Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]1[C:5]2([CH2:9][CH2:8][O:7][CH2:6]2)[CH2:4][NH:3]1.C(N(CC)CC)C.[CH3:17][C:18]1[CH:25]=[C:24]([O:26][CH:27]2[CH2:30][N:29]([C:31]([C:33]3[O:34][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[N:36][N:37]=3)=[O:32])[CH2:28]2)[CH:23]=[CH:22][C:19]=1[CH:20]=O.[Na].C([O-])(O)=O.[Na+]>ClCCl>[CH2:2]1[C:5]2([CH2:9][CH2:8][O:7][CH2:6]2)[CH2:4][N:3]1[CH2:20][C:19]1[CH:22]=[CH:23][C:24]([O:26][CH:27]2[CH2:30][N:29]([C:31]([C:33]3[O:34][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[N:36][N:37]=3)=[O:32])[CH2:28]2)=[CH:25][C:18]=1[CH3:17]
Reactant: Cc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1C=O
Reactant: C1CC2(CNC2)CO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1CN1CC2(CCOC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
6-Oxa-2-azaspiro[3.4]octane HCl salt (0.064 g, 0.43 mmol) was dissolved in dichloromethane (2 ml). Triethylamine (0.064 ml, 0.47 mmol) was added, followed by 2-methyl-4-(1-(5-phenyl-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.13 g, 0.36 mmol) and sodium triacetoxyhydroborate (0.152 g, 0.72 mmol). The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with dichloromethane (10 ml) and then shaken with NaHCO3. The two phases were separated by the use of a phase separator. Evaporation of dichloromethane afforded crude material, which was purified by preparative reverse-phase HPLC at pH 10 to give 66 mg (40%) of the desired product as a solid. 1H NMR (600 MHz, DMSO) δ 2.01 (t, 2H), 2.27 (s, 3H), 3.13 (q, 4H), 3.47 (s, 2H), 3.64 (t, 2H), 3.70 (d, 2H), 4.08 (dd, 1H), 4.51-4.56 (m, 1H), 4.63 (dd, 1H), 5.06-5.15 (m, 2H), 6.65 (dd, 1H), 6.71 (d, 1H), 7.18 (d, 1H), 7.62-7.73 (m, 3H), 8.06-8.11 (m, 2H). MS (APCI+) m/z 461.2 [M+H]+, LC purity: 98%
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][C:12]=1[O:21][CH3:22].[NH2:24][C@@H:25]([CH3:44])[CH2:26][O:27][C:28]1[CH:43]=[CH:42][C:31]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH:24][C@@H:25]([CH3:44])[CH2:26][O:27][C:28]2[CH:43]=[CH:42][C:31]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:33])=[CH:30][CH:29]=2)=[O:20])=[CH:13][C:12]=1[O:21][CH3:22]
Reactant: C[C@H](N)COc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(CC(=O)N[C@@H](C)COc2ccc(C(=O)OCc3ccccc3)cc2)ccc1NC(=O)Nc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 4-[N′-(2-bromophenyl)ureido]-3-methoxyphenylacetic acid (480 mg, 1.27 mmol), benzyl (S)-4-(2-amino-1-propoxy)benzoate (361 mg, 1.27 mmol), EDC.HCl (364 mg, 1.90 mmol), HOBt (256 mg, 1.89 mmol) and DMAP (31 mg, 0.25 mmol) in DMF (8 ml) was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3 to 5% MeOH in CHCl3 as eluent to give benzyl (S)-4-[2-[4-[N′-(2-bromophenyl) ureido]-3-methoxyphenylacetamido]-1-propoxy]benzoate (476 mg, 58%) as a brown solid. 1H-NMR (CDCl3) δ 1.25–1.28 (m, 3 H), 3.51 (s, 2 H), 3.74 (s, 3 H), 3.95–3.97 (m, 2 H), 4.36–4.39 (m, 1 H), 5.33 (s, 2 H), 6.75–6.94 (m, 5 H), 7.26–7.70 (m, 8 H), 7.99–8.26 (m, 5 H).
