Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].C(OC([N:8]1[C@H:12]([CH2:13][C:14]2[S:18][C:17]3=[CH:19][N:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:21]([CH3:22])=[N+:16]3[CH:15]=2)[CH2:11][C@H:10]([S:29][C:30]2[C@H:31]([CH3:47])[C@@H:32]3[C@@H:42]([C@H:43]([OH:45])[CH3:44])[C:41](=[O:46])[N:33]3[C:34]=2[C:35]([O:37]CC=C)=[O:36])[CH2:9]1)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCOCC1>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.C1COCC1.C(O)C>[CH2:27]([O:26][C:24]([CH2:23][N:20]1[CH:19]=[C:17]2[S:18][C:14]([CH2:13][C@H:12]3[NH:8][CH2:9][C@@H:10]([S:29][C:30]4[C@H:31]([CH3:47])[C@@H:32]5[C@@H:42]([C@H:43]([OH:45])[CH3:44])[C:41](=[O:46])[N:33]5[C:34]=4[C:35]([O-:37])=[O:36])[CH2:11]3)=[CH:15][N+:16]2=[C:21]1[CH3:22])=[O:25])[CH3:28]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3c[n+]4c(C)n(CC(=O)OCC)cc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1cc2sc(C[C@@H]3C[C@H](SC4=C(C(=O)[O-])N5C(=O)[C@H]([C@@H](C)O)[C@H]5[C@H]4C)CN3)c[n+]2c1C
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 4.4 %

Procedure:
Anhydrous THF (0.6 ml) and 0.6 ml of dry ethanol are added to 49.7 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-ethoxycarbonylmethyl-5-methylimidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate bromide. Triphenylphosphine (6.9 mg), 0.014 ml of morpholine, and 3.8 mg of tetrakis(triphenylphosphine)palladium(0) are successively added thereto, and the mixture is stirred in an argon atmosphere at room temperature for 55 min. THF (10 ml) is added, the resultant precipitate is further washed twice with 3 ml of THF and dried in vacuo to give a yellow powder which is then purified by column chromatography on Cosmosil 40C18-PREP (water-methanol) to give 1.6 mg of the title compound as a colorless flocculent material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([O:34][CH3:35])[C:32]=1[CH3:33])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:12][C:11]=1[N:22](C)[C:23](=O)C(F)(F)F)=[O:7].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:35][O:34][C:31]1[CH:30]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:32]=1[CH3:33])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:12][C:11]=1[NH:22][CH3:23])=[O:7]
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N(C)C(=O)C(F)(F)F)cc(OC)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNc1cc(-c2noc(C)n2)ccc1CNC(=O)c1cc(OC)c(C)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
A suspension of compound 1i (0.11 g, 0.22 mmol) and potassium carbonate (92.5 mg, 0.67 mmol) in a mixture of methanol (2.5 mL) and water (0.4 mL) was stirred at rt for 3 h. The reaction mixture was filtered and concentrated on a rotary evaporator. The residue was dissolved in ethyl acetate and washed with water and brine, dried MgSO4, and concentrated to give compound 1j (30 mg, 34%). ESI-MS m/e 397.3 (M+1).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Reaction time: 3 h
Yield: 106.9 %

Procedure:
A mixture of tert-butyl (3S)-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate 8 (0.22 g, 0.48 mmol) and Pd/C (0.070 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 9 (0.19 g, quant. yield) as a light yellow foam.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.Cl.[O:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>CCOC(C)=O>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:37][CH:34]1[CH2:35][CH2:36][O:31][CH2:32][CH2:33]1)=[O:6]
Reactant: Nc1c(Br)cccc1C(=O)O
Reactant: NC1CCOCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Nc1c(Br)cccc1C(=O)NC1CCOCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 52.4 %

