Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](C)=[C:5]([C:18]([O:20][CH3:21])=[O:19])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH2:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[CH3:1][C:2]12[CH2:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:5]([C:18]([O:20][CH3:21])=[O:19])([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]1[C:8]([O:10][CH3:11])=[O:9])[CH:4]=[N:3]2
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1
Reactant: C=Cc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1C(c2ccccc2)C2(C(=O)OC)C=NC1(C)CC2c1ccccc1
Reaction time: 3 h

Procedure:
To 0.45 g (1.5 mmol) dimethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (1) in 25 ml CHCl3 under N2 and cooled to 0°-10° in an ice bath there was added 3.12 g (30.0 mmol) of commercially obtained styrene (4) followed by 0.64 g (4.5 mmol) boron trifluoride etherate added dropwise via syringe. The resulting solution was stirred at 0°-10° for 3 hours and then at room temperature for 16 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O)([O-:12])=[O:11]>C1(C)C=CC=CC=1>[N+:10]([C:13]1[CH:14]=[C:15](/[CH:16]=[N:1]/[C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:18]=[CH:19][CH:20]=1)([O-:12])=[O:11]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: N#Cc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(/N=C/c2cccc([N+](=O)[O-])c2)cc1

Procedure:
A mixture of 4-amino-benzonitrile (23.6 g, 0.2 mmol) in toluene (200 mL) was treated with a solution of 3-nitro-benzaldehyde (30.2 g, 0.2 mmol) in toluene (50 mL). The resultant mixture was allowed to reflux for 6 h. Toluene was removed under vacuum. The residue was purified by recrystallization from ethanol to afford 4-{[1-(3-nitro-phenyl)-meth-(E)-ylidene]-amino}-benzonitrile as yellow solid (50 g, yield %: 95.0%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=O)[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: COC(=O)C1CC(=O)CN1Cc1ccccc1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C1CC(NCc2ccccc2)CN1Cc1ccccc1
Reaction time: 3 h

