Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:16]([N:29]1[CH2:32][CH:31]([CH2:33]O)[CH2:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[C:17]1([CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:29]2[CH2:32][CH:31]([CH2:33][O:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)=[CH:4][CH:3]=3)[CH2:30]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: N#CC1(c2ccc(OCC3CN(C(c4ccccc4)c4ccccc4)C3)cc2)CCOCC1
Yield: 41 %

Procedure:
4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (6.18 g, 30.4 mmol), (1-benzhydryl-azetidin-3-yl)-methanol (7 g, 28 mmol), PPh3 (8 g, 30.4 mmol), and DIAD (69 mL, 30.4 mmol), were reacted together similarly to general procedure C. The crude material was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate:diethylamine (50:45:5 to 0:95:5) to provide the title compound (5.03 g, 41%) as a yellow solid. LRMS APCI+ m/z 439 [MH]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2)([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:34]1([CH2:40][NH2:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>O.CN(C)C=O>[CH:34]1([CH2:40][NH:41][C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)=[O:3])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NCC1CCCCC1
Reactant: O=C(O)CCCOc1ccc2c(c1)CCC(=O)N2
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCCOc1ccc2c(c1)CCC(=O)N2)NCC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.5 Grams of 6-(3-carboxy)propoxy-3,4-dihydrocarbostyril and 1.6 ml of triethylamine are added to 150 ml of dimethylformamide, and the mixture is further added dropwise with 1.3 ml of isobutyl chloroformate under external ice cooling and agitation while maintaining the internal temperature at 10° to 20° C. After this dropwise addition, the mixture is agitated at room temperature for 30 minutes, added with 1.3 ml of cyclohexylmethylamine and further agitated for 1 hour. After the reaction, the reaction solution is poured into about 1 liter of water and the precipitated crystals are filtered out and washed with water. The obtained crystals are dried and recrystallized from chloroform-petroleum ether to obtain 3.0 g of 6-{3-[N-(cyclohexylmethyl)aminocarbonyl]propoxy}-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with m.p. of 170°-172° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:22]=[CH:21][N:20]=2)[CH:17]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19]3[N:24]=[C:23]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=[CH:21][N:20]=3)[CH:17]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Reactant: O=C(O)c1ccc(O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc(O)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 4-hydroxybenzoic acid (10 mmol) and (A) (10 mmol) in DMF (40 ml) was added EDC (12.5 mmol) and HOBt (10 mmol). The reaction was stirred at RT for 4 hours and diluted with DCM (100 ml). The mixture was washed with water three times and dried with Na2SO4. The solution was evaporated and the residue was further purified by column chromatography to give the title compound (Z).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([N:19]2[CH2:23][CH2:22][CH2:21][C@@H:20]2[CH3:24])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:25]([O:27]C)=[O:26])[CH:15]=2)[N:10]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([N:19]2[CH2:23][CH2:22][CH2:21][C@@H:20]2[CH3:24])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:25]([OH:27])=[O:26])[CH:15]=2)[N:10]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3F)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a solution of (S)-methyl 2-(2,4-difluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (100 mg, 0.39 mmol) in MeOH (20 mL) was added sodium hydroxide (63 mg, 1.57 mmol) and water (2 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (2 mL) and adjusted to pH 6 with hydrochloric acid (1N). The solids were collected by filtration to afford (S)-2-(2,4-difluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a brown solid (82.4 mg, 86%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]1[C:15]([CH:20]=O)=[N:16][CH:17]=[CH:18][CH:19]=1.[BH-](O[C:32]([CH3:34])=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:18][C:17]1[C:32]([CH3:34])=[CH:13][CH:14]=[CH:15][N:16]=1)[CH2:20][C:15]1[C:14]([CH3:13])=[CH:19][CH:18]=[CH:17][N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccnc1C=O
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cccnc1CN(CCCNC(=O)OC(C)(C)C)Cc1ncccc1C
Yield: 55 %

