Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C@H:29]3[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]3)[CH2:23][CH2:22]2)[CH:18]=[C:17]([CH:36]2[CH2:39][CH2:38][CH2:37]2)[N:16]=1)([CH3:14])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][C@H:29]3[CH2:30][CH2:31][C@H:32]([NH:35][C:8]([C@H:5]4[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]4)=[O:10])[CH2:33][CH2:34]3)[CH2:25][CH2:26]2)[CH:18]=[C:17]([CH:36]2[CH2:39][CH2:38][CH2:37]2)[N:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CC[C@H]3CC[C@H](NC(=O)[C@H]4CC[C@H](O)CC4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Trans-4-hydroxycyclohexanecarboxylic acid (1,991 g, 13.81 mmol) was added to a solution of trans-4-(2-(4-(2-(tert-butyl)-6-cyclobutylpyrimidin-4-yl)piperazin-1-yl)ethyl)cyclohexanamine (4.6 g, 11.51 mmol) in dichloromethane. HATU (2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate, 5.25 g, 13.8 mmol) and diisopropylethylamine (6.03 mL, 34.5 mmol) were added and the mixture stirred at room temperature for 14 h. The solvent was evaporated and the residue partitioned between dichloromethane and water. The aqueous phase was extracted several times with dichloromethane. The combined organic layers were washed twice with 5% aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. Purification via silica gel chromatography (330 g Reveleris NP cartridge) with di-chloromethane/methanol (0-80%) as eluent yielded 6.05 g of the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1([CH3:18])[C:14]([O:16][CH3:17])=[O:15])C1C=CC=CC=1>CCO.[Pd]>[CH3:18][C:9]1([C:14]([O:16][CH3:17])=[O:15])[CH2:10][O:11][CH2:12][CH2:13][NH:8]1
Reactant: COC(=O)C1(C)COCCN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1(C)COCCN1
Reaction time: 16 h

