Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[C:14]#[N:15])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:29]1[N:36]=[CH:35][CH:34]=[C:33]([I:37])[C:30]=1[CH:31]=[O:32].[NH4+].[Cl-]>O.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[C:14]#[N:15])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:29]1[C:30]([CH:31]=[O:32])=[C:33]([I:37])[CH:34]=[CH:35][N:36]=1)[CH:8]=[CH:7]2
Reactant: O=Cc1c(I)ccnc1F
Reactant: CC(C)(C#N)c1cc(F)c2c(=O)[nH]ccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C#N)c1cc(F)c2c(=O)n(-c3nccc(I)c3C=O)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.9 %

Procedure:
In a 100 mL round-bottomed flask 2-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanenitrile (800 mg, 3.47 mmol, 1 equiv.) was combined with THF (32.0 ml) to give a yellow suspension. A solution of lithium bis(trimethylsilyl)amide in THF 1M (4.52 ml, 4.52 mmol, 1.3 equiv.) was added. The reaction mixture was stirred at room temperature for 15 min. To the resultant amber solution was added 2-fluoro-4-iodonicotinaldehyde (1.31 g, 5.21 mmol, 1.5 equiv.). The reaction mixture was heated at 50° C. with stirring for 15 h. The reaction mixture was poured into 5 mL saturated NH4Cl and 100 mL H2O and extracted with DCM (3×100 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0%, then 0% to 0.5% MeOH in DCM), followed by trituration with ether:hexanes (1:8) to afford 2-[8-fluoro -2-(3-formyl-4-iodo-pyridin-2-yl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile as a pale yellow solid (830 mg). (M+H)+=462 m/e.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:5]=[C:6]([Cl:17])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][C@@H:12](CO)[O:11][C:10]1=[O:16].[OH-].[Na+].I(O)(=O)(=O)=[O:28].Cl>C1COCC1.O.CCOC(C)=O>[Cl:17][C:6]1[CH:5]=[C:4]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH:12]([OH:28])[O:11][C:10]1=[O:16]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: O=C1O[C@H](CO)C[C@H]1Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1OC(O)C[C@H]1Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Reaction time: 0.67 h
Yield: 75724.9 %

Procedure:
To (3R,5S)-3-(3,5-dichloro-4′-fluoro-biphenyl-4-ylmethyl)-5-hydroxymethyl-dihydro-furan-2-one (375 g, 1.015 mmoles) dissolved in 5 vols of THF, add 750 mL of 2 N NaOH. After 40 min, add periodic acid (375 g, 1,644 mmoles), dissolved in 1,125 mL of water, over 17 min (Tmax 33° C.). Add EtOAc (3 L) followed by 800 mL of 5.0 N HCl and 600 mL of water. Agitate the layers and then separate. Wash the organic layer with 100 g of sodium thiosulfate in 1 L of water, then 1 L of water, and then 700 mL of saturated NaCl in water. Dry the organic layer over sodium sulfate and then solvent exchange into 4 volumes (1500 mL) of heptane. Collect the solid by filtration and dry under vacuum. Reslurry the resulting solid in 3 volumes (1 L) of acetonitrile at 55° C. Cool the mixture in an ice bath and collect the solid by filtration. Dry the solid under vacuum to afford 273 g (78% yield) of the title compound as a white solid. MS (m/z): 355 (M+1, 35Cl), 357 (M+1, 37Cl).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][C:14]([OH:16])=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:29]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]1.Cl>O1CCCC1.C(OCC)(=O)C.O.C(N(CC)CC)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][C:14]([N:29]3[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]3)=[O:16])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: OC1CCNC1
Reactant: O=C(O)COCCc1ccc2occc2c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(COCCc1ccc2occc2c1)N1CCC(O)C1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
In 13.0 mL of tetrahydrofuran was dissolved 1.28 g of 2-[2-(1-benzofuran-5-yl)ethoxy]acetic acid and the solution was cooled to 5° C., after which 1.41 g of 1,1′-carbonyldiimidazole was added thereto and the resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture were added 1.22 mL of triethylamine and 0.72 mL of 3-pyrrolidinol, followed by stirring at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture and the pH was adjusted to 1 with 6 mol/L hydrochloric acid, after which the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 1.39 g of 2-[2-(1-benzofuran-5-yl)ethoxy]-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanone as a colorless oil.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([N:27]([CH3:29])[CH3:28])(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24](=[O:26])(=[O:25])[N:27]([CH3:28])[CH3:29])[CH:10]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccccc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 9.7 %

