Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11].Cl>[OH-].[Na+].O>[CH:7](=[C:2]1[CH2:3][CH2:4][CH2:5][C:1]1=[O:6])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C1CCCC1
Reactant: CCCCC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC=C1CCCC1=O
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
A 3-L reaction flask was charged with cyclopentanone (500 g, 6 mol), water (H2O) (500 mL) and sodium hydroxide (NaOH) (10 g, 0.25 mol). Valeraldehyde (430 g, 5 mol) was fed into the reaction flask over 3 hours while the temperature was maintained at 25-30° C. After the feeding was completed, the reaction was aged for 2 hours and neutralized with hydrochloric acid (HCl) (30 g, 0.3 mol) while the temperature was maintained at 25-30° C. The reaction mass was further aged for 2 hours. The organic layer was separated and washed with saturated aqueous sodium bicarbonate (NaHCO3) (200 mL). The obtained crude product was fractionated to provide 2-pentylidene-cyclopentanone (523 g) having a boiling point of 122° C. at 3 mmHg A 1-L zipper autoclave was charged with 2-pentylidine cyclopentanone (523 g) and palladium on carbon (Pd/C) (2 g). The autoclave was purged three times with nitrogen followed by three times with hydrogen. The autoclave agitator was then turned on to 1500 rpm and the pressure was set to 100 psi. The reaction was allowed to exotherm to about 120° C. and maintained at this temperature for 2 hours. The autoclave was cooled to an ambient temperature. The hydrogen was then vented and the autoclave was subsequently purged three times with nitrogen. The Pd/C was removed by filtration through Celite®. The crude product 2-pentyl-cyclopentanone (520 g) was obtained and used in following steps without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][C:8]([NH:21][C:22](=[O:24])[CH3:23])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])[CH2:9][CH2:10][CH3:11])(=[O:5])[CH3:4].[CH2:25](Br)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].O>CN(C)C=O.O1CCCC1>[C:3]([O:6][CH2:7][C:8]([NH:21][C:22](=[O:24])[CH3:23])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][CH2:10][CH3:11])(=[O:5])[CH3:4]
Reactant: CCCC(CCc1ccccc1O)(COC(C)=O)NC(C)=O
Reactant: CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccccc1CCC(CCC)(COC(C)=O)NC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a suspension of sodium hydride (85 mg) in dimethylformamide (5 ml), a solution of 2-acetamido-2-(2-(2-hydroxyphenyl)ethyl)pentyl acetate (0.65 g) in dimethylformamide (5 ml) was added under ice-cooling and the mixture was stirred at room temperature for an hour. To the solution, a solution of heptyl bromide (0.42 g) in tetrahydrofuran (4 ml) was added. The mixture was stirred at the same temperature for 6 hours and left standing overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and a saturated brine and dried over magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was subjected to silica gel chromatography (eluent; chloroform-methanol=12:1) to give the subject compound (0.36 g).
Reaction SMILES: C(CC[O:5][C:6]([C:8]1[CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:10]([C:20](O)=[O:21])=[C:11]([CH2:15][O:16][CH2:17]CCl)[NH:12][C:13]=1[CH3:14])=[O:7])#N.C[CH2:31][N:32]=C=NCCCN(C)C.Cl.[C:42]1([CH:48]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:49][CH2:50][NH2:51])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[NH2:32][CH2:31][CH2:17][O:16][CH2:15][C:11]1[N:12]=[C:13]([CH3:14])[C:8]([C:6]([OH:5])=[O:7])=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:10]=1[C:20](=[O:21])[NH:51][CH2:50][CH2:49][CH:48]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)O)=C(COCCCl)N1
Agent: Cl
Solvent: ClCCl
Product: Cc1nc(COCCN)c(C(=O)NCCC(c2ccccc2)c2ccccc2)c(-c2cccc(Cl)c2)c1C(=O)O

Procedure:
250 mg (0.560 mmol) of 2-(2-chloroethoxy) methyl-4-(3-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 5-(2-cyanoethyl) ester, 110 mg (0.570 mmol) of WSC hydrochloride and 120 mg (0.570 mmol) of 3,3-diphenylpropylamine were stirred at room temperature for 15 hours in 4 ml of dichloromethane. After evaporating dichloromethane under reduced pressure, 0.1 N hydrochloric acid was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/1) to obtain the title compound.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)S1
Temperature: 80 °C

