Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C@@:7]2([OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]2[OH:13])=[CH:5][CH:4]=[N:3]1.CN(C1C=CC=CN=1)C.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:6]([C@@:7]23[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]2[O:13][C:24](=[O:25])[O:14]3)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1[C@@]1(O)CCCC[C@@H]1O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Product: Cn1nccc1[C@@]12CCCC[C@@H]1OC(=O)O2
Reaction time: 3 h
Yield: 86.1 %

Procedure:
A solution of the (1S,2S)-1-(1-methyl-1H-pyrazol-5-yl)cyclohexane-1,2-diol (1.21 g, 6.17 mmol) prepared in Example 123c, dimethylaminopyridine (75.3 mg, 0.62 mmol) and carbonyldiimidazole (2.0 g, 12.3 mmol) in toluene (20 mL) was stirred for 3 hours under heated reflux. To the reaction solution, carbonyldiimidazole (1.0 g, 6.17 mmol) was added, and the reaction solution was further stirred for 3 hours under heated reflux. To the reaction solution, carbonyldiimidazole (0.50 g, 3.08 mmol) was further added, and the reaction solution was stirred for 3 hours under heated reflux. After allowing to cool, the reaction solution was vacuum concentrated, and the residue was purified with silica gel chromatography (hexane/ethyl acetate=7:3) to yield the title compound (1.18 g, 86%) as a colorless solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:16]1[CH2:20][CH:19]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:18][C:17]1=[O:30])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:31](=[O:33])[CH3:32].[Cl-].[Na+]>O1CCCC1>[CH2:9]([N:16]1[CH2:20][CH:19]([CH2:21][O:22][Si:23]([C:26]([CH3:27])([CH3:29])[CH3:28])([CH3:25])[CH3:24])[CH:18]([CH:31]([OH:33])[CH3:32])[C:17]1=[O:30])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC=O
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(=O)N(Cc2ccccc2)C1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)C1C(=O)N(Cc2ccccc2)CC1CO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of lithium diisopropylamide (4.7×10-3 mole) in tetrahydrofuran was added a solution of 1-benzyl-4-(t-butyldimethylsilyloxymethyl)-2-oxopyrrolidine (1.0 g) in tetrahydrofuran (20 ml) at -78° C. under nitrogen. The mixture was stirred for 30 minutes at -78° C., and acetaldehyde (5 ml) was added to the reaction mixture. After stirring for 30 minutes at -78° C., the solution was poured into ice water, and sodium chloride was added to saturate the aqueous phase. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over magnesium sulfate, and concentrated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (3:1~2:1, V/V) to give 1-benzyl-3-(1-hydroxyethyl)-4-(t-butyldimethylsilyloxymethyl)-2-oxopyrrolidine (1.01 g).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[O:10][CH:11]1[CH:15]([CH:16]=O)[CH2:14][CH:13](OC)O1>CC(O)=O>[I:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:13]=[CH:14][C:15]([CH:11]=[O:10])=[CH:16]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: COC1CC(C=O)C(OC)O1
Solvent: CC(=O)O
Product: O=Cc1ccn(-c2ccc(I)cc2)c1
Yield: 100 %

Procedure:
A solution of 4-iodoaniline (0.684 g, 3.12 mmol) and 2,5-dimethoxy-3-tetrahydrofurancarboxaldehyde (90%, 0.492 mL, 3.12 mmol) in HOAc (10 mL) was stirred at 90° C. for 1 h. The solvent was removed in vacuo. The residue was partitioned between EtOAc and H2O. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, and concentrated in vacuo to give 1-(4-iodophenyl)-1H-pyrrole-3-carbaldehyde (0.927 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:16])([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][CH:8]=1)[CH2:5][OH:6].[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:21]Br>CN(C)C=O>[CH3:3][C:4]([CH3:16])([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH3:15])=[CH:11][CH:12]=1)[CH2:5][O:6][CH2:21][C:20]1[CH:23]=[CH:24][C:25]([F:26])=[C:18]([Br:17])[CH:19]=1