Procedure:
1-Benzyl-4-oxo-pyrrolidine-2-carboxylic acid methyl ester and a corresponding benzylamine are dissolved in DCM, acetic acid and NaBH(OAc)3 is then added. After stirred for about 3 hours the reaction mixture is diluted with DCM, washed, dried and concentrated. The residue is purified to afford 1-benzyl-4-(benzylamino)-pyrrolidine-2-carboxylic acid methyl ester (26).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzylamine (16.0 mL, 145.2 mmol) is dissolved in chloroform (110 mL), and the solution is cooled to 0° C. To this solution is added 4-methoxybenzenesulfonyl chloride (10.0 g, 48.4 mmol). The reaction is stirred at room temperature for 1 hour, and then refluxed for 1 hour. After cooling back to room temperature, the reaction is washed three times with 4N hydrochloric acid (200 mL), twice with water (100 mL), once with brine (50 mL), then dried (Na2SO4), and the solvent is evaporated to give N-[4-methoxybenzenesulfonyl]-benzylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]([CH3:24])[CH:12]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.CC(C)([O-])C.[K+].C(O)(=O)C>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:9]=[C:10]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:24])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc2c(C#Cc3cc(Cl)cnc3N)cn(C)c2cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: COc1cc2c(-c3cc4cc(Cl)cnc4[nH]3)cn(C)c2cc1OC
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
A suspension of 0.44 g of 5-chloro-3-(5,6-dimethoxy-1-methyl-1H-indol-3-ylethynyl)pyridin-2-ylamine and 0.58 g of potassium tert-butoxide in 25 ml of 1-methylpyrrolidin-2-one is heated at a temperature in the region of 70° C. for approximately 4 hours 30 minutes. The mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 40 ml of water and the pH of the suspension obtained is brought to approximately 4-5 by adding glacial acetic acid. After agitation for approximately 10 minutes, the solid is filter-dried, washed with three times 5 ml of water and then air-dried. After recrystallization from 160 ml of propan-1-ol, 0.28 g of 5-chloro-2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine is obtained in the form of a beige solid, the characteristics of which are as follows:
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C([Mg]C(C)C)(C)C.[CH:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.C(OC)(C)(C)C>[OH:27][CH:20]([C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: CC(C)[Mg]C(C)C
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOC(=O)c1ccc(C(O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A solution of 552 mg (2 mmol) of ethyl 4-iodobenzoate in 20 ml of THF was cooled to −40° C. and 1.06 mmol of diisopropylmagnesium in methyl tert-butyl ether were added. After 1 h at −40° C. 233 mg (2.2 mmol) of benzaldehyde were added. After 3 h, the reaction mixture was hydrolyzed and the org. phase was concentrated. Chromatography of the crude product with 4/1 pentane/ether afforded 460 mg (90%) of the alcohol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:15][CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH:17]([OH:21])[C:18](O)=[O:19].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CN1CCOCC1.[Cl-].[Na+]>CN(C)C=O>[OH:21][C@H:17]1[C:18](=[O:19])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][C:3]=2[S:15][C@H:16]1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(Sc2cc(Oc3ccccc3)ccc2N)C(O)C(=O)O)cc1
Agent: [Cl-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc([C@@H]2Sc3cc(Oc4ccccc4)ccc3NC(=O)[C@@H]2O)cc1
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
2.2 g of 3-(2-amino-5-phenoxyphenyl)thio-2-hydroxy-3-(4-methoxyphenyl)propionic acid [prepared as described in step (b) above] were dissolved in 11 ml of dimethylformamide, and 1.38 ml of diphenylphosphorylazide was added, whilst ice-cooling, the mixture was then stirred for 30 minutes. At the end to this time, 1.38 ml of N-methylmorpholine was added to the mixture, which was then stirred at the same temperature for 30 minutes, and then at room temperature for 2 hours. After this, an aqueous solution of sodium chloride was added and the mixture was extracted twice with ethyl acetate. The extracts were combined, washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was triturated in diethyl ether, filtered and washed with diethyl ether, to give 1.13 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:8][C:7]2=[C:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([OH:13])=[CH:11][CH:12]=[C:6]2[O:5]1)[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22](S(C)(=O)=O)[N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([O:13][C:10]2[C:9]([C:14]([O:16][CH3:17])=[O:15])=[C:7]3[CH2:8][CH:4]([O:3][CH2:1][CH3:2])[O:5][C:6]3=[CH:12][CH:11]=2)[N:21]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CCOC1Cc2c(ccc(O)c2C(=O)OC)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC1Cc2c(ccc(Oc3nc(OC)cc(OC)n3)c2C(=O)OC)O1
Temperature: 100 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture comprising 1.0 g of methyl 2-ethoxy-5-hydroxy-2,3-dihydrobenzofuran-4-carboxylate, 1.0 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.78 g of potassium carbonate in 30 ml of N,N-dimethylformamide, was heated and stirred at 100° C. for two hours. The mixture was returned to room temperature, then poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the oily substance thereby obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to obtain 1.5 g (yield: 95%) of the desired compound.
Reaction SMILES: [O:1]1[CH2:26][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[N:12]=[CH:11][N:10]=1.[CH3:27][NH2:28]>C(O)C.O>[CH3:27][NH:28][CH2:26][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: Cc1cccc(Nc2cc(Nc3cccc(OCC4CO4)c3)ncn2)c1
Reactant: CN
Solvent: O
Solvent: CCO
Product: CNCC(O)COc1cccc(Nc2cc(Nc3cccc(C)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
Using an analogous reaction procedure to that described in Example 33, a mixture of 4-[3'-(2,3-epoxypropoxy)anilino]6-(3'-methylanilino) pyrimidine and 33% methylamine in ethanol and NHP was stirred over 2 days at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The product so obtained was washed with water and with brine, dried (MgSO4) and evaporated. The residue was recrystallised from a mixture of methylene chloride, methanol and hexane to give 4-[3'-(3-methylamino-2-hydroxypropoxy)anilino]6-(3'-methylanilino) pyrimidine is 46% yield, m.p. 88°-90° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[Cl:48][C:49]1[CH:60]=[CH:59][C:52]2[NH:53][C:54]([C@@H:56]([NH2:58])[CH3:57])=[N:55][C:51]=2[CH:50]=1>CN(C=O)C>[Cl:48][C:49]1[CH:60]=[CH:59][C:52]2[NH:53][C:54]([C@@H:56]([NH:58][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([N:12]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]4=[O:18])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH3:57])=[N:55][C:51]=2[CH:50]=1
Reactant: COc1cc(C(=O)O)ccc1N1CCCCC1=O
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCCCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methoxy-4-(piperidin-2-on-1-yl)benzoic acid, TBTU, NMM and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in DMF and subsequent purification by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:22]1([NH2:26])[CH2:25][CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:26][CH:22]3[CH2:25][CH2:24][CH2:23]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC1CCC1
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
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: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)NC4CCC4)c3)nc12

