Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:23](=O)[CH3:24])[C:15]([O:17][CH2:18][CH:19]1[CH2:22][CH2:21][CH2:20]1)=[O:16].[NH2:26][C:27]([CH3:31])=[CH:28][C:29]#[N:30]>C(O)C>[C:29]([C:28]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:14]([C:15]([O:17][CH2:18][CH:19]2[CH2:22][CH2:21][CH2:20]2)=[O:16])=[C:23]([CH3:24])[NH:26][C:27]=1[CH3:31])#[N:30]
Reactant: CC(N)=CC#N
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)OCC1CCC1
Solvent: CCO
Product: CC1=C(C#N)C(c2cccc3c(=O)cc(C)oc23)C(C(=O)OCC2CCC2)=C(C)N1

Procedure:
66 mg (0.19 mmol) of cyclobutylmethyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate are dissolved with 16 mg (0.19 mmol) of 3-aminobut-2-enenitrile in 3 ml of ethanol and heated under reflux under argon for 24 h. The suspension is allowed to cool and filtered with suction, and the remaining solid is washed with methanol. 45 mg (57% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(OCC1C=CC=CC=1)=O)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[ClH:32]>CCO.[Pd]>[ClH:32].[C:1]([O:5][C:6](=[O:31])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C
Reaction time: 7 h
Yield: 99 %

Procedure:
Nα-BOC-Nε-CBZ-L-lysine tert-butyl ester (22) (34.51 g, 79.15 mmol) was dissolved in a mixture of 300 ml absolute EtOH and 1 N HCl (88 ml). Prior to the introduction of H2 gas, 10% Pd-C (2.95 g) was added. After 7 hours, additional catalyst (1.0 g) was added. After 5 hours, the black suspension was filtered through a bed of Celite and washed with EtOH. The filtrate was concentrated and the residue dried under high vacuum to give the Nα-BOC-L-lysine tert-butyl ester as its hydrochloride salt (23) (26.59 g, 99%). 1H NMR (CD3OD) δ 3.95 (dd, 1H, J=8.8, 5.0 Hz), 2.93 (t, 2H, J=7.7 Hz), 1.84-1.60 (m, 6H), 1.45 (s, 9H), 1.43 (s, 9H); 13C NMR (CD3OD) δ 173.5, 15 8.2, 82.7, 80.5, 79.5, 5 5.5, 40.6, 32.1, 28.7, 28.3, 23.9. HRMS m/z calcd. for C15H31N2O4 303.2284, found 303.2272. [α]26D−10.1° (c=1.00, CH3OH).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:18]O.[Al]>>[CH3:1][N+:2]([O-:18])([CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCN(C)C
Reactant: OO
Agent: [Al]
Product: CCCCCCCCCCCCCC[N+](C)(C)[O-]
Temperature: 41 °C

Procedure:
N,N-dimethyl-N-tetradecyl amine (ADMA®14 amine; Albemarle Corporation) (752 g, 3.12 mol) was charged into a 2-liter resin kettle and heated to 41° C. under CO2 blanket before the heating source was removed. Hydrogen peroxide (142 mL, 70%, 3.74 mol) was added over 3.5 hours. The reaction mixture was monitored by 1H-NMR (see Table below). During peroxide addition, the reaction temperature ranged from 41 to 59° C. depending on the peroxide rate of addition. At the end of addition, the slurry was poured into an aluminum pan and was left to stand in a hood over the weekend, after which time 1H-NMR showed complete conversion of the N,N-dimethyl-N-tetradecyl amine to the corresponding oxide. The resulting N,N-dimethyl-N-tetradecyl amine oxide was obtained as snow-white solid block.
Reaction SMILES: C1(COC([NH:11][CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH:18]([C:24]([O:26]CC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=O)C=CC=CC=1>CCO.[Pd]>[O:26]=[C:24]1[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:14]2[CH2:15][CH2:16][CH2:17][C@H:13]2[CH2:12][NH:11]1
Reactant: CCOC(=O)C(C(=O)OCC)N1CCC[C@H]1CNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1C(=O)NC[C@@H]2CCCN12
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 101.8 %