Reactant: CCOc1ccc(C(C)(C)CO)cc1
Reactant: Fc1ccc(CBr)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(C)(C)COCc2ccc(F)c(Br)c2)cc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 41.6 %

Procedure:
657 Milligrams of sodium hydride (as 60% oil suspension) was added to 10 ml of dimethylformamide, and 3.19 g of 2,2-dimethyl-2-(4-ethoxyphenyl)ethanol was added dropwise. Thereafter, the reaction solution was warmed to 50° C. and stirred for 10 minutes, and 4.0 g of 3-bromo-4-fluorobenzyl bromide was added dropwise thereto at 20° C. After completion of the dropwise addition, stirring was continued at 50° C. for further 5 hours, and the reaction solution was then poured into a 5% hydrochloric acid/ice water mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous sodium chloride liquor and dried over anhydrous magnesium sulfate. After removing the solvent by evaporation, the residual oil was purified by column chromatography on a column packed with 60 g of silica gel to obtain 2.37 g of 3-bromo-4-fluorobenzyl 2,2-dimethyl-2-(4-ethoxyphenyl)ethyl ether. 1H-NMR spectrum (CDCl3, TMS). δ 7.4-6.5 (7H, m), δ 4.30 (2H, s), δ 3.99 (2H, q), δ 3.34 (2H, s), δ 1.36 (3H, t), δ 1.30 (6H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([O:20]C2CCCCO2)[CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCc1cccc(OC2CCCCO2)c1)OCc1ccccc1
Solvent: CCO
Product: O=C(NCCc1cccc(O)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 16.8 g. (47.3 mMol) {3-[2-(benzyloxycarbonylamino)-ethyl]-phenyl}-tetrahydropyranyl ether, 80 ml. ethanol and 3 g. Amberlyst is stirred for 2 hours at ambient temperature, then filtered and evaporated. The last traces of ethanol are removed by blowing in air with the application of a slight vacuum at 70° C. The product is obtained in the form of a colourless oil. Yield quantitative.
Reaction SMILES: [I-].O[C@@H]([C@H:5]1[C:11](=[O:12])[N:10]2[C@@H:6]1[C@@H:7](C)[C:8]([S:26][C@@H:27]1[CH2:31][N:30](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H:29]([CH2:45][N+:46]3[CH:50]=[CH:49][N:48]([CH3:51])[CH:47]=3)[CH2:28]1)=[C:9]2[C:13]([O:15]CC1C=CC([N+]([O-])=O)=CC=1)=[O:14])C.[H][H]>O1CCCC1.P([O-])([O-])([O-])=O.[OH-].[OH-].[Pd+2]>[CH3:51][N:48]1[CH:49]=[CH:50][N+:46]([CH2:45][C@@H:29]2[CH2:28][C@H:27]([S:26][C:8]3[CH2:7][CH:6]4[N:10]([C:11](=[O:12])[CH2:5]4)[C:9]=3[C:13]([O-:15])=[O:14])[CH2:31][NH:30]2)=[CH:47]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C[n+]4ccn(C)c4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Product: Cn1cc[n+](C[C@@H]2C[C@H](SC3=C(C(=O)[O-])N4C(=O)CC4C3)CN2)c1
Yield: 77.1 %

Procedure:
A solution of 4-nitrobenzyl (4R,5S,6S)-6-[(lR)-1-hydroxyethyl]-4-methyl-3-[(2S, 4S)-2-(3-methyl-1-imidazolio)methyl-1-4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-7-oxo -1-azabicyclo-3.2.0]hept-2-ene-2-carboxylate iodide (0.79 g) obtained in Example 3-1) in a mixture of tetrahydrofuran (50 ml) and 0.1 M phosphate buffer (pH 6.5) (50 ml) was stirred in the presence of 20 % palladium hydroxide on carbon (0.3 g) under atmospheric pressure of hydrogen at ambient temperature for 5 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to remove the tetrahydrofuran. The residual solution was washed with ethyl acetate (50 ml ×2) and the organic solvent was removed by evaporation. The equeous solution was subjected to a column chromatography on nonionic adsorption resin, "Diaion HP-20" (50 ml), washed with water, eluted with a mixture of acetone and water (1:99 V/V). The fractionscontaining the desired compound were collected and lyophilized to give (4R,5S,6S)-6-[(lR)-1-hydroxyethyl]4-methyl-3-[(2S,4S)-2-(3-[(2S,4S)-2-(3-methyl-1-imidazolio)methylpyrrolidin-4-yl]thio-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylate (0.25 g).
