Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:4](Cl)Cl)[CH2:2][CH3:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:3]([C:11]2[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=2)[CH2:2][CH2:1][PH2:4])=[CH:10][CH:9]=1
Reactant: CCCP(Cl)Cl
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: ClC(Cl)Cl
Product: PCCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
Bis(p-chlorophenyl)propylphosphine was prepared by reacting 0.2 mole of propyldichlorophosphine with 0.4 mole of p-chlorophenylmagnesium bromide. The product was isolated by chloroform extraction and distillation as previously described. The portion boiling between 160° and 165° C. under a pressure of 2 mm. Hg was collected. The analysis corresponded to bis(p-chlorophenyl)propylphosphine.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24](Cl)(=[O:28])[CH2:25][CH2:26][CH3:27].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:24](=[O:28])[CH2:25][CH2:26][CH3:27])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCC(=O)NCc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.6 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.53 g, 1.6 mmol) in acetonitrile (10 mL), was added butyryl chloride (0.25 mL, 2.4 mmol) and N,N-diisopropyl ethylamine (0.65 mL, 3.9 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-butyramide as a light yellow solid (270 mg, 46% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.18 min (98.6%); mp, 250-252° C.; 1HNMR (DMSO-d6)0.88 (t, J=7 Hz, 3H, CH3), 1.56 (m, J=7 Hz, 2H, CH2CH2CH3), 2.15-2.20 (m, 3H, CH2, CHH), 2.57-2.89 (m, 6H, CHCH2, CH3), 4.77-4.85 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.30-7.76 (m, 3H, Ar), 8.18 (t, J=5 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.65, 18.67, 20.77, 23.27, 30.58, 37.32, 41.39, 56.47, 117.63, 124.28, 125.38, 133.83, 141.23, 148.44, 154.76, 160.95, 169.51, 172.14, 172.60. LCMS MH=371; Anal Calcd For C19H22N4O4: C, 61.61; H, 5.99; N, 15.13. Found: C, 61.49; H, 5.76; N, 15.00.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22])=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])(C)(C)C.C1(C[C@H]2NC(=O)N([C@H](C3NC(C4C=CC(I)=CC=4F)=C(C)N=3)[C@H](C3C=CC=CC=3)C)C2=O)CC1.N[C@H](C1C=CC(OC(CO)CO)=CC=1)C([NH:63][C@H:64]([C:73]1[NH:74][C:75]([C:79]2[CH:84]=[CH:83][C:82]([I:85])=[CH:81][C:80]=2[F:86])=[C:76]([Cl:78])[N:77]=1)[C@H:65]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[CH3:66])=O>>[Cl:78][C:76]1[N:77]=[C:73]([C@@H:64]([N:63]2[C:10](=[O:12])[C@@H:9]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH:20]([CH2:21][OH:22])[CH2:23][OH:24])=[CH:17][CH:18]=3)[NH:8][C:6]2=[O:7])[C@H:65]([C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH3:66])[NH:74][C:75]=1[C:79]1[CH:84]=[CH:83][C:82]([I:85])=[CH:81][C:80]=1[F:86]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC(CO)CO)cc1
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OC(CO)CO)cc1)c1nc(Cl)c(-c2ccc(I)cc2F)[nH]1
Agent: Cc1nc([C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](CC3CC3)C2=O)[nH]c1-c1ccc(I)cc1F
Product: C[C@@H](c1ccccc1)[C@@H](c1nc(Cl)c(-c2ccc(I)cc2F)[nH]1)N1C(=O)N[C@H](c2ccc(OC(CO)CO)cc2)C1=O

