Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2nc(COc3ccc4[nH]ccc4c3)ccc2c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 48.5 %

Procedure:
A mixture of 5-hydroxyindole (5.0 g), 2-chloromethylquinoline (7.0 g) and potassium carbonate (10.0 g) in N,N-dimethyl formamide (50 ml) was stirred at 80° C. for 4 hours. The cooled mixture was poured into water, and extracted with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, and concentrated in vacuo. The crude product was recrystallized from ethanol to yield the title product (5.0 g), m.p. 134°-137° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:13][C:14]1[C:15]([CH2:21][CH3:22])=[N:16][NH:17][C:18]=1[CH2:19][CH3:20]>CN(C=O)C>[CH3:6][O:5][C:3](=[O:4])[CH2:2][N:16]1[C:15]([CH2:21][CH3:22])=[C:14]([O:13][C:12]2[CH:23]=[C:24]([Cl:26])[CH:25]=[C:10]([Cl:9])[CH:11]=2)[C:18]([CH2:19][CH3:20])=[N:17]1
Reactant: CCc1n[nH]c(CC)c1Oc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nn(CC(=O)OC)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Yield: 23.9 %

Procedure:
Methyl bromoacetate (984 μL, 10 mmol) and then sodium hydride (60% dispersion in oil, 801 mg, 20.1 mmol) were added to a stirred solution of the pyrazole (2.6 g, 9.12 mmol) of Example 3 in dry N,N′-dimethylformamide (25 ml) at 0° C. under nitrogen. After stirring for 1 hour at 0° C. ice-water (100 ml) was added and the mixture was extracted with ether (3×50 ml). The combined ether layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate:pentane (20:80, by volume) to provide the title compound (780 mg) as a yellow oil which partly crystallised on standing.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([OH:27])([CH3:26])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[C:31]([C:2]2[C:3]([N:22]3[CH2:25][C:24]([OH:27])([CH3:26])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)[CH:32]=[N:33][CH:34]=1
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cncc(F)c1
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncc(F)c2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 128.1) and (5-fluoropyridin-3-yl)boronic acid. HPLC (Condition 4) tR=5.15 min, UPLC-MS (Condition 3) tR=1.04 min, m/z=463.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.29 (s, 3H) 3.57 (m, J=2.70 Hz, 4H) 5.48 (s, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.84 (d, J=8.99 Hz, 3H) 8.01-8.10 (m, 1H) 8.53 (s, 1H) 8.61 (d, J=2.74 Hz, 1H) 8.72-8.84 (m, 1H) 10.20 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH3:8].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Cl)nnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccccc2)nnc1Cl
Temperature: 80 °C

Procedure:
3,6-Dichloro-4-methylpyridazine (1.00 g, 6.1 mmol) was mostly dissolved in dioxane (22.5 mL) then added phenylboronic acid (0.82 g, 6.7 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.25 g, 0.31 mmol) and a solution of cesium carbonate (6.0 g, 18 mmol) in water (7.5 mL). The reaction mixture was heated at 80° C. for 6 hours. The reaction mixture was concentrated under vacuum and the remaining solid was triturated with water. The solid was collected on a glass frit, washing well with water. The sample was purified by flash chromatography eluting with 1:4 ethyl acetate/hexane to afford 3-chloro-4-methyl-6-phenylpyridazine as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Cl[C:23]([O:25][CH3:26])=[O:24]>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C#N)c2ccccc12
Reactant: COC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(C#N)c2ccccc12
Temperature: 0 °C

Procedure:
To a solution of 4-methyl-1-cyanonaphthalene (4.35 g, 25.9 mmol) in THF (100 mL) was cooled to −78° C. and treated with commercially available LDA (2 M, 60 mL). The reaction mixture was then warmed to 0° C. and maintained at 0° C. for 30 min. The resulting red-colored solution was cooled to −78° C. and methyl chloroformate (10 mL, 130 mmol) was added. The reaction mixture was stirred while warming to rt until the displacement was complete (4 h) and then quenched with sat'd NH4Cl. The THF layer was evaporated and extracted with EtOAc (3×20 mL). The EtOAc was dried over Na2SO4 and concentrated in vacuo to afford an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:13])=[C:9]([Br:12])[C:10]=1[CH3:11])=[O:5])C.B(Br)(Br)Br>C(Cl)Cl>[Br:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[NH:7][C:8]=1[CH3:13]
Reactant: CCOC(=O)c1[nH]c(C)c(Br)c1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1[nH]c(C(=O)O)c(C)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 150.5 %