Procedure:
A yellow mixture of 2-amino-3-bromobenzoic acid (Oakwood Products, Inc., West Columbia, S.C., 2.125 g, 9.83 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (6.37 mL, 10.82 mmol), tetrahydro-2H-pyran-4-amine hydrochloride (Combi-Blocks, Inc., San Diego, Calif., 4.06 g, 29.5 mmol), and DIEA (5.15 mL, 29.5 mmol) was stirred at 0° C. for 5 min; the reaction mixture was then warmed to RT and stir for 30 min when product was observed via LCMS. The reaction mixture was diluted with EtOAc (150 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (4×100 mL); the organic layer was separated, dried over Na2SO4, and concentrated to give 2-amino-3-bromo-N-(tetrahydro-2H-pyran-4-yl)benzamide (515a, 1.54 g, 5.15 mmol, 52% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.49-1.63 (m, 2H) 2.00 (dd, J=12.52, 2.15 Hz, 2H) 3.53 (td, J=11.69, 2.05 Hz, 2H) 3.95-4.05 (m, 2H) 4.10-4.21 (m, 1H) 5.87 (d, J=7.24 Hz, 1H) 6.06 (br. s., 2H) 6.54 (t, J=7.92 Hz, 1H) 7.25-7.30 (m, 1H) 7.51 (dd, J=7.82, 1.17 Hz, 1H). MS (ESI, pos. ion) m/z: 299.0/301.0 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3]([C:9]#[N:10])=[N:2]1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[N:10]1[NH:11][N:12]=[N:13][C:9]=1[C:3]1[C:4]2[CH2:8][CH2:7][CH2:6][C:5]=2[NH:1][N:2]=1
Reactant: N#Cc1n[nH]c2c1CCC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1Cc2[nH]nc(-c3nn[nH]n3)c2C1
Temperature: 175 °C
Yield: 41.2 %

Procedure:
1,4,5,6-Tetrahydro-cyclopentapyrazole-3-carbonitrile (0.022 g, 0.165 mmol) and sodium azide (0.086 g, 1.30 mmol) were taken up in DMF (3 cm3) at heated under microwave irradiation to 175° C. for 20 minutes. The solution was cooled to room temperature, filtered and the filtered solid washed with ethyl acetate. The combined solutions was added to saturated aqueous sodium bicarbonate (20 cm3) and washed with ethyl acetate. The aqueous layer was acidified to pH 1 with the addition of 1M aqueous hydrochloric acid and extracted into ethyl acetate. The ethyl acetate washes were combined and solvent removed under reduced pressure, the resulting solid purified by preparative HPLC to give 3-(2H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole as a white solid (0.012 g, 0.068 mmol, 41%). 1H NMR δ (CD3OD): 2.88 (t-like, 2H, J=7.0), 2.82 (t-like, 2H, J=7.3), 2.64 (quintet-like, 2H, J=7.1); m/z (ES+): 177 [M+H]+.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:9][C:10]([C@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](O)=[O:16])=[O:11])[CH3:8]>C(Cl)Cl>[CH2:7]([O:9][C:10]([C@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([Cl:4])=[O:16])=[O:11])[CH3:8]
Reactant: CCOC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: 4.0 g of (S,S)-2,4-dibenzylglutaric anhydride is refluxed in 40 ml of ethanol:toluene (3:2) overnight. The reaction mixture is concentrated to yield 4-ethoxycarbonyl-(S,S)-2,4-dibenzylbutyric acid as an oil. Oxalyl chloride (3.5 ml) is added to the solution of 4.5 g of 4-ethoxycarbonyl-(S,S)-2,4-dibenzylbutyric acid in 10 ml of methylene chloride. The mixture is stirred at room temperature overnight and evaporated to yield 4-ethoxycarbonyl-(S,S)-2,4-dibenzylbutyryl chloride, which is used as such without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:13]Br.S([O-])([O-])=O.[Na+].[Na+].O>C(O)(=O)C>[Br:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: COc1ccc(C(=O)O)c(F)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(F)c(C(=O)O)cc1Br
Temperature: 60 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
2-Fluoro-4-methoxybenzoic acid (10.0 g) was suspended in acetic acid (80 mL). To the suspension was slowly added dropwise bromine (20.7 g)/acetic acid (20 mL) solution. After completion of the dropwise addition, the mixture was stirred at 25° C. for 3 hr and further at 60° C. for 4 hr, the completion of the reaction was confirmed by HPLC. After cooling to room temperature, to the suspension was added dropwise an aqueous solution of sodium sulfite (9.63 g) and water (100 mL). After completion of the dropwise addition, the mixture was stirred at 25° C. for 2 hr, and then for 2 hr under ice-cooling. The precipitated crystals were collected by filtration, washed four times with water (30 mL), and vacuum dried to give 5-bromo-2-fluoro-4-methoxybenzoic acid as white crystals (14.5 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:23]#[C:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:9]=1[NH:10][C@@H:11]([CH3:22])[CH2:12][CH2:13][O:14][Si](C(C)(C)C)(C)C)=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:23]#[C:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:8][C:9]=1[NH:10][C@@H:11]([CH3:22])[CH2:12][CH2:13][OH:14])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N[C@@H](C)CCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N[C@@H](C)CCO
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
3-[3-(tert-Butyl-dimethyl-silanoxy)-1-(S)-methyl-propylamino]-5-(3,3-dimethyl-but-1-ynyl)thiophene-2-carboxylic acid methyl ester (8.2 g, 18.24 mmol) was taken up in THF (200 mL). TBAF 1.0M in THF (88.15 mL, 88.15 mmol) was added in 20 mL increments at rt. The reaction was monitored by LC/MS. The reaction was determined to be complete at 30 min. and was quenched with sat NH4Cl(aq) (200 mL). After stirring at it for 1 h. the organics were removed under reduced pressure and treated with EtOAc. The solution was dried over Na2SO4, solids were filtered and the solvent removed under reduced pressure. 5-(3,3-dimethyl-but-1-ynyl)3-(3-hydroxy-1-(S)-methyl-propylamino)-thiophene-2-carboxylic acid methyl ester (4.0 g, 73%) was isolated by silica gel chromatography as a yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([N:15]1[CH:20]=[CH:19][C:18](=[O:21])[CH2:17][CH:16]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:14].O.[CH3:29][N:30](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:11][O:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([C:29]#[N:30])=[C:3]([CH2:12][C:13](=[O:14])[N:15]2[CH:20]=[CH:19][C:18](=[O:21])[CH2:17][CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1cc(I)c(CC(=O)N2C=CC(=O)CC2c2ccccc2)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COc1cc(C#N)c(CC(=O)N2C=CC(=O)CC2c2ccccc2)cc1OC
Temperature: 80 °C
Yield: 20.3 %