Procedure:
Prepared by the same method as described in example 1 except that (i) (R)-tert-butoxycarbonylamino-[4-(2-hydroxy-1-hydroxymethyl-ethoxy)-phenyl]-acetic acid (prepared as described in steps 57-V, 57-W and 57-X) was used in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid in step 75-G and (ii) cyclization of (R)-2-amino-N-{(1S,2S)-1-[4-chloro-5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-2-[4-(2-hydroxy-1-hydroxymethyl-ethoxy)-phenyl]-acetamide in step 75-H was performed as described in step 34-H. HR-MS: calcd for C30H27ClFlN4O5 [M+H+] 705.0772. Found 705.0772.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][CH:24]2[CH2:26][CH2:25]2)=[C:8]([C:10]2[C:11]3[NH:18][CH:17]=[C:16]([C:19]([OH:21])=O)[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:9]=1)(=[O:3])[CH3:2].[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34](=[O:36])[CH3:35])[CH2:30][CH2:29]1>>[C:34]([N:31]1[CH2:32][CH2:33][CH:28]([NH:27][C:19]([C:16]2[C:12]3[N:13]=[CH:14][N:15]=[C:10]([C:8]4[CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=4[O:22][CH2:23][CH:24]4[CH2:26][CH2:25]4)[C:11]=3[NH:18][CH:17]=2)=[O:21])[CH2:29][CH2:30]1)(=[O:36])[CH3:35]
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)c1
Reactant: CC(=O)N1CCC(N)CC1
Product: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(5-acetyl-2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A81) and 1-(4-Amino-piperidin-1-yl)-ethanone (A191) the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([Cl:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C([O-])([O-])=O.[K+].[K+].[N:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>CS(C)=O>[Cl:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:29]1[CH2:30][CH2:31][CH:26]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:27][CH2:28]1
Reactant: COc1cc(F)c(Cl)cc1[N+](=O)[O-]
Reactant: C1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCC(N3CCCCC3)CC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
4-Chloro-5-fluoro-2-nitrophenyl methyl ether (2.19 g, 10.7 mmol) was dissolved in DMSO (10 mL). K2CO3 (2.2 g, 16 mmol) and 1,4′-bipiperidine (1.8 g, 11 mmol) were added and the reaction mixture was allowed to stir overnight at rt. The mixture was then poured into H2O and extracted with EtOAc (2×) and then the combined organics were extracted with H2O (5×). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step C (2.69 g, 71%). MS (M+H, ES+) 354.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]1=[O:13].FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C1C(=O)N([I:41])C(=O)C1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5]([CH3:12])=[C:4]([I:41])[C:3]1=[O:13]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(C(F)(F)F)n(C)c(=O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(F)(F)F)n(C)c(=O)c1I
Temperature: 77.5 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
To a solution of 1,4-dimethyl-6-(trifluoromethyl)-1H-pyridin-2-one (1.44 g, 7.23 mmol), trifluoroacetic acid (9 mL) and trifluoroacetic anhydride (1.53 mL, 10.85 mmol) was added NIS (2.569 g, 10.85 mmol) at room temperature. Then, the mixture was heated to 70-85° C. and was stirred for 2 h. The reaction mixture was cooled to room temperature and saturated sodium carbonate solution was added slowly to neutralize the solution. Then, the aqueous mixture was extracted with ethyl acetate (2×50 mL). The combined extracts were washed successively with saturated sodium thiosulfate solution (100 mL) and brine solution (100 mL) and were dried over anhydrous sodium sulfate. Filtration of the drying agent and concentration of the solvent gave a crude product, which was purified by silica gel chromatography on a Biotage (40m) column to afford 1.02 g (45% yield) of 1,4-dimethyl-3-iodo-6-(trifluoromethyl)-1H-pyridin-2-one as an amorphous white solid. ES-LRMS: m/z 318.1 (M+H), 381.2 (M+Na+CH3CN).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:29]3[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=3)[CH2:23][N:22]([CH3:32])[CH2:21]2)=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH3:33][C:34]([CH3:55])([C:45]([O:47]N1C(=O)CCC1=O)=O)[C:35]([O:37]N1C(=O)CCC1=O)=O>>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[C:25]([Cl:31])[CH:26]=1)[CH2:23][N:22]([CH3:32])[CH2:21][CH:20]2[C:17]1[CH:16]=[CH:15][C:14]([S:11]([NH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:45](=[O:47])[C:34]([CH3:33])([CH3:55])[C:35]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]3[C:29]4[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=4)[CH2:23][N:22]([CH3:32])[CH2:21]3)=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[O:37])(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCN)cc2)C1
Reactant: CC(C)(C(=O)ON1C(=O)CCC1=O)C(=O)ON1C(=O)CCC1=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCNC(=O)C(C)(C)C(=O)NCCOCCOCCNS(=O)(=O)c3ccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)cc3)cc2)C1

