Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[CH:11]=[CH:12][S:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[N+:14]([C:17]1[CH:22]=[CH:21][C:20](O)=[C:19](I)[CH:18]=1)([O-:16])=[O:15].C([O-])(=O)C.[Na+].Cl>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[CH:11]=[C:12]([C:20]3[CH:21]=[CH:22][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=3)[S:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)c(I)c1
Reactant: CCOC(=O)c1cc2sccc2[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc2sc(-c3ccc([N+](=O)[O-])cc3)cc2[nH]1
Temperature: 150 °C
Reaction time: 24 h
Yield: 31.2 %

Procedure:
The resulting fused thiophene-pyrrole product, 4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (250 mg, 1.28 mmol) and 4-nitro-iodophenol (266 mg, 1.07 mmol) were dissolved in dimethylacetamide (10 ml). Sodium acetate (209.6 mg, 1.6 mmol) and tetrakis-(triphenylphosphine)palladium (61.8 mg, 0.005 mmol) were added thereafter and the reaction mixture was heated at 150° C. while stirring for 24 hours. A solution of HCl 0.1 M (50 ml) and ethyl acetate (20 ml) was then added, the organic and aqueous phases were separated, and the aqueous phase was extracted with ethyl acetate (3×20 ml). The combined organic phase was dried over Na2SO4 and the organic solvents were evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography to give 105.5 mg of pure 2-(4-nitro-phenyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (yield 31.2%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:34])=[C:11]([C:15]4[CH:16]=[C:17]5[C:21](=[CH:22][CH:23]=4)[CH2:20][N:19](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:18]5)[C:12]=3[CH3:14])[C:7](=[O:35])[C:6]([C:36]([OH:38])=[O:37])=[CH:5]2)[CH2:3][CH2:2]1.C1(O)C=CC=CC=1.C(O)(=O)CC.[BrH:51]>>[BrH:51].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:34])=[C:11]([C:15]4[CH:16]=[C:17]5[C:21](=[CH:22][CH:23]=4)[CH2:20][NH:19][CH2:18]5)[C:12]=3[CH3:14])[C:7](=[O:35])[C:6]([C:36]([OH:38])=[O:37])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccc(-c4c(F)cc5c(=O)c(C(=O)O)cn(C6CC6)c5c4C)cc3C2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: CCC(=O)O
Product: Cc1c(-c2ccc3c(c2)CNC3)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
In 5.3 ml of 47% hydrobromic acid was suspended 0.53 g of 1-cyclopropyl-6-fluoro-8-methyl-7-[2-(p-toluenesulfonyl)isoindolin-5-yl]-1,4-dihydro-4-oxoquinoline-3 carboxylic acid, and 0.28 g of phenol and 3.2 ml of propionic acid were added to the suspension, after which the resulting mixture was heated under reflux for one hour under a nitrogen stream. The reaction mixture was concentrated under reduced pressure, and ethanol was added to the residue obtained, after which the crystals formed were collected by filtration, to obtain 0.38 g of colorless, crystalline 1-cyclopropyl-6-fluoro-8-methyl-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrobromide. The hydrobromide obtained was suspended in 3.8 ml of ethanol and then dissolved in 7.6 ml of 0.5N aqueous sodium hydroxide solution, after which a carbon dioxide gas was blown into the solution. The crystals formed were collected by filtration, to obtain 0.27 g of colorless, crystalline 1-cyclopropyl-6-fluoro-8-methyl-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH2:18][CH2:19][O:20][CH3:21])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[C:27]([Cl:34])[CH:26]=1>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH2:18][CH2:19][O:20][CH3:21])=[O:33])=[C:27]([Cl:34])[CH:26]=1
Reactant: COCCNc1c2ccccc2nn1-c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Solvent: Cc1ccccc1
Product: COCCN(C(=O)Nc1ccc(C(=O)OC)cc1Cl)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-(2-methoxy-ethyl)-amine (example 17.1) was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester (example 9.1) in toluene for 7 d under reflux conditions to give the title compound as yellow foam. MS: m/e=513.0 [M+H+].
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]([CH2:12][CH2:13][O:14][CH3:15])[C:9]([CH3:11])=[N:10][C:6]=2[CH:5]=[C:4]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:7][N:8]([CH2:12][C:3]1[C:4]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:5][C:6]2[N:10]=[C:9]([CH3:11])[N:8]([CH2:12][CH2:13][O:14][CH3:15])[C:7]=2[C:2]=1[OH:1])[CH3:9]
Reactant: COCCn1c(C)nc2cc(C(=O)N(C)C)cc(O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1c(C)nc2cc(C(=O)N(C)C)c(CN(C)C)c(O)c21
Reaction time: 4 h
Yield: 142 %

