Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[N:5][CH:4]=[C:3]1[C:19]([O:21]CC)=[O:20].O=C1NC(C2C=CC=CC=2OCCCC)=NC=C1C(O)=O>>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]2[CH2:17][CH2:18]2)=[N:5][CH:4]=[C:3]1[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)c1cnc(-c2ccccc2OCC2CC2)[nH]c1=O
Agent: CCCCOc1ccccc1-c1ncc(C(=O)O)c(=O)[nH]1
Product: O=C(O)c1cnc(-c2ccccc2OCC2CC2)[nH]c1=O

Procedure:
The title compound was prepared from ethyl 1,6-dihydro-6-oxo-2-(2-cyclopropylmethoxyphenyl)pyrimidine-5-carboxylate in a manner similar to that described for the preparation of 1,6-dihydro-6-oxo-2-(2-n-butoxyphenyl)pyrimidine-5-carboxylic acid in Example 23. The product had m.p. 219°-220°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.N12CCN(CC1)CC2.[Cl:16][C:17]1[C:18]([F:28])=[CH:19][C:20]([F:27])=[C:21]([S:23](Cl)(=[O:25])=[O:24])[CH:22]=1>C(#N)C>[Cl:16][C:17]1[C:18]([F:28])=[CH:19][C:20]([F:27])=[C:21]([S:23]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][N:3]=2)(=[O:25])=[O:24])[CH:22]=1
Reactant: Nc1ccncn1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: O=S(=O)(Nc1ccncn1)c1cc(Cl)c(F)cc1F
Reaction time: 72 h
Yield: 4.6 %

Procedure:
A mixture of 4-aminopyrimidine (1.30 g, 13.7 mmol) and 1,4-diazabicyclo[2.2.2]octane (1.54 g, 13.7 mmol) were added concurrently to a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (3.4 g, 14 mmol) in anhydrous acetonitrile (63 mL). The reaction mixture immediately turned yellow and a precipitate formed. The reaction mixture was stirred under argon. After 72 hours, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was partitioned between 1M hydrochloric acid and ethyl acetate. The organic phase was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was partially purified by automated flash column chromatography using an 80 g silica gel ISCO™ column using hexanes to 1% v/v acetic acid in ethyl acetate gradient elution. The product was purified a second time by reverse phase HPLC to give the title compound (193 mg, 5%) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=4)[CH:5]=3)=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:13][CH:14]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2cccc(C(F)(F)F)c2)cn1
Yield: 11 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluorophenyl)-isoxazole (72.9 mg, 0.3 mmol) was converted, using 3-trifluoromethylphenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (13 mg, 11%) which was obtained as an off-white solid. MS: m/e=388.6 [M+H]+.
Reaction SMILES: CC1[N:3]([C:8]2[N:13]=[CH:12][C:11]([CH:14]([OH:17])[CH2:15][CH3:16])=[CH:10][CH:9]=2)C(C)=CC=1.Cl.NO.[CH2:21](O)[CH3:22]>O>[NH2:3][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([O:17][CH2:21][CH3:22])[CH2:15][CH3:16])=[CH:12][N:13]=1
Reactant: CCC(O)c1ccc(-n2c(C)ccc2C)nc1
Reactant: CCO
Agent: Cl
Agent: NO
Solvent: O
Product: CCOC(CC)c1ccc(N)nc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 1.07 g of 1-[6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl]propan-1-ol in 20 mL of ethanol heated to 80° C. is added a solution of 1.94 g of hydroxylamine hydrochloride in 1.6 mL of water, and the mixture is stirred for 24 hours at 80° C. After cooling to room temperature, the reaction medium is filtered and concentrated to dryness. The residue is purified by flash chromatography on a column of 100 g of silica, eluting with 400 mL of dichloromethane, then with 300 mL of ethyl acetate and then with a 95/5 mixture of dichloromethane and methanol. The fractions containing the expected product are combined and concentrated under vacuum to give 0.186 g of 2-amino-5-(1-ethoxypropyl)pyridine in the form of a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:7]=2[CH:13]=1.C([O-])([O-])=O.[K+].[K+].[C:20](#N)[CH3:21]>ICC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:20][CH3:21])[C:7]=2[CH:13]=1
Reactant: COc1ccc2c(c1)NCCCC2
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Product: CCN1CCCCc2ccc(OC)cc21
Reaction time: 18 h

