Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(O)(C(F)(F)F)=O.[CH3:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:47])[CH2:43][C:44](=O)[CH3:45])=[CH:38][CH:37]=1>>[CH3:45]/[C:44](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:43]/[C:42]([C:39]1[CH:38]=[CH:37][C:36]([CH3:35])=[CH:41][CH:40]=1)=[O:47]
Reactant: CC(=O)CC(=O)c1ccc(C)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: C/C(=C/C(=O)c1ccc(C)cc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 790 mg (1.64 mmol) of Intermediate 45 (as the TFA salt) and 0.29 g (1.64 mmol) of Intermediate 27 (with 660 μL of DCA replacing Et3N) to yield crude product contaminated with DCA). A second silica gel chromatography column eluting with 8:1 DCM:MeOH gave 70 mg of Example 19 as a beige-colored solid: TLC (DCM/MeOH (4:1): Rf=0.58; 1H NMR (DMSO-d6, 400 MHz) δ11.43 (d, 1H, J=9.0), 7.96 (m, 2H), 7.74 (d, 2H, J=8.1), 7.54 (m, 3H), 7.24 (d, 2H, J=8.1), 7.18 (d, 2H, J=8.4), 6.87 (d, 2H, J=8.4), 5.57 (s, 1H), 4.21 (t, 2H, J=6.6), 4.08 (m, 1H), 3.23 (m, 2H), 2.95 (t, 2H, J=6.6), 2.80(dd, 1H, J=13.8, 9.0), 2.39 (s, 3H), 2.37 (s, 3H), 1.71 (s, 3H); low resolution MS (ES+)m/e 525.2 (MH+).
Reaction SMILES: C([O:8][C:9]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:12]2[N:13]([CH2:35][O:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([C:20]3[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][C:25]([O:29][CH3:30])=[C:24]([O:31][CH3:32])[C:23]=4[O:33][CH3:34])=[O:19])[C:11]=2[CH:10]=1)C1C=CC=CC=1>[Pd]>[OH:8][C:9]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:12]2[N:13]([CH2:35][O:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([C:20]3[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][C:25]([O:29][CH3:30])=[C:24]([O:31][CH3:32])[C:23]=4[O:33][CH3:34])=[O:19])[C:11]=2[CH:10]=1
Reactant: COc1cc2cc(C(=O)C3CCCN(COS(C)(=O)=O)c4c3cc(OCc3ccccc3)c3ccccc43)[nH]c2c(OC)c1OC
Agent: [Pd]
Product: COc1cc2cc(C(=O)C3CCCN(COS(C)(=O)=O)c4c3cc(O)c3ccccc43)[nH]c2c(OC)c1OC

Procedure:
Following the general procedure detailed for 85, 94 (0.024 g, 0.037 mmol, 1 equiv) was treated 10% Pd—C (0.006 g, 0.15 equiv) followed by aqueous HCO2NH4 (0.165 mL, 25% w/v, 18 equiv). Filtration and concentration gave 96 as an analytically pure colorless oil in quantitative yield (0.020 g, 0.020 g theoretical): 1H NMR (500 MHz, acetone-d6) major rotamer δ 10.17 (s, 1H), 9.20 (s, 1H), 8.37-8.34 (m, 2H), 7.68-7.56 (m, 2H), 6.66 (s, 1H), 6.51 (s, 1H), 5.42 (s, 1H), 5.23-5.22 (m, 1H), 4.95-4.92 (m, 1H), 4.60-4.59 (m, 1H), 3.98 (s, 3H), 3.79 (s, 3H), 3.68 (s, 3H), 3.21-3.13 (m, 1H), 3.05 (s, 3H), 2.55-2.43 (m, 1H), 2.19-2.16 (m, 1H), 1.40-1.37 (m, 3H); 13C NMR (125 MHz, acetone-d6) major rotamer δ 161.1, 153.4, 150.8, 141.3, 141.1, 139.8, 135.1, 130.6, 128.3, 126.0, 125.8 (2C), 125.0, 124.6, 124.3, 123.8, 110.7, 108.8, 98.7, 81.6, 61.4, 61.3, 56.3, 41.8, 38.1, 37.5, 31.2, 17.4; IR (film) νmax 3313, 2936, 2836, 1731, 1592, 1584 cm31 1; FABHRMS (NBA-CsI) m/z 687.0751 (M+Cs+, C28H30N2O8S requires 687.0774).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][CH:17]=[CH:16][CH2:15][CH:14]([CH2:19][S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]2[C:27]([OH:29])=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH:30][NH:31]C(C1C(COC(=O)C)CC=CCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O>>[OH:30][NH:31][C:27]([CH:13]1[CH:14]([CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH:16]=[CH:17][CH2:18][N:12]1[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])=[O:29]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(CSc3ccccc3)C2C(=O)O)cc1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(COC(C)=O)C2C(=O)NO)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(CSc3ccccc3)C2C(=O)NO)cc1