Procedure:
The solution of diethyl {(2S)-2-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinyl}propanedioate (D115, 1.40 g, 3.67 mmol) in EtOH (ca. 20 ml) was degassed, (10%) Pd/C (778 mg, 0.734 mmol) was added and the reaction mixture was stirred under a H2 atmosphere for 2.5 hrs. The catalyst was filtered off and the volume of the filtrated solution was reduced in vacuo. The solution was warmed-up to 50° C. and it was stirred at this temperature for 7 hrs. The solvent was evaporated to dryness to give the title compound as a yellowish oil (793 mg) as a mixture of diastereoisomers. This crude was used in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:9][CH:8]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[CH:5]([CH2:6][CH2:7]2)[CH2:4]1.[Cl:23][CH2:24][CH2:25][C:26](Cl)=[O:27].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:23][CH2:24][CH2:25][C:26]([NH:2][CH:3]1[CH2:4][CH:5]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[CH:8]([CH2:7][CH2:6]2)[CH2:9]1)=[O:27]
Reactant: N#Cc1ccc(N2C3CCC2CC(N)C3)c2ccccc12
Reactant: O=C(Cl)CCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2C3CCC2CC(NC(=O)CCCl)C3)c2ccccc12

Procedure:
This compound was synthesized in the same way as 165RL23 using 165RL21 (320 mg, 1.15 mmol), 3-chloropropionyl chloride (120 μL, 1.27 mmol), DIPEA (220 μL, 1.27 mmol) and DMF (10 mL). The crude product was purified by column chromatography using ethyl acetate/MeOH (95:5) to give the title compound (318 mg, 75
Reaction SMILES: C(COC1C2CC(=CCCN3CCC(C4C=CC(Cl)=CC=4)(O)CC3)C3[C:15](OC=2C=CC=1)=[N:16][CH:17]=CC=3)(O)=O.[C:38]([C:41]([O:44][C:45]1[C:50]2[CH2:51][C:52](=[CH:60][CH2:61][CH2:62][N:63]3[CH2:68][CH2:67][C:66]([C:70]4[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][CH:71]=4)([OH:69])[CH2:65][CH2:64]3)[C:53]3[C:54]([O:59][C:49]=2[CH:48]=[CH:47][CH:46]=1)=[N:55][CH:56]=[CH:57][CH:58]=3)([CH3:43])[CH3:42])(O)=[O:39]>>[Cl:76][C:73]1[CH:74]=[CH:75][C:70]([C:66]2([OH:69])[CH2:67][CH2:68][N:63]([CH2:62][CH2:61][CH:60]=[C:52]3[C:53]4[C:54](=[N:55][CH:56]=[CH:57][CH:58]=4)[O:59][C:49]4[CH:48]=[CH:47][CH:46]=[C:45]([O:44][C:41]([C:38]([N:16]([CH3:17])[CH3:15])=[O:39])([CH3:43])[CH3:42])[C:50]=4[CH2:51]3)[CH2:64][CH2:65]2)=[CH:71][CH:72]=1
Reactant: O=C(O)COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Reactant: CC(C)(Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2)C(=O)O
Product: CN(C)C(=O)C(C)(C)Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2

Procedure:
The titled compound was prepared by following the procedure of example 134, but replacing the product of example 133 with the product of example 139.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[S:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)O)[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:10]2[S:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(C(O)c2cccc(Br)c2)s1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc(Cc2cccc(Br)c2)s1
Temperature: -78 °C
Yield: 93.7 %

