Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C:10]1[CH:18]=[CH:17][C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=1)=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[ClH:26]>O1CCOCC1>[NH2:1][C@H:2]([C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[CH:17][CH:18]=1)=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[ClH:26]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCC[C@H](N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
BocNle-pNA (prepared in 1 (1); 2.96 g) was dissolved into a solution of 4N—HCl in dioxane (30 ml). After stirring the obtained solution for 1 hour at room temperature, dioxane was distilled off under reduced pressure and then by adding toluene (30 ml). The reaction mixture was crystallized in ether to give Nle-pNA.HCl (2.08 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:9]2[NH:10][C:11](=[O:18])[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=3[C:8]=2[C:7]([C@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[N:6]1)#N.C(O)(=[O:36])C>[Ni]>[O:18]=[C:11]1[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=2[C:8]2[C:7]([C@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])=[N:6][N:5]([CH2:4][CH2:3][CH:1]=[O:36])[C:9]=2[NH:10]1
Reactant: N#CCCn1nc([C@H]2CCCN2C(=O)OCc2ccccc2)c2c3c(c(=O)[nH]c21)CCCC3
Reactant: CC(=O)O
Agent: [Ni]
Product: O=CCCn1nc([C@H]2CCCN2C(=O)OCc2ccccc2)c2c3c(c(=O)[nH]c21)CCCC3
Reaction time: 6 h

Procedure:
A solution of Example 72A (2.0 g, 4.5 mmol) in acetic acid (10 ml) was treated with Raney nickel (200 mg) at rt. The reaction mixture was stirred under hydrogen for 6 h. Solid material was filtered off and the filtrate was concentrated. The residue was separated by flash chromatography to give Example 77A. Yield: 0.5 g (25%). MS (DCI): m/z 449 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[N:24][CH:23]=[CH:22]3)(=[O:18])=[O:17])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:29](I)[CH2:30][CH2:31][CH3:32]>CN(C)C=O>[C:3]([O:7][C:8]([N:10]([C@H:11]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[N:24][CH:23]=[CH:22]3)(=[O:18])=[O:17])[CH2:12]1)[CH2:29][CH2:30][CH2:31][CH3:32])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCCCI
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2ccc3cnccc3c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN(C(=O)OC(C)(C)C)[C@H]1CCN(S(=O)(=O)c2ccc3cnccc3c2)C1
Reaction time: 0.5 h

Procedure:
265 mg of sodium hydride was added with stirring under ice cooling to an N,N-dimethylformamide (10 mL) solution of 500 mg of (S)-6-{3-(tert-butoxycarbonylamino)pyrrolidin-1-ylsulfonyl}isoquinoline obtained in Step 1 of Example 10. After stirring in this state for 30 minutes, 0.8 mL of butyl iodide was added dropwise to the reaction solution, and the mixture was further stirred for 30 minutes for reaction. The reaction was terminated by the dropwise addition of water in small portions under ice cooling to the reaction solution. Then, 50 mL of water was added thereto, followed by three extractions with 50 mL of ether. The combined organic layer was washed with 100 mL of saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (acetone:hexane=1:1) to obtain 350 mg of the compound of interest as a colorless oil (61%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(#N)C.C(=O)([O-])O.[Na+]>[O:17]=[C:16]1[C:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]2[N:36]=[CH:37][N:38]=[C:12]2[N:11]1[C@H:8]1[CH2:7][CH2:6][C@H:5]([O:4][CH2:3][CH:2]=[O:1])[CH2:10][CH2:9]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCO)CC2)c2ncnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4′-({4-[trans-4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.19 g) in acetonitrile (20 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.27 g) under ice-cooling, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=65/35→40/60 (volume ratio)] to give the title compound as a colorless amorphous compound (739 mg, 63%).
Reaction SMILES: C1C=CC([C@@H](N)C(O)=O)=CC=1.[CH3:12][C:13]1([CH3:36])[S:17][C@@H:16]2[C@H:18]([NH:21][C:22]([C@H:24]([NH2:32])[C:25]3[CH:26]=[CH:27][C:28](O)=[CH:29][CH:30]=3)=[O:23])[C:19](=[O:20])[N:15]2[C@H:14]1[C:33]([OH:35])=[O:34].CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.CC(OCC1CS[C@@H]2[C@H](N)C(=O)N2C=1C(O)=O)=O>>[CH3:36][C:13]1[CH2:12][S:17][C@@H:16]2[C@H:18]([NH:21][C:22]([C@H:24]([NH2:32])[C:25]3[CH2:26][CH:27]=[CH:28][CH2:29][CH:30]=3)=[O:23])[C:19](=[O:20])[N:15]2[C:14]=1[C:33]([OH:35])=[O:34]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccc(O)cc3)C(=O)N2[C@H]1C(=O)O
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: N[C@@H](C(=O)O)c1ccccc1
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)C3=CCC=CC3)[C@H]2SC1