Procedure:
To a solution of 8-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.5 g) in acetonitrile (25 mL), iodoethane (0.45 mL) and K2CO3 (1.2 g) was added, and the reaction heated to reflux. After stirring for 18 hours, the heat was removed, and the reaction was concentrated. The resulting residue was partitioned between water (30 mL) and EtOAc (25 mL), the layers separated, and the organic layer washed with brine, dried (Na2SO4) and concentrated to provide the title compound (0.54 g) as a clear oil: 1H NMR (DMSO-d6) δ 6.93 (d, 1H); 6.39 (d, 1H), 6.33 (dd, 1H), 3.67 (s, 3H), 3.07 (q, 2H), 2.85-2.82 (m, 2H), 2.62-2.58 (m, 2H), 1.66-1.59 (m, 2H), 1.51-1.43 (m, 2H), 1.10 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:12])[C:5](Br)=[CH:4][CH:3]=1.[CH:14]([C:16]1[O:17][CH:18]=[CH:19][C:20]=1B1OC(C)(C)C(C)(C)O1)=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(OCC)(=O)C.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]>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:12])[C:5]([C:20]2[CH:19]=[CH:18][O:17][C:16]=2[CH:14]=[O:15])=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccoc2C=O)OC1(C)C
Reactant: COC(=O)c1c(N)ccc(Br)c1O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1c(N)ccc(-c2ccoc2C=O)c1O
Temperature: 65 °C
Yield: 88 %

Procedure:
A mixture of methyl 6-amino-3-bromo-2-hydroxybenzoate (prepared according to Wang et al, Bioorg Med Chem Lett 2007 17 2817, 1.84 g), 2-formylfuran-3-boronic acid pinacol ester (1.99 g), tri-tert-butylphosphinium tetrafluoroborate (0.218 g), cesium carbonate (7.33 g) and tris-(dibenzylideneacetone)dipalladium (0.343 g) in dioxane (75 mL) and water (9.4 mL) was heated at 65° C., under nitrogen, for 1 hour. After cooling, the mixture was diluted with ethyl acetate and water and the organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-50% to give methyl 6-amino-3-(2-formylfuran-3-yl)-2-hydroxybenzoate (1.72 g) as a yellow solid. The material was used without further characterisation.
Reaction SMILES: [CH:1]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([O:21][CH2:20][CH2:19][C:1]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3][CH2:2]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCCOCc1ccccc1
Reactant: CCOC(=O)C1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCOCc2ccccc2)CCC1
Temperature: 0 °C
Yield: 71.3 %

Procedure:
A solution of 3.0 g (23 mmol) of ethyl cyclobutanecarboxylate in 10 mL of tetrahydrofuran was added to a −78° C. solution of 25.74 mmol of lithium diisopropylamide in 45 ml tetrahydrofuran. The reaction was warmed to 0° C. over 15 min and then cooled to −78° C., followed by the addition of 3.64 mL (25.74 mmol) of benzyl 2-bromoethyl ether in 10 mL of tetrahydrofuran. The reaction was gradually warmed to room temperature over 16 h and then quenched with 20 mL of saturated ammonium chloride. The reaction was concentrated and ethyl acetate was added. The organic layer was isolated, dried with magnesium sulfate, and concentrated under vacuum to afford an oil, which was purified by silica gel chromatography eluting with ethyl acetate:hexane (2:8) to afford 4.3 g (70%) of ethyl 1-[2-(benzyloxy)ethyl]cyclobutanecarboxylate as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.31-7.22 (m, 5H), 4.01 (q, J=7 Hz, 2H), 4.40 (s, 2H), 2.40 (t, J=7 Hz, 2H), 1.92-1.84 (m, 6H), 1.14 (t, J=7 Hz, 3H). GC-MS m/z 263 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([CH3:27])([CH3:26])[CH2:24][CH3:25])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:27][C:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:28])([CH3:26])[CH2:24][CH3:25]
Reactant: CCOC(=O)C1(NC(=O)c2ccccc2C(C)(C)CC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(C)(C)c1ccccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
2-[2-(1,1-Dimethyl-propyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (220 mg, 0.58 mmol) is dissolved in EtOH (8 mL), and solid KOH (600 mg, 10 mmol) and water (0.8 mL) are added. The mixture is stirred at RT for 30 minutes then concentrated in vacuo. The residue is dissolved in water (10 mL) and acidified with concentrated HCl until no more white solid precipitated. The solid is collected by vacuum filtration to give product (248) as white solid (158 mg, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:18]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2ccc(C(=O)CCC(=O)O)cc2)cc1
Yield: 12.2 %

