Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C1N=CN([C:15](N2C=NC=C2)=[O:16])C=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[O:16]=[C:15]1[O:1][N:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[NH:9]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C(=N)NO
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1noc(=O)[nH]1
Temperature: 80 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of ethyl 2-(hydroxyamino)-2-iminoacetate (2 g, 15.14 mmol) in dioxane (15.00 mL) is added CDI (2.7 g, 16.65 mmol) and DBU (2.5 ml, 16.65 mmol) at room temperature. After stirring for 1 hour at 80° C., the reaction is quenched with 1N HCl, and the crude is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give ethyl 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylate (2.4 g). HPLC retention time=0.72 minutes (condition D); MS 159.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:17]=O)[CH:14]=[N:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[O:20]([NH2:22])[CH3:21]>>[CH3:21][O:20]/[N:22]=[CH:17]/[C:13]1[CH:14]=[N:15][CH:16]=[C:11]([C:10]#[C:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:12]=1
Reactant: CON
Reactant: COc1cccc(C#Cc2cncc(C=O)c2)c1
Agent: Cl
Product: CO/N=C/c1cncc(C#Cc2cccc(OC)c2)c1
Yield: 78 %

Procedure:
Prepare essentially as described in EXAMPLE 6 using 5-(3-methoxyphenylethynyl)-pyridine-3-carbaldehyde, (prepared essentially as described in EXAMPLE 91), (290 mg, 1.22 mmol) and methoxylamine hydrochloride (520 mg, 9.78 mmol). The E/Z Isomers were separated during the purification to give the title compound (254 mg, 78%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].N1(/[C:15](/[CH3:25])=[CH:16]\[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)CCCC1>C(O)(=O)C>[CH3:7][C:4]1[C:3]([C:8]#[N:9])=[C:2]2[N:1]=[C:15]([CH3:25])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:6]2[N:5]=1
Reactant: C/C(=C/C(=O)c1ccccc1)N1CCCC1
Reactant: Cc1n[nH]c(N)c1C#N
Solvent: CC(=O)O
Product: Cc1cc(-c2ccccc2)n2nc(C)c(C#N)c2n1
Yield: 78.3 %

Procedure:
A mixture of 4.88 g of 5-amino-3-methyl-4-pyrazolecarbonitrile and 8.61 g of 3-(1-pyrrolidinyl)crotonophenone in 50 ml of glacial acetic acid is stirred and heated at reflux for 6 hours. The reaction mixture is cooled and the procedure described in Example 2 is then followed to obtain 7.77 g of the desired product, mp 175°-177° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:17][OH:18])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:4][O:5][N:6]=1.C(N(CC)C(C)C)(C)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>ClCCl>[NH2:1][C:2]1[C:3]([C:7](=[N:17][O:18][C:28](=[O:31])[CH2:29][CH3:30])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:4][O:5][N:6]=1
Reactant: CCC(=O)Cl
Reactant: Nc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)ON=C(Nc1ccc(F)c(Cl)c1)c1nonc1N
Reaction time: 1 h
Yield: 47 %

Procedure:
A solution of 4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (0.1 g, 0.37 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.92 mmol) in dichloromethane (4 mL) was treated with propanoyl chloride (38 μL, 0.44 mmol) and stirred for 1 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (57 mg, 47%). LCMS for C12H12ClFN5O3 (M+H)+: m/z=328.0.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([Sn](CCCC)(CCCC)[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)CCC.[F-].[NH4+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:20]1[CH:21]=[CH:22][C:17]([C:2]2[CH:6]=[CH:5][O:4][C:3]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:18][CH:19]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: CCOC(=O)c1occc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1occc1-c1ccncc1
Yield: 45.4 %

Procedure:
Ethyl 3-bromofuran-2-carboxylate (296 mg, 1.35 mmol) obtained in Step 1 of Reference Example 29, 4-(tri-n-butylstannyl)pyridine (550 mg, 1.51 mmol) and tetrakis(triphenylphosphine)palladium(0) (157 mg, 0.136 mmol) were dissolved in THF (10 mL), followed by stirring under heating and reflux for 4 hours. Aqueous ammonium fluoride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=2:3) to afford ethyl 3-(4-pyridyl)furan-2-carboxylate (133 mg, 45%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][C:49]1[NH:53][N:52]=[C:51]([C:54](O)=[O:55])[CH:50]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:54]([C:51]2[CH:50]=[C:49]([CH3:48])[NH:53][N:52]=2)=[O:55])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1cc(C(=O)O)n[nH]1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)n[nH]1
Yield: 29 %