Procedure:
1-[2-(2-Iodo-4,5-dimethoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one (269 mg, 0.56 mmol), zinc cyanide (1.5 eq, 99 mg) and tetrakis(triphenylphosphine)palladium(0) (0.15 eq, 98 mg) were dissolved in DMF. The mixture was heated to 80° C. overnight. Upon cooling, the mixture was poured into water and extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulfate and concentrated en vacuo. The residue was purified by flash chromatography (7:3 Hexanes/Ethyl Acetate) to give 4,5-dimethoxy-2-[2-oxo-2-(4-oxo-2-phenyl-3,4-dihydro-2H-pyridin-1-yl)-ethyl]-benzonitrile (43 mg, 20.3%) viscous oil.
Reaction SMILES: [CH:1]([NH:14][C:15]([C:17]1[C:18]([OH:34])=[N:19][C:20]([N:23]2[CH:27]=[C:26]([P:28]([CH3:33])(=[O:32])[O:29]CC)[CH:25]=[N:24]2)=[N:21][CH:22]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[CH:1]([NH:14][C:15]([C:17]1[C:18]([OH:34])=[N:19][C:20]([N:23]2[CH:27]=[C:26]([P:28]([CH3:33])(=[O:29])[OH:32])[CH:25]=[N:24]2)=[N:21][CH:22]=1)=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOP(C)(=O)c1cnn(-c2ncc(C(=O)NC(c3ccccc3)c3ccccc3)c(O)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CP(=O)(O)c1cnn(-c2ncc(C(=O)NC(c3ccccc3)c3ccccc3)c(O)n2)c1
Temperature: 80 °C

