Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:3]=1[C:4]([OH:6])=O.N1[CH:24]=[CH:23]N=C1.C(Cl)(=O)C.Cl.[NH2:30][CH:31]1[CH2:36][CH2:35][C:34](=[O:37])[NH:33][C:32]1=[O:38].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C.O>[C:16]([O:15][C:13](=[O:14])[NH:12][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:6])[N:30]([CH:31]1[CH2:36][CH2:35][C:34](=[O:37])[NH:33][C:32]1=[O:38])[C:23]([CH3:24])=[N:1]2)([CH3:19])([CH3:18])[CH3:17]
Reactant: c1c[nH]cn1
Reactant: NC1CCC(=O)NC1=O
Reactant: CC(C)(C)OC(=O)NCc1cccc(N)c1C(=O)O
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Solvent: CC(=O)Cl
Solvent: CC#N
Product: Cc1nc2cccc(CNC(=O)OC(C)(C)C)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a stirred solution of 2-amino-6-(tert-butoxycarbonylamino-methyl)-benzoic acid (13.0 g, 48.8 mmol), imidazole (3.99 g, 58.6 mmol) in acetonitrile (160 mL), was added acetyl chloride (4.18 mL, 58.6 mmol), and the mixture was stirred at room temp overnight. To the mixture, e was added 3-amino-piperidine-2,6-dione hydrogen chloride (8.03 g, 48.8 mmol), imidazole (6.65 g, 97.6 mmol) and triphenyl phosphite (15.4 mL, 58.6 mmol), and the mixture was heated to reflux for 6 hours. The mixture was cooled to room temperature, and water (500 mL) was added. The suspension was filtered, washed with water (50 mL), ethyl acetate (20 mL), ether (50 mL), and suction dried to give [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-carbamic acid tert-butyl ester as a brown solid (10.5 g, 54% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 5.50 min (98.5%); mp: 206-208° C.; 1H NMR (DMSO-d6) δ 1.40 (s, 9H, 3CH3), 2.15-2.20 (m, 1H, CHH), 2.55-2.68 (m, 5H, C3, 2C H), 2.79-2.86 (m, 1H, CHH), 4.63-4367 (m, 2H, CH2), 5.22 (dd, J=6, 11 Hz, 1H, NCH), 7.20 (t, J=6 Hz, 1H, NH), 7.32 (d, J=8 Hz, 1H, Ar), 7.48 (d, J=8 Hz, 1H, Ar), 7.76 (t, J=8 Hz, 1H, Ar), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.79, 23.27, 28.19, 30.57, 42.82, 56.47, 77.91, 117.53, 123.86, 125.33, 133.92, 141.76, 148.44, 154.76, 155.67, 161.01, 169.51, 172.59; LCMS: MH=401; Anal Calcd for C20H24N4O5+0.5H2O: C, 58.67; H, 6.15; N, 13.68. Found: C, 58.45; H, 5.88; N, 13.34.
Reaction SMILES: [CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][C@H:6]1[OH:21].[H][H].C(OCC)C>CO.[Pd]>[CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@H:6]1[OH:21]
Reactant: [H][H]
Reactant: Cc1cccc(O[C@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)c1C
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Product: Cc1cccc(O[C@H]2CCNC[C@H]2O)c1C
Yield: 67.8 %

Procedure:
A solution of cis-benzyl 4-(2,3-dimethylphenoxy)-3-hydroxypiperidine-1-carboxylate (5.0 g, 14.0 mmol) in methanol (60 ml) was added to 5% palladium on charcoal (500 mg) under an atmosphere of nitrogen. The vessel was placed under an atmosphere of hydrogen and stirred vigorously until hydrogen uptake ceased. The resulting suspension was filtered over a short pad of celite (pre-washed with methanol) and the pad washed with a further portion of methanol (150 ml). Concentration of the methanolic solution in vacuo gave a yellow oil. Dilution with diethyl ether (150 ml) yielded cis-4-(2,3-dimethylphenoxy)-3-hydroxypiperidine as a white solid (2.1 g, 67%).
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[CH:4][N:3]=1.[C:15]([O:19][C:20](=[O:29])[NH:21][CH2:22][CH:23]1[O:28][CH2:27][CH2:26][NH:25][CH2:24]1)([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C=O)C>[C:15]([O:19][C:20](=[O:29])[NH:21][CH2:22][CH:23]1[O:28][CH2:27][CH2:26][N:25]([C:2]2[C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[N:5]=[CH:4][N:3]=2)[CH2:24]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC1CNCCO1
Reactant: Clc1ncnc2[nH]c3ccccc3c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC1CN(c2ncnc3[nH]c4ccccc4c23)CCO1
Temperature: 120 °C
Yield: 24.8 %