Procedure:
Compound 183 was prepared from intermediate 175.1 and bis(2,5-dioxopyrrolidin-1-yl) 2,2-dimethylmalonate (prepared using the methods outlined in example 168) following the procedure outlined in example 175. The crude product was purified by Prep-HPLC with acetonitrile:water (0.05% CF3COOH)(10%-100%). This resulted in 29.5 mg (5%) of a TFA salt of N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2,2-dimethylmalonamide as a white solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 7.94-7.92 (m, 4H), 7.57 (m, 2H), 7.51-7.49 (m, 4H), 6.87 (m, 2H), 4.83-4.74 (m, 4H), 4.55-4.50 (m, 2H), 3.92-3.87 (m, 2H), 3.67-3.48 (m, 8H), 3.40-3.38 (m, 4H), 3.18 (s, 6H), 3.14-3.00 (m, 4H), 1.41 (s, 6H). MS (m/z): 551 [1/2M+H]+.
Reaction SMILES: Cl[CH2:2][C@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Br:12].[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C@@H:3]([CH3:13])[CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@@H](CCl)COc1ccccc1Br
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3ccccc3Br)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 2-bromophenyl(2R)-3-chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[Cl:5][C:6]1[S:10][C:9]([C:11](Cl)=[O:12])=[CH:8][CH:7]=1>N1C=CC=CC=1.C1COCC1>[CH2:1]([NH:4][C:11]([C:9]1[S:10][C:6]([Cl:5])=[CH:7][CH:8]=1)=[O:12])[CH:2]=[CH2:3]
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: C=CCN
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CCNC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An ice-cooled solution of 2.63 ml (35 mmol) of allylamine in 14.2 ml of absolute pyridine and 14.2 ml of absolute THF is admixed dropwise with 5-chloro-thiophene-2-carbonyl chloride (7.61 g, 42 mmol). Ice-cooling is removed and the mixture is stirred at room temperature for 3 h and then concentrated under reduced pressure. The residue is admixed with water and the solid is filtered off. The crude product is purified by flash chromatography over silica gel (dichloromethane).
Reaction SMILES: C=O.F[C:4](F)(F)[C:5]([O-:7])=O.C[NH2+]C1C=CC=CC=1.[CH2:18]1[CH2:28][C:26](=O)C2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1.C(OCC)C>C1COCC1>[CH2:24]=[C:23]1[CH2:22][CH2:21][C:20]2[C:4](=[CH:26][CH:28]=[CH:18][CH:19]=2)[C:5]1=[O:7]
Reactant: O=C([O-])C(F)(F)F
Reactant: O=C1CCCc2ccccc21
Agent: C=O
Agent: C[NH2+]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C1CCc2ccccc2C1=O
Yield: 92.4 %

Procedure:
To a suspension of paraformaldehyde (46.2 g, 1.54 mol) and N-methylanilinium trifluoroacetate (TAMA, 46.2 g, 1.54 mol) in 340 mL of dry THF was added α-tetralone (50 g, 0.342 mol). The solution was heated at reflux under nitrogen with stirring for 4 h, during which time the paraformaldehyde dissolved. After cooling, diethyl ether (700 mL) was added to the reaction mixture. The solvent was separated from the reaction mixture and washed with 500 mL of saturated sodium bicarbonate. Additional diethyl ether was added to the reaction mixture, separated and used to back extract the aqueous sodium bicarbonate layer. The combined organic layers were dried over magnesium sulfate, and the solution was then concentrated to a volume of approximately 300 mL and filtered through Celite. Complete evaporation of the ether yielded 50 g (90%) of crude 2-methylene-3,4-dihydronaphthalen-1-one, which was used immediately for the next reaction to prevent polymerization of the product.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.CS(O[CH2:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[C:44]([Cl:48])[C:45]([Cl:47])=[CH:46][C:41]=2[NH:40][C:39]1=[O:49])(=O)=O>O>[Cl:47][C:45]1[C:44]([Cl:48])=[CH:43][C:42]2[N:38]([CH2:37][CH2:36][CH2:35][N:14]3[CH2:15][CH2:16][CH:11]([C:9](=[O:10])[C:6]4[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=4)[CH2:12][CH2:13]3)[C:39](=[O:49])[NH:40][C:41]=2[CH:46]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CS(=O)(=O)OCCCn1c(=O)[nH]c2cc(Cl)c(Cl)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C(c1ccc(F)cc1)C1CCN(CCCn2c(=O)[nH]c3cc(Cl)c(Cl)cc32)CC1
Yield: 25 %