Procedure:
To a stirred solution of 7-hydroxy-1-(2-methoxyethyl)-N,N,2-trimethyl-1H-benzimidazole-5-carboxamide (1.0 g, 3.6 mmol, Step 2) and potassium carbonate (748 mg, 5.4 mmol) in N,N-dimethylformamide (36 mL) at 0° C. was added N,N-dimethylmethyleneiminium iodide (867 mg, 4.7 mmol). After stirring at the same temperature for 4 hours, the reaction mixture was quenched with saturated sodium hydrogencarbonate aqueous solution and extracted with dichloromethane. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on NH-gel eluting with ethyl acetate/methanol (30:1) to afford the title compound (855 mg, 71%) as a white amorphous.
Reaction SMILES: [CH3:1][N:2]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][OH:10])[N:8]=1)[CH3:3].[CH3:11][O:12][C:13](=[O:22])[C@:14]([N:19]=[C:20]=[O:21])([CH:16]([CH3:18])[CH3:17])N>CN(C)C1C=CN=CC=1.ClCCl>[CH3:11][O:12][C:13](=[O:22])[C@H:14]([CH:16]([CH3:17])[CH3:18])[NH:19][C:20]([O:10][CH2:9][C:7]1[N:8]=[C:4]([N:2]([CH3:3])[CH3:1])[S:5][CH:6]=1)=[O:21]
Reactant: CN(C)c1nc(CO)cs1
Reactant: COC(=O)[C@](N)(N=C=O)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)OCc1csc(N(C)C)n1)C(C)C
Yield: 94.4 %

Procedure:
A solution of 505 mg (3.19 mmol) of 2-(N,N-dimethylamino)-4-(hydroxymethyl)thiazole, 3.19 mmol of α-isocyanato-L-valine methyl ester, and 100 mg of 4-dimethylaminopyridine in 30 ml of dichloromethane was heated at reflux for 3 h. The resulting solution was allowed to cool, diluted with dichloromethane, washed sequentially with 10% citric acid, aqueous Na2CO3, and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography using 2% methanol in chloroform to provide 0.95 g (95%) of the desired compound, Rf 0.42 (4% methanol in chloroform). 1H NMR (CDCl3) δ 0.84 (d, J=7 Hz, 3 H), 0.93 (d, J=7 Hz, 3 H), 2.12 (m, 1 H), 3.11 (s, 6 H), 3.73 (s, 3 H), 4.24 (dd, J=8, 4 H), 4.99 (s, 2 H), 5.26 (br d, 1 H), 6.49 (s, 1 H). Mass spectrum: (M+H)+ =316.
Reaction SMILES: [CH2:1]([C:6]1[O:10][N:9]=[C:8]([NH:11][CH:12]([P:21](=[O:28])([O:25]CC)[O:22]CC)[P:13](=[O:20])([O:17]CC)[O:14]CC)[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]>Cl>[CH2:1]([C:6]1[O:10][N:9]=[C:8]([NH:11][CH:12]([P:21](=[O:22])([OH:28])[OH:25])[P:13](=[O:14])([OH:20])[OH:17])[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1cc(NC(P(=O)(OCC)OCC)P(=O)(OCC)OCC)no1
Agent: Cl
Product: CCCCCc1cc(NC(P(=O)(O)O)P(=O)(O)O)no1
Yield: 80.5 %