Procedure:
1-(4-Methoxy-benzenesulfonyl)-3-phenylsulfanylmethyl-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid hydroxyamide was synthesized from 1-(4-Methoxy-benzenesulfonyl)-3-phenylsulfanylmethyl-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid in the same manner as the procedures used for the preparation of Acetic acid 2-hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepin-3-ylmethyl ester: MS (M+H)+ =449, (M+NH4)+ =466.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCC1>C(OC)(C)(C)C>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNC1
Solvent: COC(C)(C)C
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (5.0 g 0.018 moles) and 5-Fluoro-1,3-dihydro-indol-2-one (2.705 g; 0.018 moles) in methyl tertiary butyl ether were reacted in presence of catalytic amount of pyrrolidine (0.08 mL) as base at reflux temperature for 2-8 hours. The resultant Sunitinib base was triturated in methyl tertiary butyl ether at reflux temperature for 1-2 hours and isolated at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:32]([N:40]2[CH2:51][CH2:50][N:49]3[C:42](=[CH:43][C:44]4[CH2:45][C:46]([CH3:53])([CH3:52])[CH2:47][C:48]=43)[C:41]2=[O:54])=[N:33][CH:34]=[CH:35][C:36]=1B(O)O)(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:26]([O:29][CH2:30][C:31]1[C:32]([N:40]2[CH2:51][CH2:50][N:49]3[C:42](=[CH:43][C:44]4[CH2:45][C:46]([CH3:53])([CH3:52])[CH2:47][C:48]=43)[C:41]2=[O:54])=[N:33][CH:34]=[CH:35][C:36]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:28])[CH3:27]
Reactant: C[C@H]1COCCN1C(=O)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOC[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 47.1 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 257a (203 mg, 0.50 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (640 mg, 1.6 mmol), K3PO4 (212 mg, 1.0 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (18 mg, 0.025 mmol), sodium acetate (82 mg, 1.0 mmol), acetonitrile (10 mL), and water (0.2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2.5 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and water (20 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with 60:1 dichloromethane/methanol to afford 257b (160 mg, 47%) as black solid. MS-ESI: [M+H]+ 680.1
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[C:3]1=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]2[C:17]([C:2]3[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[C:3]=3[NH:16]2)=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1ccc(N)cc1Cl
Reactant: O=C(O)C1CCCC(Br)C1=O
Product: Cc1cc2c3c([nH]c2cc1Cl)C(C(=O)O)CCC3

Procedure:
Under the conditions of Example 7(a), 10 g. of the ethyl ester of 3-bromo-2-oxocyclohexanecarboxylic acid is reacted with 3-chloro-4-methylaniline to obtain the ethyl ester of 7-chloro-6-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid and the ethyl ester of 5-chloro-6-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid, which are separated by chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:16][C:15]3[CH:14]=[CH:13][N:12]([C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([CH3:26])[CH:18]=4)[C:11](=[O:27])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([N:12]2[CH:13]=[CH:14][C:15]3[O:16][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)=[CH:9][C:10]=3[C:11]2=[O:27])=[CH:18][C:19]=1[CH3:26]
Reactant: Cc1cc(-n2ccc3oc(-c4cccc(Cl)c4)cc3c2=O)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc(-n2ccc3oc(-c4cccc(Cl)c4)cc3c2=O)ccc1N
Yield: 92.3 %

