](N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nc(OC)ccc2N1C(=O)OC(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2nc(OC)ccc2N1C(=O)OC(C)C
Temperature: 120 °C
Yield: 56.4 %

Procedure:
Heat at 120° C. a mixture of (+/−)-cis-4-[(3,5-bis-trifluoromethyl-benzyl)-cyano-amino]-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (100 mg, 0.184 mmol), sodium azide (17 mg, 0.258 mmol) and triethyl amine hydrochloride (35 mg, 0.258 mmol) in dry toluene under an atmosphere of nitrogen for 8 h. Then add more sodium azide (6 mg) and triethyl amine hydrochloride (13 mg) and heat the mixture for 4 h. Cool to room temperature, dilute with ethyl acetate, and wash with 1 N HCl. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (61 mg, 50%). MS (ES+): 588 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH:11](Br)[CH2:12]CC)[CH:5]=1.C(C([O:24][CH2:25][C:26]([NH2:28])=[S:27])=O)(C)(C)C>CCO>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:28]=[C:26]([CH2:25][OH:24])[S:27][C:11]=2[CH3:12])[CH:5]=1
Reactant: CCCC(Br)C(=O)c1cccc(C(=O)OC)c1
Reactant: CC(C)(C)C(=O)OCC(N)=S
Solvent: CCO
Product: COC(=O)c1cccc(-c2nc(CO)sc2C)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
A sample of rac-3-(2-bromo-pentanoyl)-benzoic acid methyl ester (0.60 g) and and 2-(tert.-butylcarbonyloxy)thioacetamide (0.36 g) in EtOH (4 mL) was heated at reflux for 5 h. The mixture was partitioned between AcOEt and 5% NaHCO3 solution, the organic layer was washed with brine, dried and evaporated. A solution of the residual oil and of NaOMe (0.13 g) in MeOH (10 mL) was stirred at 60° C. for 30 min. The solution was diluted with AcOEt, washed with 1N HCl and brine, dried and evaporated to give 3-(2-hydroxymethyl-5-methyl-thiazol-4-yl)-benzoic acid methyl ester (0.44 g) as an oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:5]=1[C:6]#[N:7])[CH3:2]>[Fe]>[NH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([NH:3][CH2:1][CH3:2])[C:5]=1[C:6]#[N:7]
Reactant: CCNc1cccc([N+](=O)[O-])c1C#N
Agent: [Fe]
Product: CCNc1cccc(N)c1C#N

Procedure:
Crude 2-amino-6-ethylaminobenzonitrile is prepared by iron reduction of 2-ethylamino-6-nitrobenzonitrile as in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:19][CH2:20]O>>[CH2:19]([O:12][C:11]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:10][CH2:9]1)=[O:13])[CH3:20]
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(c2ccc(Br)cc2)CC1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid (5 g, 20.7 mmol) in EtOH (50 mL) was treated with sulfuric acid (2 mL) and the reaction was stirred at 75° C. for 1 hour. Standard aqueous workup afforded title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([CH:12]2[N:16]3[C:17](=[O:22])[C@H:18]([C@H:19]([OH:21])[CH3:20])[C@H:15]3[C@@H:14]([CH3:23])[C:13]2=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:51][N:52]1[CH2:56][C@H:55]([SH:57])[CH2:54][C:53]1=[S:58].P([O-])([O-])([O-])=O>C(#N)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:16]3[C:17](=[O:22])[C@H:18]([C@H:19]([OH:21])[CH3:20])[C@H:15]3[C@@H:14]([CH3:23])[C:13]=2[S:57][C@H:55]2[CH2:56][N:52]([CH3:51])[C:53](=[S:58])[CH2:54]2)=[O:11])=[CH:25][CH:26]=1)([O-:3])=[O:2]
Reactant: CN1C[C@H](S)CC1=S
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@@H]3CC(=S)N(C)C3)[C@H](C)[C@H]12
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
(1R, 5R, 6S)-6-[(1R)-1-Hydroxyethyl]-1-methyl-2- oxocarbapenam-3-carboxylic acid 4-nitrobenzyl ester (25.2 g) is dissolved in anhydrous acetonitrile (173 ml), and thereto are added dropwise diisopropylethylamine (13 ml) and diphenylphosphoryl chloride (15.5 ml) in this order under nitrogen gas below 0° C. After stirring the mixture at the same temperature for 30 minutes, a solution of (4R)-N-methyl-4- mercaptopyrrolidine-2-thione (13 g) and diisopropylethylamine (11.5 g) in anhydrous acetonitrile (173 ml) is added dropwise to the reaction mixture below -5° C. After stirring the mixture at 0° C. for 1.5 hour, the reaction mixture is poured into phosphate buffer (pH 7.0, one liter). The precipitated crystal is separated by filtration and dissolved in a mixture of chloroform (2 liters) and tetrahydrofuran (1 liter), and the solution is washed with water, dried and concentrated to dryness under reduced pressure. The residue is crystallized from diethyl ether to give (1R, 5S, 6S)-2-[(4R)-N-methyl- pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen -2-em-3-carboxylic acid 4-nitrobenzyl ester (23.5 g) as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:29])[C:5]=2[NH:4][N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH:63]1[CH2:68][CH2:67][CH:66]([N:69]2[C:77]3[C:72](=[N:73][CH:74]=[CH:75][CH:76]=3)[NH:71][C:70]2=[O:78])[CH2:65][CH2:64]1>CN(C)C=O>[Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:19])[N:63]4[CH2:64][CH2:65][CH:66]([N:69]5[C:77]6[C:72](=[N:73][CH:74]=[CH:75][CH:76]=6)[NH:71][C:70]5=[O:78])[CH2:67][CH2:68]4)[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:29])[C:5]=2[NH:4][N:3]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CCN2CCCCC2)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CCN2CCCCC2)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
(S)-2-(1,4-dichloro-8-oxo-9-(2-(piperidin-1-yl)ethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (74 mg, 0.168 mmol) was dissolved in N,N-dimethylformamide (2.0 ml). N,N-Diisopropylethylamine (120 μl, 0.689 mmol) was added to the mixture followed successively by TBTU (58 mg, 0.181 mmol) and 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one dihydrochloride (58 mg, 0.199 mmol). Reaction stirred at room temperature for 5 hours. Reaction was quenched with 50% acetonitrile-water. Material was purified by reverse phase prep HPLC (water-acetonitrile-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 71% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.86 (s, 1H) 11.55 (s, 1H) 7.90 (s, 1H) 7.84 (d, J=7.63 Hz, 0.6H) 7.59 (d, J=8.24 Hz, 0.4H) 7.33 (s, 1H) 6.84-7.06 (m, 1 H) 5.22-5.36 (m, 2H) 4.40-4.64 (m, 2H) 4.16 (t, J=14.65 Hz, 1H) 3.80-4.02 (m, 2H) 3.12-3.29(m,3H) 2.95-3.09(m, 1H) 2.84-2.96(m, 1H) 2.62-2.78(m, 1 H) 2.53-2.60 (m, 1H) 2.39-2.49 (m, 1H) 2.01-2.33 (m, 5H) 1.62-1.98 (m, 4H) 1.09-1.22 (m, 6H). High resolution MS m/e (M+H)+=639.2393.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:26][N:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4]1)[CH3:2].O[Li].O>C1COCC1.O>[CH2:1]([CH:3]1[CH2:26][N:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:6]2=[N:7][C:8]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[CH2:4]1)[CH3:2]
Reactant: CCOC(=O)CCCCCCN1CC(CC)Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCC1Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N(CCCCCCC(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A (0° C.) cooled solution of ethyl 7-(7-ethyl-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (0.22 g, 0.44 mmol) in THF:H2O (4:1, 5 ml) was treated with LiOH.H2O (0.072 g, 1.76 mmol) and stirred at RT overnight. A further 2 equivalents of LiOH.H2O was added and the reaction mixture was heated to 50° C. for 4 hours. The solvent was removed under reduced pressure and the aqueous layer was acidified to pH 3 and partitioned between water and ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous sodium sulphate and concentrated under vacuum. The crude material was purified by chromatography on silica eluting with 10% EtOAc in hexane followed by preparative HPLC (MeCN in water eluent) to afford the titled compound;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([NH:13]C(OCC1C=CC=CC=1)=O)=[CH:5][CH:6]1[CH:10]2[CH2:11][CH2:12][CH:7]1[CH2:8][CH2:9]2.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:24])[CH:4]([NH2:13])[CH2:5][CH:6]1[CH:10]2[CH2:9][CH2:8][CH:7]1[CH2:12][CH2:11]2
Reactant: [H][H]
Reactant: COC(=O)C(=CC1C2CCC1CC2)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)CC1C2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.7 %