Procedure:
To 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (900 mg) was added 10 mL of a solution of boron tribromide (1 M) in DCM. The mixture was stirred at RT for 16 hours (h), then heated under reflux for 5 h. To complete the reaction neat boron tribromide (1.5 mL) was added dropwise and refluxing was continued for 3 h. After cooling to RT the mixture was poured onto crushed ice and extracted with DCM. The combined organic phases were filtered through a plug of diatomaceous earth and concentrated under reduced pressure to give crude 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1.2 g) which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12][C:13]1[C:14]([C:19](O)=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Cl:12][C:13]1[C:14]([C:19]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=2)=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ncccc1Cl
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cn1)c1ncccc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
A mixture of 0.81 g of 2-amino-5-trifluoromethylpyridine, 0.78 g of 3-chloropicolinic acid, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at 60° C. for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.51 g of 3-chloro-N-(5-trifluoromethylpyridin-2-yl)picolinamide.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([Sn](CCCC)(CCCC)[C:82]1[CH:87]=[CH:86][N:85]=[N:84][CH:83]=1)CCC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:24]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:19]2[N:18]=[C:17]([C:4]3[C:5]([NH:8][C:9]4[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=4)=[N:6][CH:7]=[C:2]([C:82]4[CH:87]=[CH:86][N:85]=[N:84][CH:83]=4)[CH:3]=3)[N:22]=[C:21]([CH3:23])[N:20]=2)=[CH:27][CH:28]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(-c4ccnnc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 110 °C
Yield: 76.9 %

Procedure:
4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (190 mg, 0.325 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (15.51 mg, 0.033 mmol) (Strem Chemicals), tris(dibenzylideneacetone)dipalladium(0) (14.89 mg, 0.016 mmol) (Strem Chemicals) and 4-(tributylstannyl)pyridazine (156 mg, 0.423 mmol) (Synthonix) were weighed in a vial, purged with argon, and then treated with toluene (1.6 mL). The vial was sealed and heated at 110° C. in an oil bath for 21 h. The reaction mixture was treated with water and extracted with EtOAc (2×30 mL), washed with brine (20 mL) and dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography using an ISCO Combiflash Companion (12 g column, 20-100% EtOAc in hexanes) to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(pyridazin-4-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (157.1 mg, 0.250 mmol, 77% yield) as a bright yellow crystalline solid. m/z (ESI, +ve ion) 628.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.96 (1H, s); 9.44 (1H, d, J=1.4 Hz); 9.16 (1H, d, J=5.1 Hz); 9.10 (1H, d, J=2.7 Hz); 8.64 (1H, d, J=2.7 Hz); 8.30 (1H, d, J=2.5 Hz); 7.88 (1H, dd, J=8.7, 2.6 Hz); 7.58 (1H, dd, J=5.4, 2.6 Hz); 7.23 (2H, d, J=8.6 Hz); 7.17 (2H, d, J=8.8 Hz); 6.87 (4H, dd, J=12.7, 8.6 Hz); 6.75 (1H, d, J=8.8 Hz); 4.91 (2H, s); 4.83 (2H, s); 3.95 (3H, s); 3.81 (3H, s); 3.78 (3H, s); 2.62 (3H, s).
Reaction SMILES: C(N(CC)CC)C.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][OH:25])[CH2:22][S:23][C@H:18]12)=[O:15].[C:31]1(=[O:41])[O:36][C:34](=[O:35])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12>ClCCl>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][O:25][C:31](=[O:41])[C:32]3[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=3[C:34]([OH:36])=[O:35])[CH2:22][S:23][C@H:18]12)=[O:15]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)c3ccccc3C(=O)O)CS[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
In dichloromethane (25 ml) was dissolved 7β-(2-thienylacetamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt (3.60 g), followed by addition of phthalic anhydride (1.80 g). The mixture was stirred at room temperature for 2 hours, after which time it was treated in a manner similar to that described in Example 8. The procedure provided 7β-(2-thienylacetamido)-3-(2-carboxybenzoyloxy)methyl-3-cephem-4-carboxylic acid (3.44 g).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH:11]([CH2:14][CH2:15][CH3:16])[C:12]#[N:13].Cl>CC(C)=O.[Cl-].[Na+].O>[CH:2]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH:11]([CH2:14][CH2:15][CH3:16])[C:12]#[N:13])=[O:1]
Reactant: CCCC(C#N)c1sccc1C1OCCO1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCC(C#N)c1sccc1C=O
Temperature: 70 °C
Yield: 94.3 %