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6](=O)[CH2:7][CH2:8][N:9]([CH3:36])[C:10](=[O:35])[CH2:11][CH2:12][O:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([N:20]([CH3:34])[S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:16][CH2:15]1)C.C1COCC1.CO>O>[OH:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:36])[C:10](=[O:35])[CH2:11][CH2:12][O:13][C@H:14]1[CH2:15][CH2:16][C@H:17]([N:20]([CH3:34])[S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)(=[O:22])=[O:23])[CH2:18][CH2:19]1
Reactant: CCOC(=O)CCN(C)C(=O)CCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCCO)C(=O)CCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
181 mg (4.78 mmol, 10 eq) of NaBH4 were added portionwise to a solution of 250 mg (0.48 mmol) of trans-3-[methyl-(3-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionyl)-amino]-propionic acid ethyl ester in 6 mL of a mixture of THF:MeOH (1:1) at 0° C. The reaction mixture was stirred at RT for 4 h. Water was added and the reaction was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography with a gradient of CH2Cl2:MeOH 98:2 to 95:5 to yield 55 mg (24%) of trans-N-(3-hydroxy-propyl)-N-methyl-3-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionamide as colorless oil, MS: 481(MH+).
Reaction SMILES: Cl.[C:2]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])([O-:19])=[O:18]>C(Cl)Cl>[C:5]([O:4][C:2](=[O:3])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N+:17]([O-:19])=[O:18])(=[O:27])=[O:28])([CH3:6])([CH3:7])[CH3:8]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.2 %

Procedure:
To a stirred solution of N-Boc 1,6-diaminohexane hydrochloride (1.51 g, 6 mmol) and triethyle amine (1.31 g, 13 mmol) in 50 mL methylene chloride was added 2-Nitrobenzenesulfonyl chloride (1.326 g, 6 mmol). The reaction mixture was stirred for 6 h at room temperature, quenched with brine, and extracted with methylene chloride (2×50 mL). The organic layer was washed with brine (a saturated solution of sodium chloride in water, unless otherwise specified), dried over anhydrous sodium sulfate, and concentrated in vacuo to yield the titled compound as yellow oil (2.1 g, 87%).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[C:12]3=[O:26])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Br[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[CH3:1][C:2]1([CH3:27])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:17])([CH3:18])[N:13]([CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[C:12]3=[O:26])=[CH:8][CH:9]=2)[N:4]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:3]1
Reactant: BrCc1ccccn1
Reactant: CC1(C)CNc2cc(N3C(=O)N(Cc4ccncc4)C(C)(C)C3=O)ccc21
Product: CC1(C)CN(Cc2ccccn2)c2cc(N3C(=O)N(Cc4ccncc4)C(C)(C)C3=O)ccc21

Procedure:
prepared as described for example 96 by reaction of 3-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethyl-1-pyridin-4-ylmethylimidazolidine-2,4-dione with 2-bromomethylpyridine
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:11][O:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH:24]([NH:23][S:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22])[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)CCCC=NS(=O)C(C)(C)C
Reactant: COc1cccc(OC)c1I
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A cooled (−78° C.) yellow solution of commercially available 2-iodo-1,3-dimethoxybenzene (9.930 g; 37.60 mmol) in anh. THF (170 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (23.5 ml; 37.60 mmol). The resulting slightly yellow solution was further stirred at −78° C. for 15 min. A yellow solution of methyl 5-((tert-butylsulfinyl)imino)pentanoate (5.850 g; 25.07 mmol) in anh. THF (12 ml) was then added dropwise to the cooled reaction mixture, and stirring at −78° C. was continued for 45 min. The resulting yellow reaction mixture was treated successively with aq. sat. NH4Cl (80 ml), Et2O (250 ml) and water (75 ml). The separated yellow organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded methyl 5-(2,6-dimethoxyphenyl)-5-(1,1-dimethylethylsulfinamido)pentanoate as a yellow oil. LC-MS (conditions B): tR=0.85 min.; [M+H]+: 372.34 g/mol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CN(C)C=O>[Cl:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: N#CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(OCCCCl)cc1