Procedure:
(Step 3) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.56 g), 2-(aminomethyl)-N,N-dimethylbenzenesulfonamide hydrochloride obtained in Step 2 (2 g) and potassium carbonate (2.3 g) were stirred in ethanol (20 ml) at 80° C. for 16 hr. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and extracted with a mixed solvent of ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=4:1). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (3 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized to give the title compound (0.13 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=O)[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:25].CN(C)C1C=CC=CC=1>>[Cl:25][C:17]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:12][CH:11]=2
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(c1ccc(F)cc1)N2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 2-(4-fluorophenyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (1.2 g, 4.00 mmol, 1.00 equiv), POCl3 (12.2 g, 80.26 mmol, 20.00 equiv), N,N-dimethylbenzenamine (4.9 g, 40.50 mmol, 10.00 equiv). The resulting solution was stirred for overnight at 110° C. in an oil bath. The resulting mixture was concentrated under vacuum and diluted with 50 mL of water. The pH value of the aqueous solution was adjusted to 7 with sodium bicarbonate (4 mol/L). The resulting mixture was concentrated under vacuum and purified by silica gel chromatography with ethyl acetate/petroleum ether (1:40).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[CH:17])=[CH:12][CH:11]=2)=[CH:6][CH2:5]1)[CH2:2][CH3:3].C([CH:21]1[CH2:26][CH2:25][CH:24]([C:27]2C=[CH:31][C:30](C#C)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)CC>>[CH2:1]([CH:4]1[CH2:9][CH2:8][C:7]([C:10]2([C:11]#[C:12][C:21]3[CH:22]=[CH:23][C:24](/[CH:27]=[CH:28]/[CH2:29][CH2:30][CH3:31])=[CH:25][CH:26]=3)[CH:17]=[CH:16][CH:13]=[CH:14][CH2:15]2)=[CH:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: C#Cc1ccc(C2CCC(CCC)CC2)cc1
Reactant: C#Cc1ccc(C2=CCC(CCC)CC2)cc1
Product: CCC/C=C/c1ccc(C#CC2(C3=CCC(CCC)CC3)C=CC=CC2)cc1
Yield: 72 %

Procedure:
In the same manner as in Example 17 except that 4-(4-propylcyclohexenyl)phenylacetylene, (3.4 g, 0.015 moll was used in place of 4-(4-propylcyclohexyl)phenylacetylene, the reaction was carried out to obtain 1-(4-propylcyclohexenyl)phenyl-2-[4-(1-trans-pentenyl)phenyl]acetylene (2.7 g). Yield: 72%.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[S:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=3)[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:30][N:31]=[C:32]=[O:33]>CN(C=O)C.C(Cl)Cl>[C:19]([C:16]1[S:15][C:14]([NH:13][C:9]2[N:10]=[CH:11][N:12]=[C:7]([N:1]3[CH2:6][CH2:5][N:4]([C:32]([NH:31][CH3:30])=[O:33])[CH2:3][CH2:2]3)[CH:8]=2)=[N:18][CH:17]=1)#[N:20]
Reactant: CN=C=O
Reactant: N#Cc1cnc(Nc2cc(N3CCNCC3)ncn2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)N1CCN(c2cc(Nc3ncc(C#N)s3)ncn2)CC1

Procedure:
12-3 (0.25 g, 0.88 mmol) was dissolved in a minimal amount of DMF (2 mL) and DIEA (0.57 g, 4.38 mmol) before it was diluted with methylene chloride (5 mL). Then a methylene chloride solution (1 mL) of methylisocyanate (0.050 g, 0.88 mmol) was added. A precipitate quickly formed and was filtered off, washed with methylene chloride and air dried to afford 43-1. Hi-Res MS: calc: 345.1241 found: 345.1269. 1H-NMR (DMSO-d6): 12.09(s, 1H); 8.44(s, 1H); 8.26(s, 1H); 6.52(d, 1H); 6.21(s, 1H); 3.54(m, 4H); 3.40(m, 4H); 2.58(d, 3H).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:10](Cl)=[O:11])[CH2:6][CH2:5]1)(=O)C.[Cl-].[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29]>C(O)C.O.CCOCC>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[CH2:28]([O:29][C:10]([C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1)=[O:11])[CH3:27]
Reactant: CC(=O)N1CCC(C(=O)Cl)(c2ccccc2Sc2ccccc2)CC1
Agent: O=C(O)C(=O)O
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(c2ccccc2Sc2ccccc2)CCNCC1