Procedure:
A mixture of 4-chloro-9H-pyrimido[4,5-b]indole (0.045 g, 0.221 mmol), morpholin-2-ylmethyl-carbamic acid tert-butyl ester (0.055 g, 0.25 mmol) and triethylamine (0.10 mL, 0.75 mmol) in DMF (0.70 mL) was heated to 120° C. in a microwave reactor for 1 hour. The cooled solution was partitioned between water (20 mL) and ethyl acetate (20 mL). The organic extract was dried (Na2SO4), filtered and concentrated. Flash column chromatography, eluting with ethyl acetate, gave the title compound as a yellow solid (0.021 g, 0.0548 mmol, 25%). LC-MS (3) Rt 5.57 min; m/z (ESI) 384 [MH+].
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1.C(N(C(C)C)CC)(C)C.Cl.F[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1>C(O)C>[ClH:1].[ClH:1].[N:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[NH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1
Reactant: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](N)CC3)C[C@H]1CO2
Reactant: Fc1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](Nc4ccccn4)CC3)C[C@H]1CO2

Procedure:
A mixture of 0.482 g of the compound of Example 1 (1.48 mmol) and 0.245 ml of diisopropylethylamine in 5 ml of 2-fluoropyridine is heated at reflux for 24 hours. After evaporating off the solvents and then diluting with water, the mixture is extracted with ethyl acetate, dried (MgSO4) and evaporated. The residue obtained is purified by chromatography on a silica column using a mixture of dichloromethane/methanol/ammonium hydroxide (97/3/0.3) as eluant to yield, after converting to a salt in ethanol in the warm state using 1N ethereal HCl, the title product.
Reaction SMILES: [F:1][CH2:2][O:3][NH2:4].[NH2:5][C:6]1[S:10][N:9]=[C:8]([C:11](=O)[C:12]([OH:14])=[O:13])[N:7]=1.[OH-].[Na+]>C(O)C.O>[NH2:5][C:6]1[S:10][N:9]=[C:8](/[C:11](=[N:4]/[O:3][CH2:2][F:1])/[C:12]([OH:14])=[O:13])[N:7]=1
Reactant: NOCF
Reactant: Nc1nc(C(=O)C(=O)O)ns1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(/C(=N/OCF)C(=O)O)ns1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a mixture of a solution of fluoromethoxyamine (0.58 g) in ethanol (25 ml) and water (0.45 ml), 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid (1 g) was added. After adjusting the pH of the resulting mixture to 4-5 with a 10% aqueous solution of sodium hydroxide, the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, water (20 ml) and sodium chloride (10 g) were added, and the pH of the solution was adjusted to 1 with concentrated hydrochloric acid. The solution was extracted four times with ethyl acetate (30 ml). After washing the extract with saturated saline, anhydrous magnesium sulfate was added to the extract to dry the same. The solvent was distilled off and the residue was crystallized from a 1:3 mixture of acetone and isopropyl ether, thereby obtaining the target product (0.38 g).
Reaction SMILES: [C:1]([NH:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(SC)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C(S)(C)C.C(=O)([O-])[O-].[K+].[K+].CO.O>O>[C:1]([NH:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CSC(NC(C)=O)(C(=O)O)c1ccccc1
Agent: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)NC(C(=O)O)c1ccccc1
Yield: 90 %