Procedure:
A solution containing 0.59 g (0.005 mol) of thiazolidine-2,4-dione, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.05 ml of piperidine in 5 ml of acetic acid was heated for 7-8 h at 80° C. The crystals were filtered and washed with ethanol. Yield 1.0 g (72%), mp 295°-298° C.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:10]([CH3:11])=[C:9]([Cl:12])[N:8]=[C:7]([NH:13][NH2:14])[C:6]1=[O:15])([OH:3])=[O:2].C([O-])(O)=O.[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O.O1CCOCC1>[CH2:25]([O:24][C:22]([NH:14][NH:13][C:7]1[C:6](=[O:15])[N:5]([CH2:4][C:1]([OH:3])=[O:2])[C:10]([CH3:11])=[C:9]([Cl:12])[N:8]=1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1c(Cl)nc(NN)c(=O)n1CC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(Cl)nc(NNC(=O)OCc2ccccc2)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.8 %

Procedure:
To a solution of the compound of Example 14 (1.9 g, 8.26 mmol) and NaHCO3 (2.08 g, 24.75 mmol) in water, (60 mL) was added drop-wise a solution of benzyl chloroformate (1.9 mL, 13.21 mmol) in dioxane (100 mL). The resulting mixture was stirred at room temperature for 4 hours, then was diluted with water (60 mL) and washed with ether (100 mL). The aqueous solution was acidified with 2 M KHSO4 and extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine (200 mL), dried (Na2SO4), and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (1:1 EtOAc/hexane, then 9:1 DCM/MeOH) to afford the title compound (1.6 g, 53%) as a pale yellow solid. 1H NMR (DMSO-d4) δ 2.24 (s, 2H), 4.64 (s, 2H), 5.13 (s, 2H), 7.20-7.45 (m, 5H), 9.22 (s, 1H), 9.29 (s, 1H). HPLC Rt 11.4 minutes (water/ACN/TFA, 5 to 75%, 0.1% TFA, 20 minutes).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[Cs+].[Cs+].C([NH:23][C@H:24]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:25]([OH:29])[C:26]([OH:28])=[O:27])(OC(C)(C)C)=O.CCOC(C)=O>CN(C=O)C>[CH3:8][C:7]1[O:6][C:5](=[O:9])[O:4][C:3]=1[CH2:2][O:28][C:26](=[O:27])[C@H:25]([OH:29])[C@H:24]([NH2:23])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1.[ClH:1]
Reactant: Cc1oc(=O)oc1CCl
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1oc(=O)oc1COC(=O)[C@H](O)[C@H](N)Cc1ccccc1
Product: Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 587.7 %