Procedure:
The desired compound was prepared according to the procedure of Example A27, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 5-methyl-1H-pyrazole-3-carboxylic acid as starting materials in 29% yield. LCMS for C29H31ClN9O2 (M+H)+: m/z=572.2.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[O:21]=[CH:22][C:23]1[CH:31]=[CH:30][C:28]([OH:29])=[C:25]([O:26][CH3:27])[CH:24]=1.CN(C)C=O>O>[CH3:27][O:26][C:25]1[CH:24]=[C:23]([CH:31]=[CH:30][C:28]=1[O:29][CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8])[CH:22]=[O:21]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1sc(N2CCCCC2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCc1nc(N2CCCCC2)sc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A mixture of 1-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)piperidine (0.57 g), potassium carbonate (0.35 g), vanillin (0.38 g) and N,N-dimethylformamide (20 mL) was stirred at 80° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-methoxy-4-[(5-methyl-2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde as colorless crystals (0.61 g, yield 70%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 80-81° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([S:7]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([CH2:15][CH2:16][CH2:17]3)=[CH:13][C:12]=2[O:20][CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)(=[O:9])=[O:8])[S:5][CH:6]=1.[F:32][CH:33]([CH3:36])[CH2:34]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:32][CH:33]([CH3:36])[CH2:34][N:10]([S:7]([C:4]1[S:5][CH:6]=[C:2]([CH3:1])[N:3]=1)(=[O:8])=[O:9])[C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][CH2:17]2)=[CH:13][C:12]=1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1
Reactant: CC(F)CO
Reactant: COC(=O)c1ccc(COc2cc3c(cc2NS(=O)(=O)c2nc(C)cs2)CCC3)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(COc2cc3c(cc2N(CC(C)F)S(=O)(=O)c2nc(C)cs2)CCC3)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 103.5 %

Procedure:
311 mg of methyl 4-{[(6-{[(4-methyl-1,3-thiazol-2-yl)sulfonyl]amino}-2,3-dihydro-1H-inden-5-yl)oxy]methyl}benzoate, 63.6 mg of 2-fluoro-1-propanol, and 356 mg of triphenylphosphine were dissolved in 4.0 mL of THF, and 591 mg of diethyl azodicarboxylate was added thereto under ice-cooling, followed by stirring at room temperature for 20 hours. The reaction liquid was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 60:40) to obtain 364 mg of methyl 4-{[(6-{(2-fluoropropyl)[(4-methyl-1,3-thiazol-2-yl)sulfonyl]amino}-2,3-dihydro-1H-inden-5-yl)oxy]methyl}benzoate.
Reaction SMILES: [CH:1]([N:4]1[C:8](Cl)=[N:7][C:6]([OH:10])=[N:5]1)([CH3:3])[CH3:2].[F-:11].[K+]>S1(CCCC1)(=O)=O>[CH:1]([N:4]1[C:8]([F:11])=[N:7][C:6]([OH:10])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1nc(O)nc1Cl
Reactant: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: CC(C)n1nc(O)nc1F

Procedure:
16.2 g of 1-isopropyl-5-chloro-3-hydroxy-1,2,4-triazole, 29 g of dry potassium fluoride and 150 ml of sulpholane are heated together for 16 hours to 160°-200°C. The solvent is evaporated in a high vacuum and the residue then treated with 10 % acetic acid and extracted with ethyl acetate. The ethyl acetate is evaporated off and the residueal solid is recrystallised from water, in the process of which 1-isopropyl-5-fluoro-3-hydroxy-1,2,4-triazole is obtained in the form of white crystals with a melting point of 80°-95°C. The product can be recrystallised from an organic solvent in order to purify it further.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1>>[CH3:1][C:2]1[S:3][C:4]([C:14]2([OH:17])[CH2:15][CH2:16][C:11]3([O:10][CH2:9][CH2:8][O:7]3)[CH2:12][CH2:13]2)=[CH:5][N:6]=1
Reactant: Cc1nccs1
Reactant: O=C1CCC2(CC1)OCCO2
Product: Cc1ncc(C2(O)CCC3(CC2)OCCO3)s1