Procedure:
In a manner similar to that described in Example 3, 4-methoxy-benzoyl chloride (0.057 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.010 g of 4-[4-(4-methoxy-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+328.
Reaction SMILES: Cl.C([O:4][C:5](=[O:18])[C@H:6]([CH3:17])[NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)C>Cl>[CH:8]1([NH:7][C@H:6]([C:5]([OH:18])=[O:4])[CH3:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)[C@H](C)NC1CCc2ccccc21
Agent: Cl
Product: C[C@H](NC1CCc2ccccc21)C(=O)O
Yield: 84.7 %

Procedure:
N-(1-Indanyl)alanine ethyl ester hydrochloride (9.0 g) is dissolved in 100 ml of 5N hydrochloric acid, and the mixture is refluxed for 3 hours. The reaction mixture is concentrated to dryness under reduced pressure, 10 ml of water is added to the residue, and the mixture is neutralized with aqueous ammonia. The resulting crystalline precipitates are collected by filtration, washed with water, and dried, to give 5.8 g of N-(1-indanyl)alanine as colorless scales. Melting point: 248°-250° C.
Reaction SMILES: [C-:1]#[N:2].[CH3:3][C@H:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:5]=[O:6].[NH4+].[Cl-].O>C1(C)C=CC=CC=1>[C:1]([CH:5]([OH:6])[C@@H:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:3])#[N:2]
Reactant: C[C@@H](C=O)NC(=O)OCc1ccccc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)C(O)C#N
Temperature: -78 °C
Reaction time: 6 h

Procedure:
Diethylalumninum cyanide (4.53 mL, 1M in toluene, 4.53 mmol) was added dropwise to a stirred solution of benzyl [(1S)-1-methyl-2-oxoethyl]carbamate (0.853 g, 4.12 mmol) in dry toluene (33 mL) at −78° C. under N2. The mixture was stirred at −78° C. for 6 h and then allowed to warm to room temperature overnight. Saturated NH4Cl (20 mL) and water (10 mL) were added then the mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl [(1S)-2-cyano-2-hydroxy-1-methylethyl]carbamate as a 3:1 mixture of diastereoisomers. Rf=0.63 (50% EtOAc in hexanes). LCMS calc.=257.1; found=257.1 (M+1)+. 1H NMR (500 MHz, CDCl3) major diastereoisomer: δ 7.39-7.31 (m, 5H), 5.11 (m, 2H), 4.60 br (s, 1H), 3.96 (m, 1H), 1.34 (d, J=6.7 Hz, 3H), minor diastereoisomer: δ 7.39-7.31 (m, 5H), 5.14 (m, 2H), 4.50 br (s, 1H), 4.10 (m, 1H), 1.30 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[N:12]=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:36]([F:47])[CH:35]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[F:47][C:36]1[CH:35]=[C:34]([NH:33][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([CH2:14][N:13]3[C:9]([CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:10][C:11]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=4)=[N:12]3)=[CH:16][CH:17]=2)[CH:39]=[CH:38][C:37]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]
Reactant: CCOC(=O)CCc1ccc(N)cc1F
Reactant: O=Cc1ccc(Cn2nc(-c3ccc(C(F)(F)F)cc3)cc2CCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc(NCc2ccc(Cn3nc(-c4ccc(C(F)(F)F)cc4)cc3CCc3ccccc3)cc2)cc1F
Reaction time: 1 h

Procedure:
To a mixture of 4-({5-(2-phenylethyl)-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)benzaldehyde (868 mg, 2.0 mmol), ethyl 3-(4-amino-2-fluorophenyl)propanoate (420 mg, 2.0 mmol), acetic acid (300 mg, 5.0 mmol) and 1,2-dichloroethane (15 mL) was added sodium triacetoxyborohydride (1.20 g, 6.0 mmol) by small portions at room temperature and the mixture was stirred for 1 hr. The reaction mixture was poured into 10% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) to give the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][C:6]=1[CH:7]=O.[CH3:15][N:16]([CH3:36])[C:17]([C@@H:19]1[C@H:24]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([NH2:33])[C:27]=2[NH2:34])[C@@H:23]2[CH2:35][C@H:20]1[CH:21]=[CH:22]2)=[O:18].C([O-])(=O)C.[NH4+]>>[CH3:15][N:16]([CH3:36])[C:17]([C@@H:19]1[C@H:24]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28]3[NH:33][C:7]([C:6]4[S:5][C:4]([N:9]5[CH2:14][CH2:13][O:12][CH2:11][CH2:10]5)=[N:3][C:2]=4[Cl:1])=[N:34][C:27]=23)[C@@H:23]2[CH2:35][C@H:20]1[CH:21]=[CH:22]2)=[O:18]
Reactant: O=Cc1sc(N2CCOCC2)nc1Cl
Reactant: CN(C)C(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CN(C)C(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4sc(N5CCOCC5)nc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 15.7 %