Procedure:
4-Chloromethyl-5-methyl-1,3-dioxol-2-one (212 mg, 1.4 mmol, 1.0 eq.) was dissolved in dry DMF (2 mL) and cooled to 0° C. Dicesium carbonate (465 mg, 1.4 mmol, 1.0 eq.) was added and the mixture was stirred for 30 minutes at 0° C. (2R,3R)-3-(BOC-amino)-2-hydroxy-4-phenylbutyric acid (421 mg, 1.4 mmol, 1.0 eq.) was added and the mixture was stirred for 1 hour at 0° C. and then warmed to room temperature, while stirring. EtOAc (20 mL) was added and the mixture was washed with saturated aqueous NaCl (100 mL) then vacuumed to dryness. The product was purified using reverse phase chromatography (10-70% MeCN gradient). Acid deprotection was accomplished by dissolving the product in 4N HCl in dioxane (10 mL). The product was then vacuumed to dryness, taken up in toluene and vacuumed to dryness again to yield the title compound as an HCl salt (0.3 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH2:25]/[CH:26]=[CH:27]/[C:28](Cl)=[O:29])[CH3:24]>CN1C(=O)CCC1>[CH3:22][N:23]([CH3:24])[CH2:25]/[CH:26]=[CH:27]/[C:28]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:12]=[CH:11][N:10]=2)[N:7]=1)=[O:29]
Reactant: Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Reactant: CN(C)C/C=C/C(=O)Cl
Solvent: CN1CCCC1=O
Product: CN(C)C/C=C/C(=O)Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Synthesis of (E)-4-(dimethylamino)-N-(6-(6-(phenylamino)pyrimidin-4-ylamino)pyridine-2-yl)but-2-enamide (I-73) To a stirred solution of acetonitrile (20 mL) and DMF (0.05 mL) under N2 was added N,N-dimethylamino crotonic acid hydrochloride (0.47 g, 2.8 mmol). After 10 min this solution was cooled to 0-5° C. Oxalyl chloride (0.44 g, 3.5 mmol) was added and the reaction mixture was maintained at 0-5° C. for 30 min. It was allowed to warm to rt and stirring was continued for 2 h. It was then heated to 40° C. for 5 min and again brought to rt and stirred for 10 min to get a light greenish colored solution of dimethylaminocrotonyl chloride that was used as such for next step. To a stirred solution of N4-(6-aminopyridin-2-yl)-N6-phenylpyrimidine-4,6-diamine (0.2 g, 0.7 mmol) in NMP (10 mL) was added dropwise under N2 atmosphere at 0° C. the solution of dimethylaminocrotonyl chloride. The reaction mixture was maintained at this temperature for 30 min and was warmed to rt and stirred for 2 h. The mixture was quenched with sodium bicarbonate solution (1 mL) and was extracted with EtOAc (2×35 mL). The combined ethyl acetate extract was washed with water (20 mL) and brine (20 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, product was eluted at 4-6% methanol in chloroform) to give (E)-4-(dimethylamino)-N-(6-(6-(phenylamino)pyrimidin-4-ylamino)pyridine-2-yl)but-2-enamide (I-73) as a yellowish solid. 1H NMR (DMSO-d6) δ ppm: 2.24 (s, 6H), 3.13 (d, J=5.76 Hz, 2H), 6.56 (d, J=15.52 Hz, 1H), 6.80 (d, J=15.36 Hz, 1H), 6.95 (t, J=7.36 Hz, 1H), 7.11 (t, J=1.16 Hz, 1H), 7.29 (t, J=7.56 Hz, 2H), 7.58 (s, 1H), 7.65-7.7 (m, 4H), 8.31 (d, J=2.44 Hz, 1H), 9.23 (s, 1H), 9.68 (s, 1H), 10.16 (s, 1H); LCMS: m/e 390.3 (M+1).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:32])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30]Br)=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:39][C:40]([F:49])([F:48])[C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1>CN(C=O)C.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:32])[CH2:15][C@H:16]([C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:47][C:44]2[CH:45]=[CH:46][C:41]([C:40]([F:39])([F:48])[F:49])=[CH:42][CH:43]=2)=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C[C@@H](c1ccc(OCCBr)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(C[C@@H](c1ccc(OCCOc2ccc(C(F)(F)F)cc2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
The bromide 47.1 (100 mg, 0.2 mmol) was dissolved in DMF (2.0 mL). Cesium carbonate (260 mg, 0.8 mmol) and 4-trifluoromethylphenol (130 mg, 0.8 mmol) were added to the solution and the mixture was then heated with stirring for three hours. The reaction mixture was then cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with 1M lithium chloride solution (1×25 mL), water (1×25 mL) and brine (1×25 mL) and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue purified by medium pressure chromatography (silica, 0 to 60% EtOAc: hexanes) to obtain 47.2 (58 mg). MS ESI (pos.): m/e 581.2 (M+H).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]([NH2:22])[CH2:14]1.[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]([NH:22][C:6]2[CH:5]=[CH:4][C:3]3[C:2]([NH:23][CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=2)[CH2:14]1
Reactant: NCc1cccnc1
Reactant: NC1COc2ccccc21
Reactant: Clc1ccc2c(I)cccc2n1
Product: c1cncc(CNc2cccc3nc(NC4COc5ccccc54)ccc23)c1

Procedure:
The title compound, MS: m/e=369.0 (M+H+), was prepared in accordance with the general method of example 6 from 5-iodo-2-chloroquinoline, rac-2,3-dihydro-benzofuran-3-ylamine (CAS 109926-35-4) and 3-(aminomethyl)pyridine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)=[O:23])=[C:17]([Cl:28])[CH:16]=1)#[N:2].[Br:29][CH2:30][CH2:31][CH2:32]Br>>[Br:29][CH2:30][CH2:31][CH2:32][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH:25]4[CH2:26][CH2:27]4)=[O:23])=[C:17]([Cl:28])[CH:16]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1O
Reactant: BrCCCBr
Product: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1OCCCBr
Yield: 15.6 %

Procedure:
The title compound (129 mg, 0.250 mmol, 15.6%) was obtained as light brown crystals from an N-(4-(6-cyano-7-hydroxy-4-quinolyl)oxy-2-chlorophenyl)-N′-cyclopropylurea crude product (500 mg, 1.60 mmol) and 1,3-dibromopropane, by the same procedure as in Example 7.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[O:3]1.C(N(CC)CC)C.[C:20](Cl)(=[O:28])[CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24]>ClCCl>[CH3:1][CH:2]1[N:6]([C:20](=[O:28])[CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[O:3]1
Reactant: CCCC(CCC)C(=O)Cl
Reactant: CC1NCC2(CCN(C)CC2)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(CCC)C(=O)N1CC2(CCN(C)CC2)OC1C
Temperature: 0 °C