Procedure:
The title compound was prepared as a white solid from 2-methyl-thiazole (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 33.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:19][C:20](=[O:33])[CH:21]=[CH:22][C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.Cl.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([NH:1][CH2:2][C@@H:3]([NH:19][C:20](=[O:33])/[CH:21]=[CH:22]/[C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)(=[O:44])[CH3:43]
Reactant: COc1ccc(C#N)cc1C=CC(=O)N[C@H](CN)CN1CCC(Oc2ccc(F)cc2)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CNC(C)=O)CN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of E)-N-{(R)-1-aminomethyl-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-3-(5-cyano-2-methoxy-phenyl)-acrylamide.HCl salt (0.35 g, 0.66 mmol) and triethylamine (0.27 ml, 1.99 mmol) in DCM (5 ml) is treated with acetyl chloride (0.042 ml, 0.6 mmol) at 5° C. The reaction mixture is stirred at ambient temperature for 1 hour then washed with water, saturated aqueous NaHCO3 and brine. The organic phase is dried over MgSO4 and the solvent evaporated. The crude product is purified by flash chromatography (elution methanol:DCM; 4:96) to afford (E)-N-{(R)-1-(acetylamino-methyl)-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-3-(5-cyano-2-methoxy-phenyl)-acrylamide. [MH]+ 495.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C(N(CC)CC)C.O.[Cu]I>[CH2:15]([N:14]([CH2:18][CH2:19][CH3:20])[C:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:13])[CH2:16][CH3:17]
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C#C[Si](C)(C)C)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A solution of methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (25) (200 mg, 0.58 mmol), PdCl2(Ph3P)2 (16 mg, 0.03 mol %) and CuI (6 mg, 0.05 mol %) in triethylamine (1.2 mL) was heated to reflux. (Trimethylsilyl)acetylene (100 μL, 0.7 mmol) was added, and the bright yellow solution quickly turned orange then went brown within a minute. The reaction mixture was stirred for 3 h, cooled to room temperature, diluted with H2O (20 mL), and extracted with CHCl3 (3×15 mL). The combined organics were washed with saturated NaCl (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 3-[(dipropylamino)carbonyl]-5-[(trimethylsilyl)ethynyl]benzoate 26 (185.5 mg): 1H NMR (300 MHz, CDCl3): δ 7.95 (s, 1H), 7.75 (s, 1H), 7.43 (s, 1H), 3.74 (s, 3H), 3.25 (br s, 2H), 2.95 (br s, 2H), 1.49 (br s, 2H), 1.34 (br s, 2H), 0.79 (br s, 3H), 0.56 (br s, 3H), 0.06 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]3=[N:10][C:9]=2[CH:20](O)[CH3:21])[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]3=[N:10][C:9]=2[CH:20]([N:46]2[C:42](=[O:52])[C:43]3[C:44](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:45]2=[O:47])[CH3:21])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2nc(C(C)O)c(-c3cccc(F)c3)c(=O)n12
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc2nc(C(C)N3C(=O)c4ccccc4C3=O)c(-c3cccc(F)c3)c(=O)n12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 3-(3-fluorophenyl)-2-(1-hydroxyethyl)-6-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one (0.6500 g, 2.179 mmol), triphenylphosphine (0.6858 g, 2.615 mmol), phthalimide (0.3847 g, 2.615 mmol), and THF (14.53 mL) was stirred at rt for 5 min to dissolve all reactants. The mixture was then cooled to 0° C. and to the cooled homogenous mixture was added dropwise over 3 min to diisopropyl azodicarboxylate (0.5148 mL, 2.615 mmol) at 0° C. The reaction mixture was allowed to warm to rt and stirred at rt. After 5 h, the mixture was concd under reduced pressure and partitioned between EtOAc (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concd under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and 50% isocratic of EtOAc for 10 min as eluent to give 2-(1-(3-(3-fluorophenyl)-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethypisoindoline-1,3-dione as a bright yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75-7.82 (2 H, m), 7.65-7.74 (3 H, m), 7.35-7.42 (1 H, m), 7.13-7.24 (1 H, m), 6.90-7.01 (4 H, m), 5.43 (1 H, q, J=7.0 Hz), 2.89 (3 H, s), 1.62 (3 H, d, J=7.4 Hz); Mass Spectrum (ESI) m/e=427.9 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[NH2:16][C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24]2)=[N:21][CH:22]=1>>[C:13]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:16][C:17]1[CH:22]=[N:21][C:20]([N:23]3[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24]3)=[N:19][CH:18]=1)=[N:10][C:9]([Cl:12])=[CH:8][CH:7]=2)(=[O:15])[CH3:14]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncc(N)cn2)C1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1cnc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 80.6 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (300 mg, 1.2 mmol) was reacted with tert-butyl 1-(5-aminopyrimidin-2-yl)pyrrolidin-3-ylcarbamate (380 mg, 1.4 mmol) to afford the desired product (468 mg, 78%) as a yellow-orange solid: 1H NMR (500 MHz, CDCl3) δ 11.72 (s, 2H), 9.09 (s, 2H), 8.21 (s, 3H), 8.11 (d, J=8.7 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.26 (s, 2H), 4.70 (s, 2H), 4.38 (s, 2H), 3.90 (dd, J=11.6, 6.1 Hz, 2H), 3.78-3.66 (m, 4H), 3.52 (dd, J=11.6, 4.3 Hz, 2H), 2.77 (s, 5H), 2.31 (dq, J=13.4, 7.2 Hz, 2H), 1.57 (s, 2H), 1.47 (s, 17H), 1.19 (s, 1H); ESI MS m/z 484 [M+H]+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:15](=[O:34])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:43]>C(OCC)(=O)C>[ClH:43].[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15](=[O:34])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:17]=2)=[CH:40][CH:39]=1
Reactant: COc1ccc(N(C(=O)c2cccc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(N(C(=O)c2cccc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[3-(3,4,5-trimethoxypheny)benzoyl]amino]piperidine (416 mg) in ethyl acetate (5 mL) was added 4 M hydrogen chloride in ethyl acetate (5 mL). The mixture was stirred at room temperature for 4 hr, resulting precipitates were collected and washed with ethyl acetate on a funnel to give the title compound.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([NH:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:4]
Reactant: NCCC(=O)O
Reactant: CC(Br)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Br)C(=O)NCCC(=O)O