Procedure:
Following the same reaction and purification procedure as above, the acid 3 (50 mg, 0.18 mmol) was reacted with cyclobutanamine (CAS-2516-34-9) (0.03 mL, 0.35 mmol), HATU (103 mg, 0.35 mmol) and DIPEA (0.15 mL, 0.88 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-cyclobutyl-5-fluorobenzamide 6. LC/MS (ESI+): m/z 338 (M+H). 1H NMR (400 MHz, DMSO) δ 8.84 (d, J=7.3 Hz, 1H), 8.63 (d, J=10.3 Hz, 1H), 8.55 (dd, J=7.6, 5.1 Hz, 2H), 8.47-8.40 (m, 1H), 8.29 (d, J=12.0 Hz, 1H), 8.19 (dd, J=15.7, 10.5 Hz, 1H), 8.04 (s, 1H), 7.73 (d, J=9.2 Hz, 1H), 4.47 (dq, J=15.8, 7.9 Hz, 1H), 2.36-2.21 (m, 2H), 2.21-2.03 (m, 2H), 1.84-1.61 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH:12]=[O:13])[CH:9]=[C:8]([OH:14])[C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl.CCO>CO>[F:1][C:2]1[CH:11]=[C:10]([CH:12]=[O:13])[CH:9]=[C:8]([OH:14])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(O)cc(C=O)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: O=Cc1cc(O)c(C(=O)O)c(F)c1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
A mixture of methyl 2-fluoro-4-formyl-6-hydroxybenzoate (Intermediate 7) (300 mg, 1.50 mmol) and aqueous NaOH (2 M, 10 mL) in MeOH (10 mL) was stirred at 20° C. for 5 hours. The mixture was acidified with aqueous HCl until pH=2 followed by a standard aqueous/EtOH workup. The residue was used for next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[N:17]1[O:18][N:19]=[C:20]2[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][C:21]=12>>[N:17]1[O:18][N:19]=[C:20]2[CH:25]=[C:24]([C:2]3[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=[C:4]([CH:3]=3)[C:14]([OH:16])=[O:15])[CH:23]=[CH:22][C:21]=12
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: OB(O)c1ccc2nonc2c1
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc3nonc3c2)c1

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1211586-75-2) and B-2,1,3-benzoxadiazol-5-yl-boronic acid, (CAN 426268-09-9) as starting materials; LC-MS (UV peak area/ESI) 48%, 338.0 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[CH2:29][O:18][C:15]1[CH:16]=[CH:17][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=3)[CH:8]=2)[C:13](=[O:19])[CH:14]=1
Reactant: OCc1cc2ccccc2o1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4cc5ccccc5o4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 21.2 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (50 mg), 1-benzofuran-2-ylmethanol (58 mg) and triphenylphosphine (154 mg) in tetrahydrofuran (5 ml) was added bis(2-methoxyethyl)azodicarboxylate (138 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (16 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].C(=O)([O-])[O-:22].[K+].[K+].CC(C)=O.NC(N)=O.OO>O>[NH2:2][C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:6]([OH:8])=[O:7])=[O:22]
Reactant: CCCN(CCC)C(=O)c1cc(C#N)cc(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: NC(N)=O
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)O)c1

Procedure:
A mixture of 3-cyano-5-[(dipropylamino)carbonyl]benzoic acid (IX/XXXII, PREPARATION 7, 0.602 g, 2.19 mmol), potassium carbonate (0.212 g, 1.53 mmol), and acetone (2.5 mL) is stirred at 20–25 degrees C. Water (2.5 mL) and urea-hydrogen peroxide adduct (0.825 g, 8.78 mmol) are added and the mixture is stirred for 15 hours at 20–25 degrees C., at which time additional urea-hydrogen peroxide adduct (0.204 g) is added; after stirring for another 3 hours, an additional 0.205 g of urea-hydrogen peroxide is added. After a total of 39 hours has elapsed, the acetone is removed under reduced pressure and the residue is acidified with hydrochloric acid (3N) to pH=2–4. The mixture is extracted with dichloromethane, the organic layer is separated and washed with hydrochloric acid (0.5 N), and the organic phase is dried with anhydrous magnesium sulfate to a solid. The solid is crystallized from dichloromethane/hexane/methanol to give the title compound, MS (ESI+) for C15H20N2O4 m/z (M+H)+=293.2.
Reaction SMILES: [CH2:1]([CH:4]1[N:7]([C:8]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6](=[O:38])[CH:5]1[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:2]=C.FC(F)(F)C(O)=O.O=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C>[CH2:39]([CH:5]1[C:6](=[O:38])[N:7]2[CH:4]1[CH2:1][CH:2]=[C:8]2[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: C=CCC1C(Cc2ccccc2)C(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C1=CCC2C(Cc3ccccc3)C(=O)N12
Reaction time: 0.5 h