Reaction SMILES: [CH2:1]([N:4]([CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([C:22]#[N:23])=[CH:17][CH:18]=2)[CH2:13]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=C.N1C=CC=CC=1.[O:30]=[O+][O-]>C(Cl)Cl.CO>[C:22]([C:16]1[CH:15]=[C:14]2[C:19]([CH2:20][CH2:21][CH:12]([N:4]([CH2:1][CH:2]=[O:30])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:13]2)=[CH:18][CH:17]=1)#[N:23]
Reactant: O=[O+][O-]
Reactant: C=CCN(C(=O)OC(C)(C)C)C1CCc2ccc(C#N)cc2C1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CC=O)C1CCc2ccc(C#N)cc2C1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl allyl(7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (320 mg, 1.0 mmol) in 1:1 CH2Cl2/MeOH (20 mL) containing pyridine (0.16 mL, 2.0 mmol) was cooled to −78° C., and O3 was passed through until a blue color was present. N2 was then bubbled through to discharge the blue color and Me2S (3 ml) was added. The reaction mixture was allowed to warm and left overnight. The mixture was washed with 1 N HCl and aqueous NaHCO3 and then dried and concentrated to give the title compound. MS m/z: 315 [M+1]+.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11](C(O)=O)[CH2:10][CH2:9]1)([O:3]C(C)(C)C)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(NC(C)C)(C)C.C([Li])CCC.[C:41]([C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)(=[O:43])[CH3:42].[N-]1C=CN=C1>CCCCCC.CCOC(C)=O.C1COCC1>[OH:43][C:41]([C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)=[CH:42][C:1]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:15][CH2:16]1)=[O:3]
Reactant: CC(=O)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Agent: c1c[n-]cn1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(C=C(O)c1cccnc1)N1CCCCC1
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
To an oven dried 50 mL round bottomed flask with a stirring bar, argon inlet and septum was added Boc-isonipecotic acid (2.50 g, 10.90 mmol), 1,1'-carbonyldiimidazole (1.77 g, 10.90 mmol) and dry THF (20 mL). This solution was stirred at 20° C. for 45 min. To a separate, oven dried, 100 mL round bottomed flask with a stirring bar, argon inlet, low temperature thermometer, and septum was added dry THF (30 mL) and distilled diisopropylamine (1.60 mL, 11.45 mmol). This solution was cooled to -78° C. and n-Butyllithium (4.58 mL, of a 2.5M solution in hexane, 11.45 mmol) was added with a syringe. This solution was aged 20 min. then 3-acetylpyridine (1.25 mL, 11.45 mmol) was added dropwise with a syringe. This mixture was stirred for 30 min. at -78° C. then the imidazolide solution was added via a cannula. The mixture was warmed to 20° C. then diluted with EtOAc (350 mL). This solution was washed with 10% aqueous citric acid, saturated aqueous NaHCO3 solution and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on 120 g of silica gel using 3% 2-propanol in CHCl3 as eluant. 1-(1,1-dimethylethoxycarbonyl)-4-(1-(3-hydroxy-1-oxo-3-(3-pyridinyl)-2-propenyl)piperidine was obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].[CH:26](OCC)(OCC)[O:27][CH2:28][CH3:29]>CC1C=CC=CC=1>[C:19]([C:4]1[C:3]([S:21][C:22]([F:25])([F:24])[F:23])=[C:2]([N:1]=[CH:26][O:27][CH2:28][CH3:29])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: CCOC(OCC)OCC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC=Nc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
5-Amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (4.0 g) was added to triethyl orthoformate (19.0 ml) and p-toluene/-sulphonic acid (0.019 g) added. The mixture was heated under reflux for 21 hours, cooled, and the triethyl orthoformate evaporated in vacuo to give a brown oil as residue. This was purified by chromatography eluting with a mixture of dichloromethane and hexane (1:1). Evaporation of the eluates in vacuo gave 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethyleneamino-4-trifluoromethylthiopyrazole as a colourless solid, m.p. 70-71.5° C.