Procedure:
2.16 g (9.10 mmol) of 2-[3-(1,3-dioxolan-2-yl)-2-thienyl]-4-methylbutyronitrile was dissolved in 40 ml of acetone, 115 ml of 5N HCl was added, and the mixture was heated at 70° C. for 3 minutes. After completion of the reaction, brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated, to give a crude product. The crude product was subjected to 75 g of silica gel (ethyl acetate:hexane=1:2), to give 1.66 g (8.58 mmol, 94.3%) of the title compound as a brown oil.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([C:10]([OH:12])=O)[O:8][CH:9]=1)([OH:4])(=[O:3])=[O:2].S(Cl)([Cl:15])=O>>[S:1]([C:5]1[CH:6]=[C:7]([C:10]([Cl:15])=[O:12])[O:8][CH:9]=1)([OH:4])(=[O:3])=[O:2]
Reactant: O=C(O)c1cc(S(=O)(=O)O)co1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(S(=O)(=O)O)co1

Procedure:
4-Sulfo-2-furoic acid (0.1 mole) is stirred with 30 ml of thionyl chloride (SOCl2) for 40 minutes at 60° C. The reaction mixture is evaporated to dryness to give 4-sulfo-2-furoyl chloride.
Reaction SMILES: [N:1]([CH:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1)=[N+]=[N-]>CCOC(C)=O>[NH2:1][CH:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1
Reactant: N#Cc1ccc2c(c1)OCCC2N=[N+]=[N-]
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)OCCC2N

Procedure:
4-Azido-7-cyanochroman (Step D) (4.3 g, 21 mmol) was dissolved in EtOAc (200 mL) and purged with N2. Pd/C (10%, 0.6 g) was added and the reaction was purged with N2. The reaction was purged with H2 and rapidly stirred under a H2 atmosphere until consumption of starting material was complete by TLC analysis (approximately 1 h). The reaction was purged with N2, and filtered through Celite®. The Celite®was washed with MeOH. The solution was concentrated in vacuo to provide a residue which was purified by column chromatography (silica, 3% MeOH in CH2Cl2 plus 0.5% NH4OH) to provide the title compound. TLC Rf=0.3 (5% MeOH in CH2Cl2 plus 0.5% Et3N.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[NH:20][C:21](=[O:35])[CH2:22][CH:23]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH3:24])=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][C:6]=1[NH:20][C:21](=[O:35])[CH2:22][CH:23]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH3:24])([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2)cc1NC(=O)CC(C)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(CC(=O)Nc1cc(NC(=O)c2ccccc2)ccc1C(=O)O)c1ccc2ccccc2c1