Procedure:
Following the procedure described in example 1§E, but starting from 4-hydroxyphenylacetonitrile (4.65 g), potassium carbonate (24 g) and 1-bromo-3-chloropropane (17.3 mL) in N,N-dimethylformamide (23 mL) affords 6.86 g of 4-(3-chloropropoxy)phenylacetonitrile as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([CH2:13][CH3:14])[C:10](O)=[O:11])=[C:4]([N+:15]([O-])=O)[CH:3]=1.Cl.C(O)C.O.O.[Sn](Cl)Cl>>[CH2:13]([CH:9]1[NH:8][C:5]2[C:4](=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH:15][C:10]1=[O:11])[CH3:14]
Reactant: CCC(Nc1ccc(F)cc1[N+](=O)[O-])C(=O)O
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCC1Nc2ccc(F)cc2NC1=O
Temperature: 78 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
The heterogeneous mixture of 2-(4-fluoro-2-nitrophenylamino)butanoic acid (181.7 g, 750.0 mmol), 3 N aq. HCl (750.0 ml, 2250 mmol), and ethanol (1923 ml, 750.0 mmol) in 5-L three neck round bottom flask was added Tin(II) chloride dihydrate (507.7 g, 2250 mmol) and the organe mixture was heated at 78° C. with stirring using an overhead stirrer for 4 h ([Note 1]: The orange heterogeneous mixture became an orange homogeneous mixture and the orange color changed to a red color over ˜2 hour). After 4 h, the mixture was cooled to rt and concentrated under reduced pressure to remove ethanol, and left at rt for 48 h. The resulting yellow precipitate was collected by filtration and washed with water (500 mL). The yellow solid was suspended in ice water (1 L) and the mixture was adjusted ˜pH 13 with KOH (˜250 g). The heterogeneous mixture was extracted with DCM (1 L×3). The combined organic layers were washed with water (1 L×1) and brine (1 L×1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 3-ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one (60.92 g, 41.8% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.26 (s, 1H), 6.68 (dd, J=8.6, 5.5 Hz, 1H), 6.47-6.61 (m, 2H), 5.95 (d, J=1.2 Hz, 1H), 3.62 (ddd, J=6.7, 5.0, 2.0 Hz, 1H), 1.50-1.72 (m, 2H), 0.92 (t, J=7.4 Hz, 3H), Mass Spectrum (ESI) m/e=195.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[K+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: F[B-](F)(F)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(CCc2ccccc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.299 mmol), potassium trifluoro(phenethyl)borate (76 mg, 0.359 mmol) and PdCl2(PPh3)2 (42.0 mg, 0.060 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2.0 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 3 hours. The reaction mixture was subsequently diluted with water (5 mL) and extracted with EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-3-oxo-4-phenethyl-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was treated with TFA (4 mL) at room temperature for 1 hour to remove the protecting groups. TFA was subsequently evaporated from the reaction mixture. The residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with a gradient of 20-55% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a light yellow solid (42 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58-1.75 (m, 1H), 1.95-2.17 (m, 1H), 2.83-3.04 (m, 2H), 3.16-3.32 (m, 1H), 3.32-3.46 (m, 1H), 3.47-3.61 (m, 1H), 3.66 (d, J=11.37 Hz, 1H), 3.83-4.03 (m, 2H), 4.22-4.39 (m, 3H), 6.99 (d, J=5.05 Hz, 1H), 7.09-7.33 (m, 5H), 7.93 (br s, 2H), 8.32 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H23FN4O2, 371. found, 371.