Procedure:
A solution of 1,3-dibromobenzene (3.7 g) in tetrahydrofuran (25 ml) was cooled to −78° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (2.44 M hexane solution, 5.55 ml). The reaction mixture was stirred at the same temperature for 10 minutes, and thereto was added dropwise a solution of 5-ethyl-2-thiophenecarboxaldehyde (2.0 g) in tetrahydrofuran (10 ml). The mixture was stirred at the same temperature for 30 minutes, and thereto was added a saturated ammonium chloride solution, and the reaction mixture was warmed to room temperature. The mixture was extracted with ethyl acetate, and the extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3-85:15) to give 3-bromophenyl-5-ethyl-2-thienylmethanol (2.97 g) as a pale yellow syrup. APCI-Mass m/Z 279/281 (M+H—H2O). (2) The above 3-bromophenyl-5-ethyl-2-thienylmethanol (2.90 g) was dissolved in dichloromethane (38 ml), and the mixture was cooled to −78° C. under argon atmosphere. To the mixture were added triethylsilane (6.18 ml) and boron trifluoride•diethyl ether complex (2.45 ml), and the mixture was gradually warmed to room temperature over a period of one hour. The mixture was basified with a saturated aqueous sodium hydrogen carbonate solution, and the dichloromethane layer was collected, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give the desired 3-bromo-(5-ethyl-2-thienylmethyl)benzene (2.57 g) as a colorless syrup. APCI-Mass m/Z 281/283 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29](C(F)(F)F)[CH:28]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].NC1C=CC=CC=1>>[C:1]([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Solvent: Nc1ccccc1
Product: Cc1ccc(C(=O)Nc2ccccc2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Yield: 3 %

Procedure:
The procedures of Steps (1), (2) and (3) of Example 2 were repeated step by step, except for using aniline instead of 3-trifluoro-aniline in Step (1) of Example 2 to obtain the title compound (1.2 mg, 3%).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:19])=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:9]2)[CH:2]=[CH2:3]>C(O)C.[Pd]>[OH:19][C:5]1[C:4]([CH2:1][CH2:2][CH3:3])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12]2)=[CH:7][CH:6]=1
Reactant: C=CCc1c(O)ccc2ccc(C(=O)OCC)cc12
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(O)ccc2ccc(C(=O)OCC)cc12
Yield: 79.4 %

Procedure:
Ethyl 8-allyl-7-hydroxynaphthalene-2-carboxylate (4 g) in ethanol was hydrogenated at 3 atmospheres in the presence of a 5% palladium charcoal catalyst for 1 hour. Filtration and evaporation of the filtrate gave a solid, which crystallised from benzene-petroleum ether (b.p. 60-80) to give ethyl 7-hydroxy-8-propylnaphthalene-2-carboxylate (3.2 g), m.p. 114°-115°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH3:12])=[CH:5][CH:4]=1.[Sn](Cl)Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH:10][C@@H:11]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[CH3:12])[C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(N[C@H](C)c2ccc(C)cc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COc1ccc(C(N[C@H](C)c2ccc(C)cc2)c2cccc(N)c2)cc1

Procedure:
7.72 g of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-[(R)-1-p-tolylethyl]amine [prepared as described in step (a) above] were dissolved in 150 ml of ethanol. Tin (II) chloride (15.6 g) was added to the resulting solution, which was then heated under reflux for 3 hours. The reaction mixture was allowed to cool, and the ethanol was distilled off. The residue was dissolved in ethyl acetate. The organic solution was washed with a 1N aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. The yellow oil thus obtained was purified by chromatography through a silica gel column using an 8:1 by volume mixture of toluene and tetrahydrofuran as eluant, to obtain 1.43 g and 0.78 g of isomer A and isomer B of the title compound, respectively, each as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:39][CH3:40])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH:27]5[CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][CH:26]5[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:39][CH3:40])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH:27]5[CH:26]([CH2:31][NH:30][CH2:29]5)[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CN(C(=O)OC(C)(C)C)CC2C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.7 %

Procedure:
To a solution of tert-butyl 5-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.70 g) in DCM (30 mL) was added a solution of HCl in EtOAc. The reaction mixture was stirred at room temperature for 6 h and filtered to obtain the crude product. The crude product was recrystallized from MeOH/EA to give the title compound as a white solid (1.30 g, 80.00%), HPLC: 85.68%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 472.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.81-1.88 (m, 4H), 2.35-2.43 (m, 6H), 2.68-2.74 (m, 4H), 3.99 (s, 3H), 4.13 (t, J=7.2 Hz, 2H), 7.16 (s, 1H), 7.26 (s, 1H), 7.45 (s, 1H), 7.57-7.62 (m, 1H), 7.91-7.93 (m, 1H), 8.64 (s, 1H) ppm.
Reaction SMILES: C(OC([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([C:16]2[N:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>CO.ClCCl.[Pd]>[CH3:8][NH:9][C:10]1[CH:11]=[C:12]([C:16]2[N:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C=Cc1ccc(-c2cccc(NCC(=O)OC(C)(C)C)c2)nc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCOC(=O)CCc1ccc(-c2cccc(NC)c2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 112 %