Procedure:
Using General Procedure B: Reaction of (3-aminopropyl)-carbamic acid tert-butyl ester (Houssin, R. et al. Synthesis 1988, 3, 259-261), 3-methylpyridine-2-carboxaldehyde and NaBH(OAc)3 gave {3-[Bis-(3-methyl-pyridin-2-ylmethyl)-amino]-propyl}-carbamic acid tert-butyl ester as a light brown solid (0.17 g, 55%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.70 (m, 2H), 2.16 (s, 6H), 2.64 (t, 2H, J=7.5 Hz), 3.02 (m, 2H), 3.74 (s, 4H), 6.02 (br, 1H(NH)), 7.07 (m, 2H), 7.38 (d, 2H, J=6.0 Hz), 8.40 (d, 2H, J=2.8 Hz). Deprotection with TFA following General Procedure F gave N,N-Bis-(3-methyl-pyridin-2-ylmethyl)-propane-1,3-diamine (0.14 g, excess) was isolated, which was used immediately in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[Cl:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Cl:1])[N:10]=1)[C:5]([NH:15][CH:12]1[CH2:14][CH2:13]1)=[O:7]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: NC1CC1
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: CN(C)C=O
Product: O=C(NC1CC1)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2,6-dichloroisonicotinic acid (1 eq.) in DMF (0.05 M) was added sequentially cyclopropylamine (1.05 eq.), Hunig's base (3 eq.) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.2 eq.). The resulting solution was stirred at RT for 4 h. The reaction was quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 10:1 (v/v) CH2Cl2:EtOAc) afforded the title compound as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[Br:20][C:21]1[CH:34]=[CH:33][C:24]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:23][C:22]=1[CH2:35]Br.[Cl-].[NH4+]>C1COCC1.CCCCCC>[Br:20][C:21]1[CH:34]=[CH:33][C:24]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:23][C:22]=1[CH2:35][C:13]1([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N#CC1CCCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CBr)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CC2(C#N)CCCC2)c1
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere, to a solution of diisopropylamine (0.36 mL) in THF (7.0 mL) was added a 1.6 M solution of n-butyllithium in hexane (1.6 mL) at 0° C., and the mixture was stirred for 10 min. Cyclopentanecarbonitrile (0.28 mL) was added at −78° C., and the mixture was stirred for 30 min. A solution of (4-bromo-3-(bromomethyl)phenoxy) (tert-butyl)dimethylsilane (503 mg) in THF (3.0 mL) was added, and the mixture was stirred at −78° C. for 4 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (471 mg) as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.O.C[NH:13][CH:14]1[CH2:26][C:25]2[C:24]3C(=CC(C)=CC=3)N[C:17]=2[CH2:16][CH2:15]1>C(O)C>[CH3:1][NH:2][CH:3]1[CH2:8][C:7]2[C:26]3[C:14](=[CH:15][CH:16]=[CH:17][C:25]=3[CH3:24])[NH:13][C:6]=2[CH2:5][CH2:4]1
Reactant: CNC1CCC(=O)CC1
Reactant: CNC1CCc2[nH]c3cc(C)ccc3c2C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNC1CCc2[nH]c3cccc(C)c3c2C1

Procedure:
A solution of 15 g. of 4-methylaminocyclohexanone and 18.4 g. of 3-methylhydrazine hydrochloride in 200 ml. of absolute ethyl alcohol and 50 ml. of 4-N hydrogen chloride in absolute ethyl alcohol was heated under reflux for six hours, cooled, and filtered to give 12.3 g. of solids which were slurried in 50 ml. of water. The slurry was cooled, the solids were collected by filtration, suspended in ether-chloroform, and the suspension was treated with dilute potassium hydroxide. The ether-chloroform extract was evaporated to dryness under pressure to give 7.6 g. of 3-(methylamino)-7-methyl-1,2,3,4-tetrahydrocarbazole, m.p. 163°-166° C. The alcoholic reaction mixture filtrate was evaporated to dryness under reduced pressure, the residue was boiled in isopropyl alcohol, and the insoluble material was collected by filtration, dissolved in water and the resulting solution was made alkaline with dilute potassium hydroxide. The resulting solids were collected by filtration to give, after recrystallization from ethyl acetate, 3.6 g. of 3-(methylamino)-5-methyl-1,2,3,4-tetrahydrocarbazole, m.p. 187°-190° C., which contained about 6% of the 7-methyl isomer as determined by gas chromatographic analysis.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.CN(C)C=O.[H-].[Na+].[CH:21]([Si:24](Cl)([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])([CH3:23])[CH3:22]>O>[CH3:1][N:2]([CH3:13])[CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:21]([CH3:23])[CH3:22])[CH:5]=1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(CN(C)C)c2cccnc21
Temperature: 20 °C
Reaction time: 12 h
Yield: 58.9 %