Reaction SMILES: C(Cl)(=[O:6])CCCC.OC1C=CC([N+]([O-])=O)=CC=1C[P+:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Br-].N1C=CC=CC=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[C:13]1([P:12](=[O:6])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
113.5 g (0.94 mole) of pentanoyl chloride are added slowly with stirring to a mixture of 370 g (0.75 mole) of 2-hydroxy 5-nitrobenzyltriphenylphosphonium, bromide and 120.2 g (1.52 mole) of pyridine in 700 ml of chloroform. The mixture is heated at reflux for 2 hours. 2800 ml of toluene are added and 1400 ml of solvents are distilled. 228 g (2.28 moles) of triethylamine are then added and the mixture is heated at reflux for 3 hours. It is allowed to cool, the triphenylphosphine-oxide, formed is filtered off, washed with ethyl acetate and the filtrate is concentrated in a vacuum. The viscous residue obtained is dissolved in acetonitrile and extracted with pentane in a liquid-liquid, extraction apparatus. The solution is dried over sodium sulfate, filtered and evaporated to dryness.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([CH2:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1.O>[CH2:1]([N:8]1[CH2:9][C@@H:10]([OH:11])[C@H:12]([NH:22][CH2:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Reactant: NCCc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1NCCc1ccccc1

Procedure:
19.4 g (0.1 mol) of 90% strength 3-benzyl-6-oxa-3-azabicyclo[3.1.0]hexane are heated under reflux with 14.5 g (0.12 mol) of benzylmethylamine in 100 ml of dioxane and 200 ml of water overnight. The mixture is extracted with CHCl3, the extracts are dried with K2CO3 and concentrated and the residue is subjected to incipient distillation up to 160° C. (oil bath temperature).
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][CH:7]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[NH3:18].[BH4-].[Na+]>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]([Si:5]([CH3:17])([CH3:16])[O:6][CH:7]1[CH2:14][CH2:13][CH2:12][CH:11]([NH2:18])[CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(=O)CCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC1CCCC(N)CCC1
Reaction time: 6 h

Procedure:
11.0 g (38.6 mmol) of titanium isopropoxide were added to a solution of 5.0 g (19.3 mmol) of 5-(tert-butyl-dimethyl-silanyloxy)-cyclooctanone (58) in 48.3 mL (96.5 mmol) of a 2M solution of ammonia in ethanol and stirred for 6 hours. After addition of 1.1 g (29 mmol) of sodium borohydride the mixture was stirred at room temperature for 4 days. The reaction was quenched by addition of 50 mL of a 2M aqueous ammonia solution. A white precipitate was removed by filtration and washed with ethyl acetate. The filtrate was extracted with ethyl acetate and the combined organic layers dried over magnesium sulfate, filtered and evaporated to yield 4.5 g of 5-(tert-butyl-dimethyl-silanyloxy)-cyclooctylamine (59) as a mixture of diastereomers as a yellow oil which was used without purification. Rt=2.14 min (Method J). Detected mass: 258.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([OH:18])=O.[CH3:19][CH:20]([CH3:40])[CH2:21][NH:22][C@@H:23]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][C@H:25]([C:36]([O:38][CH3:39])=[O:37])[CH2:24]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([N:22]([CH2:21][CH:20]([CH3:40])[CH3:19])[C@@H:23]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][C@H:25]([C:36]([O:38][CH3:39])=[O:37])[CH2:24]1)=[O:18]
Reactant: COC(=O)[C@@H]1C[C@H](NCC(C)C)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCCn1c(C(=O)O)cc2ccccc21
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)cc2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 7.4 %

Procedure:
1-(4-Methoxybutyl)-1H-indole-2-carboxylic acid (247 mg), 1-tert-butyl 3-methyl (3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (314 mg) and diisopropylethylamine (862 μl) were dissolved in methylene chloride (5 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (337 mg) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give 1-tert-butyl 3-methyl (3R,5S)-5-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (40 mg) as an oil. The obtained 1-tert-butyl 3-methyl (3R,5S)-5-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (40 mg) was dissolved in methanol (2 ml), 4M hydrogen chloride-ethyl acetate (2 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated under reduced pressure. An aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give the object product (13 mg).