Procedure:
340 Milligrams of N-acetylamino-α-methylthiophenylacetic acid, 240 mg of isopropyl mercaptan, and 351 mg of potassium carbonate were added to 10 ml of a methanol-water mixture (9:1), and refluxed for 3 hours. Following a reduced pressure concentration of the reaction mixture to approximately 1 ml, 20 ml of water was added to the concentrate, which was then extracted with ethyl acetate. The organic phase was dried with Glauber's salt, and concentrated under reduced pressure. The residue was crystallized from an ether-n-hexane system, to provide 247 mg of α-acetylaminophenylacetic acid. The yield was 90%.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH:11][C:12]2[N:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)=[CH:2]1.[NH2:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([CH3:34])([CH3:33])[CH2:27][C:28](=[O:32])[NH:29]2)=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>O.CN(C=O)C>[CH3:33][C:26]1([CH3:34])[C:25]2[C:30](=[CH:31][C:22]([NH:21][C:14]([C:13]3[C:12]([NH:11][CH2:10][C:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:1][CH:2]=4)=[N:20][CH:19]=[CH:18][CH:17]=3)=[O:16])=[CH:23][CH:24]=2)[NH:29][C:28](=[O:32])[CH2:27]1
Reactant: CC1(C)CC(=O)Nc2cc(N)ccc21
Reactant: O=C(O)c1cccnc1NCc1c[nH]c2ncccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1(C)CC(=O)Nc2cc(NC(=O)c3cccnc3NCc3c[nH]c4ncccc34)ccc21
Reaction time: 24 h

Procedure:
2-((1H-Pyrrolo[2,3-b]pyridin-3-yl)methylamino)nicotinic acid (100 mg, 0.37 mmol), 7-amino-4,4-dimethyl-3,4-dihydroquinolin-2(1H)-one (65 mg, 0.37 mmol), TBTU (133 mg, 0.41 mmol) and DIEA (0.07 mL, 0.41 mmol) was added to DMF (1 mL). The reaction was run at RT for 24 h. The reaction was then diluted with water and the resultant precipitate was filtered and purified using flash column to afford product. MS (ES+): 441.5 (M+H). Calc'd. for C25H24N6O2—440.20.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Cl-:6].[Cl-].[Cl-].C[Zr:10](C)(C)(C)(C)[CH:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.O1CCC[CH2:21]1>>[Cl-:6].[Cl-:6].[CH3:1][C:2]1[C:11]([Zr+2:10])([CH3:12])[C:15]([CH3:21])=[C:14]([CH3:13])[C:3]=1[CH3:4]
Reactant: C[Zr](C)(C)(C)(C)C1C=CC=C1
Reactant: [Li]CCCC
Reactant: C1CCOC1
Agent: [Cl-]
Product: CC1=C(C)C(C)([Zr+2])C(C)=C1C
Temperature: 25 °C

Procedure:
A solution of 1.39 g of 1′H, 1′H, 2′H, 2′H-perfluorooctylcyclopentadiene from Example 5 in 50 ml of tetrahydrofuran is admixed at −78° C. with 2.1 ml of 1.65 M butyllithium solution and then admixed with a cooled suspension of 1.11 g of pentamethylcyclopentadienylzirconium trichloride in 30 ml of tetrahydrofuran. The mixture is allowed to warm to room temperature and the solvent is removed under reduced pressure. The product is isolated by means of extraction with methylene chloride and pentane.
Reaction SMILES: [N+:1]([O:4][CH:5]([CH2:33][O:34][N+:35]([O-:37])=[O:36])[CH2:6][O:7][C:8]([O:10][CH2:11]/[C:12](/[C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[C:13](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)\[C:14]([OH:16])=[O:15])=[O:9])([O-:3])=[O:2].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:1]([O:4][CH:5]([CH2:33][O:34][N+:35]([O-:37])=[O:36])[CH2:6][O:7][C:8]([O:10][CH2:11]/[C:12](/[C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][CH:28]=1)=[C:13](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)\[C:14]([O:16][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:15])=[O:9])([O-:3])=[O:2]
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(/C(=O)O)c2ccccc2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(/C(COC(=O)OCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(/C(=O)OCc2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 300 mg of (2Z)-4-({[2,3-bis(nitrooxy)propoxy]carbonyl}oxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid in 5 mL of DMF was added 69 μL benzyl bromide followed by 81 mg of potassium carbonate (325 mesh). The resulting mixture was stirred at rt for 30 min. The reaction was then quenched with saturated solution of NH4Cl and extracted with Et2O/hexanes (½, 2 times). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give a pale yellow residue. Flash chromatography of the crude material over silica gel (10-70% EtOAc/hexane) afforded 250 mg of the title compound as a white solid. 1H NMR (500 μL, acetone-d6): δ 7.80 (d, 2H), 7.48 (d, 2H), 7.42-7.35 (m, 5H), 7.21-7.18 (m, 3H), 7.13-7.10 (m, 2H), 5.77-5.73 (m, 1H), 5.36 (s, 2H), 5.33 (s, 2H), 5.04 (dd, 1H), 4.84 (dd, 1H), 4.64 (dd, 1H), 4.48 (dd, 1H), 3.08 (s, 3H).
Reaction SMILES: OC1C=CC(C(O)=O)=CC=1.S(Cl)(Cl)=O.[OH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>N1C=CC=CC=1>[CH2:32]([O:31][C:29]([C:28]1[CH:27]=[C:26]([NH:25][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([OH:15])=[CH:17][CH:18]=2)[CH:36]=[CH:35][CH:34]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1ccc(O)cc1
Agent: O=C(O)c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cccc(NC(=O)c2ccc(O)cc2)c1