Procedure:
A solution of 4-allyl-3-benzyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidine-2-one (36) (0.38 g) in ethyl acetate (20 ml) was treated with trifluoroacetic acid (1.0 ml). The solution was cooled to -78° and ozone passed through it until it just became blue in colour. The excess ozone was blown off in a stream of argon and a solution of triphenylphosphine (0.16 g) in ethyl acetate (2 ml) was then added. The reaction solution was purged with argon for the next 30 minutes and the reaction flask was then transferred to an ice bath. Saturated aqueous sodium bicarbonate (30 ml) was added with vigorous stirring and after a further 30 minutes the ethyl acetate solution was separated, washed with brine and dried over sodium sulphate. Column chromatography on silica gel 60 (<230 mesh) eluting with ethyl acetate/60°-80° petroleum ether 3:7 gave benzyl 6-benzyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate as the trans isomer (37) (0.09 g. 42). It was a colourless gum; νmax (CHCl3) 3020, 2960, 1785, 1725 and 1610 cm-1 ; τ (CDCl3) 2.6-3.0 (10H, m, phenyls), 3.66 (1H, t, J 3 Hz, C3--H), 4.80 (2H, s, benzyl CH2 --O), 6.02 (1H, td, J 81/2 and 3 Hz, C5--H), 6.60 (1H, ddd, J 9, 6 and 3 Hz, C6--H), 6.88 (1H, d, J 6 Hz, inner signal of ABX for PhCH2 --C6), 6.97 (1H, d, J 9 Hz, inner signal of ABX for PhCH2 --C6), 7.29 and 7.32 (2H, each a dd, J 81/2 and 3 Hz, inner signals of AB for CH4--H2 ).
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:50]2[N:51]=[C:52]([NH:55]C(OC(C)(C)C)=O)[S:53][CH:54]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][NH:42]C(OC(C)(C)C)=O)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:42][CH2:41][C:39]1[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]3)/[C:50]3[N:51]=[C:52]([NH2:55])[S:53][CH:54]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:33])=[O:32])[N:40]=1
Reactant: CC(C)(C)OC(=O)NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Yield: 25.6 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(((tert-butoxycarbonyl)amino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (1.98 g, 2.21 mmol), DCM (18.4 mL) and TFA (10.2 mL, 133 mmol). Half of the crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (300 mg, ca 50%) as an off-white powder. LCMS: Rt=0.29 min, m/z=530.1 (M+1) Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 7.69 (s, 1H), 7.04 (br s, 1H), 5.43 (d, J=5.5 Hz, 1H), 4.93-4.78 (m, 2H), 4.74-4.67 (m, 1H), 4.22-4.12 (m, 2H), 1.36-1.20 (m, 2H), 1.20-1.00 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:10](O)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.ClC(OCC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:10][OH:11])[CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:4]
Reactant: COC(=O)C1(C(=O)O)CCCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C1(CO)CCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.1 %

Procedure:
To a solution of cyclopentane-1,1-dicarboxylic acid methyl ester (1.00 g, 5.81 mmol) and triethylamine (808 uL, 5.81 mmol) in THF (15 mL) is added isobutyl chloroformate (750 uL, 5.81 mmol) at 0° C. The mixture is stirred at 0° C. for 20 minutes. The mixture is filtrated, and the filtrate is added to a suspension of NaBH4 (242 mg) in THF (15 ml) at 0° C. The mixture is stirred at 0° C. for 3 hours and at room temperature for 12 hours. To the mixture, H2O is added and the mixture is extracted with AcOEt. The organic layer is dried over MgSO4, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give 1-hydroxymethyl-cyclopentanecarboxylic acid methyl ester (433 mg, 47%); TLC (hexane/AcOEt, 1:1) Rf 0.43, 1H NMR (400 MHz, chloroform-d) 8 ppm 1.61-1.77 (m, 6H), 1.93-2.00 (m, 2H), 2.53 (m, 1H), 3.57 (d, 2H), 3.72 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1)=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O-:25])=[O:24])C=CC=CC=1.[Na+].O.S(=O)(=O)(O)O>CS(C)=O>[C:23]([CH2:22][CH2:21][CH2:20][CH:19]=[CH:1][C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1)([OH:25])=[O:24]
Reactant: O=Cc1cccc2cncn12
Reactant: O=C([O-])CCCC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCCC=Cc1cccc2cncn12

Procedure:
A solution of 5-formylimidazo[1,5-a]pyridine (1.46 g) in 15 ml of dry dimethylsulfoxide is added to a solution of sodium 5-(triphenylphosphoranyl)valerate (4.4 g) in 50 ml of dry dimethylsulfoxide at room temperature (Helv. Chem. Acta 63 1430 (1980)). The reaction is stirred for 3 hours, hydrolyzed with water and neutralized with dilute sulfuric acid. Extraction with ethyl acetate and chromatography or silica gel yields 5-(5-carboxypent-1-enyl)-imidazo[1,5-a]pyridine.