Procedure:
Dissolve methyl 4-benzyl-3-methylmorpholine-3-carboxylate in EtOH (10 volumes) and add 10% Pd/C (0.1 eq.). Hydrogenate for 16 hours, filter through Celite®, and concentrate to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:12][S:13]([C:8]1[C:7]([F:11])=[C:3]([C:2]([F:1])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])(=[O:15])=[O:14]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1c(F)ccc(S(=O)(=O)Cl)c1F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
95 mmol of 2,6-difluorobenzoic acid in 19 ml of chorosulfonic acid was stirred for 2 h at 150°. The mixture was poured into 200 ml of ice and stirred for 20 min. The resulting slurry was filtered, washed with water and dried (20° overnight in the dessicator) to yield the title compound as a colorless solid. MS (m/e): 279.4 (MNa+, 81%)
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][O:28][C:29]([C:31]2[CH:32]=[N:33][C:34]3[C:39]([CH:40]=2)=[CH:38][C:37]([O:41][CH3:42])=[CH:36][CH:35]=3)=[O:30])[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([CH2:27][O:28][C:29]([C:31]4[CH:32]=[N:33][C:34]5[C:39]([CH:40]=4)=[CH:38][C:37]([O:41][CH3:42])=[CH:36][CH:35]=5)=[O:30])[CH2:23][CH2:22]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](N)CC3)cc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](NCc4ccc5c(c4)OCCO5)CC3)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2,3-Dihydro-benzo[1,4]dioxine-6-carbaldehyde (188 mg, 1.14 mmol, 1.8 eq) is added at room temperature to a stirred solution of the trifluoroacetic acid salt of 6-methoxy-quinoline-3-carboxylic acid trans-4-amino-cyclohexylmethyl ester (200 mg, 0.64 mmol, 1.0 eq) in 1,2-dichloroethane (10 mL), followed by sodium triacetoxyborohydride (1.35 g, 6.36 mmol, 10.0 eq). After 18 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×10 mL) and a saturated sodium hydrogen carbonate aqueous solution (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 6-methoxy-quinoline-3-carboxylic acid trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexylmethyl ester as a white powder (123 mg, 40% yield).
Reaction SMILES: [AlH4-].[Li+].O1CCCC1.[CH2:8]([N:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21](O)=[O:22])=[CH:20][C:15]=2[N:14]=[N:13]1)[CH2:9][CH2:10][CH3:11]>O>[CH2:8]([N:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH2:21][OH:22])=[CH:20][C:15]=2[N:14]=[N:13]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCn1nnc2cc(C(=O)O)ccc21
Agent: [AlH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCn1nnc2cc(CO)ccc21
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a stirred and cooled (0° C.) suspension of 23.4 parts of lithium tetrahydroaluminate in 270 parts of dry tetrahydrofuran were added portionwise 45 parts of 1-butyl-1H-benzotriazole-5-carboxylic acid. Upon complete addition, stirring was continued for 1 hour at 0° C. The reaction mixture was hydrolysed with 50 parts of water. The whole was filtered and washed with a mixture of dichloromethane and methanol (90:10 by volume). The filtrate was evaporated to dry and the residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 18 parts (42.7%) of 1-butyl-1H-benzotriazole-5-methanol as an oily residue (int. 10).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=O)[CH2:2]1.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:24]>C(Cl)Cl.CN(C=O)C>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([NH2:24])=[O:16])[CH2:2]1
Reactant: O=C(O)C1CCc2[nH]c3ccccc3c2C1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)C1CCc2[nH]c3ccccc3c2C1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (30.4 g, 141 mmol), was suspended in 450 ml of methylene chloride and cooled to 0° C. Oxalyl chloride (14.8 mL, 169 mmol) was added dropwise, followed by two drops of DMF. The resulting mixture was allowed to warm to room temperature and was stirred for 24 h. After re-cooling to 0° C., 450 mL of conc. aqueous ammonium hydroxide were added dropwise. The yellow precipitate that formed was collected by vacuum filtration. After drying, the title compound weighed 17.4 g (58%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.C1C(=O)N([Br:26])C(=O)C1.[Cl-].[NH4+]>C1COCC1>[Br:26][C:3]1[S:4][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:10]2[C:2]=1[Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Brc1csc2cnccc12
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Brc1sc2cnccc2c1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a cooled (−78° C.) solution of 3-bromo-thieno[2,3-c]pyridine (6.42 g, 30.0 mmol) in dry THF (150 mL) under nitrogen was added 2.0 M LDA (30.0 mL, 60.0 mmol) dropwise. The mixture was stirred at −78° C. for 1 h. A solution of NBS (10.7 g, 60 mmol) in THF (50 mL) was added to the reaction mixture dropwise keeping the temperature below −70° C. The mixture was then warmed to room temperature overnight. Saturated aqueous ammonium chloride (50 mL) was added to the mixture and layers were separated. The aqueous layer was extracted with EtOAc (2×60 mL). The combined organic fractions were washed with brine (50 mL), dried over sodium sulfate, and concentrated. Purification by column chromatography (100% DCM) afforded 4.5 g (55%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.62 (d, J=5.4
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[N:14]([O-])=O.[Na+].[ClH:18]>O>[ClH:18].[NH:1]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][CH:3]=1)[NH2:14]
Reactant: CS(=O)(=O)NCc1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)NCc1ccc(NN)cc1
Temperature: -55 °C
Yield: 100 %