Procedure:
A solution of 852 mg (2.23 mmol) of ethyl 3-{6-[3-(tert-butoxycarbonylmethylamino)phenyl}pyrid-3-yl}acrylate in 10 mL of methanol is stirred for 4 hours at room temperature in the presence of 100 mg of 10% palladium-on-charcoal under a hydrogen atmosphere. The catalyst is filtered off and the solvents are then evaporated off. The oil obtained is dissolved in 15 mL of dichloromethane. 2 mL of trifluoroacetic acid are added and the reaction mixture is stirred for 4 hours at room temperature. The reaction is stopped by adding 100 mL of saturated sodium hydrogen carbonate solution and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 710 mg of ethyl 3-[6-(3-methylaminophenyl)pyrid-3-yl]propanoate are obtained. Yield=68%.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[F:12][C:13]1([F:21])[C@H:17]([OH:18])[C@H:16]([CH3:19])[NH:15][C:14]1=[O:20].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([N:15]2[C@@H:16]([CH3:19])[C@@H:17]([OH:18])[C:13]([F:21])([F:12])[C:14]2=[O:20])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: C[C@@H]1NC(=O)C(F)(F)[C@@H]1O
Reactant: COc1cc(Br)ccc1C#N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc(N2C(=O)C(F)(F)[C@H](O)[C@@H]2C)ccc1C#N

Procedure:
Using 4-bromo-2-methoxybenzonitrile (2.34 g), (4R,5S)-3,3-difluoro-4-hydroxy-5-methylpyrrolidin-2-one (2.00 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (976 mg), tris(dibenzylideneacetone)dipalladium(0) (504 mg) and cesium carbonate (5.30 g), and in the same manner as in Reference Example 18, the title compound was obtained as a colorless solid (yield: 201 mg, 7%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>COCCOC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([O:16][C:14]([NH:13][C@@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:21])[CH:27]=2)=[CH:3][CH:4]=1)[C:10]([OH:12])=[O:11])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1cccc(-c2ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc2)c1
Temperature: 25 °C