Reaction SMILES: [C:1]([C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([C:30](=[O:43])[CH2:31][O:32][C:33]1[C:38]([F:39])=[C:37]([F:40])[CH:36]=[C:35]([F:41])[C:34]=1[F:42])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CO.C1COCC1.[BH4-].[Na+]>[NH4+].[Cl-]>[C:1]([C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([CH:30]([OH:43])[CH2:31][O:32][C:33]1[C:34]([F:42])=[C:35]([F:41])[CH:36]=[C:37]([F:40])[C:38]=1[F:39])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)C(=O)OCc1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)C(=O)OCc1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of N-[(carbobenzyloxycarbonyl)valinyl]-3-amino-4-oxo-5-(2,3,5,6-tetrafluorophenyloxy)-pentanoic acid, tert-butyl ester (6.18 g, 10.57 mmol) in 1:1 MeOH/THF (100 ml) was cooled to 0° C. and NaBH4 (1.20 g, 31.72 mmol) was added and stirred for 2 hours. The reaction was diluted with saturated NH4Cl and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the titled product as a white solid (6.14 g, 10.46 mmol, 98%). MS C28H34N2O7, [M+Na]+ =609, [M−H]−=585.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=[C:12]2S)[CH2:3]1.[N+:21]([O-:24])([OH:23])=[O:22].[OH-].[Na+]>>[N+:21]([O-:24])([OH:23])=[O:22].[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=[CH:12]2)[CH2:3]1
Reactant: COC(=O)c1cnc(S)n1C1CC(C)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Product: COC(=O)c1cncn1C1CC(C)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
A mixture of 10 parts of methyl 1-(2,3-dihydro-3-methyl-1H-inden-1-yl)-2-mercapto-1H-imidazole-5-carboxylate and 120 parts of a nitric acid solution 30% is stirred for 30 minutes at room temperature (intense reaction). The reaction mixture is poured into crushed ice and treated with a sodium hydroxide solution. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is converted into the nitrate salt in 2-propanone and 2,2'-oxybispropane. The salt is filtered off and dried, yielding 6.8 parts (62.6%) of methyl 1-(2,3-dihydro-3-methyl-1H-inden-1-yl)-1H-imidazole-5-carboxylate mononitrate; mp. 140.3° C. (compound 2.35).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH3:19])=[N:17][C:16]([CH3:20])=[C:15]([C:21](=[O:23])[NH2:22])[N:14]=2)=[CH:9][C:8]=1[F:24])(=O)=O.[Cl:27][C:28]1[CH:29]=[C:30]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[CH:31]=[CH:32][C:33]=1B1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[Li+]>COCCOC.CO.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[C:21]([C:15]1[N:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:33]3[CH:32]=[CH:31][C:30]([CH2:43][C:44]([O:46][CH3:47])=[O:45])=[CH:29][C:28]=3[Cl:27])=[C:8]([F:24])[CH:9]=2)[C:18]([CH3:19])=[N:17][C:16]=1[CH3:20])(=[O:23])[NH2:22]
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(Cl)c1
Reactant: Cc1nc(C)c(-c2ccc(OS(=O)(=O)C(F)(F)F)c(F)c2)nc1C(N)=O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (68.2 g, 83.5 mmol) was added in one go to a stirred mixture, which had been degassed for 30 minutes with nitrogen, of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl trifluoromethanesulfonate (Intermediate 31-6; 730 g, 1856 mmol), methyl 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (Intermediate 31-3; 1164 g, 1948 mmol) (52% strength by proton NMR), tripotassium phosphate (690 g, 3248 mmol) and lithium chloride (138 g, 3248 mmol) in DME (5 L), methanol (2.5 L) and water (2.5 L) at 20° C. The reaction was heated to reflux and stirred under a nitrogen atmosphere overnight. The reaction was cooled to room temperature. The organic layer was filtered through a glass sinter. Ethyl acetate (10.0 L) and 30% brine/water (5.0 L) were added. The aqueous layer was separated and extracted with ethyl acetate (5.0 L), the organic layers were combined, washed with 50% brine/water (10.0 L), dried (magnesium sulphate), filtered and the solvents removed in vacuo. The crude product was dissolved in dichloromethane and then chromatographed on silica (5 Kg of Merck lichro prep silica 15-25 μm, 200 mm diameter column), eluting with a solvent gradient of 0-70% ethylacetate/isohexane. Pure fractions were evaporated to dryness to afford methyl 2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]acetate (389 g, 49%) as a white solid.