Procedure:
A solution of 3 g of tetraethyl [(5-n-pentyl-3-isoxazolyl)amino]methylene-bis(phosphonate) in 30 ml of concentrated hydrochloric acid was heated under reflux for 3 hours. After the reaction mixture was concentrated, the solid obtained was washed with acetonitrile to give 1.8 g of [(5-n-pentyl-3-isoxazolyl)amino]methylene-bis(phosphonic acid) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc(C)cc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cc(C)cc(C)c1
Reaction time: 0.05 h
Yield: 72.4 %

Procedure:
40% Methanolic Triton B (0.13 mL, 0.28 mM) was added to a solution of the 9-[(3,5-dimethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (80 mg, 0.23 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (43 mg, 0.28 mM) was added and the resultant mixture stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate, washed with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 70 mg (72%) of the {9-[(3,5-dimethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.6 (d, 1H, J=8 Hz), 7.55 (br s, 1H), 7.45-7.3 (m, 2H), 7.25 (d, 1H, J=8 Hz), 7.2 (br s, 1H), 7.1 (d, 1H, J=8 Hz), 6.9 (s, 1H), 6.8 (s, 2H), 6.6 (d, 1H, J=8 Hz), 5.65 (s, 2H), 4.9 (s, 2H), 3.75 (s, 3H), and 2.2 (s, 6H). IR (KBr, cm−1) 3362, 3173, 1758, 1638, 1583, 1500, 1454, 1434, 1330, 1215, 1151, 1106, 772, 715, and 706. MS (FD) m/e 417.
Reaction SMILES: [F:1][C:2]1[C:3]([C:15]([F:18])([F:17])[F:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8]C(=O)C)[CH:7]=1.C([O-])(O)=O.[Na+]>Cl>[F:1][C:2]1[C:3]([C:15]([F:16])([F:17])[F:18])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH2:8])[CH:7]=1
Reactant: CC(=O)Nc1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 91.2 %

Procedure:
A suspension of N-(5-fluoro-2-nitro-4-trifluoromethyl-phenyl)-acetamide (17.8 g, 67.0 mmol) in aqueous HCl (3M, 400 mL) was heated at reflux for 3 h. The resulting suspension was cooled to 0° C. and brought to pH 8 with NaHCO3. The resulting solid was collected to yield the titled compound (13.7 g, 91% yield). The compound did not yield MS data. 1H NMR (400 MHz, CDCl3): 8.48 (d, J=7.3 Hz, 1H), 6.75-6.18 (m, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:7](=[O:14])[CH:8]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[N:10]=1)[CH2:2][CH2:3][CH3:4].[Br:30]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:30][C:8]1[C:7](=[O:14])[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:10][C:9]=1[CH:11]1[CH2:13][CH2:12]1
Reactant: CCCCc1nc(C2CC2)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCc1nc(C2CC2)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 4′-[(2-butyl-4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (5.22 g) in acetic acid (60 mL) was added bromine (1.39 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (5.4 g, 80%) as a colorless solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][O:15][C:16]([C:18]2([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[C:8]1([CH2:14][O:15][C:16]([C:18]2([NH:24][C:32](=[O:33])[CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:17])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC1(C(=O)OCc2ccccc2)CCCCC1
Reaction time: 8 h
Yield: 91.3 %