Procedure:
As an example, D-(-)-(4-hydroxyphenyl)-glycine and D-(-)-phenylglycine are key intermediates in the industrial synthesis of amoxycillin and ampicillin respectively; while D-(-)-2-amino-2-(1,4-cylcohexadien-1-yl)acetic acid may be conveniently be employed in the acylation of 7-amino-cephalosporanic acid to give cefradin.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=O.[CH3:12][CH:13]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][PH:15](=[O:17])[OH:16]>C1(C)C(C)=CC=CC=1>[O:3]=[C:1]1[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([P:15]([CH2:14][CH:13]([CH3:12])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:16])[OH:17])[O:7]1
Reactant: O=Cc1ccccc1C(=O)O
Reactant: CC(C[PH](=O)O)CC(C)(C)C
Solvent: Cc1ccccc1C
Product: CC(CC(C)(C)C)CP(=O)(O)C1OC(=O)c2ccccc21
Yield: 55.4 %

Procedure:
A mixture of 15 grams (0.1 moles) of 2-carboxybenzaldehyde and 17.82 grams of 2,4,4-trimethylpentyl phosphinic acid in 100 mL of xylene is heated to reflux and 1.8 mL of water is collected by azeotropic distillation using a Dean-Stark receiver. The xylene solvent is removed in vacuo and the residue is crystallized with a mixture of 50 mL of ethyl acetate and 100 mL heptane to yield 17.2 grams (56% yield) (3-oxo-1,3-dihydro-isobenzofuran-1-yl)-(2,4,4-trimethylpentyl)-phosphinic acid as an off-white powder, mp 117-121° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C(O)C.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>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8](=[O:10])[CH3:9])=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(=O)c1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CC(=O)c1ccccc1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of 1-(2-bromophenyl)ethanone (3.1 g, 15.57 mmol)-4-chlorophenylboronic acid (2.92 g), (Ph3P)2PdCl2 (bis(triphenylphosphine)palladium(II) dichloride) (1.202 g) and Na2CO3 (3.30 g) in dimethoxyethane-ethanol-water (7:2:3, 50 mL) was heated at 100° C. for 3 hours and concentrated. The concentrate was suspended in dichloromethane (30 mL) and the insoluble material was removed by filtration. The filtrate was loaded onto a silica gel column, eluted with 0%-50% dichloromethane in hexane to provide the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][C:46]1[N:47]=[C:48]([CH:62]([CH3:64])[CH3:63])[N:49](COCC[Si](C)(C)C)[C:50]=1[C:51](O)=[O:52].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:51]([C:50]2[NH:49][C:48]([CH:62]([CH3:63])[CH3:64])=[N:47][C:46]=2[CH3:45])=[O:52])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: Cc1nc(C(C)C)n(COCC[Si](C)(C)C)c1C(=O)O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(C)C)[nH]c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
HATU (103 mg, 0.27 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (56.2 mg, 0.18 mmol), 4-methyl-2-(1-methylethyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (54 mg, 0.18 mmol) and diisopropylethylamine (47 uL, 0.27 mmol) in DMF (1 mL). The reaction mixture was stirred at RT overnight and the solvent was removed under vacuum. The residue was dried in vacuo and the residue was treated with TFA (0.5 mL) in DCM (1.0 mL) at RT and stirred overnight. Neutralized with saturated NaHCO3 and extracted with 10% MeOH in DCM. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (0-5% 2M NH3 solution of MeOH in DCM) and HPLC to afford the title compound (50 mg, 60%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.68 (1H, br. s.) 7.56 (1H, br. s.) 7.31-7.40 (2H, m) 7.23 (1H, s) 7.14 (1H, d, J=1.3 Hz) 7.02 (1H, s) 4.62 (2H, d, J=6.4 Hz) 2.96 (1H, dt, J=13.7, 6.8 Hz) 2.56 (3H, s) 1.30 (6H, d, J=7.0 Hz). LCMS: m/z 461 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7](C)=[N:6][C:5]=1[N:11]1[CH2:14][CH:13]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:17]=3[N:16]=2)[CH2:12]1.O.[Li+].[OH-].Cl>CO>[Cl:24][C:22]1[CH:21]=[CH:20][C:18]2[NH:19][C:15]([CH:13]3[CH2:12][N:11]([C:5]4[N:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:25])=[O:2])[CH2:14]3)=[N:16][C:17]=2[CH:23]=1