Procedure:
A solution of 2-(3-chlorophenyl)-5-(3-methyl-4-nitrophenyl)furo[3,2-c]pyridin-4(5H)-one (1.20 g, 3.15 mmol) in EtOH (21.2 mL) and H2O (5.16 mL) was treated with iron powder (152 g, 28.3 mmol) and NH4Cl (72.2 mg, 1.35 mmol). After stirring at reflux for 18 h, the reaction mixture was filtered through Celite® and the filtrate was concentrated to yield the title compound (1.02 g, 92%) as a light orange solid: 1H NMR (300 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.84 (d, J=7.5 Hz, 1H), 7.67 (s, 1H), 7.55-7.42 (m, 3H), 6.94-6.78 (m, 3H), 6.67 (d, J=8.4 Hz, 1H), 5.11 (s, 2H), 2.09 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([O:24][C:25]([CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36]2[N:41]=[C:40]3[CH2:42][O:43][C:44](=O)[C:39]3=[CH:38][CH:37]=2)[CH2:29][CH2:28]1)=[O:26])C.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:44]1[C:39]2[C:40](=[N:41][C:36]([CH2:35][CH2:34][CH2:33][N:30]3[CH2:29][CH2:28][CH:27]([C:25]([OH:26])=[O:24])[CH2:32][CH2:31]3)=[CH:37][CH:38]=2)[CH2:42][O:43]1
Reactant: CCOC(=O)C1CCN(CCCc2ccc3c(n2)COC3=O)CC1
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CCCN3CCC(C(=O)O)CC3)ccc21
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 33.2 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (150 mg, 1.0 mmol) in THF (5 mL) at room temperature is treated with lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 2.0 mL, 2.0 mmol) and stirred for 10 min. A solution of 1-[3-(5-oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propyl]-piperidine-4-carboxylic acid ethyl ester (110 mg, 1 equiv) in anhydrous THF (2 mL) is added. The reaction mixture is stirred at room temperature for 3 h. The reaction mixture is poured into aqueous 2N HCl solution (10 mL) with stirring. Then it is heated at 60° C. for 2 h. To the mixture is then added ice water (100 mL) followed by the careful addition of saturated aqueous NaHCO3 to adjust the pH to 8. The foamy suspension is filtered and a greenish yellow solid is obtained. This material is purified by column chromatography to give the title compound as a yellow solid (48 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]#[N:11])[C:3]=1[Cl:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B2OCCCO2)=[C:16]([F:26])[C:15]=1[O:27][CH3:28].[F-].[K+].C(#N)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.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([O:27][CH3:28])[C:16]=2[F:26])[N:5]=[C:4]([C:10]#[N:11])[C:3]=1[Cl:12]
Reactant: N#Cc1nc(Cl)c(F)c(N)c1Cl
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1c(Cl)ccc(-c2nc(C#N)c(Cl)c(N)c2F)c1F
Temperature: 75 °C
Yield: 57.2 %