Procedure:
The product of step D, 1-1-d, (500 mg, 1.05 mmol) was dissolved in 10 mL of dioxane and treated with 2 mL of 5N NaOH. The mixture was heated at 80° C. for 30 min. The mixture was then diluted with water and extracted with dichloromethane. The aqueous layer was adjusted to pH=5 with AcOH and evaporated to dryness. The residue was used for prep-HPLC to afford the product, 1-1, (130 mg, 28%). 1H NMR (300 MHz, DMSO-d6): δ 10.38 (br, 1H), 8.79 (s, 1H), 8.48 (s, 1H), 8.18 (s, 1H), 7.37 (m, 10H), 6.29 (d, 1H), 1.63 (d, 3H). (M+H)+ =450.1.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[S:11][CH:12]=2)[N:5]=[C:4]2[C:19]3[C:25]([Br:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:20]=3[O:21][C:3]=12.O=P(Cl)(Cl)[Cl:31]>>[Br:26][C:25]1[C:19]2[C:4]3[C:3]([O:21][C:20]=2[CH:22]=[CH:23][C:24]=1[O:27][CH3:28])=[C:2]([Cl:31])[CH:7]=[C:6]([C:8]1[N:9]=[C:10]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[S:11][CH:12]=1)[N:5]=3
Reactant: COc1ccc2oc3c(O)cc(-c4csc(NC(=O)C(C)C)n4)nc3c2c1Br
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2oc3c(Cl)cc(-c4csc(NC(=O)C(C)C)n4)nc3c2c1Br
Temperature: 110 °C
Yield: 27 %

Procedure:
A mixture of 16C (0.7 g, 1.5 mmol) in POCl3 (10 mL) was heated to 110° C. and reacted for 30 min. TLC monitored the reaction. After the reaction completed, POCl3 in the reaction mixture was evaporated. The residue was added dropwise into ice-water. The precipitated solids were collected by filtration and purified by short column chromatography to give M16 (0.2 g, 27% yield).
Reaction SMILES: [C:1]1(=[O:16])[N:5]([CH2:6][CH2:7][C:8]([OH:10])=O)[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:29][N:30]1[C:39]([OH:47])([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([Cl:48])[CH:37]=2)[N:32]=[CH:31]1>O1CCCC1>[Cl:48][C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][N:30]([NH:29][C:8](=[O:10])[CH2:7][CH2:6][N:5]1[C:1](=[O:16])[C:2]3[C:3](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]1=[O:11])[C:39]2([OH:47])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:46]
Reactant: NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reactant: O=C(O)CCN1C(=O)c2ccccc2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(CCN1C(=O)c2ccccc2C1=O)NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cold solution of β-phthalimidopropionic acid (2.41 g., 0.011 mole) in dry tetrahydrofuran (20 ml.) is added 1,1'-carbonyldiimidazole (1.94 g., 0.011 mole) under nitrogen. The ice bath is removed and the reaction stirred for 11/2 hours before the bath is replaced and 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-(o-chlorophenyl)-quinazoline (3.22 g., 0.01 mole) in tetrahydrofuran (25 ml.) is added. The reaction is stirred for 18 hours at ambient temperature before the reaction is concentrated in vacuo. The residue is mixed with water, neutralized with sodium bicarbonate and extracted with methylene chloride. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give N-[6-chloro-4-hydroxy-4-(o-chlorophenyl)-3(4H)-quinazolinyl]-1,3-dioxo-2-isoindolinepropionamide.
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[O:38][C:34]4=[CH:35][CH:36]=[CH:37][C:33]4=[CH:32][CH:31]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[O:38]1[C:34]2=[CH:35][CH:36]=[CH:37][C:33]2=[CH:32][CH:31]=[C:30]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:20]1[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:39])=[O:3])=[CH:14][CH:13]=2)[N:19]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3-c3ccc4cccc-4o3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccccc2-c2ccc3cccc-3o2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-benzofur-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4-benzofur-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 8.04 (2H, d), 7.92 (2H, d), 7.58 (2H,dd), 7.26 (2H, m), 6.91(2H, d), 6.79 (2H, d), 4.17 (2H, t), 3.00 (2H, t) 2.39 (3H, s), 1.53 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[C:28]([CH3:29])=[CH:27][C:5]2[NH:6][C:7]([C:9]3[NH:10][N:11]=[C:12]4[C:17]=3[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][N:19]=3)[CH2:13]4)=[N:8][C:4]=2[CH:3]=1.[H][H]>C(O)C.[Pd].C([O-])([O-])=O.[Ca+2]>[CH3:1][C:2]1[C:28]([CH3:29])=[CH:27][C:5]2[NH:6][C:7]([C:9]3[NH:10][N:11]=[C:12]4[C:17]=3[CH2:16][CH2:15][N:14]([C:18]3[N:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[CH2:13]4)=[N:8][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc2nc(-c3[nH]nc4c3CCN(c3ccc([N+](=O)[O-])cn3)C4)[nH]c2cc1C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: Cc1cc2nc(-c3[nH]nc4c3CCN(c3ccc(N)cn3)C4)[nH]c2cc1C
Yield: 59.6 %