Procedure:
In a similar fashion to Compound LXXXVII, 4-Chloro-2-morpholin-4-yl-thiazole-5-carbaldehyde (75.00 mg, 0.3223 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid dimethylamide (93.35 mg, 0.2901 mmol) and Ammonium acetate (44.72 mg, 0.5802 mmol) were reacted to produce 24.34 mg (16%) of the title compound. (300 MHz, DMSO-d6) 12.80 (s, 1H), 7.96 (s, 1H), 6.42-6.32 (m, 2H), 5.11 (t, J=17 Hz, 8.5 Hz, 1H), 3.73 (m, 4H), 3.48 (m, 4H), 3.01 (d, J=9 Hz, 1H), 2.94 (s, 3H), 2.86 (m, 4H), 2.82 (s, 1H), 2.11 (d, J=8 Hz, 1H), 1.42 (d, J=8 Hz, 1H). MS=533 (M+H), HPLC: 2.73 min. (G Method)
Reaction SMILES: [NH3:1].[ClH:2].[Br:3][C:4]1[C:12]([F:13])=[CH:11][C:7]([C:8](=[NH:10])O)=[CH:6][C:5]=1[F:14]>C(O)C>[ClH:2].[Br:3][C:4]1[C:12]([F:13])=[CH:11][C:7]([C:8]([NH2:1])=[NH:10])=[CH:6][C:5]=1[F:14]
Reactant: N
Reactant: N=C(O)c1cc(F)c(Br)c(F)c1
Agent: Cl
Solvent: CCO
Product: N=C(N)c1cc(F)c(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
450 cm3 of anhydrous ethanol saturated with dried gaseous ammonia was added to 4-bromo-3,5-difluorobenzimidate hydrogen chloride and stirred overnight at room temperature. About one-half of the volume of the solvent was distilled off and the residue was recrystallized to yield 90 g (0.36 mol) of 4-bromo-3,5-difluorobenzamidine hydrogen chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[CH2:14](Cl)Cl.CO>O=S(Cl)Cl>[N+:1]([C:4]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:14])=[O:7])([O-:3])=[O:2]
Reactant: ClCCl
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Nitro-4-aminobenzoic acid (261 mg, 1.43 mmol) was dissolved in 1 ml of SOCl2. The solution was refluxed for 1 hour. Excess SOCl2 was removed under reduced pressure and 5 ml of CH2Cl2, 1 ml of MeOH and TEA (0.24 ml, 1.7 mmol) were added to the residue. The reaction mixture was stirred at room temperature for 2 hours. Excess MeOH and TEA were removed and the residue was purified by column chromatography with ethyl acetate/hexane (1/3) to yield the title compound as a yellow solid (316 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([N:14]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]2=[O:20])[CH:8]=[CH:9][C:10]=1CC=C)[CH:2]=[CH2:3].C(OC1C=C(N2C(=O)C=CC2=O)C(CC=C)=CC=1)C=C>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([N:14]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]2=[O:20])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(N2C(=O)C=CC2=O)ccc1CC=C
Agent: C=CCOc1ccc(CC=C)c(N2C(=O)C=CC2=O)c1
Product: C=CCOc1cccc(N2C(=O)C=CC2=O)c1