Procedure:
A mixture of 4.4 parts of (4-fluorophenyl) (4-piperidinyl) methanone hydrochloride, 6 parts of sodium carbonate and 160 parts of 4-methyl-2-pentanone is stirred and refluxed for 30 minutes with water-separator. After cooling, 6.2 parts of 3-(5,6-dichloro-2,3-dihydro-2-oxo-1H-benzimidazol-1yl)propyl methanesulfonate are added and the whole is stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The solid residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is stirred in trichloromethane. The product is filtered off, stirred in methanol, filtered off again and dried, yielding 2 parts (25%) of 5,6-dichloro-1-{3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 198°-202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][C:8]=1[Cl:16].C(Cl)(=O)C([Cl:23])=O>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:23])=[O:12])=[CH:9][C:8]=1[Cl:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OCc2cccc(Cl)c2)c(Cl)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)c1ccc(OCc2cccc(Cl)c2)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of compound 27d (67 mg, 0.33 mmol) in THF (2 mL) was added oxalyl dichloride (43 μL, 0.50 mmol) dropwise at 0° C., followed by the addition of 2 drops of DMF. The resultant mixture was stirred at 0° C. for 3 h, and then was warmed up to room temperature over 18 h. The solvents were removed under reduced pressure. The resultant residue, crude compound 27e, was dried under reduced pressure for 2 h and used in the following step without further purification.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][O:6]1.[CH2:23]([NH2:25])[CH3:24]>C(O)C.C1COCC1>[CH2:23]([NH:25][CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][O:6]1)[CH3:24]
Reactant: N#Cc1ccc2c(c1)COC2(CCCI)c1ccc(F)cc1
Reactant: CCN
Solvent: CCO
Solvent: C1CCOC1
Product: CCNCCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Yield: 56.7 %

Procedure:
To a stirred solution of 1-(3-iodopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (12.9 g, 30 mmol, 8% pure) in ethanol (150 mL) was added a solution of ethylamine (20.3 g, 450 mmol) in THF (50 mL) portionwise, and the mixture was stirred over night. The solution was evaporated, and was dissolved/suspended in water. The pH was adjusted to 12 using aqueous sodium hydroxide solution (2M) and was extracted with ether. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give an oil. This oil was purified by silica chromatography using 50% v/v ethyl acetate/heptane as eluent, followed by 10% v/v triethylamine/40% v/v ethyl acetate/heptane followed by 20% v/v triethylamine/ethyl acetate to give the title compound (5.52 g, 57%) as a pale yellow oil. 1H NMR (CDCl3) δ 1.05 (t, 3H), 1.2-1.6 (m, 2H), 2.15 (ddd, 1H), 2.24 (ddd, 1H), 2.57 (q, 2H) 2.58 (t, 2H), 5.12 (dt, 1H), 5.20 (dt, 1H), 7.00 (t, 2H), 7.38 (d, 1H), 7.42 (dd, 2H), 7.49 (s, 1H), 7.58 (ddt, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>N1C=CC=CC=1>[CH2:25]([NH:27][C:28]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1)=[O:29])[CH3:26]
Reactant: CCN=C=O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Solvent: c1ccncc1
Product: CCNC(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.1 %

Procedure:
To a solution of N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) in pyridine (4.0 mL) was added ethyl isocyanate (490 μL, 6.19 mmol), and the mixture was stirred at room temperature for 16 hr. The solvent was evaporated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate/ethanol and filtrated to give the title compound (142 mg, 58%) as a white powder.
Reaction SMILES: C(C1C=CC2OC(C(O)=O)=CC=2C=1)#[N:2].NC1C=CC(CCC(OC)=O)=CC=1.[C:28]([C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38]([NH:40][C:41]3[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])=[CH:43][CH:42]=3)=[O:39])=[CH:35][C:34]=2[CH:53]=1)#[N:29]>>[C:28]([C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38]([NH:40][C:41]3[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])=[CH:43][CH:42]=3)=[O:39])=[CH:35][C:34]=2[CH:53]=1)(=[NH:2])[NH2:29]
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Reactant: COC(=O)CCc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1
Agent: COC(=O)CCc1ccc(N)cc1
Product: COC(=O)CCc1ccc(NC(=O)c2cc3cc(C(=N)N)ccc3o2)cc1