Procedure:
In a flask was placed 2-benzyloxycarbonylamino-3-bicyclo[2.2.1]hept-7-yl-acrylic acid methyl ester (130 mg, 0.40 mmol) and methanol (5 mL). To the mixture was added 10% palladium on activated carbon (15 mg) and the flask was fitted with a balloon filled with hydrogen. The mixture was allowed to stir at 25° C. for 1 h. After such time, the mixture was filtered through celite and concentrated in vacuo to afford crude 2-amino-3-bicyclo[2.2.1]hept-7-yl-propionic acid methyl ester (100 mg) which was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][SH:14].[Na]>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:13]([S:14][CH:13](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])=[CH:4][CH:3]=1
Reactant: SCc1ccccc1Cl
Reactant: C#Cc1ccc(F)cc1
Agent: [Na]
Product: Fc1ccc(/C=C\C(SC(/C=C\c2ccc(F)cc2)c2ccccc2Cl)c2ccccc2Cl)cc1

Procedure:
A solution of 4-fluorophenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to Procedure 2 to form (Z)-4-fluorostyryl 2-chlorobenzylsulfide. The title compound was obtained in 74% yield following oxidation. 1HNMR (CDC13) δ4.55 (2H, s), 6.66 (1H, d, JH,H=11.94), 7.20-7.65 (8H aromatic+1H ethylenic).
Reaction SMILES: O[C:2]1([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]([CH2:8][CH2:9][C:10]2([CH3:18])OCC(C)(C)C[O:11]2)[CH2:6][C:5](=[O:19])[CH:4]=[CH:3]1.[Cl-].[NH+]1C=CC=C[CH:30]=1>CO>[CH3:30][O:19][C:5]1[CH:4]=[CH:3][C:2]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:7]([CH2:8][CH2:9][C:10](=[O:11])[CH3:18])[CH:6]=1
Reactant: c1cc[nH+]cc1
Reactant: CC1(C)COC(C)(CCC2CC(=O)C=CC2(O)C#Cc2ccccc2)OC1
Agent: [Cl-]
Solvent: CO
Product: COc1ccc(C#Cc2ccccc2)c(CCC(C)=O)c1
Yield: 98 %

Procedure:
A mixture of 4-hydroxy-4-(phenylethynyl)-5-[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]-2-cyclohexene-1-one (4 g, 0.011 mole), the title product of Example 1c, pyridinium chloride (2.5 g, 0.022 mole) and absolute methanol (30 mL) were combined and heated to reflux for 4 hr. The reaction mixture was quenched into 50 mL of water, ether was added, the resulting layers separated, the aqueous layer extracted with ether, the ether extracts combined, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 3.0 g of the title product.