Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.COCN[C:17](=[O:48])[CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([C:32]2([C:38]([NH:40][O:41]C3CCCCO3)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O1CCCC1>[OH:41][NH:40][C:38]([C:32]1([S:29]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]([C:5]3[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=3)=[O:48])=[CH:24][CH:25]=2)(=[O:30])=[O:31])[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1)=[O:39]
Reactant: COCNC(=O)CCCCOc1ccc(S(=O)(=O)C2(C(=O)NOC3CCCCO3)CCOCC2)cc1
Reactant: COc1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CCCCOc2ccc(S(=O)(=O)C3(C(=O)NO)CCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
Part A. To a mixture of magnesium turnings (344 mg, 14.18 mmol) etched with iodine in anhydrous tetrahydrofuran (4 mL) at reflux was added 4-bromoanisole (1.2 mL, 9.45 mmol) dropwise over 10 min. The reaction mixture was heated at reflux for 45 min, and then cooled to ambient temperature. The prepared grignard reagent was added to a mixture of tetrahydro-4-[[4-[[5-(methoxymethylamino)-5-oxopentyl]oxy]phenyl]sulfonyl]-N-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-pyran-4-carboxamide (1.0 g, 1.9 mmol, as prepared in Example 7) in anhydrous tetrahydrofuran (10 mL) at 0° C. The reaction mixture was warmed to ambient temperature and left stirring overnight. The reaction was quenched with saturated ammonium chloride, and then partitioned between ethyl acetate and water. The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography using 50-100% ethyl acetate/hexanes to afford 320 mg (29%) of the desired ketone as a white powder. ESMS m/z=593 [M+NH4]+. HRMS calculated for C29H37NO9S: 593.2533 [M+NH4]+. found: 593.2555.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:21][N:22]1[C:26]([CH3:27])=[C:25]([NH2:28])[C:24]([CH3:29])=[N:23]1.C1(P(C2CCCCC2)C2(P(C3CCCCC3)C3CCCCC3)CC=CC=C2C2C=CC=CC=2)CCCCC1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:28][C:25]4[C:24]([CH3:29])=[N:23][N:22]([CH3:21])[C:26]=4[CH3:27])[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: Cc1nn(C)c(C)c1N
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Agent: C1=CCC(P(C2CCCCC2)C2CCCCC2)(P(C2CCCCC2)C2CCCCC2)C(c2ccccc2)=C1
Product: Cc1nn(C)c(C)c1Nc1nc2c(-c3ccc(S(C)(=O)=O)cc3)cccn2n1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(1,3,5-trimethyl-1H-pyrazol-4-yl)-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.200 g, 0.65 mmol) and 1,3,5-trimethyl-1H-pyrazol-4-ylamine (0.106 g, 0.845 mmol) with 2,2-bis-dicyclohexylphosphanyl-biphenyl (0.048 g, 0.088 mmol) as the ligand in a manner analogous to Example 2d. Product was isolated as an orange solid (0.157 g, 61%). MP=194-196° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.65 (d, J=6.56 Hz, 1H), 8.37 (d, J=7.50 Hz, 2H), 8.13 (s, 1H), 8.04 (d, J=7.52 Hz, 2H), 7.86 (d, J=7.47 Hz, 1H), 7.04 (t, J=7.26 Hz, 1H), 3.65 (s, 3H), 3.27 (s, 3H), 2.09 (s, 3H, 1.99 (s, 3H). MS=397 (MH)+.
Reaction SMILES: [C:1]([C:9]1[O:13][C:12]2[C:14](=[O:24])[C:15]3[C:20]([C:21](=[O:22])[C:11]=2[CH:10]=1)=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)(=[O:8])[C:2]1C=CC=CC=1.C(C1OC2C(=O)C3C(C(=O)C=2C=1)=CC=C([Cl:41])C=3)C>>[C:1]([C:9]1[O:13][C:12]2[C:14](=[O:24])[C:15]3[C:20]([C:21](=[O:22])[C:11]=2[CH:10]=1)=[CH:19][CH:18]=[C:17]([Cl:41])[CH:16]=3)(=[O:8])[CH3:2]
Reactant: O=C(c1ccccc1)c1cc2c(o1)C(=O)c1cc(Br)ccc1C2=O
Reactant: CCc1cc2c(o1)C(=O)c1cc(Cl)ccc1C2=O
Product: CC(=O)c1cc2c(o1)C(=O)c1cc(Cl)ccc1C2=O
Yield: 30 %