Procedure:
Prepared analogously to Example 2 from 3-(naphth-2-yl)-butanoic acid-N-(2-methoxycarbonyl-5-benzoylamino-phenyl)-amide and sodium hydroxide solution in methanol.
Reaction SMILES: [Cl:1][C:2]1[C:12]([C:13](=[O:19])[C:14]2[S:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:5]2[CH2:6][CH:7]([CH:9]=O)[O:8][C:4]=2[C:3]=1[Cl:20].C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+].Cl>CO>[NH2:27][C:7]1([CH3:9])[CH2:6][C:5]2[CH:11]=[C:12]([C:13](=[O:19])[C:14]3[S:18][CH:17]=[CH:16][CH:15]=3)[C:2]([Cl:1])=[C:3]([Cl:20])[C:4]=2[O:8]1
Reactant: [BH3-]C#N
Reactant: O=CC1Cc2cc(C(=O)c3cccs3)c(Cl)c(Cl)c2O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CC1(N)Cc2cc(C(=O)c3cccs3)c(Cl)c(Cl)c2O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A stirred solution containing 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxaldehyde (3.27 g., 0.01 mole) and ammonium acetate (6.16 g., 0.08 mole) in methanol (100 ml.) is treated with sodium cyanoborohydride (0.72 g., 0.0115 mole). After stirring 24 hours at 25° C., the reaction is acidified (pH below 2) with concentrated hydrochloric acid and the methanol is distilled at reduced pressure. The residue is stirred in water (25 ml.) for 15 minutes and then the mixture is extracted with ether (two 10 ml. portions). The aqueous layer is made basic (pH above 10) with potassium hydroxide pellets, saturated with sodium chloride and extracted with ether (two 10 ml. portions). The ether extract is dried over magnesium sulfate and the ether distilled under reduced pressure to give 2-amino-methyl-6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:30])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:14][CH:13]=3)=[C:9]([C:27]#[N:28])[CH:8]=[N:7][N:6]2[CH:29]=1.[C:31]([NH:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39])(=[O:33])[CH3:32].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:31]([NH:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH:2][C:3]1[C:4]([CH3:30])=[C:5]2[C:10]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:16][CH:17]=3)=[C:9]([C:27]#[N:28])[CH:8]=[N:7][N:6]2[CH:29]=1)=[O:39])(=[O:33])[CH3:32]
Reactant: CC(=O)Nc1cccc(C(=O)O)c1
Reactant: COc1ccccc1Oc1ccc(Nc2c(C#N)cnn3cc(N)c(C)c23)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1ccc(Nc2c(C#N)cnn3cc(NC(=O)c4cccc(NC(C)=O)c4)c(C)c23)cc1
Yield: 69.5 %

Procedure:
A solution of 430F (42 mg, 0.10 mmol), 3-acetylamino-benzoic acid (27 mg, 0.15 mmol), PyBrop (73 mg, 0.15 mmol) and DIEA 70 μl, 0.40 mmol) in DMF (1 ml) was stirred at room temperature for 16 h under argon. Treated with EtOAc (30 ml), the mixture was washed with H2O (3×10 ml) and brine (10 ml), dried with Na2SO4. Removal of the solvent followed by flash chromatography of the residue on silica gel (50% EtOAc-CH2Cl2) gave 430 (38 mg, 70%) as a light yellow solid. It has a retention time of 6.16 min (standard LC1 method, 8 min run). MS Found: (M+H)+=547.2
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:24])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccccn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2ccccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.6 %