Procedure:
Into a round bottom flask 7-Azagramine 2 (5.38 g, 30.7 mmol), N,N-dimethylformamide (25.0 mL), and sodium hydride (1.35 g, 33.8 mol) were combined. Into the reaction was added triisopropylsilyl chloride (6.8 mL, 0.032 mol). The reaction was stirred at 20° C. for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage to give compound 4 (6.0 g, yield=58.8%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[C:20](Br)=[CH:19][C:18]2[CH2:17][CH:16]([NH:22][C:23](=[O:25])[CH3:24])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:19][C:18]2[CH2:17][CH:16]([NH:22][C:23](=[O:25])[CH3:24])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)NC1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)c(Br)cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)NC1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)c(-c3ccccc3)cc2C1
Temperature: 95 °C

Procedure:
To 2-(6-acetylamino-3-bromo-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid tert-butyl ester (0.135 g; 0.30 mmol) dissolved in toluene (1.5 mL) was added phenylboronic acid (0.178 g; 1.46 mmol), Pd(PPh3)4 (15 mg; 0.013 mmol) and 2M Na2CO3 (0.61 mL) and the reaction mixture heated at 95° C. for 18 h. The reaction mixture was cooled, diluted with EtOAc, washed with H2O (2×), brine, dried over Na2SO4, filtered and the solvent removed under reduced pressure to yield a crude residue which was purified by flash chromatography (SiO2) eluting with a heptane-EtOAc gradient (50→100%) to yield 2-(6-acetylamino-3-phenyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methyl-propionic acid tert-butyl ester as a clear oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:14]=2)[CH2:9]1)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[N:19]1([CH2:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][CH:8]([NH2:7])[CH2:17][CH2:16]3)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(CN3CCCCC3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCc2cc(CN3CCCCC3)ccc2C1
Temperature: 25 °C

Procedure:
(6-Piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (Step E) (0.113 g, 0.327 mmol) was suspended in CH2Cl2 (2.5 mL) then TFA was added (2.5 mL). The reaction was stirred at RT until complete consumption of starting material was observed by HPLC analysis (2 h). The reaction mixture was concentrated in vacuo to afford the crude title compound as the bis-TFA salt, which was used without further purification. MS (APCI pos) 245 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11]/[C:10](=[CH:26]\N(C(C)C)C(C)C)/[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C:10](=[CH2:26])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
Crude (R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) (66.7 g) is dissolved in THF (340 ml) and cooled to 10° C. Sulphuric acid (96%; 6.9 ml) is added followed by water (152 ml). The mixture is stirred at room temperature for 0.5 h. Phases are separated. The organic phase is added to formaldehyde solution (37% in water; 138 ml). 1% Tetra-n-butylammoniumhydroxide solution (14.2 ml) is added. Potassium carbonate (27.8 g) is added portionwise over 0.5 h. Sodium hydroxide solution (15.1 g) is added over 3 h, maintaining pH 10.5. The phases are separated. The organic phase is washed with water (100 ml) followed by sodium bisulfite solution (21.4 g). Toluene (100 ml) and sodium chloride solution (50 ml) added. The phases are separated. The organic phase is extracted with sodium chloride solution (20%; 50 ml), dried (Na2SO4) and concentrated in vacuo to give (R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc) (63 g). Material can be recrystallised as follows: crude (R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc) (58.4 g) is dissolved in methanol (525 ml) at 50° C. Water (175 ml) is added and the mixture is cooled to 0° C. The solid is collected by filtration and the cake washed with a mixture of methanol (53 ml) and water (18 ml). The solid is then dried in vacuo, giving (R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc). Spectroscopic data as in Example 23.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C:16](=[O:32])[CH2:17][C@@H:18]([O:24][Si](C(C)(C)C)(C)C)[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:12]([CH:33]([CH3:35])[CH3:34])[N:11]=[C:10]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[N:9]=2)=[CH:4][CH:3]=1.F.C(=O)(O)[O-].[Na+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C:16](=[O:32])[CH2:17][C@@H:18]([OH:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:12]([CH:33]([CH3:35])[CH3:34])[N:11]=[C:10]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@@H](CC(=O)/C=C/c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)C[C@H](O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
To a solution of 16 g of the compound 6 in 100 ml of acetonitrile is added dropwise a solution of 48% hydrogen flouride in 400 ml of acetonitrile (1:19) under ice-cooling, and the mixture is warmed to room temperature and stirred for 1.5 hours. The reaction mixture is neutralized with sodium bicarbonate and extracted with ether. The organic layer is washed with sodium chloride, dried and evaporated under reduced pressure to distil ether to give 13 g (Yield: 100%) of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate 7 as syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]4[CH2:19][CH:18]4[C:20](O)=[O:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]4[CH2:19][CH:18]4[C:20]([NH:23][C:24]4[S:25][CH:26]=[CH:27][N:28]=4)=[O:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1CC1c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: Nc1nccs1
Product: O=C(Nc1nccs1)C1CC1c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 7 %