Reactant: COC(=O)c1ccc(C)nc1N1CC(c2nc3cc(Cl)ccc3[nH]2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccnc1N1CC(c2nc3cc(Cl)ccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
A solution of methyl 2-[3-(5-chloro-1H-benzoimidazol-2-yl)-azetidin-1-yl]-nicotinic acid methyl ester (1.6 g, 4.6 mmol) and water (10 mL) in MeOH (10 mL) at RT was treated with LiOH (414 mg, 9.87 mmol). The mixture was stirred at RT overnight, and made acidic with a 10% HCl solution. The resulting solution was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was triturated with hexanes and washed several times with hexanes to give the desired carboxylic acid as a white crystalline solid (1.1 g, yield 71%).
Reaction SMILES: CS(C)=O.[OH:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:11][CH2:10]1.[NH2:27][OH:28]>O>[OH:28][N:27]=[C:23]([NH2:24])[C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][CH2:15][CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][CH2:6][OH:5])[CH2:14][CH2:13]2)=[CH:26][CH:25]=1
Reactant: NO
Reactant: N#Cc1ccc(OCCCC2CCN(CCCO)CC2)cc1
Solvent: CS(C)=O
Solvent: O
Product: NC(=NO)c1ccc(OCCCC2CCN(CCCO)CC2)cc1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
To a dimethylsulfoxide (43 mL) suspension of 4.27 g of 4-{3-[1-(3-hydroxypropyl)-4-piperidinyl]propoxy}benzonitrile was added 4.32 mL of a 50% hydroxylamine aqueous solution at room temperature, which was then stirred at 40 to 50° C. for 3 hours and 30 minutes. The reaction mixture was cooled down to room temperature, to which 50 mL of water was then added dropwise over a period of 10 minutes, followed by stirring at room temperature for 30 minutes. The precipitate was collected by filtration and washed with water to provide 4.59 g of N′-hydroxy-4-{3-[1-(3-hydroxypropyl)-4-piperidinyl]propoxy}benzamidine as white solid form.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.[Li].CON(C)[C:25]([C:27]1[S:28][C:29]([Cl:32])=[CH:30][CH:31]=1)=[O:26].[Cl-].[NH4+]>C1COCC1>[Cl:20][C:16]1[CH:15]=[C:14]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:25]([C:27]4[S:28][C:29]([Cl:32])=[CH:30][CH:31]=4)=[O:26])[CH:3]=3)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2n1
Reactant: CON(C)C(=O)c1ccc(Cl)s1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)s3)ccc2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
To a solution of 6-bromo-4-(3-chloro-phenyl)-2-methoxy-quinoline (500 mg, 1.43 mmol) in THF (2 ml) was added n-buthyl lithium (2.5 M in hexane, 0.63 ml, 1.58 mmol) dropwise at −78° C. under an atmosphere of dry N2. After stirring at −78° C. for 30 minutes, a solution of 5-chloro-thiophene-2-carboxylic acid methoxy-methyl-amide (440 mg, 2.15 mmol) in THF (1 ml) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 15 hours. To the mixture was added a saturated aqueous solution of ammonium chloride at 0° C. THF was removed from the resulting heterogeneous solution. The aqueous mixture was extracted with chloroform (CHCl3). The organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to yield the crude product. It was chromatographed on silica gel with MeOH-CHCl3NH4OH (2:98:0.2 to 5:95:0.5) as eluents to afford the title compound of example 40A (273.5 mg, 46% yield).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[O:17]1[CH2:22][CH2:21][CH:20](OS(C)(=O)=O)[CH2:19][CH2:18]1>CN1C(=O)CCC1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH:20]2[CH2:21][CH2:22][O:17][CH2:18][CH2:19]2)=[CH:4][C:3]=1[CH3:10]
Reactant: CS(=O)(=O)OC1CCOCC1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cc1cc(OC2CCOCC2)cc(C)c1Br
Temperature: 140 °C
Reaction time: 4 h