Procedure:
1.21 g (12 mmol) of triethylamine was added to a solution of 2.33 g (10 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in 100 ml of tetrahydrofuran, 1.55 g (10 mmol) of phenylacetyl chloride was added dropwise thereto under ice-cooling, and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography to obtain 3.21 g (91%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:19])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28].C(=O)(O)[O-].[Na+].C[O-].[Na+]>ClCCl>[F:19][C:7]1[CH:6]=[C:4]([NH:5][C:27](=[O:29])[CH3:28])[CH:3]=[C:2]([F:1])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12
Reactant: Nc1cc(F)c(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: CC(=O)Cl
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc(F)c(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
1.60 g (6.14 mmol) of 3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline are suspended in 45 ml of dichloromethane and cooled to 0° C. 2.57 ml (18.4 mmol) of triethylamine and 0.87 ml (12.3 mmol) of acetyl chloride are added dropwise, and stirring at 0° C. is continued for 2.5 hours. A further 0.86 ml (6.14 mmol) of triethylamine and 0.44 ml (6.14 mmol) of acetyl chloride are added, and the mixture is allowed to react for another hour. Saturated sodium bicarbonate solution is then added, and the mixture is stirred at RT for 10 min. The mixture is extracted twice with dichloromethane. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure. The crude product is taken up in 45 ml of ethanol. 1.14 ml (6.14 mmol) of 5.4M sodium methoxide solution are added, and the mixture is stirred at RT for 30 min. The mixture is concentrated and the product is purified by chromatography on silica gel (mobile phase: dichloromethane/methanol (7N ammonia) 100:1 to 100:5).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:40]([C:39]3[CH:38]=[CH:37][C:36]([N:33]4[CH2:34][CH2:35][CH:30]([OH:29])[CH2:31][CH2:32]4)=[CH:43][CH:42]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(c1ccccc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: O=Cc1ccc(N2CCC(O)CC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CC(c1ccccc1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N5CCC(O)CC5)cc4)nc23)CC1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-[4-(1-phenyl-ethyl)-piperazin-1-yl]-pyridin-2-ylamine (0.036 g, 0.09 mmol) and EtOH (4.5 ml) was added 4-(4-hydroxy-piperidin-1-yl)-benzaldehyde (0.025 g, 0.12 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.38 ml, 0.38 mmol). The reaction mixture was stirred at 80° C. for 22 h, then allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 5%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.016 g, 32%); 1H-NMR (500 MHz, DMSO-d6) 1.35 (d, J=6.7 Hz, 3H, CHCH3), 1.45 (m, 2H) and 1.82 (m, 2H) (piperidine CH2), 2.54 (m, 2H), 2.62 (br s, 2H), 2.98 (t, 2H) and 3.70 (m, 3H) (piperazine N—(CH2)2, piperidine CH2 and piperidine CHOH), 3.50 (q, J=6.7 Hz, 1H, CHCH3), 3.67 (br s, 4H, piperazine N(CH2)2), 4.67 (d, J=4.1 Hz, CHOH, exchangeable with D2O), 7.03 (d, J=8.9 Hz, 2H) and 8.00 (d, J=8.8 Hz, 2H) (3,5-C6H4—N and 2,6-C6H4—N), 8.14 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.16 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=3.39 min—561, 563 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 561.1975, calculated for C29H34BrN6O (M+H)+: 561.1977.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][N:3]=1.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:8]([C:7]1[C:2]([NH:1][C:30](=[O:31])[CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:3][CH:4]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[N:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(-c2cnc(NC(=O)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 96.2 %