Procedure:
The 2-acetyl-7-chloro-4H,9H-naphtho [2,3-b]furan-4,9-dione 3-2 (R1=Cl, R3=CH3, R7=H) was obtained according to the procedure described in example 13 by using 2-ethyl-7-chloro-4H,9H-naphtho[2,3-b]furan-4,9-dione 1-3 (R1=C1, R4=CH3) as starting materials with yield of 30%. 1H NMR (in CDCl3) δ 2.67 (s, 3H), 7.61 (s, 1H), 7.74-7.78 (m, 1H), 8.17-8.23 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:13][NH2:14])=O)[CH2:10][CH2:9]2)=[C:4]([F:15])[CH:3]=1.[Si:16]([O:23][CH2:24][C:25]1([CH3:34])[S:31][CH2:30][CH2:29][N:28]=[C:27](SC)[CH2:26]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:28]4[CH2:29][CH2:30][S:31][C:25]([CH2:24][O:23][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])([CH3:34])[CH2:26][C:27]4=[N:14][N:13]=3)[CH2:10][CH2:9]2)=[C:4]([F:15])[CH:3]=1
Reactant: NNC(=O)C1(c2ccc(Br)cc2F)CC1
Reactant: CSC1=NCCSC(C)(CO[Si](C)(C)C(C)(C)C)C1
Solvent: CCCCO
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4F)CC3)n2CCS1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A solution of the compound (2.73 g, 10 mmol) obtained in Example 14-4) and 7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-methyl-5-(methylthio)-2,3,6,7-tetrahydro-1,4-thiazepine (3.2 g, 10 mmol) in n-butanol (50 mL) was stirred at 140° C. for 7 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Isco Combiflash, 40 g, hexane:ethyl acetate=0:100 to 100:0, gradient) to obtain the title compound (2.09 g, 40%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]([C:32](=O)[CH3:33])=[CH:18][C:19]2[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=2)[C:22]([O:24]CCC#N)=[O:23])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]1([CH:41]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:42][CH2:43][O:44][C:45](=[O:50])/[CH:46]=[C:47](\[NH2:49])/[CH3:48])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC(O)C>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]([C:19]3[CH:31]=[CH:30][CH:29]=[C:21]([C:22]([OH:24])=[O:23])[CH:20]=3)[C:46]([C:45]([O:44][CH2:43][CH2:42][CH:41]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:50])=[C:47]([CH3:48])[NH:49][C:32]=2[CH3:33])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(=Cc1cccc(C(=O)OCCC#N)c1)C(=O)N1CCCN(Cc2ccccc2)CC1
Reactant: C/C(N)=C/C(=O)OCCC(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Product: CC1=C(C(=O)OCCC(c2ccccc2)c2ccccc2)C(c2cccc(C(=O)O)c2)C(C(=O)N2CCCN(Cc3ccccc3)CC2)=C(C)N1

Procedure:
2.05 g (3.99 mmol) of 2-cyanoethyl 3-[2-(4-benzyl-[1,4]diazepane-1-carbonyl)-3-oxobutenyl]benzoate and 1.18 g (3.99 mmol) of (3,3-diphenylpropyl)3-aminocrotonate were stirred in 40 ml of 2-propanol at 80° C. overnight. After the concentration under reduced pressure, the product was purified by the silica gel chromatography (chloroform/methanol=100/1) to obtain the title compound.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:7]=[C:8]3[C:18](=[CH:19][CH:20]=2)[O:17][C:11]2([CH2:16][CH2:15][CH2:14][O:13][CH2:12]2)[CH2:10][C:9]3=O)[CH2:3][CH2:2]1.C[Si]([N:26]=[C:27]=[N:28][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:1]1([C:4]#[C:5][C:6]2[CH:7]=[C:8]3[C:18](=[CH:19][CH:20]=2)[O:17][C:11]2([CH2:16][CH2:15][CH2:14][O:13][CH2:12]2)[CH2:10][C:9]3=[N:28][C:27]#[N:26])[CH2:3][CH2:2]1
Reactant: O=C1CC2(CCCOC2)Oc2ccc(C#CC3CC3)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC2(CCCOC2)Oc2ccc(C#CC3CC3)cc21
Reaction time: 1 h
Yield: 128.1 %