Procedure:
A mixture of 2 g of 1-acetyl-4-(2-phenylthiophenyl)-piperidine-4-carbonyl chloride, Example 16, in 50 ml of absolute ethyl alcohol saturated with anhydrous chloride is stirred at reflux for 64 hours. Thereafter, the excess acid and alcohol is removed under reduced pressure, leaving a clear, glassy residue. The residue is dissolved in 30 ml of water and the aqueous solution is extracted with ethyl acetate. The aqueous solution is basified with potassium carbonate, liberating an oil. The oil is dissolved in ether and the ethereal solution is dried before concentrating to dryness, leaving a brownish oil. The oil, in ether, is converted to its oxalic acid salt which is recrystallized from a methyl alcohol-acetone-ether mixture to provide 4-ethoxycarbonyl-4-(2-phenylthiophenyl)-piperidine oxalate.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=O)[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[C:13]([NH2:16])(=[S:15])[CH3:14].C(=O)(O)[O-].[Na+]>C(O)C.CCOCC.CCCCCC>[CH3:14][C:13]1[S:15][CH:8]=[C:7]([C:6]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:16]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOCC
Product: Cc1nc(-c2ccc(C#N)cc2)cs1
Yield: 92.9 %

Procedure:
Suspend 4-cyanophenacyl bromide (515 mg, 2.23 mmol) in ethanol (15 mL). Add thioacetamide (171 mg, 2.23 mmol) and sodium bicarbonate (187 mg, 2.23 mmol) and heat the mixture under reflux for 2 h. Concentrate in vacuo and dissolve the residue in DCM. Wash the organic fraction with water, dry over Na2SO4, filter and concentrate to give a solid. Suspend the solid in ether/hexane and filter under vacuum washing with hexane to obtain the desired intermediate as a white solid (415 mg, 93%). GC-MS m/z: 200 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.C([O:30][C:31]1[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:33](Cl)=[O:34])(=O)C.[OH-].[Na+].Cl>C(Cl)Cl>[OH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5])=[O:34]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: Nc1ccccc1C(=O)NCC(=O)O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CNC(=O)c1ccccc1NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 4.74 g (24.44 mmol) of 2-(2-aminobenzoylamino)ethanoic acid in 40 ml of dry methylene chloride, add 5.05 g (4.28 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 3.16 g (31.32 mmol) of triethylamine and a solution of 4.13 g (20.88 mmol) of acetylsalicyloyl chloride dissolved in 10 ml of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 40 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization (EtOH/H2O). This yields 3.54 g (54%) of 2-[2-(2-hydroxybenzoylamino) benzoylamino]ethanoic acid as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:8]=1[O:9]/[C:10](=[CH:14]\[C:15]([OH:17])=O)/[C:11]([OH:13])=[O:12].[CH2:24](O)[CH3:25]>>[Br:6][C:7]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]2[C:8]=1[O:9][C:10]([C:11]([O:13][CH2:24][CH3:25])=[O:12])=[CH:14][C:15]2=[O:17]
Reactant: CCO
Reactant: COc1ccc(O/C(=C\C(=O)O)C(=O)O)c(Br)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(=O)c2cc(OC)cc(Br)c2o1
Yield: 50 %