Procedure:
55 mg of Pd/CaCO3 10% are added to a solution of 545 mg of 3-(5,6-dimethyl-1H-benzimidazol-2-yl)-6-(5-nitropyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine in 60 ml of ethanol. After stirring for 15 hours at 35° C. under 3 bar of hydrogen, the reaction medium is brought back to ambient temperature, filtered through celite and then concentrated under reduced pressure. 300 mg of 6-[3-(5,6-dimethyl-1H-benzimidazol-2-yl)-2,4,5,7-tetrahydropyrazolo[3,4-c]pyridin-6-yl]-pyridin-3-ylamine are thus obtained in the form of a brown powder, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[N:15]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[N+:12]([C:3]1[CH:4]=[N:5][N:6]([CH2:7][C:8]([F:11])([F:10])[F:9])[C:2]=1[N:18]1[CH2:19][CH2:20][CH2:21][N:15]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16][CH2:17]1)([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=[N+]([O-])c1cnn(CC(F)(F)F)c1Br
Product: CC(C)(C)OC(=O)N1CCCN(c2c([N+](=O)[O-])cnn2CC(F)(F)F)CC1
Yield: 91 %

Procedure:
Following the procedure for Intermediate 22 starting from 5-bromo-4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole and tert-butyl 1,4-diazepane-1-carboxylate gave tert-butyl 4-(4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate as a pale yellow gum (197 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 8.19-8.12 (m, 1H), 4.76-4.66 (m, 2H), 3.65-3.49 (m, 4H), 3.32-3.23 (m, 4H), 1.92-1.78 (m, 2H), 1.52-1.47 (m, 9H).
Reaction SMILES: C(OC(N1CCC([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.N[C@@H:32]([CH2:41][OH:42])[C@H:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[OH:34]>>[OH:34][C@@H:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@@H:32]([NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[CH2:41][OH:42]
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(N[C@@H](CO)[C@@H](O)c1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using (1S,2S)-2-amino-1-phenyl-1,3-propanediol instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 409 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (1H, br. s.) 9.67 (1H, s) 7.99 (1H, d, J=5.37 Hz) 7.76 (1H, d, J=5.32 Hz) 7.45 (1H, d, J=8.64 Hz) 7.33 (1H, d, J=5.37 Hz) 7.27 (1H, dd, J=3.54, 2.22 Hz) 7.21-7.25 (2H, m) 7.10-7.21 (3H, m) 6.62 (1H, d, J=5.42 Hz) 6.36 (1H, dd, J=3.54, 1.73 Hz) 5.55 (1H, d, J=4.73 Hz) 4.90 (1H, dd, J=4.83, 3.17 Hz) 4.84 (1H, t, J=5.64 Hz) 4.07 (1H, dt, J=7.80, 5.30 Hz) 3.50 (1H, dt, J=10.58, 6.96 Hz) 3.40 (1H, dt, J=10.55, 5.34 Hz)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C:19]#[N:20])=[C:14]([CH3:28])[CH:13]=1.[O:29](C(OC(C)(C)C)=O)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=O.[BH4-].[Na+]>CCO.C1COCC1>[C:33]([O:32][C:30](=[O:29])[NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[CH:17][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:13][C:14]=1[CH3:28])[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COCCCc1ccccc1-c1ccc(C(C#N)Cc2cccnc2)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2cccnc2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[2′-(3-methoxypropyl)-3-methylbiphenyl-4-yl]-3-pyridin-3-ylpropanenitrile from step 2 (1 eq.) in EtOH/THF (3:1; 0.1M) at room temperature was added cobaltous chloride hexahydrate (CoCl2.6H2O; 2 eq.), followed by (BOC)2O (2 eq.) and finally sodium borohydride (10 eq.) portionwise. The final black mixture was stirred for 3 h at room temperature, quenched with HCl (1N). The pH was adjusted to 8 using saturated aqueous Na2CO3 and the resulting mixture was extracted several times with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 75% in 30 min) afforded the desired compound as a colorless oil.