Procedure:
4-Hydroxybenzoic acid can be converted into the corresponding acid chloride upon treatment with thionyl chloride in pyridine. The reaction of equimolar amounts of 4-hydroxybenzoyl chloride and ethyl 3-aminobenzoate in pyridine yields N-(3-ethoxycarbonylphenyl)4-hydroxybenzamide which can be transferred into ethyl 5-{[3-(ethoxycarbonylphenyl)amino]carbonyl}-2-hydroxybenzenepropanoate according to the procedure of Example 92A. Alkylation of this phenol according to the procedure of Example 60 followed by hydrolysis of the resulting diester by the method of Example 56 will provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:19]([OH:21])=O)=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:30])=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:19]([Cl:30])=[O:21])=[CH:4][CH:3]=1
Reactant: CSc1ncc2cc(C(=O)O)n(-c3ccc(F)cc3)c2n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1ncc2cc(C(=O)Cl)n(-c3ccc(F)cc3)c2n1
Temperature: 25 °C

Procedure:
To a cold (0° C.) solution of 7-(4-fluoro-phenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid, 24, (4.7 g, 15.5 mmol) in dichloromethane (100 mL) is added DMF (0.5 mL) followed by dropwise addition of oxalyl chloride (2.7 mL, 31.1 mmol). The mixture is allowed to slowly warm to room temperature over a period of 3 hours. The reaction mixture is concentrated in vacuo and can be dried azeotropically with toluene to afford 4.7 g of the desired product, which is used without further purification: 1H NMR (300 MHz, CDCl3) δ 9.38 (s, 1H), 8.04 (s, 1H), 7.40-7.20 (m, 4H), 2.58 (s, 3H); ESI+ MS: m/z (rel intensity) 322.0 (100, M++H).
Reaction SMILES: [H-].[Na+].O[C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=2[CH3:16])[CH:7]=[CH:8][CH:9]=1.Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].CN(C=[O:33])C>>[C:24]([CH2:23][CH2:22][CH2:21][O:33][C:7]1[CH:8]=[CH:9][CH:4]=[CH:5][C:6]=1[C:10]1[CH2:11][CH:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=1[CH3:16])([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1cccc(O)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCOc1ccccc1C1=C(C)NC(=O)C(C#N)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A dispersion of 337 mg (14.0 mmol) of 60% sodium hydride in mineral oil and5 ml of DMF is treated, dropwise, with a solution of 1.60 g (7.0 mmol) of 5-(3-hydroxyphenyl)-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile. Thereaction is stirred 30 min at RT, then cooled in an ice bath and 1.36 g (7.0 mmol) of ethyl 4-bromobutyrate in 5 ml of DMF is added dropwise. The reaction is allowed to slowly come to RT and stirred over night. The mixture is concentrated under vacuum, the residue is taken up in 80 ml of water, extracted with EtOAc, acidified to pH=5 with 1N HCl, and the aqueous phase extracted with EtOAc (4×80 ml). The EtOAc is dried (MgSO4) and the solvent removed to leave a light yellow solid. This solid is triturated with hot ether and filtered to give 1.40 g of 5-(3-carboethoxypropyloxyphenyl)-6-methyl-2-oxo-1,3-dihydro-3 -pyridinecarbonitrile as a pale yellow solid, m.p. 168°-169°C. 1H-NMR (d6 -DMSO): δ 1.20 (t,3H); 1.95 (m,2H); 2.15 (s,3H); 2.50 (t,2H); 4.03 (q,2H); 4.05 (t,2H); 6.95 (m,3H); 7.30 (m,1H); 8.10 (s,1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:11])[CH:6]([NH2:10])[C:7]([OH:9])=[O:8])[CH3:3].[CH2:12]([O:16][C:17](Cl)=[O:18])[CH2:13][CH2:14][CH3:15].[CH2:20](N(CC)CC)[CH3:21]>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:11])[CH:6]([NH:10][C:17]([O:16][CH2:12][CH2:13][CH2:14][CH3:15])=[O:18])[C:7]([O:9][CH2:20][CH3:21])=[O:8])[CH3:3]
Reactant: CCCCOC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C(N)C(=O)O
Agent: Cl
Solvent: ClCCl
Product: CCCCOC(=O)NC(C(=O)OCC)C(=O)OCC
Temperature: 20 °C
Reaction time: 1.25 h
Yield: 96.4 %