Procedure:
A mixture of 4-amino-3,6-dichloro-5-fluoropicolinonitrile (0.37 g, 1.80 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (0.549 g, 2.24 mmol) and KF (0.209 g, 3.59 mmol) was taken into acetonitrile (6.75 mL) and water (2.25 mL). The mixture was stirred and sparged with a nitrogen atmosphere. Pd(PPh3)2Cl2 (63 mg, 0.1 mmol) was added, and the mixture was again sparged with nitrogen. The solution was then heated to 75° C. under nitrogen for 2 h. Upon cooling down, a precipitate formed and was collected by filtration, washed with water and dried under vacuum to give the product (0.34 g) as an off-white solid. The aqueous phase was extracted with EtOAc (3×), and the combined organic extracts were washed with brine, dried, and concentrated. Purification by silica gel chromatography gave additional product (0.12 g) as a white solid. Total yield 78%. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (dd, J=8.5, 1.4 Hz, 1H), 7.45 (s, 2H), 7.33 (dd, J=8.5, 7.2 Hz, 1H), 3.94 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 152.97 (d, J=253.2 Hz), 145.73 (d, J=260.8 Hz), 143.82 (d, J=13.7 Hz), 141.83 (d, J=14.7 Hz), 138.45 (d, J=14.8 Hz), 133.93-132.79 (m), 128.93 (d, J=3.3 Hz), 127.74 (s), 126.37-125.10 (m), 122.08 (dd, J=13.6, 3.9 Hz), 119.34 (d, J=4.5 Hz), 114.99 (s), 61.61 (s); 19F NMR (376 MHz, DMSO-d6) δ −129.00 (dd, J=28.2, 7.0 Hz, 1F), −133.76 (d, J=28.2 Hz, 1F); ESIMS m/z 330.1 ([M+H]+).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([S:13][CH2:14][C:15]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:16]=2[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[CH:10]=[CH:11][CH:12]=1>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]([S:13][CH2:14][C:15]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:16]=2[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(SCc2cccc(C)c2C(=O)OCC(C)C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cccc(CSc2cccc(O)c2)c1C(=O)OCC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Boron tribromide (1.3 mL, 1.0 M in dichloromethane, 1.3 mmol) is added to a solution of isobutyl 2-[3-(methoxy)-phenylsulfanylmethyl]-6-methyl-benzoate (194 mg, 0.56 mmol, example 82) in dichloromethane (3 mL) at 0° C. and then the reaction is stirred at room temperature 3 h. The reaction is then partitioned between sodium bicarbonate solution and ethyl acetate. The organic phase is dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 15% ethyl acetate in hexanes) to provide the title compound. MS (EI) 330 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:22]=[C:23]([O:28][CH3:29])[CH:24]=[CH:25][C:26]=1Br)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=[CH2:32].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:22]=[C:23]([O:28][CH3:29])[CH:24]=[CH:25][C:26]=1[CH:32]=[CH:31][C:30]([O:34][CH3:35])=[O:33])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Br)c(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C=Cc1ccc(OC)cc1CN(Cc1ccc(C(F)(F)F)cc1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution of 3-[N-(tert-butoxycarbonyl)-N-(4-trifluoromethylbenzyl)aminomethyl]-4-bromoanisole (37.08 g, 78 mmol), methyl acrylate (35 mL, 390 mmol), palladium acetate (0.88 g, 3.9 mmol), tri-o-tolylphosphine (2.38 g, 7.8 mol), and diisopropylethylamine (31 mL, 178 mmol) in acetonitrile (200 mL) was deoxygenated (3 evacuation/argon purge cycles), then was heated to reflux under argon (oil bath set at 80° C.). After 6 hr additional palladium acetate (0.88 g, 3.9 mmol) and tri-o-tolylphosphine ((2.38 g, 7.8 mmol) were added and the reaction was stirred under reflux for an additional 18 h. The reaction was concentrated to dryness, and the residue was taken up in 1:1 Et2O/petroleum ether (300 mL) and allowed to stand for 4 h. A gray-colored precipitate was filtered off and washed with a small volume of 1:1 Et2O/petroleum ether (100 mL). The orangish-red filtrate was concentrated and purified by flash chromatography on silica gel (15% ethyl acetate/hexanes). The resulting residue was taken up in hexane, and the mixture was allowed to stand for several hr, then was filtered to remove a yellow precipitate. Concentration of the filtrate left the title compound (34.52 g, 92%) as a thick yellow oil: TLC (silica, 20% EtOAc/hexanes) Rf 0.45; 1H NMR (400 MHz, CDCl3) δ 7.80 (br s, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.6 Hz, 1H), 7.29 (br s, 2H), 6.83 (dd, 1H), 6.72 (br s, 1H), 6.23 (d, J=15.7 Hz, 1H), 4.58 and 4.53 (2 br s, 2H), 4.46 and 4.37 (2 br s, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[OH:28].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:27][C:23]1[C:24]([F:26])=[CH:25][C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[C:21]([OH:28])[CH:22]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cc(F)c(F)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cc(F)c(F)cc1O
Yield: 71306.5 %

Procedure:
The product is prepared according to the procedure described in stage 1 of Example 2, but using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (Example 1, stage 2), 425 mg of 2-amino-4,5-difluorophenol and 600 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 4 ml of pyridine and 4 ml of dimethylformamide. 500 g of N-(4,5-difluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: I[Si](C)(C)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:21][CH2:20][CH2:19][C@@H:18]3[N:14]2[C:15](=[O:22])[CH2:16][CH2:17]3)=[CH:9][CH:8]=1.CN(C)CCN(C)C.[I:31]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:21][CH2:20][CH2:19][C@H:18]3[N:14]2[C:15](=[O:22])[CH:16]([I:31])[CH2:17]3)=[CH:9][CH:8]=1
Reactant: O=C1CC[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Reactant: II
Agent: CN(C)CCN(C)C
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1C(I)C[C@H]2CCC[C@@H](c3ccc(F)cc3)N12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.6 %