Reaction SMILES: [NH2:1][CH:2]([C:26]([OH:28])=[O:27])[CH2:3][CH2:4][CH2:5][C:6]([NH:8][CH:9]1[C:24](=[O:25])[N:11]2[C:12]([C:21]([OH:23])=[O:22])=[C:13]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[CH2:14][S:15][C@H:10]12)=[O:7].C(N1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44])(OCC)=O.P(=O)(O)(O)O>P([O-])([O-])(O)=O.[K+].[K+].CC(C)=O.O>[C:35]1(=[O:44])[N:1]([CH:2]([C:26]([OH:28])=[O:27])[CH2:3][CH2:4][CH2:5][C:6]([NH:8][CH:9]2[C:24](=[O:25])[N:11]3[C:12]([C:21]([OH:23])=[O:22])=[C:13]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[CH2:14][S:15][C@H:10]23)=[O:7])[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]12
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCCC(N)C(=O)O)[C@H]2SC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCCC(C(=O)O)N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 15 grams of 7-(5-amino-5-carboxyvaleramido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid in 150 milliliters of 10 percent potassium hydrogen phosphate buffer solution (adjusted to pH 9.1 by addition of 25 percent potassium phosphate solution) was added 9.9 grams of N-carbethoxy phthalimide in 75 milliliters of acetone. The reaction mixture was stirred at room temperature for one hour at pH 9.1, diluted with water to 300 milliliters, and the pH adjusted to 7.0 by addition of phosphoric acid. The acetone was then evaporated and the reaction mixture extracted with ethyl acetate:ethanol (88:12) to remove the phthalimide. The pH of the aqueous layers was adjusted to 2 by addition of phosphoric acid and the mixture extracted with ethyl acetate:ethanol (88:12). The extract was dried with anhydrous magnesium sulfate and filtered, and the filtrate evaporated to dryness, leaving as a residue the desired 7-(5-phthalimido-5-carboxyvaleramido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid as a foam. It was digested three times with 500-milliliter aliquots of ether. The ether washed product amounted to 17.05 grams.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH:30]1([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCOCC1.CN(C=O)C>[CH:30]1([O:36][C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OC4CCCCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and cyclohexanol in dioxane and DMF. ES-MS m/e (%): 469 (M+H+, 100).
Reaction SMILES: [C:1]1([N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:30]1[CH:35]=[C:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH:33]=[CH:32][C:31]=1[CH2:41][O:42][C:43](=[O:45])[CH3:44].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:1]1([N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:32]3[CH:33]=[C:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH:35]=[CH:30][C:31]=3[CH2:41][O:42][C:43](=[O:45])[CH3:44])=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OCc1ccc(COC(C)=O)c(Br)c1
Reactant: CC1(C)OB(c2ccc(N(c3ccccc3)c3ccccc3)cc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)OCc1ccc(COC(C)=O)c(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)c1
Yield: 75.2 %

Procedure:
4-Diphenylamino-1-(4,4,5,5-tetramethyl-1,3,2-Dioxaborolan-2-yl)benzene (6.09 g) (prepared by successive reaction of 4-bromo-triphenylamine with butyllithium and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane), 2-bromo-1,4-bis(acetyloxymethyl)benzene (4.9 g), tetrakis(triphenylphosphine)-palladium(0) (0.15 g), toluene (15 mL), and an aqueous solution of sodium carbonate (2M, 25 mL) were mixed under argon. The resulting mixture was stirred at reflux for 2 days, cooled, and poured into water. The aqueous mixture was then extracted with ether. The etheral solution was washed with dilute HCl, brine, dried with magnesium sulfate, and evaporated. The residue was recrystallized in methanol to yield 5.70 g of 2-(4-diphenylamino-phenyl)-1,4-bis(acetyloxymethyl)benzene.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:36][C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[CH2:39][CH2:40][N:41]([CH3:47])[CH2:42]2.Cl>CN(C=O)C.CO.ClCCl>[ClH:11].[CH3:47][N:41]1[CH2:40][CH2:39][C:38]2[C:43](=[CH:44][CH:45]=[CH:46][C:37]=2[NH:36][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[CH:3][C:4]=2[O:12][CH3:13])[CH2:42]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)Nc1cccc2c1CCN(C)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.5 %