Procedure:
To a suspension of 18.0 g (89.9 mmol, 1.0 equiv.) of N-[(4-aminophenyl)methyl]methanesulfonamide in 85 ml of water and 175 mL of concentrated aqueous hydrochloric acid at 0° C. was added a solution of 6.21 g (89.9 mmol, 1.0 equiv.) of sodium nitrite in 85 mL of water. The reaction mixture was stirred for fifteen minutes. Meanwhile a solution of 101.6 g of stannous chloride dihydrate in 175 mL of concentrated aqueous hydrochloric acid was prepared and cooled to -55° C. The solution of the diazonium salt was filtered into the stannous chloride solution. The reaction was maintained between -55° C. and -35° C. for one hour. The crystalline material was collected by filtration and dried under high vacuum at 65° C. for 16 hours to yield 23.9 g (>100%) of crude N-[(4-hydrazinylphenyl)methyl]methanesulfonamide hydrochloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[C:14]([Cl:17])=[N:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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].O1CCOCC1>[Cl:17][C:14]1[C:13]([NH:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[CH:16][N:15]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: CN(C)S(=O)(=O)Nc1cc(-c2cnc3cc(Br)ccn23)cnc1Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)Nc1cc(-c2cnc3cc(-c4cccnc4)ccn23)cnc1Cl
Temperature: 110 °C
Yield: 51.7 %

Procedure:
To a 5 mL microwave tube was added N-(5-(7-bromoimidazo[1,2-a]pyridin-3-yl)-2-chloropyridin-3-yl)dimethylaminosulfonamide (0.107 g, 0.248 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.061 g, 0.298 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(II) (0.018 g, 0.025 mmol), sodium carbonate (0.311 mL, 0.621 mmol), and dioxane (3 mL). The resulting mixture was sealed and heated in a microwave at 110° C. for 20 min. Solvent was removed and the residue was partitioned between pH 7-buffer (1M TRIS-HCL) and DCM. The aqueous layer was extracted with DCM (2×15 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude material was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-340, 40 g SiO2, DCM:MeOH=97%:3% Flow=40 mL/min) to afford the desired product as light brown solid (55.0 mg). MS (EI, pos.) calcd for C19H17ClN6O2S: 428.1; found: 428.9.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][C:27]([C:48]#[N:49])=[N:28][C:29]=3[NH:33][CH2:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:12][C@@H:11]1[CH2:50][O:51][CH3:52])(=O)C1C=CC=CC=1.N>CO>[OH:15][C@@H:14]1[C@H:10]([OH:9])[C@@H:11]([CH2:50][O:51][CH3:52])[O:12][C@H:13]1[N:24]1[CH:32]=[N:31][C:30]2[C:25]1=[N:26][C:27]([C:48]#[N:49])=[N:28][C:29]=2[NH:33][CH2:34][CH:35]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: N
Solvent: CO
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C#N)nc32)[C@H](O)[C@@H]1O
Yield: 46.5 %

Procedure:
A solution of (2R,3R,4R,5R)-4-(benzoyloxy)-5-{2-cyano-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-2-(methoxymethyl)tetrahydro-3-furanyl benzoate (preparation 11) (6.75 g, 9.72 mmol) in methanol (300 ml) saturated with ammonia gas was stirred at room temperature for 72 hr. The solvent was removed under reduced pressure, the residue dissolved in dichloromethane and the solvent removed under reduced pressure (repeated). The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (98:2) gradually changing to dichloromethane:methanol (96:4). The residue was triturated with diethyl ether, filtered, washed with diethyl ether and dried to afford the title compound as a solid (2.20 g). MS: 487(MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:37]2[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:36])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH2:28][C:29]3([CH:33]([OH:35])[CH3:34])[CH2:32][CH2:31][CH2:30]3)[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[C:33]([C:29]1([CH2:28][O:27][C@H:24]2[CH2:23][CH2:22][C@H:21]([N:11]3[C:10](=[O:36])[C:9]([CH2:8][C:7]4[CH:6]=[CH:5][C:4]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:3][C:2]=4[F:1])=[C:14]([CH2:15][CH2:16][CH3:17])[N:13]4[N:18]=[CH:19][N:20]=[C:12]34)[CH2:26][CH2:25]2)[CH2:32][CH2:31][CH2:30]1)(=[O:35])[CH3:34]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC3(C(C)O)CCC3)CC2)c2ncnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC3(C(C)=O)CCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3′-Fluoro-4′-{[4-(trans-4-{[1-(1-hydroxyethyl)cyclobutyl]methoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.72 g) was dissolved in acetonitrile (20 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.77 g) was added, and the mixture was stirred at room temperature for 4 hr. Saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.65 g, 89%).
Reaction SMILES: [C:1]1(C#C)C=CC=C[CH:2]=1.[C:9]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10](Br)=[CH:11][CH:12]=[CH:13][CH:14]=1.C[Si](C#C)(C)C>>[C:9]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:1]#[CH:2]
Reactant: C#Cc1ccccc1
Reactant: Brc1ccccc1C#Cc1ccccc1
Agent: C#C[Si](C)(C)C
Product: C#Cc1ccccc1C#Cc1ccccc1