Procedure:
To a solution of 6-(cyclopropylethynyl)-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (76 mg, 0.27 mmol) in anhydrous DCM (15 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.54 mL, 0.54 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (0.16 mL, 0.427 mmol) dropwise. The resulting mixture was stirred 80 h. The reaction mixture was quenched with ice-water (15 g), and stirred for 30 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted 2 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give 106 mg the crude desired product as light yellow solid, which was used for next step without further purification. MS ESI +ve m/z 307 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2([CH2:10][C:11]([OH:13])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:25][N:26]1[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:40]>ClCCl>[O:40]=[C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]([C:36]([F:37])([F:39])[F:38])=[N:35][N:26]1[NH:25][C:11](=[O:13])[CH2:10][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: O=C(O)CC1(c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CC1(c2ccccc2)CC1)Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reaction time: 2 h
Yield: 38.4 %

Procedure:
A solution of 2-(1-phenylcyclopropyl)acetic acid (0.063 g, 0.36 mmol) and oxalyl dichloride (0.042 mL, 0.48 mmol) in dichloromethane (1 mL) with a catalytic amount of DMF was stirred for 90 minutes, and concentrated. The material was re-dissolved in dichloromethane (1 mL) and the product from Example 11B (0.080 g, 0.35 mmol) was added, stirred for 2 hours, and concentrated. The residue was chromatographed on SiO2 (0-2% diethyl ether/dichloromethane) to give the title compound (52 mg) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 11.56 (s, 1H), 8.41-8.45 (m, 1H), 8.10-8.16 (m, 1H), 7.97-8.07 (m, 2H), 7.32-7.40 (m, 2H), 7.23-7.29 (m, 2H), 7.13-7.20 (m, 1H), 2.74 (s, 2H), 1.04-1.10 (m, 2H), 0.84-0.89 (m, 2H); MS (ESI−) M/Z 386 (M−H)−.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:27]=[CH:26][C:12]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[C:22]([F:25])([F:24])[F:23])=[C:11]([F:28])[CH:10]=2)[S:3]1.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[F:28][C:11]1[CH:10]=[C:9]([CH:8]=[C:4]2[S:3][C:2](=[O:1])[N:6]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:5]2=[O:7])[CH:27]=[CH:26][C:12]=1[O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[C:22]([F:25])([F:23])[F:24]
Reactant: ClCCN1CCOCC1
Reactant: N#Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2F)c(C(F)(F)F)c1
Product: N#Cc1ccc(Oc2ccc(C=C3SC(=O)N(CCN4CCOCC4)C3=O)cc2F)c(C(F)(F)F)c1

Procedure:
The title compound was prepared using 4-[4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2-fluoro-phenoxy]-3-trifluoromethyl-benzonitrile and 4-(2-Chloro-ethyl)-morpholine as described in Example 1. 1H NMR (400 Hz, CDCl3) δ 8.01 (s, 1H), 7.83 (s, 1H), 7.74 (dd, 1H), 7.34 (m, 3H), 6.91 (d, 1H), 3.92 (t, 2H), 3.69 (bt, 2H), 2.69 (bt, 2H), 2.57 (bs, 2H); LC/MS (m/z) [M+1]+ 522.2 (calculated for C24H20F4N3O4S, 522.49).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]([CH2:19][C:18]3[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Cc1cc2nc[nH]c2cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2ncn(Cc3ccc([N+](=O)[O-])cc3)c2cc1C
Temperature: 60 °C
Reaction time: 14 h
Yield: 32.4 %

Procedure:
A mixture of 5,6-dimethyl-1H-benzimidazole (5.0 g), 4-nitrobenzyl bromide (6.16 g), potassium carbonate (7.88 g) and N,N-dimethylformamide (60 ml) was stirred at 60° C. for 14 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give 5,6-dimethyl-1-(4-nitrobenzyl)-1H-benzimidazole (2.6 g, 32%) as crystals from a fraction eluted with methanol-ethyl acetate (1:20, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-red prism crystals. melting point: 175-177° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:16]2[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=2[F:23])([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:16]2[CH:21]=[C:20]([NH:22][C:32]([C:29]3[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][N:30]=3)=[O:33])[CH:19]=[CH:18][C:17]=2[F:23])([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](CF)(c2cc(N)ccc2F)COC1
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@](CF)(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)COC1
Reaction time: 14 h