Procedure:
(S)-3-(4-bromophenyl)-2-(tert-butoxycarbonylamino)propanoic acid (2.0 g, 5.81 mmol), 3-methylphenylboronic acid (0.948 g, 6.97 mmol), Pd(PPh3)4 (0.336 g, 0.291 mmol) and 2M NaCO3 aqueous solution (4.36 mL) were stirred in 1,2-dimethoxyethane (30 mL) at 80° C. for 2.5 hours. After being cooled to room temperature, the reaction mixture was diluted with EtOAc and washed with 1M HCl and brine. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel flash column chromatography (10% MeOH in DCM/DCM) to give(S)-2-(tert-butoxycarbonylamino)-3-(3′-methylbiphenyl-4-yl)propanoic acid. MS: m/z (MH+-Boc) 256. Retention time=1.45 min. (condition A).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH2:15][C@@:14]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=3[F:30])([OH:22])[CH2:13][CH2:12]2)=O)=CC=1)([O-])=O.[OH-].[Li+]>O1CCCC1.C(OCC)(=O)C.O>[F:30][C:24]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=1[C@:14]1([OH:22])[CH2:13][CH2:12][C@@H:11]([OH:10])[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH2:15]1
Reactant: O=C(O[C@@H]1CC[C@@](O)(c2cccc(F)c2F)Cc2cccnc21)c1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O[C@@H]1CC[C@@](O)(c2cccc(F)c2F)Cc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
In a 250 mL round-bottom flask was dissolved (6S,9R)-6-(2,3-difluorophenyl)-6-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-nitrobenzoate (125 mg, 0.284 mmol) in tetrahydrofuran (2 mL) to give a colorless solution. Lithium hydroxide (0.568 mmol) was added, and the mixture was stirred at room temperature for 2 h. LCMS indicated complete conversion. It was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated to a white solid. Purification by FCC up to 6% methanol/methylene chloride afforded the desired product as a white crystalline solid (71 mg, 86%). A few crystals were picked out and an x-ray structure was obtained to confirm the cis-diol stereochemistry. MS(ESI)[M+H+]=292.21; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.44 (d, J=4.58 Hz, 1H) 7.38-7.51 (m, 2H) 7.19 (dd, J=7.48, 5.04 Hz, 1H) 7.04-7.16 (m, 2H) 5.99 (br. s., 1H) 4.90 (dd, J=11.29, 2.14 Hz, 1H) 3.80-3.91 (m, 1H) 2.92 (dd, J=14.65, 2.14 Hz, 1H) 2.57-2.70 (m, 1H) 2.37 (br. s., 1H) 2.11 (ddd, J=14.19, 5.95, 3.97 Hz, 1H) 1.96-2.06 (m, 1H) 1.74-1.91 (m, 1H); 19F NMR (470 MHz, CHLOROFORM-d) δ ppm −138.91-−138.74 (m, 1F) −139.22-−139.06 (m, 1F); 13C NMR (126 MHz, CHLOROFORM-d) δ ppm 160.64 (s, 1C) 152.00-150.10 (dd, J=21.42 and 254.52 Hz, 1C) 148.75-146.71 (dd, J=11.52 and 244.44 Hz, 1C) 145.55 (s, 3C) 139.91 (s, 3C) 138.44 (d, J=8.64 Hz, 1C) 129.37 (s, 1C) 123.89-124.57 (m, 2C) 122.48 (s, 3C) 120.84 (s, 1C) 116.22 (d, J=17.28 Hz, 2C) 71.79 (m, 3C) 71.70 (m, 4C) 44.30 (d, J=4.80 Hz, 2C) 39.65 (s, 1C) 31.29 (s, 2C).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=4)[N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[N:25]=3)[N:21]=[N:20]2)=[CH:15][CH:14]=1)=[O:12]>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[Br:8][CH2:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[N:25]=[C:24]2[C:22]1[N:21]=[N:20][N:19]([C:16]2[CH:17]=[CH:18][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:14][CH:15]=2)[CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(-n2cc(-c3nn(C(=O)OC(C)(C)C)c4ccc(C)cc34)nn2)cc1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2cc(-c3nn(C(=O)OC(C)(C)C)c4ccc(CBr)cc34)nn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
Zirconium tetrachloride (23 mg; 0.10 mmol; 0.1 eq.) was added in one portion to a solution of NBS (160 mg; 0.90 mmol; 0.9 eq.) in DCM (10 mL) at 0° C. A solution of tert-butyl 3-{1-[4-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-5-methyl-1H-indazole-1-carboxylate (434 mg; 1.00 mmol; 1.0 eq.) in DCM (10 mL) was then added dropwise to the reaction mixture which was subsequently stirred at RT for 16 h. The reaction mixture was then diluted with DCM and washed sequentially with saturated NaHCO3 and brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow solid (392 mg, 76%) 1H NMR (300 MHz, DMSO) δ 9.70 (s, 1H), 8.62 (d, J=1.0 Hz, 1H), 8.30 (d, J=8.8 Hz, 2H), 8.21 (d, J=8.8 Hz, 2H), 8.16 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.8 Hz, 1.7, 1H), 4.99 (s, 2H), 3.92 (s, 3H), 1.70 (s, 9H). MS (ESI+): 512.3.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30](O)(=O)[C:31]([OH:33])=[O:32].[CH3:36][OH:37]>ClCCl>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:31]([O-:33])(=[O:32])[CH2:30][C:36]([O-:10])=[O:37]
Reactant: CO
Reactant: O=C(O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: ClCCl
Product: O=C([O-])CC(=O)[O-]
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
Sunitinib (1.0 g) was suspended in 10% methanol in dichloromethane (30mL) at 25° C. , followed by addition of oxalic acid (0.22 g) .The reaction mass was maintained under stirring at 25-30° C. for 60 minutes. The solids obtained were filtered, suck dried and dried under vacuum for a period of 10 hrs at 60° C. to obtain sunitinib malonate. (0.9 g; yield: 75%)