Procedure:
Sulfuric acid (50 ml) was added to (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioic acid (24.3 g, 86.6 mmol; as prepared in Reference Example 2b above). After heating the mixture with a heat gun for 5–10 min a clear deep brown solution was obtained. This solution was slowly added to refluxing absolute ethanol (250 ml). After the addition the reaction was refluxed for 30 min then allowed to cool. Crystals started to form after 20 min and the reaction was put in the refrigerator overnight. The solid was filtered, washed with cold ethanol/water 9:1 and dried to give ethyl 8-bromo-6-methoxy-4-oxo-4H-chromene-2-carboxylate as an off-white solid (12.3 g, 50% yield, mp 159–161° C.).
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1>C(#N)C>[N:1]1([C:7]2[O:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)=[CH:16][CH:15]=3)=[CH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=c1cc(-c2ccc(O)cc2)oc(N2CCOCC2)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1cc(-c2ccc(OCc3ccc4ccccc4n3)cc2)oc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
2-Morpholinyl-6-(4-hydroxyphenyl)-4-pyrone, as prepared in Example 5, (273 mg, 1.0 mmole) was suspended in 8 ml acetonitrile in a 25 ml one neck round bottom flask under nitrogen. The suspension was treated successively with potassium carbonate (829 mg, 6.0 mmole) and 2-chloromethyl-quinoline (533 mg, 3.0 mmole). The reaction mixture was stirred at 70° C. overnight. The acetonitrile was removed in vacuo and the residue was washed with 1×25 ml dichloromethane. The insoluble material was removed by filtration and the filtrate was concentrated in vacuo to a yellow solid. The crude material was washed with diethyl ether and was recrystallized from ethyl acetate to give 377 mg (91%) of Compound 8 as an orange solid.
Reaction SMILES: CC(C)([O-])C.[K+].C([Si](C)(C)[C:12]#[C:13][CH2:14][N:15]1[C:20]2[N:21]=[C:22](S(C)(=O)=O)[N:23]=[CH:24][C:19]=2[CH:18]=[C:17]([C:29]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:36])[C:16]1=[O:37])(C)(C)C.[N:40]1[S:41][N:42]=[C:43]2[CH:48]=[C:47]([NH2:49])[CH:46]=[CH:45][C:44]=12>CS(C)=O.O.C(OCC)(=O)C>[N:40]1[S:41][N:42]=[C:43]2[CH:48]=[C:47]([NH:49][C:22]3[N:23]=[CH:24][C:19]4[CH:18]=[C:17]([C:29]5[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=5[Cl:36])[C:16](=[O:37])[N:15]([CH2:14][C:13]#[CH:12])[C:20]=4[N:21]=3)[CH:46]=[CH:45][C:44]=12
Reactant: Nc1ccc2nsnc2c1
Reactant: CC(C)(C)[Si](C)(C)C#CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc4nsnc4c3)nc21

Procedure:
62 mg of potassium tert-butoxide are added in 3 installments, at ambient temperature under argon, to 180 mg of compound of formula (II), described below, 8-[3-((tert-butyl)dimethylsilanyl)prop-2-ynyl]-6-(2,6-dichlorophenyl)-2-methylsulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one, and 81 mg of the compound of formula (III), 2,1,3-benzothiadiazol-5-ylamine, in solution in 5 ml of DMSO. After a contact time of 75 min, the reaction medium is diluted with a mixture of water and ethyl acetate. The aqueous phase is brought back to neutral pH and extracted with dichloromethane. After drying the organic phase over sodium sulfate and filtering, the residue is chromatographed on silica (gradient: CH2Cl2 100 to CH2Cl2/MeOH 98:2) to give 52 mg of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:18])[C:9]=2I)=[CH:4][CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:18])[C:9]=2[CH:20]=[CH2:21])=[CH:4][CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1c(C)cc2ccccc2c1-c1ccc(Cl)cc1
Yield: 89.2 %

Procedure:
A solution of 1-(4-chlorophenyl)-2-iodo-3-methylnaphthalene (3E) (1.50 g, 3.98 mmol), tributyl(vinyl)tin (1.28 mL, 4.37 mmol) and PdCl2(PPh3)2 (0.279 g, 0.398 mmol) in DMF (20 mL) was stirred at 90° C. under argon overnight. The reaction mixture was cooled, diluted with ethyl acetate and washed with 5% LiCl solution (2×), brine and dried (MgSO4). The mixture was filtered, concentrated and purified by flash column chromatography (silica gel, hexanes) to give 3F as a white solid (0.9894 g). 1H-NMR: 300 MHz, (CDCl3) δ 7.74 (d, J=7.8 Hz, 1H), 7.66 (s, 1H), 7.40-7.13 (m, 5H), 7.15 (d, J=8.1 Hz, 2H), 6.50 (dd, J=18, 11.7 Hz, 1H), 5.27 (d, J=11.7 Hz, 1H), 5.03 (d, J=18 Hz, 1H), 2.50 (s, 3 H).
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([O:28][CH3:29])[CH:19]=1>C(Cl)Cl>[NH2:5][C:3](=[O:4])[CH2:2][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([O:28][CH3:29])[CH:19]=1
Reactant: COC(=O)c1ccc(O)cc1OC
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC(N)=O)cc1OC
Temperature: 85 °C
Yield: 91.4 %