Procedure:
In an especially contemplated arm extension strategy depicted in FIG. 4, in which AD represents an admantane or diamantane group. Phenylacetylene is a starting molecule that is reacted (A1) with TBA (supra) to yield tetrakis(mono-tolanyl)-adamantane. Alternatively, phenylacetylene can be converted (B1) to tolanylbromide that is subsequently reacted (C1) with trimethylsilylacetylene to form tolanylacetylene. TBA can then be reacted (A2) with tolanylacetylene to tetrakis(bis-tolanyl)-adamantane. In a further extension reaction, tolanylacetylene is reacted (B2) with 1-bromo-4-iodobenzene to bistolanylbromide that is further converted (C2) to bistolanylacetylene. The so formed bistolanylacetylene may then be reacted (A3) with TBA to yield tetrakis(tristolanyl)-adamantane.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:11][O:10][C:9]1=[O:21])=[O:7].[CH3:22][CH:23]([CH3:39])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=1)=[O:25]>>[F:20][C:15]1[CH:14]=[C:13]([C@H:12]2[CH2:11][O:10][C:9](=[O:21])[N:8]2[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:36]2[CH2:37][CH2:38][CH:33]([C:29]3[CH:28]=[C:27]([NH:26][C:24](=[O:25])[CH:23]([CH3:22])[CH3:39])[CH:32]=[CH:31][CH:30]=3)[CH2:34][CH2:35]2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)N1C(=O)OC[C@@H]1c1ccc(F)c(F)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)N3C(=O)OC[C@@H]3c3ccc(F)c(F)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using (4S)-3-(5-chloropentanoyl)-4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 528.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:15])=[C:9]([C:12](=[O:14])[CH3:13])[C:10]=1[CH3:11])=[O:5])[CH3:2].CC(O[CH:21](N(C)C)[N:22]([CH3:24])[CH3:23])(C)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:15])=[C:9]([C:12](=[O:14])[CH:13]=[CH:21][N:22]([CH3:24])[CH3:23])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C)c(C(C)=O)c1C
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c(C)c(C(=O)C=CN(C)C)c1C
Temperature: 50 °C
Reaction time: 20 h

Procedure:
In a dry flask containing THF (15 mL) was added 4-acetyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.0 g, 9.3 mmol) then Bredereck's reagent (5 mL). The reaction was stirred at 50° C. for 20 hours. The resulting precipitate formed during the reaction was removed by filtration and washed with hexanes. The enaminone was recovered as a yellow solid (2.2 g), HPLC Rt=4.0 minutes; FIA, ES+=265.1
Reaction SMILES: [CH2:1]([NH:4][C:5](=[S:8])[NH:6][NH2:7])[CH:2]=[CH2:3].[Cl:9][C:10]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:11]=1[C:12](=O)[CH2:13]Cl>>[Cl:9][C:10]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:11]=1[C:12]1[CH2:13][S:8][C:5]([NH:4][CH2:1][CH:2]=[CH2:3])=[N:6][N:7]=1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: C=CCNC(=S)NN
Product: C=CCNC1=NN=C(c2ccc(Cl)cc2Cl)CS1
Yield: 88.8 %