Procedure:
To an ice-cold suspension of 15 g (70.87 mmol) of amino malonic acid ethyl ester hydrochloride in 180 ml of methylene chloride, 10.8 g (75 mmol) of chloroformic acid butyl ester and then 14.7 g (145 mmol) of triethylamine were added within several minutes. In this case the temperature was constantly maintained under 20° C. After the addition was completed, the reaction was stirred for another 75 minutes at room temperature. The reaction solution was diluted with 80 ml of CH2Cl2, washed with two portions of water, and dried on Na2SO4. After concentration by evaporation on a rotary evaporator, 18.8 g (96 percent) of pure title product was obtained. Other data concerning the product was:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9](=[O:11])=O.O.[ClH:13]>O1CCCC1.CCCCCC>[Cl:8][C:4]1[N:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:9]([Cl:13])=[O:11]
Reactant: Cl
Reactant: O=C=O
Reactant: Clc1cccc(Cl)n1
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=C(Cl)c1ccc(Cl)nc1Cl
Temperature: -10 °C
Reaction time: 1 h

Procedure:
(1)-1 2,6-Dichloropyridine (20 g) was dissolved in tetrahydrofuran (200 ml), and, to the resulting solution, there was added dropwise a solution of n-butylithium (1.6M) in n-hexane (84.5 ml) in a flow of argon gas at a temperature of -78° C. over a period of 30 minutes. After the resulting solution was stirred for one hour at the same temperature, greatly excess carbon dioxide (solid) was added. After stirring for one hour, temperature was raised to -10° C., and, then, water and hydrochloric acid were added in order so that pH might be 1-2, and, thereafter, the resultant solution was extracted with ethyl acetate. After the obtained extract was dried over anhydrous sodium sulfate, solvent was distilled off under reduced pressure to dryness. To the obtained solid, there was added thionyl chloride (40 ml), and the resulting mixture was heated to reflux for three hours. The excess thionyl chloride was distilled off under reduced pressure, and, then, crude product was distilled under reduced pressure to form 2,6-dichloronicotinoyl chloride (19.8 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([Si:15](Cl)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].[CH2:21]([Si:23]([CH2:38][CH3:39])([CH2:36][CH3:37])[O:24][CH2:25][C:26]([O:28][Si:29]([CH2:34]C)([CH2:32]C)[CH2:30]C)=[O:27])[CH3:22]>C1COCC1>[CH2:13]([Si:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[O:27][C:26]([O:28][Si:29]([CH3:34])([CH3:32])[CH3:30])=[CH:25][O:24][Si:23]([CH2:38][CH3:39])([CH2:21][CH3:22])[CH2:36][CH3:37])[CH3:14]
Reactant: CC[Si](CC)(CC)OCC(=O)O[Si](CC)(CC)CC
Reactant: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC=C(O[Si](C)(C)C)O[Si](CC)(CC)CC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (15.5 mL, 0.11 mol) in THF (100 mL) at −78° C. was added a 1.6 M hexanes solution of n-butyl lithium (70 mL, 0.11 mol) over 15 minutes. After stirring for an additional 15 minutes at this temperature, triethylsilylchloride (16.7 mL, 0.1 mol) was added over 10 minutes followed by the addition of triethylsilyl 2-(triethylsiloxy)acetate (37.6 g, 0.1 mol) over 30 minutes. The reaction was stirred at −78° C. for 30 minutes and warmed to ambient temperature by removing the cryogenic bath and the THF solvent was removed by vacuum rotary evaporation at 40° C. to precipitate the lithium chloride. The mixture was taken up in 300 mL of hexanes and 5 mL of triethylamine and stirred for 5 minutes and the salt was allowed to settle. The supernatant was twice filtered through a pad of diatomaceous earth to give a clear solution. The solution was concentrated under rotary evaporation to give the lightly yellow colored oil product as a 1:1 mixture of geometrical isomers.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C:11]1([CH2:14][OH:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:16])[NH:10][C:11]1([CH2:14][O:15][CH3:17])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: O=C(NC1(CO)CC1)OCc1ccccc1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCC1(NC(=O)OCc2ccccc2)CC1
Reaction time: 5 h
Yield: 42.5 %