Procedure:
[(R)-5-(5-Amino-2-fluoro-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (75 mg, 0.22 mmol), 5-chloro-pyridine-2-carboxylic acid (38.1 mg, 0.242 mmol), HOAt (38.9 mg, 0.286 mmol), EDC (63.2 mg, 0.33 mmol) and Et3N (77 μl, 0.549 mmol) were dissolved in CH2Cl2 and stirred for 14 h. The solution was evaporated and the crude product was purified by chromatography on silica gel (heptane/EtOAc 6/1) to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]([CH3:31])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:22]4[CH:27]=[C:26]([NH2:28])[C:25]([F:29])=[CH:24][C:23]=4[Cl:30])[C:15](=[O:21])[N:16]3[CH2:19][CH3:20])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1[N:42]=[C:43]=[O:44]>N1C=CC=CC=1>[Cl:30][C:23]1[C:22]([C:14]2[C:15](=[O:21])[N:16]([CH2:19][CH3:20])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:33][CH:32]=2)[CH3:31])[CH:18]=3)=[CH:27][C:26]([NH:28][C:43]([NH:42][C:36]2[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=2[F:34])=[O:44])=[C:25]([F:29])[CH:24]=1
Reactant: O=C=Nc1cc(F)ccc1F
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: c1ccncc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)ccc3F)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A solution of Example A4 (250 mg, 0.535 mmol) in pyridine (2 mL) was treated with 2,5-difluorophenyl isocyanate (91 mg, 0.589 mmol) and stirred at RT overnight. Additional 2,5-difluorophenyl isocyanate (30 μL, 0.256 mmol) was added and stirred at RT for 4 h. The mixture was concentrated to near-dryness, treated with EtOAc and brine and the resulting solid was collected via filtration and dried to afford 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea (314 mg, 94% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 2H), 8.51 (s, 1H), 8.19 (d, J=8.6 Hz, 1H), 7.98 (m, 1H), 7.78 (s, 1H), 7.56 (d, J=10.9 Hz, 1H), 7.29 (m, 1H), 7.18 (d, J=8.4 Hz, 2H), 6.89-6.78 (m, 3H), 6.33 (s, 1H), 4.85 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 3.70 (s, 3H), 3.13 (s, 3H), 1.13 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 622.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[O:37][C:38]([CH3:54])=[C:39]([CH2:41][CH2:42]OS(C4C=CC(C)=CC=4)(=O)=O)[N:40]=3)[CH:31]=2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:42][CH2:41][C:39]2[N:40]=[C:36]([C:32]3[CH:31]=[C:30]([C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=4)[CH:35]=[CH:34][CH:33]=3)[O:37][C:38]=2[CH3:54])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccc(F)cc4)c3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3cccc(-c4ccc(F)cc4)c3)oc2C)cc1)Oc1ccccc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (495 mg, 1.7 mmol) (see Ex. 1, Part C), toluene-4-sulfonic acid 2-[2-(4′-fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethyl ester (2.2 mmol) and Cs2CO3 (700 mg, 2.2 mmol) are combined in anhydrous DMF (25 mL) and stirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixture was then cooled and diluted with ethyl acetate (100 mL), and washed with water then brine. The organic layer was dried with Na2SO4 and concentrated in vacuo to a viscous yellow oil. The residue was purified by flash column chromatography (100 g silica, 60×15 mL fractions, gradient elution 0–20% ethyl acetate in hexanes) to provide the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.18–8.17 (m, 1H), 7.96–7.94 (m, 1H), 7.62–7.57 (m, 3H), 7.51–7.47 (m, 1H), 7.23–7.11 (m, 2H), 7.16–7.11 (m, 3H), 6.98–6.94 (m, 1H), 6.84–6.81 (m, 4H), 6.78–6.75 (m, 1H), 4.24 (t, J=6.4 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 3.26 (d, J=14.0 Hz, 1H), 3.10 (d, J=14.0 Hz, 1H), 2.99 (t, J=6.4 Hz, 2H), 2.40 (s, 3H), 1.38 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); MS (EI) 580.2 (M+)+.
Reaction SMILES: [NH2:1][C@H](C1N(C2C=CC=CC=2)C(=O)C2C(C=1)=CC=CC=2C)C.ClC1N=C(Cl)C(Cl)=CN=1.C(N(CC)CC)C.[Cl:38][C:39]1[N:44]=[C:43]([NH:45][C@H:46]([C:48]2[N:49]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[C:50](=[O:59])[C:51]3[C:56]([CH:57]=2)=[CH:55][CH:54]=[CH:53][C:52]=3[CH3:58])[CH3:47])[C:42]([Cl:66])=[CH:41][N:40]=1>CCCCO>[NH2:1][C:39]1[N:44]=[C:43]([NH:45][C@H:46]([C:48]2[N:49]([C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:50](=[O:59])[C:51]3[C:56]([CH:57]=2)=[CH:55][CH:54]=[CH:53][C:52]=3[CH3:58])[CH3:47])[C:42]([Cl:66])=[CH:41][N:40]=1.[Cl:38][C:39]1[N:44]=[C:43]([NH:45][C@H:46]([C:48]2[N:49]([C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:50](=[O:59])[C:51]3[C:56]([CH:57]=2)=[CH:55][CH:54]=[CH:53][C:52]=3[CH3:58])[CH3:47])[C:42]([Cl:66])=[CH:41][N:40]=1
Reactant: Cc1cccc2cc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: Cc1cccc2cc([C@H](C)Nc3nc(Cl)ncc3Cl)n(-c3ccccc3)c(=O)c12
Agent: Clc1ncc(Cl)c(Cl)n1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cc1cccc2cc([C@H](C)Nc3nc(N)ncc3Cl)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C