Procedure:
3.93 g (0.03 mole) of 4-allyl-thiosemicarbazide and 7.00 g (0.03 mole) of 2,4-dichlorophenacyl chloride are reacted in accordance with the conditions of Example 1. Recrystallization from methanol/methyl acetate produces 8 g of 5-(2,4-dichlorophenyl)-N-2-propenyl-6H-1,3,4-thiadiazin-2-amine. m.p. 188°-189° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[O:16][C:15]([CH3:17])=[N:14][CH:13]=1)[C:6](O)=[O:7].O.[NH2:19][NH2:20]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[O:16][C:15]([CH3:17])=[N:14][CH:13]=1)[C:6]([NH:19][NH2:20])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1-c1cnc(C)o1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)NN)ccc1-c1cnc(C)o1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (115 g) was added to a suspension of 3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)benzoic acid (83.0 g) in THF (1 L) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was cooled to −10° C., hydrazine monohydrate (173 mL) was added, and the mixture was stirred at room temperature for 16 hr. The solvent in the reaction mixture was evaporated under reduced pressure, and water was added to the residue. The resultant solid was collected by filtration, washed with water, dried under reduced pressure, and washed with IPE to give the title compound (85.8 g). 1H NMR (300 MHz, DMSO-d6) δ 2.48 (3H, s), 3.97 (3H, s), 4.53 (2H, brs), 7.44-7.58 (3H, m), 7.68 (1H, d, J=8.0 Hz), 9.85 (1H, s).
Reaction SMILES: [ClH:1].C([O:6][C:7]([CH2:9][O:10][N:11]=[C:12]([C:38]1[N:39]=[C:40]([NH2:43])[S:41][CH:42]=1)[C:13]([NH:15][CH:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([OH:35])=[O:34])=[C:20]([CH2:23][S:24][C:25]3[N:29]([CH2:30][C:31]#[CH:32])[N:28]=[N:27][N:26]=3)[CH2:21][S:22][C@H:17]12)=[O:14])=[O:8])(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>>[ClH:1].[C:7]([CH2:9][O:10][N:11]=[C:12]([C:38]1[N:39]=[C:40]([NH2:43])[S:41][CH:42]=1)[C:13]([NH:15][CH:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([OH:35])=[O:34])=[C:20]([CH2:23][S:24][C:25]3[N:29]([CH2:30][C:31]#[CH:32])[N:28]=[N:27][N:26]=3)[CH2:21][S:22][C@H:17]12)=[O:14])([OH:8])=[O:6]
Reactant: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Reaction time: 3 h
Yield: 95.9 %

Procedure:
A mixture of 7-[2-tert-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (1.57 g.), anisole (1.57 ml.) and trifluoroacetic acid (8 ml.) was stirred for 3 hours at 10° to 15° C. After the addition of diisopropyl ether to the reaction mixture with stirring, the precipitates were collected by filtration, washed with diisopropyl ether and then dried to give 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (1.38 g.).
Reaction SMILES: Cl[CH:2]([CH3:19])[C:3](=[O:18])[C:4](=[N:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[SH:20][CH2:21][CH2:22][OH:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:23][CH2:22][CH2:21][S:20][CH:2]([CH3:19])[C:3](=[O:18])[C:4](=[N:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCCCCCON=C(C(=O)OCC)C(=O)C(C)Cl
Reactant: OCCS
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCON=C(C(=O)OCC)C(=O)C(C)SCCO
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.7 %

Procedure:
Ethyl 4-chloro-3-oxo-2-n-hexyloxyiminovalerate (255.0 g.), 2-mercaptoethanol (86.1 g.), triethylamine (11.13 g.) and chloroform (2.8 l.) were treated in a similar manner to that of Example I-(i) and stirred at room temperature for 3.5 hours. The resultant solution was treated in a similar manner to that of Example I-(i) to give ethyl 4-(2-hydroxyethylthio)-3-oxo-2-n-hexyloxyiminovalerate (290.5 g.).