Procedure:
To a solution of benzyl[1-(hydroxymethyl)cyclopropyl]carbamate (0.32 g, 0.0014 mol) in methylene chloride (5.0 mL) was added sequentially powdered MS 4A, N,N,N′,N′-tetramethyl-1,8-naphthalenediamine (0.77 g, 0.0036 mol), and trimethyloxonium tetrafluoroborate (0.43 g, 0.0029 mol) at RT. The mixture was stirred for 5 h, filtered through a pad of Celite, and washed with EtOAc. The filtrate was washed with 1N HCl, water, brine, dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with EtOAc in hexanes (0-30%) to afford the desired product (140 mg, 41%). LCMS: (M+H)=236.1.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1)=[O:14].Br[C:31]1[N:32]([CH3:36])[CH:33]=[CH:34][N:35]=1>>[CH3:36][N:32]1[CH:33]=[CH:34][N:35]=[C:31]1[C:18]1[CH:19]=[CH:20][C:15]([C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[CH2:7][N:3]2[CH2:4][CH2:5][CH2:6][C@H:2]2[CH3:1])=[O:14])=[CH:16][CH:17]=1
Reactant: Cn1ccnc1Br
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2nccn2C)cc1
Yield: 11 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure A using [2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (439 mg, 1.1 mmol) and 2-Bromo-1-methyl-1H-imidazole (CAS 16681-59-7) (161 mg, 1.0 mmol) to give 39 mg (11% yield). MS (ES+) 353.2 (M+H)+
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[C:10](=[O:21])[NH:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN1C(=O)CCC1>[O:21]=[C:10]1[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:3][CH:4]=2)=[CH:14][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:12][NH:11]1
Reactant: C1CCNCC1
Reactant: O=C(Nc1cc(-c2ccncc2)c[nH]c1=O)c1ccc(Br)cc1
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc(-c2ccncc2)c[nH]c1=O)c1ccc(N2CCCCC2)cc1
Temperature: 160 °C
Yield: 43 %

Procedure:
4-Bromo-N-(1,2-dihydro-2-oxo-5-(pyridin-4-yl)pyridin-3-yl)benzamide (30 mg, 0.081 mmol) I-20 was placed in a microwave tube equipped with a stirrer bar. NMP (0.75 mL) was added, followed by piperidine (1.5 mL). The reaction vessel was heated at 160° C. for 2 hours in a microwave. After cooling, the solvent and excess piperidine were removed in vacuo. The crude compound was recrystallized from methanol to give the title compound as a white solid (13 mg, 43% yield).). MS (ES+) m/e=375. 1H NMR (DMSO-d6) δH 1.54-1.65 (6H, m), 3.30-3.38 (4H, m), 7.02 (2H, d), 7.61 (2H, d) 7.72-7.80 (1H, m), 7.78 (2H, d), 8.59 (2H, d), 8.77 (1H, d), 9.13 (1H, s), 12.58 (1H, bs).