Procedure:
Reaction under argon atmosphere: 3.0 g (15 mmol) of 4-bromo-3,5-dimethylphenol are dissolved in 20.0 ml NMP. 20.0 g (61.4 mmol) of cesium carbonate and 11.0 g (61.0 mmol) of methanesulfonic acid tetrahydropyran-4-yl ester are added. The reaction mixture is stirred at 140° C. for 4 h. The solvent is evaporated. The residue is diluted with EtOAc and washed with water and brine. The organic layer is dried and the solvent is evaporated. The residue is chromatographed on silica gel (CH/EtOAc=99/1→60/40) to give the title compound. Yield: 4.0 g; LC (method 1): tR=1.15 min; Mass spectrum (ESI+): m/z=285 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:20]=[O:21])[O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:8](F)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:22]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[NH:29]1)=[O:27])[CH:23]=[CH2:24].CCN(C(C)C)C(C)C>CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:20]=[O:21])[O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:8]([N:29]2[CH:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32][N:28]2[C:26]([O:25][CH2:22][CH:23]=[CH2:24])=[O:27])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCOC(=O)N1CCC(C(=O)O)N1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)F)OC1CCCCO1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N1CCC(C(=O)O)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.2 %

Procedure:
(2R)-3-Cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl fluoride (784 mg, 2.6 mmol) was added into the solution of 1-[(2-propen-1-yloxy)carbonyl]-3-pyrazolidine carboxylic acid (677 mg, 3.38 mmol) and Hunig's base (1811 μl, 10.40 mmol) in N,N-dimethylformamide (DMF) (11.1 ml). The reaction was stirred for 5 hrs at ambient temperature. The reaction was purified by RP-HPLC to give 2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-1-[(2-propen-1-yloxy)carbonyl]-3-pyrazolidinecarboxylic acid (428 mg, 0.889 mmol, 34% yield). MS (ES+) m/z 482.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][C:25]1[C:29]([C:30](O)=[O:31])=[C:28]([C:33]([F:36])([F:35])[F:34])[O:27][N:26]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:30]([C:29]3[C:25]([CH3:24])=[N:26][O:27][C:28]=3[C:33]([F:36])([F:34])[F:35])=[O:31])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cc1noc(C(F)(F)F)c1C(=O)O
Product: Cc1noc(C(F)(F)F)c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 3-methyl-5-trifluoromethyl-isoxazole-4-carboxylic acid. LC-MS (basic): tR=0.85 min; [M+H]+=510.2.
Reaction SMILES: C(OC([CH2:8][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[CH:13]=[CH:12][CH:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].[CH2:41]([N:48]=[C:49]=[O:50])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].CN(C1C=CC=CN=1)C>ClCCl.C(N(CC)CC)C.O>[CH2:41]([NH:48][C:49](=[O:50])[N:9]([C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:21]=2)[CH:13]=[CH:12][CH:11]=1)[CH3:8])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCN=C=O
Reactant: CCOC(=O)C=Cc1ccc(-c2cccc(NCC(=O)OC(C)(C)C)n2)cc1
Agent: CN(C)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C=CC(=O)OCC)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.5 %