Procedure:
To a sealed tube was added 2-bromoacetamide (2.272 g, 16.47 mmol), DMF (50 mL), cesium carbonate (7.15 g, 21.96 mmol) and methyl 4-hydroxy-2-methoxybenzoate (1.00 g, 5.49 mmol). The tube was sealed and heated for 16 hours at 85° C. The reaction mixture was diluted with DCM, washed sequentially with 10 mL of 1M HCl, water, and brine. The solution was dried over sodium sulfate, filtered and the solvent removed to give 1.2 grams of methyl 4-(2-amino-2-oxoethoxy)-2-methoxybenzoate (78% yield) as a yellow powder. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Waters Sunfire 5 μm C18, 4.6×30 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 2 minutes with a 1 minute hold at a rate of 4 mL/minute. 1H NMR (400 MHz, THF-d8) δ ppm 3.71-3.76 (m, 3H), 3.80-3.84 (m, 3H), 4.45 (s, 2H), 6.56 (dd, J=8.66, 2.38 Hz, 1H), 6.65 (d, J=2.26 Hz, 1H), 6.77 (br. s., 1H), 6.92 (br. s., 1H), 7.75 (d, J=8.78 Hz, 1H). LCMS Rt=1.385 min., m/z 240.2 (M+H), 92% purity.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=O)=[N:6][CH:7]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.[BH4-].[Na+].CO>CC(O)C.CC(O)=O>[CH:27]1([NH:30][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:29][CH2:28]1
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cn3)nc3ccccc23)n[nH]1
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(C(NC3CC3)c3ccc(F)cn3)nc3ccccc23)n[nH]1
Temperature: 140 °C

Procedure:
To (5-fluoropyridin-2-yl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 1 (1 equiv) in 2-propanol are added cyclopropylamine (5 equiv) and 3 Å(8-12 mesh) molecular sieves, and the mixture is heated at 140° C. in a microwave reactor. Additional cyclopropylamine is added and microwave or conventional heating is continued until the reaction is substantially complete according to NMR. Then a suspension of sodium borohydride (10 equiv) in 2-propanol is added and the mixture is stirred at rt. Methanol, additional sodium borohydride, and traces of HOAc are added as necessary until the reaction is substantially complete, then the mixture is filtered and the filtrate is concentrated. DMSO is added and the mixture is purified by preparative HPLC to afford 2-((cyclopropylamino)(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine.
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:12]=2[C:13]=1[CH2:14][C:15]([OH:17])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[CH2:34]([NH:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH3:37].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[C:1]([C:9]1[O:10][C:11]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:12]=2[C:13]=1[CH2:14][C:15]([N:38]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:34][CH2:35][CH2:36][CH3:37])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2oc(C(=O)c3ccccc3)c(CC(=O)O)c2c1
Reactant: CCCCNCCCC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CCCC)C(=O)Cc1c(C(=O)c2ccccc2)oc2ccc(OC)cc12
Temperature: 25 °C

Procedure:
To a mixture of 10.6 mg (2-benzoyl-5-methoxy-1-benzofuran-3-yl)acetic acid from the Step B above, 7.8 mg HOBt and 13.1 mg EDC were added 6.6 mg dibutylamine and 0.5 mL DMF followed by 21 μL DIEA. After stirring at room temperature over night, it was heated in a 55° C. oil bath for 8 hours. It was purified directly on RP-HPLC using 60-95% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. 1H NMR (CDCl3, 500 MHz) 8.10˜8.13 (m, 2H), 7.62˜7.66 (m, 1H), 7.53˜7.57 (m, 2H), 7.45 (d, J=8.9 Hz, 1H), 7.275 (d, J=2.7 Hz, 1H), 7.14 (dd, J=2.7 & 9.1 Hz, 1H), 4.39 (s, 2H), 3.89 (s, 3H), 3.43˜3.47 (m, 2H), 3.37˜3.40 (m, 2H), 1.51˜1.61 (m, 4H), 1.26˜1.38 (m, 4H), 0.94 (t, J=7.3 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H). LC-MS: 4.24 min. (m/Z=422.3, 444.3).