Procedure:
To a solution of [1-hydroxy-4-methyl-6-(pyridin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (75 mg, 0.23 mmol) in THF (4 mL) was added LiOH (20 mg, 0.48 mmol) in water (2 mL). The mixture was stirred at room temperature for 5 h and acidified by 1N HCl to pH 3. The mixture was concentrated and purified by HPLC affording the title compound (52 mg, 75%) as a white solid. 1H NMR (DMSO) δ 9.26 (m, 1H), 8.19 (s, 1H), 7.89 (m, 1H), 7.24 (s, 1H), 7.17 (m, 1H), 7.08 (m, 1H), 7.05 (m, 1H), 5.55 (d, 1H), 3.13 (d, 1H), 2.31 (s, 3H), 2.13 (m, 1H). MS found: (M+H)+=300.10.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:18])[N:4]([CH2:8][C:9]([NH:11][CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:19]([O:23][C:24]([NH:26][C@@H:27]([CH2:31][CH2:32]/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].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>[C:19]([O:23][C:24]([NH:26][C@H:27]([C:28]([NH:1][C:2]1[C:3](=[O:18])[N:4]([CH2:8][C:9]([NH:11][CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[O:29])[CH2:31][CH2:32]/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: CCC(CC)CNC(=O)Cn1cccc(N)c1=O
Reactant: CCOC(=O)/C=C/CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
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: CCOC(=O)/C=C/CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccn(CC(=O)NCC(CC)CC)c1=O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of 101 mg of 2-(3-amino-2-oxopyridin-1(2H)-yl)-N-(2-ethyl-butyl)acetamide (2a, 0.40 mmol) in 2.5 mL of DMF is provided. To this solution, a solution of 121 mg of (S,E)-2-(tert-butoxycarbonylamino)-7-ethoxy-7-oxohept-5-enoic acid (ZED775, 0.40 mmol), 152 mg of HATU (0.40 mmol) and 136 μL of DIPEA (2 eq) in 2.5 mL of DMF is added. By successive addition of DIPEA the pH value is adjusted to ca. 7. The reaction mixture is stirred at 40° C. for 1.5 hours and subsequently at RT overnight, before the solvent is removed in vacuo. The obtained residue is taken up in 75 mL of ethyl acetate and subsequently washed each three times with 10% citric acid, saturated NaHCO3 solution and brine. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo in dryness. Gel is obtained and it is suitable for further processing without further purification.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[NH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCl.C(Cl)Cl>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([NH:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[O:13])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: ClCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 108.9 %

Procedure:
A mixture of Cbz-Asp(OBut)-OH (3590 mg, 11.1 mmol), HCl+H-Gly-OBn (3360 mg, 16.6 mmol), EDCI (3180 mg, 16.6 mmol), HOBt (2250 mg, 16.6 mmol) and DIEA (2900 mg, 16.6 mmol) in dry CH2 Cl2 (50 mL) was stirred at r.t. for six hours. The reaction mixture was added CH2Cl2 (150 mL) and washed with 1N HCl (200 mL), saturated NaHCO3 aq. (200 mL) and brine (200 mL). The organic layer was passed through an inch of SiO2 layer and the SiO2 was washed with 1/9=AcOEt/CH2Cl2 (200 mL). The eluent was evaporated in vacuo to give clear oil (5690 mg, 100%): 1H NMR (300 MHz, CDCl3) δ 7.368 (s, 10H), 7.082 (t, 1H), 6.013 (d, J=7.8 Hz, 1H), 5.164 (s, 2H), 5.126 (s, 2H), 4.592 (d, J=6.6 Hz, 1H), 4.072 (d, J=5.7 Hz, 2H), 2.891 (dd, J=18.2, 4.5 Hz, 1H), 2.641 (dd, J=17.1, 6.3 Hz, 1H), 1.423 (s, 9H); 13C NMR (300 MHz, CDCl3) δ 171.0, 170.9, 169.3, 136.1, 135.2, 129.7, 128.6 (2C), 128.4, 128.3, 128.2, 81.9, 67.3, 67.2, 51.1, 41.5, 37.3, 28.0.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)/[CH:9]=[CH:10]/[C:11]#N)=[CH:2]1.[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:27]>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)/[CH:9]=[CH:10]/[CH:11]=[O:27])=[CH:2]1
Reactant: O=S(=O)(O)O
Reactant: N#C/C=C/c1cccc(-c2ccsc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=C/C=C/c1cccc(-c2ccsc2)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
0.4 g of the resulting nitrile compound was dissolved in 2 ml of toluene, and under cooling at -78° C., a 1.0M toluene solution(2 ml) of diisobutylaluminum hydride was added. The mixture was stirred at this temperature for 20 minutes, and then poured into ice-cold water. The resulting solution was acidified with a small amount of a 10% aqueous solution of sulfuric acid, and extracted with ethyl ether. The extract was worked up in a customary manner, and purified by medium-pressure liquid chromatography [silica gel column, hexane/ethyl acetate=9/1→7/1] to give 0.2 g of the captioned compound as a pale yellow oil.