Procedure:
4-Amino-5-chloro-2-methoxybenzoic acid (2.08 g, 11.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.77 g 9.24 mmol) and 1-hydroxybenzotriazole (1.25 g, 9.24 mmol) were dissolved in dry DMF (40 ml) and stirred at room temperature under argon for 0.5h before 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (1.5 g, 9.24 mmol) was added. The mixture was then stirred for 18 h under argon at room temperature. The DMF was removed in vacuo and the residue taken up into ethyl acethate and washed with water, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford a yellow solid. This was then passed through a short pad of silica eluting with dichloromethane to afford a white solid which was then taken up into methanol and treated with hydrogen chloride (1M in ether, 1 equivalent). The solvent was removed in vacuo and the residue recrystallised from methanol and ethyl acethate to afford the title compound as a white solid (0.775 g).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[CH:11]=[N:12][N:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=12)=[O:9].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Pd].ClP(C1C=CC=CC=1C1C=CC=CC=1N(C)C)(C12CC(CC1)CC2)C12CC(CC1)CC2>[C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[CH:11]=[N:12][N:13]2[CH:18]=[C:17]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH:16]=[CH:15][C:14]=12)=[O:9]
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1ccccc1NC(=O)c1cnn2cc(Br)ccc12
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1[PH](Cl)(C12CCC(CC1)C2)C12CCC(CC1)C2
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3c(C(=O)Nc4ccccc4C)cnn3c2)cc1

Procedure:
6-Bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid o-tolylamide (50 mg, 0.15 mmol), 4-methoxyphenylboronic acid (27.9 mg, 0.18 mmol), chloro-[2′-(dimethylamino)-2-biphenylyl]-(dinorbornylphosphine)-palladium (4.6 mg, 7.6 μmol; Fluka, CAS # 359803-53-5) and potassium carbonate (84 mg, 0.61 mmol) are heated in 5 ml dry dioxane to 130° C. for 20 minutes in the microwave oven. The product is isolated by automated column chromatography and is dried at the high vacuum pump, yielding the title compound as a white solid.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([C:9]2[CH:10]=[C:11]3[C:21](=[CH:22][CH:23]=2)[O:20][C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:13][C:12]3=[O:24])[CH:5]=[CH:4]1.[CH:25]1([N:28]2[C:36]3[C:31](=[C:32]([C:40]4[NH:44][N:43]=[N:42][N:41]=4)[CH:33]=[C:34]([C:37](O)=[O:38])[CH:35]=3)[CH:30]=[CH:29]2)[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C.O.C(N(CC)CC)C>[CH:25]1([N:28]2[C:36]3[C:31](=[C:32]([C:40]4[NH:44][N:43]=[N:42][N:41]=4)[CH:33]=[C:34]([C:37]([N:17]4[CH2:18][CH2:19][C:14]5([CH2:13][C:12](=[O:24])[C:11]6[C:21](=[CH:22][CH:23]=[C:9]([C:6]7[CH:5]=[CH:4][C:3](=[O:2])[NH:8][CH:7]=7)[CH:10]=6)[O:20]5)[CH2:15][CH2:16]4)=[O:38])[CH:35]=3)[CH:30]=[CH:29]2)[CH2:26][CH2:27]1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3ccc(=O)[nH]c3)cc21
Reactant: O=C(O)c1cc(-c2nnn[nH]2)c2ccn(C3CC3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1CC2(CCN(C(=O)c3cc(-c4nnn[nH]4)c4ccn(C5CC5)c4c3)CC2)Oc2ccc(-c3ccc(=O)[nH]c3)cc21
Temperature: 50 °C
Reaction time: 16 h

Procedure:
6-(6-Oxo-1,6-dihydropyridin-3-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (208 mg), 1-cyclopropyl-4-(tetrazol-5-yl)-1H-indole-6-carboxylic acid (135 mg), EDCI (115 mg), HOBT (91.2 mg) and triethylamine (0.209 ml) were suspended in DMF (3 ml), and stirred at 50° C. for 16 hours. 1N hydrochloric acid and water were added to the reaction liquid, the formed solid was taken out through filtration, and the resulting solid was recrystallized from methanol to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 11.78 (1.0H, s), 7.85-7.82 (2.0H, m), 7.81-7.75 (3.0H, m), 7.67 (1.0H, d, J=2.4 Hz), 7.64 (1.0H, d, J=3.2 Hz), 7.17-7.11 (2.0H, m), 6.40 (1.0H, d, J=9.5 Hz), 4.46-4.12 (1.0H, m), 3.93-3.13 (4.0H, m), 2.92 (2.0H, s), 2.15-1.90 (2.0H, m), 1.88-1.75 (2.0H, m), 1.16-1.08 (2.0H, m), 1.04-0.98 (2.0H, m). MS [M+H]+=562.