Procedure:
300 mg (0.78 mmol) of ethyl 3-{4-[6-(tert-butoxycarbonylmethylamino)pyrid-2-yl]phenyl}acrylate are dissolved in 5 mL of dichloromethane. 2 mL of trifluoroacetic acid are added. The reaction mixture is stirred for 3 hours at room temperature. The reaction is stopped by adding 30 mL of saturated sodium hydrogen carbonate solution and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the oil obtained is then dissolved in 5 ml of dichloromethane in the presence of 1 ml of triethylamine. 630 μL (3.9 mmol, 5 eq) of heptyl isocyanate are added along with 100 mg of dimethylaminopyridine. The reaction mixture is stirred for 16 hours at reflux. The reaction is stopped by adding 30 mL of water and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (80/20 to 70/30 heptane/ethyl acetate). 170 mg of ethyl 3-{4-[6-(3-heptyl-1-methylureido)pyrid-2-yl]phenyl}acrylate are obtained. Yield=51%.
Reaction SMILES: CO[C:3]1[C:15]2[C:14]3[CH:13]=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=3[N:8]([CH3:20])[C:7]=2[C:6]([C:21]#[N:22])=[CH:5][N:4]=1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:3]1[C:15]2[C:14]3[CH:13]=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=3[N:8]([CH3:20])[C:7]=2[C:6]([C:21]#[N:22])=[CH:5][N:4]=1
Reactant: COc1ncc(C#N)c2c1c1ccc(C(F)(F)F)cc1n2C
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1c2cc(C(F)(F)F)ccc2c2c(Cl)ncc(C#N)c21

Procedure:
A solution of the product from Step 1 in POCl3 (0.057 M) was set up on the Smith Creator microwave reactor for 10 min at 175° C. The resulting solution was poured onto cold saturated NaHCO3 solution and the suspension was stirred until all the reagent was consumed and the final pH was 7-8. The suspension was then filtered to give the title compound as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:11]1([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][CH:8]=[CH:7]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cccc2cc[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-c2cccc3cc[nH]c23)cc1
Temperature: 100 °C
Yield: 93.1 %

Procedure:
To a suspension of 7-bromo-1H-indole (196 mg, 0.00100 mol) in 1,4-dioxane (4 mL) and water (1 mL) was added phenylboronic acid (146 mg, 0.00120 mol), potassium carbonate (414 mg, 0.00300 mol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (82 mg, 0.00010 mol). The flask was evacuated and refilled with nitrogen, three times then the mixture was heated at 100° C. overnight. The mixture was diluted with EtOAc (30 mL), washed with sat. aq. NaHCO3 (10 mL) and brine (10 mL), then dried over anhydrous sodium sulfate and the solvent removed in vacuo. The crude material was purified by chromatography over silica gel eluting with hexane/EtOAc to give the title compound (180 mg, 93% yield). 1H NMR (CDCl3, 400 MHz): δ 6.64 (dd, J=3.0, 2.0 Hz, 1H), 7.18-7.26 (m, 3H), 7.41 (t, J=7.5 Hz, 1H), 7.48-7.57 (m, 2H), 7.61-7.70 (m, 3H) and 8.43 (br s, 1H) ppm. LC-MS (ES+): 194 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:16]([OH:17])[CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:16]([O:17][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)[C@H](NC(=O)OCc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)[C@H](NC(=O)OCc2ccccc2)C1

Procedure:
t-Butyl (3R,4S)-3-benzyloxycarbonylamino-4-hydroxypyrrolidine-1-carboxylate (38 g) was dissolved in chloroform (380 mL), and the mixture was ice-cooled, followed by addition of triethylamine (22 mL) and methanesulfonylchloride (11 mL). The mixture was stirred for 2 h with ice cooling, and water was added to separate the layers. The organic layer was washed with water, then dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude t-butyl (3R,4S)-3-benzyloxycarbonylamino-4-methanesulfonyloxypyrrolidine-1-carboxylate. This compound was used in the subsequent step without purification.