Procedure:
Under an argon atmosphere, 2-amino-3-benzyl-5-(4-methoxyphenyl)pyrazine (c-11) (prepared by the method described in Adamczyk, M. et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (400 mg, 1.37 mmol) was dissolved in pyridine (4 mL) and to this was added 4-(dimethylamino)pyridine (17.3 mg, 142 μmol), and then cooled to 0° C. To this was added phenylacetyl chloride (540 μL, 4.08 mmol) and stirred for 3.5 h after warming to room temperature. To this was added saturated aqueous solution of sodium bicarbonate to stop the reaction and extracted 3 times with dichloromethane. The organic layer was washed with saturated aqueous solution of sodium sulfate and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, dichloromethane/ethyl acetate=15/1) to give 3-benzyl-5-(4-methoxyphenyl)-2-(phenylacetylamino)pyrazine (c-16) as a pale yellow solid (540 mg, 96.2%). Rf=0.25 (dichloromethane/ethyl acetate=15/1). Mp. 197.5-202° C. UV (MeOH) λmax (log ε) 330 (4.20), 293 (4.20), 274 (4.18). UV (pH 7.4 PB, 1% DMSO) λmax (log ε) 333.5 (3.73), 280.5 (3.85). 1H NMR (400 MHz, DMSO-d6) δ 3.68 (s, 2H), 3.81 (s, 3H), 4.03 (s, 2H), 7.01-7.08 (m, 4H), 7.11-7.24 (m, 3H), 7.24-7.30 (m, 1H), 7.32-7.38 (m, 4H), 8.01-8.06 (AA′BB′, 2H), 8.88 (s, 1H), 10.52 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6/CD3OD=2/1) δ 40.2, 42.9, 55.5, 114.8 (2C), 126.7, 127.2, 128.4 (2C), 128.6, 128.7 (2C), 128.8 (2C), 129.4 (2C), 129.7 (2C), 136.0, 137.5, 138.7, 143.9, 149.0, 151.2, 161.3, 170.6. IR (KBr, cm−1) 706, 837, 1034, 1179, 1248, 1296, 1413, 1439, 1449, 1497, 1545, 1574, 1609, 1670, 3281, 3381. HRMS (FAB+) m/z 410.1876 (M+H, C26H24N3O2 requires 410.1869).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8]1[N:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]3[CH:29]=[CH:28][C:21]([C:22]([NH:24][CH:25]4[CH2:27][CH2:26]4)=[O:23])=[CH:20][C:19]=3[O:30][CH3:31])[CH:14]=2)[N:9]=1.[C:32](O)(=[O:35])[C:33]#[CH:34].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>ClCCl>[CH:25]1([NH:24][C:22](=[O:23])[C:21]2[CH:28]=[CH:29][C:18]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[N:9]=[C:8]([NH:7][C@@H:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[NH:1][C:32](=[O:35])[C:33]#[CH:34])[N:17]=[CH:16]4)=[C:19]([O:30][CH3:31])[CH:20]=2)[CH2:27][CH2:26]1
Reactant: COc1cc(C(=O)NC2CC2)ccc1-c1ccc2nc(N[C@@H]3CCC[C@@H]3N)ncc2c1
Reactant: C#CC(=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: ClCCl
Product: C#CC(=O)N[C@H]1CCC[C@H]1Nc1ncc2cc(-c3ccc(C(=O)NC4CC4)cc3OC)ccc2n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67.8 %

Procedure:
A mixture of 4-(2-(((1R,2S)-2-aminocyclopentyl)amino)quinazolin-6-yl)-N-cyclopropyl-3-methoxybenzamide (0.11 mmol), propiolic acid (0.010 mL, 0.17 mmol), HATU (64 mg, 0.17 mmol) and DIEA (0.06 mL, 0.34 mmol) in dichloromethane (1.5 mL) was stirred at room temperature for 45 minutes. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-cyclopropyl-3-methoxy-4-(2-(((1R,2S)-2-propiolamidocyclopentyl)amino)quinazolin-6-yl)benzamide (Compound 13) (35 mg, 69%). MS (ES+) C27H27N5O3 requires: 469, found: 470 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.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.[NH2:65][C:66]1[CH:74]=[CH:73][C:69]([C:70]([NH2:72])=[O:71])=[C:68]([Cl:75])[CH:67]=1>C(Cl)Cl>[C:70]([C:69]1[CH:73]=[CH:74][C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:67][C:68]=1[Cl:75])(=[O:71])[NH2:72]
Reactant: NC(=O)c1ccc(N)cc1Cl
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)c(Cl)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (0.150 mL, 0.855 mmol) and 4-amino-2-chloro-benzamide (Chembridge, 58 mg, 0.34 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC to give a white solid. 6 mg.