Procedure:
10% of N-(3-allyloxy-4-allylphenyl)maleimide and N-(3-allyloxy-6-allylphenyl)maleimide; and
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17]C(C)(C)C)=O)[CH2:11][CH:10]2[C:22](=[O:24])[NH2:23])[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[Cl:25][C:26]1[C:31]([CH:32]2[CH2:34][CH2:33]2)=[CH:30][C:29]([NH:35][CH2:36]C(O)=O)=[C:28]([OH:40])[CH:27]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C([O-])([O-])=O.[K+].[K+]>Cl.CO.CN(C=O)C>[C:1]([N:5]1[CH2:6][CH:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH2:36][NH:35][C:29]3[CH:30]=[C:31]([CH:32]4[CH2:33][CH2:34]4)[C:26]([Cl:25])=[CH:27][C:28]=3[OH:40])[CH2:11][CH:10]2[C:22]([NH2:23])=[O:24])[CH2:8]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=C(O)CNc1cc(C2CC2)c(Cl)cc1O
Reactant: C=CC(=O)N1CC(N2CCN(C(=O)OC(C)(C)C)CC2C(N)=O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: C=CC(=O)N1CC(N2CCN(C(=O)CNc3cc(C4CC4)c(Cl)cc3O)CC2C(N)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A mixture of tert-butyl 4-(1-acryloylazetidin-3-yl)-3-carbamoylpiperazine-1-carboxylate (120 mg, 0.35 mmol) in HCl/MeOH (2.86 M, 10 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo to afford the crude residue. It was dissolved in DMF (5 mL) at 0° C., 2-(4-chloro-5-cyclopropyl-2-hydroxyphenylamino)acetic acid (31 mg, 0.427 mmol), BOP (206 mg, 0.466 mmol) and K2CO3 (150 mg, 1.164 mmol) were added and the resulting mixture was stirred at RT for 1 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=20:1) to afford the desired product (126 mg, 75% yield, 2 steps). 1H NMR (400 MHz, DMSO-d6) δ: 9.63 (bs, 1H), 7.53 (d, 1H), 7.26-6.94 (m, 2H), 6.67 (s, 1H), 6.34-6.27 (m, 1H), 6.10 (m, 2H), 5.68 (d, J=10.4, 1H), 5.08 (m, 1H), 4.30 (m, 2H), 3.93 (m, 6H), 3.52 (m, 2H), 3.29 (m, 1H), 3.15 (m, 1H), 3.06 (m, 1H), 2.47 (m, 1H), 1.98 (m, 1H), 0.87 (m, 2H), 0.64 (m, 2H). ESI-MS m/z: 462.5[M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.C([Li])CCC.[I:16]CCI>C(OCC)C>[I:16][C:8]1[S:7][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:10][CH:9]=1
Reactant: c1csc(-c2nccs2)c1
Reactant: ICCI
Agent: [Li]CCCC
Solvent: CCOCC
Product: Ic1cnc(-c2cccs2)s1
Yield: 60.8 %

Procedure:
In a manner similar to Step C of Example 1, the reaction of 3.8 grams of (0.023 mole) of 2-(thien-2-yl)thiazole with 10.0 ml of a 2.5M solution of n-butyllithium in hexanes and 6.5 grams (0.023 mole) of 1,2-diiodoethane in 60 ml of diethyl ether yielded 4.1 grams of 5-iodo-2-(thien-2-yl)thiazole as a solid, m.p. 117°-119° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH3:12])([CH3:11])[O:9][C:8]([CH3:14])([CH3:13])[C:6]=2[N:7]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:2]2[N:3]=[CH:4][C:5]3[C:10]([CH3:12])([CH3:11])[O:9][C:8]([CH3:14])([CH3:13])[C:6]=3[N:7]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC1(C)OC(C)(C)c2nc(Cl)ncc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc3c(n2)C(C)(C)OC3(C)C)CC1

Procedure:
A mixture of 2-chloro-5,5,7,7-tetramethyl-5,7-dihydro-furo[3,4-d]pyrimidine (1.60 g, 7.52 mmol, 1.0 equiv; intermediate B1) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.81 g, 9.03 mmol, 1.2 equiv; commercially available) in anhydrous DMF (6 mL) was heated by microwave irradiation to 150° C. for 30 min. The organic phase was concentrated under reduced pressure and the residue purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (10:1)→ethyl acetate providing 1.26 g (45%) of the title compound. MS (ISP): 377.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C:13](=[O:33])[C@H:14]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:15]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:46]([O:53][C:54]([NH:56][C@H:57]([C:59]([OH:61])=O)[CH3:58])=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(N1CCOCC1)C>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:34])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C:13](=[O:33])[C@H:14]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:15][C:59](=[O:61])[C@H:57]([CH3:58])[NH:56][C:54]([O:53][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:55])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)CN1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 36.8 %

Procedure:
1.3 g (2.79 mmol) of N-[[N-(benzyloxycarbonyl)-L-phenylalanyl]methyl]-L-proline tert.butyl ester was hydrogenated in a mixture of 10 ml of ethyl acetate and 10 ml ofisopropyl alcohol in the presence of 0.39 g of 5% palladium-on-carbon and 1.06 g (5.58 mmol) of toluene-4-sulphonic acid and the product was coupledwith 0.62 g (2.78 mmol) of N-(benzyloxycarbonyl)-L-alanine in the presence of 0.572 g (2.78 mmol) of dicyclohexylcarbodiimide, 0.375 g (2.78 mmol) ofhydroxybenzotriazole and 0.64 g (5.57 mmol) of N-ethylmorpholine in a manner analogous to that described in Example 1. After working-up and chromatography on silica gel using 3% isopropanol in dichloromethane for the elution there was obtained 0.55 g of N-[[N-[N-(benzyloxycarbonyl)-L-alanyl]-L-phenylalanyl]methyl]-L-proline tert.butyl ester as a solid: MS: m/e 538 [M+H]+.