Procedure:
Iodotrimethylsilane (0.08 mL) was added to a solution of (5R*,8aS*)-5-(4-fluorophenyl)hexahydroindolizin-3-one (87 mg) and N,N,N′,N′-tetramethylethylenediamine (0.2 mL) in methylene chloride (5 mL) at 0° C., and the reaction solution was stirred at 0° C. for 20 minutes. Iodine (142 mg) was added to the reaction solution, which was then stirred at 0° C. for 40 minutes. Ethyl acetate and a saturated sodium thiosulfate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 120 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH:1]([N:4]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:5]1=2)([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:25][C:20]([NH:16][C:13]2[CH:14]=[CH:15][C:5]3[N:4]([CH:1]([CH3:3])[CH3:2])[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=3[CH:12]=2)=[N:21][CH:22]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CC(C)N1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Product: CC(C)N1C(=O)CCCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc21
Yield: 61 %

Procedure:
In an analogous procedure to Example 651, part c, 1-isopropyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one was combined with N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide to yield N-{(1R,2R)-2-[5-Chloro-2-(1-isopropyl-2-oxo-2,3,4,5-tetrahydro-1H-benz o[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (66.83 mg, 61% yield) as a white powder. 1H-NMR (CDCl3) δ 7.93 (s, 1H), 7.40 (m, 2H), 7.12 (d, J=8.3 Hz, 1H), 6.99 (br s, 1H), 5.49 (d, J=7.5 Hz, 1H), 5.44 (m, 1H), 4.82 (m, 1H), 3.85 (br s, 1H), 3.23 (br s, 1H), 2.82 (m, 4H), 2.56 (m, 1H), 2.22 (m, 5H), 1.89 (m, 3H), 1.42 (d, J=6.6 Hz, 3H), 1.36 (br s, 3H), 1.03 (d, J=6.6 Hz, 3H). LC/MS (ESI+)=523 (M+H), MP=141-143° C.
Reaction SMILES: CC(C)(OC([NH:7][C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)=O)C.[ClH:22]>CCOC(C)=O>[ClH:22].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][CH:20]=1
Reactant: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(N)cc1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a 500 mL round bottomed flask with a stirring bar and a gas dispersion tube was added ethyl (4-(1,1-dimethylethoxycarbonylamino)phenoxy)acetate (11.9 g, 40.29 mmol) and dry EtOAc. This solution was cooled in an ice bath and saturated with anhydrous HCl gas over 15 min. The resulting suspension was aged 30 min. at 0° C. The excess HCl was removed with a stream of argon and the EtOAc was removed in vacuo. The solid product was triturated with EtOAc, collected on a frit, and dried in vacuo at room temperature to give 7.33 g (78%) of ethyl 4-aminophenoxyacetate, hydrochloride as a white crystalline soild.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH3:12][C:13]1[CH:20]=[C:19]([CH:21]=[O:22])[CH:18]=[CH:17][C:14]=1[CH:15]=[O:16].[OH-].[Na+]>O>[OH:16][CH2:15][C:14]1[CH:17]=[CH:18][C:19]([CH2:21][OH:22])=[CH:20][C:13]=1[CH3:12]
Reactant: Cc1cc(C=O)ccc1C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CO)ccc1CO
Yield: 94.7 %

Procedure:
A 200 ml round-bottomed flask was charged with 1 g (25 mmol) of lithium aluminum hydride, and under an argon atmosphere, 50 ml of anhydrous tetrahydrofuran was added. While the resultant mixture was stirred, 50 ml of an anhydrous tetrahydrofuran solution of 2.8 g (19 mmol) of 2-methylterephthalaldehyde was added through a dropping funnel over 20 minutes. The resultant mixture was heat-refluxed for 2 hours, and while the reaction mixture was hot, 1 ml of water, 1 ml of a 50% sodium hydroxide aqueous solution and 3 ml of water were consecutively added in this order. A white precipitate formed was separated by filtering, and the tetrahydrofuran solution was dried over magnesium sulfate, followed by distilling the solvent off with a rotary evaporator and drying under reduced pressure, whereby 2.7 g (18 mmol) of 2,5-bis(hydroxymethyl)toluene was obtained (yield 95%).