Procedure:
Example 103 was prepared from 2-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclopropanecarboxylic acid (34 mg, 0.115 mmol) and 2-aminothiazole using General Coupling Method B to give 3 mg (7% yield). MS found: (M+H)+=379.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:27][O:28][CH3:29])[C:10]([NH:12][C@@H:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH2:20]Cl)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37](=[O:46])[C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([OH:45])[CH:39]=2)[CH2:33][CH2:32]1.C(OCC)(=O)C>CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:27][O:28][CH3:29])[C:10]([NH:12][C@@H:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([O-:24])=[O:23])=[C:17]([CH2:20][N+:31]4([CH3:30])[CH2:36][CH2:35][N:34]([C:37](=[O:46])[C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([OH:45])[CH:39]=5)[CH2:33][CH2:32]4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CN1CCN(C(=O)c2ccc(O)c(O)c2)CC1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CCl)CS[C@H]12)c1csc(NC=O)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)c4ccc(O)c(O)c4)CC3)CS[C@H]12)c1csc(NC=O)n1
Temperature: 0 °C
Yield: 115.9 %

Procedure:
To a solution of 7β-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylic acid (syn isomer) (920 mg) in N,N-dimethylformamide (5 ml) was added 1-methyl-4-(3,4-dihydroxybenzoyl)piperazine (945 mg) at 0° C. and the mixture was stirred at 0° C. for 3. 5 hours. The mixture was added dropwise to ethyl acetate (200 ml) under stirring and the pulverized product was collected by filtration and washed with ethyl acetate to give 7β-[2-(2-formamidothiazol-4-yl) -2-methoxyiminoacetamido]-3-[1-methyl-4(3,4-dihydroxybenzoyl) -1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (1.53 g) .
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7](O)C)(=[O:4])[CH:2]=[CH2:3].CC1C(N=C=O)=CC([N:17]=C=O)=CC=1>>[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[NH2:17][C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C=CC(=O)OCC(C)O
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 70 °C
Reaction time: 7 h

Procedure:
In a flask equipped with a stirring blade, 260 parts (2 mol) of 2-hydroxypropyl acrylate(molecular weight of 130) was charged and 174 parts (1 mol) of TDI (2,4-tolylene diisocyanate) was added dropwise. After heating to 70° C. while paying attention to heat generation, the reaction was conducted at the same temperature for 7 hours. After confirming the disappearance of absorption of NCO by infrared absorption spectrum, the reaction product was taken out to obtain a urethane acrylate (H-1) as a radical polymerizable oligomer (A1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:7].[N:24]1([CH:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH2:39])[CH:36]=3)[CH2:31]2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13](=[O:15])[NH:39][C:35]2[CH:36]=[C:37]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH:30]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH2:38]3)[CH:11]=1)=[O:7]
Reactant: Nc1ccc2c(c1)CC(N1CCOCC1)C2
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)O)c2)cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CC(N3CCOCC3)C4)c2)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.4 %

Procedure:
To a suspension of the 3-[(3,4-dimethoxy-benzoylamino)-methyl]-benzoic acid (100 mg, 0.32 mmol) and 2-morpholin-4-yl-indan-5-ylamine (84 mg, 0.38 mmol) 1.5 mL of DMF. To this was added TBTU (122 mg, 0.38 mmol), and the vial warmed until a clear solution was obtained. The solution was stirred at room temperature. Stirring continued for 20 h total. Diluted with EtOAc and washed with Na2CO3, water and brine. The organic layer was dried over MgSO4, evaporated and purified by column chromatography, CH2Cl2/MeOH gradient 1-10%, to give 103 mg of 3,4-dimethoxy-N-[3-(2-morpholin-4-yl-indan-5-ylcarbamoyl)-benzyl]-benzamide. MS, electrospray, 516, (M+H).