Procedure:
72.69 g (311.3 mmol) of α-bromopropionic acid chloride is added in drops at 0° C. to 40 g (448.98 mmol) of β-alanine and 90 g (889.5 mmol) of triethylamine in 500 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 1000 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 500 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is recrystallized from acetone/diisopropyl ether.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:15]([F:16])=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[C:18]=2[F:26])[N:13]=[C:12]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:11]=1/[CH:37]=[CH:38]/[Si](C)(C)C>CN(C=O)C.O>[NH2:9][C:10]1[C:15]([F:16])=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[C:18]=2[F:26])[N:13]=[C:12]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:11]=1/[CH:37]=[CH:38]/[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(/C=C/[Si](C)(C)C)c(N)c2F)c1F
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(/C=C/Cl)c(N)c2F)c1F
Temperature: 50 °C
Reaction time: 24 h
Yield: 21.5 %

Procedure:
N-Chlorosuccinimide (NCS; 190 mg, 1.4 mmol, 2.0 equiv) was added to a stirred solution of (E)-benzyl 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-3-(2-(trimethylsilyl)vinyl)picolinate (350 mg, 0.70 mmol, 1.0 equiv) in DMF (7.0 mL) at 23° C. The homogeneous pale green solution was heated to 50° C. and stirred for 24 h. The cooled reaction mixture was diluted with water (400 mL) and extracted with Et2O (4×100 mL). The combined organic layers were dried (MgSO4), gravity filtered, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to afford the desired product, (E)-benzyl 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-(2-chlorovinyl)-5-fluoropicolinate as a tan powder (70 mg, 22% yield): mp 133-135° C.; IR (thin film) 3486 (s), 3345 (s), 3215 (w), 3069 (w), 3037 (w), 2953 (w), 1719 (s), 1616 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.47-7.43 (m, 2H), 7.41-7.33 (m, 3H), 7.27 (m, 2H), 6.89 (d, J=14 Hz, 1H), 6.45 (d, J=14 Hz, 1H), 5.37 (s, 2H), 4.62 (br s, 2H), 3.97 (d, J=1 Hz, 3H); ESIMS m/z 465 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21]C)=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:32])[F:31])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[I-].[Na+].C[Si](Cl)(C)C>C(#N)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[N:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:31])[F:32])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1nc(O)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (152.2 mg, 0.319 mmol) in acetonitrile (3.0 mL) were added sodium iodide (143.5 mg, 0.958 mmol) and trimethylsilyl chloride (121.6 μL, 0.958 mmol). The mixture was stirred at room temperature for 1 day. To the mixture were added sodium iodide (71.8 mg, 0.479 mmol) and trimethylsilyl chloride (60.8 μL, 0.479 mmol). The mixture was stirred at room temperature for 3 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10% methanol/ethyl acetate gradient mixture to give the title compound as a colorless amorphous (119.8 mg, 0.259 mmol, 81%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[CH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]([CH3:25])([CH3:24])[C:14]=3[C:13]=2[NH2:26])=[CH:6][CH:5]=1.[Li].[H-].[Al+3].[H-].[H-]>C1COCC1>[NH2:26][C:13]1[C:14]2[C:15]([CH3:24])([CH3:25])[CH2:16][CH2:17][C:18]([CH3:22])([CH3:23])[C:19]=2[CH:20]=[CH:21][C:12]=1[CH:11]=[N:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(N=Cc2ccc3c(c2N)C(C)(C)CCC3(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2c1ccc(C=Nc1ccc(CO)cc1)c2N
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
In a round bottom flask, there are introduced 420 mg (1.15 mmole) of the ester obtained in Example 11 (b) and 25 ml of THF. There are then introduced, by portions, 110 mg (2.88 mmoles) of the double lithium and aluminum hydride. The mixture is stirred for 8 hours at ambient temperature. The reaction medium is hydrolyzed with hydrated sodium sulfate. The resulting precipitate is filtered and the filtrate is evaporated. 350 mg (93%) of the expected alcohol whose melting point is 171°-172° C. are obtained.