Procedure:
In the same manner as in Example 1 (2), 5-cyano-2-benzofurancarboxylic acid (200 mg, 1.07 mmol) and methyl 3-(4-aminophenyl)propionate (211 mg, 1.18 mmol) were condensed to quantitatively give 371 mg of methyl 3-[4-[(5-cyano-2-benzofuranyl)carbonylamino]phenyl]propionate as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[Cl:27])N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[CH:21]=[C:22]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(Cl)c(Cl)c4)c3c2s1
Yield: 42 %

Procedure:
Prepared from VII and 3,4-dichloroaniline. Flash chromatography eluent (DCM-EtOAc, 7:3). Yield: 42%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 2851, 2225, 1644, 1612, 1579, 1456, 1378, 1355, 1308, 1270, 1241, 1168, 1122, 1026, 971, 879, 834, 816; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (d, 1H, J=8.7 Hz), 8.30 (s, 1H), 7.78 (d, 1H, J=8.7 Hz), 7.63-7.53 (m, 2H), 7.30 (m, 2H); HRMS calcd for C16H8N5SCl2 (M+H+): 371.9877, found 371.9882.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[CH3:3].Cl[C:23]1[N:31]=[C:30]([F:32])[N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C.[F:48][C:49]1[N:57]=[C:56]2[C:52]([N:53]=[C:54]([NH:64][CH:65]([C:67]3[N:68]([C:79]4[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=4)[C:69](=[O:78])[C:70]4[C:75]([CH:76]=3)=[CH:74][CH:73]=[CH:72][C:71]=4[CH3:77])[CH3:66])[N:55]2[CH:58]2[CH2:63][CH2:62][CH2:61][CH2:60][O:59]2)=[CH:51][N:50]=1>CCCCO>[F:32][C:30]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][NH:27]2)=[C:23]([NH:1][C@H:2]([C:4]2[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6](=[O:15])[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:14])[CH3:3])[N:31]=1.[F:48][C:49]1[N:57]=[C:56]2[C:52]([N:53]=[C:54]([NH:64][CH:65]([C:67]3[N:68]([C:79]4[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=4)[C:69](=[O:78])[C:70]4[C:75]([CH:76]=3)=[CH:74][CH:73]=[CH:72][C:71]=4[CH3:77])[CH3:66])[N:55]2[CH:58]2[CH2:63][CH2:62][CH2:61][CH2:60][O:59]2)=[CH:51][N:50]=1
Reactant: Cc1cccc2cc(C(C)N)n(-c3ccccc3)c(=O)c12
Reactant: Fc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Agent: Cc1cccc2cc(C(C)Nc3nc4cnc(F)nc4n3C3CCCCO3)n(-c3ccccc3)c(=O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cccc2cc([C@H](C)Nc3nc(F)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 120 °C
Reaction time: 16 h

Procedure:
3-(1-Aminoethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (200 mg, 0.72 mol), 6-chloro-2-fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (compound 5202) (369 mg, 1.44 mmol) and DIPEA (279 mg, 2.16 mmol) were dissolved in n-BuOH (20 mL) in a sealed tube, and the resulting mixture was stirred at 120° C. for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (eluting with 30% to 50% Hex/EA) to afford the desired product, 3-(1-(2-fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 5203) (167 mg, 47% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:21])[NH:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].[CH2:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:21])[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)c[nH]c1=O
Reactant: OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.6 %

Procedure:
3-(2-Cyanophenyl)-5-(2-pyridyl)-2 (1H)-pyridone (46 mg), 36 mg of benzyl alcohol and 88 mg of triphenylphosphine were dissolved in 2 ml of tetrahydrofuran, 147 mg of a 40% solution of diethylazo dicarboxylate in toluene were added with ice cooling and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated in vacuo and purified by a silica gel chromatography (hexane-ethyl acetate system) to give 12 mg of the title compound.