Procedure:
A mixture of 3-(1-aminoethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 4704) (150 mg, 0.54 mmol), 2,4,5-trichloropyrimidine (119 mg, 0.65 mmol) and triethylamine (137 mg, 1.35 mmol) in n-BuOH (10 mL) was stirred at reflux for 2 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (MeOH:CH2Cl2=1:100) to afford the desired product, (S)-3-(1-(2,5-dichloropyrimidin-4-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (2H)-one (compound 5101) (170 mg, 74% yield) as a white solid.
Reaction SMILES: C(OC([NH:8][CH:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:34].O1CCOCC1>CO>[ClH:34].[NH2:8][CH:9]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(COc2cccc(C(NC(=O)OC(C)(C)C)c3ccccc3)c2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(COc2cccc(C(N)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of methyl 4-((3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)-phenoxy)methyl)benzoate (3.21 g, 7.20 mmol) in methanol (36 mL), was added hydrogen chloride in dioxan (4 M, 9.0 mL, 36 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed at reduced pressure to afford the title compound (2.65 g, >95%).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]([CH3:22])([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:22][C:7]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:26][CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[CH:24][CH:23]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(O)cc1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(OCCOC2CCCCO2)cc1
Yield: 80.2 %

Procedure:
In a similar manner to that described in Reference example 3(e), a reaction was carried out using ethyl 2-(4-hydroxybenzyl)-2-methyl-5-phenylvalerate (1.58 g), which is the product of Reference example 7(d), 2-(2-bromoethoxy)tetrahydropyran (0.94 g) and potassium carbonate (1.86 g) in dimethylacetamide and the reaction mixture was treated to afford the desired compound (1.64 g) as a syrup.
Reaction SMILES: [CH3:1][CH:2]([CH2:19][CH3:20])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11]C(=O)OC(C)(C)C)[CH2:7][CH2:6]1)=[O:4]>Cl.CO>[NH2:11][CH:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH:2]([CH3:1])[CH2:19][CH3:20])[CH2:6][CH2:7]1
Reactant: CCC(C)C(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CCC(C)C(=O)N1CCC(N)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
Protected piperidine 15 (1.2 g, 4.55 mmol) was dissolved in HCl/MeOH (2 M). The reaction mixture was stirred at 50° C. for 2 h. The crude was concentrated under vacuo and was washed with dichloromethane twice. The crude was basified by NaOH solution (6N) to pH 12. The crude was extracted by EtOAc for 6 times. The combined organic layers was evaporated under vacuo yielding final product 16 (724 mg, 3.93 mmol, 86%). H-NMR (DMSO-d6) ∂ 0.78 (q, J=6 Hz, 3H), 0.95 (t, J=5 Hz, 3H), 1.09 (m, 2H), 1.26 (m, 1H), 1.53 (m, 1H), 1.74 (m, 2H), 2.67 (m, 2H), 2.80 (br, 1H), 3.03 (br, 1H), 3.87 (d, J=12 Hz, 1H), 4.23 (br, 1H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:23]([C:22]2[CH:26]=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[OH:24])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: COc1ccc(C(=O)O)cc1
Product: COc1ccc(C(O)=C2C(=O)N(C(C)=O)c3ccc(C(C)=O)cc32)cc1

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 4-methoxybenzoic acid
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C([O-])(=O)C.[Na+].Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:23][CH2:22]1.O>CS(C)=O>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:12])[N:2]1[O:1][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:25][CH2:26]1
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1N1CCN(CCON2C(=O)c3ccccc3C2=O)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 50.6 %

Procedure:
A mixture of 6.73 g of N-hydroxyphthalimide, 3.73 g of sodium acetate and 10 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine in 100 ml of anhydrous dimethylsulfoxide was stirred at 100° C. for 4 hours. The reaction mixture was then cooled to room temperature, poured into water and extracted with ethyl acetate. The collected organic layers were washed with 1N sodium hydroxide, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo to give 7.58 g of the title compound. A sample was crystallized from cyclohexane, m.p. (76) 80°-83° C.