Procedure:
2,8-Dimethyl-1-oxa-3,8-diaza-spiro[4.5]decane (1.52 g, 8.95 mmol) was dissolved in dry dichloromethane (5 ml) under an argon atmosphere. Distilled triethylamine (1.87 ml, 13.42 mmol) was added and the resulting solution was cooled to 0° C. Valproyl chloride (1.46 g, 8.95 mmol) was added dropwise with a syringe. The reaction flask was allowed to warm to room temperature with stirring, and a white solid started to precipitate. After 4 h of stirring, dichloromethane (100 ml) was added and the resulting solution was washed with water (10 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic phase was dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 130/10/1) to give AF712 (389 mg, 98.7% chemical purity) as a yellow powder. 1H NMR. (CDCl3, 300 MHz) δ 5.43 (q, J=5.2 Hz, 1H, CHCH3), 4.13, 3.63 (2d, J=11.35 and J=9.6 Hz, 1H, CHHNCO), 3.22, 3.00 (2d, J=9.6 and J=11.35 Hz, 1H, CHHNCO), 2.56-2.38 (m, 5H), 2.30, 2.29 (2s, 3H, NCH3), 1.84-1.53 (3m, 6H), 1.44, 1.43 (2d, J=5.2 Hz, 3H, CH3CH), 1.4-1.19 (m, 6H), 0.90 (app t, J=7.11 Hz, 6H, CH3CH2) ppm; 13C NMR. (CDCl3, 300 MHz) δ 173.92, 173.68 (C), 84.75, 84.20 (CH), 78.32, 78.09 (C), 54.24 (CH2), 52.34 (CH2), 52.02 (CH2), 46.03 (CH3), 44.34, 43.64 (CH), 35.63 (CH2), 35.05 (CH2), 34.92 (CH2), 32.83 (CH2), 23.52, 20.91 (CH3), 20.59 (CH2), 20.43 (CH2), 14.30 (CH3), 14.16 (CH3) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([NH2:19])=[O:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:25][C:26]([OH:28])=[O:27])[C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17](=[O:18])[NH2:19])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccccc2C(N)=O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccccc2C(N)=O)cc1

Procedure:
prepared by reaction of 2-(4-tert-butyl-benzenesulfonylamino)-benzamide with tert-butyl bromoacetate
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[CH:11][C:12]2[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]>O1CCCC1.CO.[C].[Pd]>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C=Cc2ccc(C(=O)O)s2)cs1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(C(=O)O)s2)cs1
Yield: 81.4 %

Procedure:
5-{2-[2-(Acetylamino)-1,3-thiazol-4-yl]vinyl}thiophene-2-carboxylic acid (900.0 mg, 3.058 mmol) was dissolved in a mixed solvent of tetrahydrofuran (250 ml) and methanol (100 ml). 20% Palladium carbon was added, and the mixture was hydrogenated at room temperature under 4 atm. After the completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Diethyl ether (100 ml) was added to the concentrated residue, and the precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give 5-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}thiophene-2-carboxylic acid (738.1 mg, 2.490 mmol, yield 81.4%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[F:16][C:17]1[CH:18]=[C:19]([CH:29]([NH:31][C:32]([C:34]2[N:35]=[C:36](Cl)[O:37][CH:38]=2)=[O:33])[CH3:30])[CH:20]=[C:21]([F:28])[C:22]=1[NH:23][S:24]([CH3:27])(=[O:26])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:28][C:21]1[CH:20]=[C:19]([CH:29]([NH:31][C:32]([C:34]2[N:35]=[C:36]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:5]=3)[O:37][CH:38]=2)=[O:33])[CH3:30])[CH:18]=[C:17]([F:16])[C:22]=1[NH:23][S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: COc1ccc(B(O)O)cc1C(F)(F)F
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(-c2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)cc1C(F)(F)F
Yield: 32.1 %

Procedure:
4-Methoxy-3-trifluoromethylbenzeneboronic acid (34 mg, 0.16 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-amide (30 mg, 0.078 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (80 mg, 0.25 mmol) as described above to give the title compound (13 mg, 32%) after purification by flash chromatography on silica gel (% EtOAc in hexane=12%˜100%).
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][CH2:9][C:10]([CH3:32])([CH3:31])[CH:11]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[N:19]=[CH:18]2)[CH2:12][CH:13]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.[OH-:42].[Na+].OO>C1COCC1.O>[C:1]([NH:5][C:6]([NH:8][CH2:9][C:10]([CH3:32])([CH3:31])[CH:11]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[N:19]=[CH:18]2)[CH2:12][CH2:13][CH2:14][OH:42])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)CNC(=O)NC(C)(C)C
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NC(=O)NCC(C)(C)C(CCCO)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 1-tert-butyl-3-(3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylhex-5-enyl)urea (5.0 mg, 0.01 mmol) in anhydrous THF (2 mL) at 0 C was added 9-BBN (50 μL, 0.02 mmol) under nitrogen. Allowed reaction mixture to warm to RT and stirred overnight then added 10% NaOH solution (0.2 mL) and 30% H2O2 (1 mL). and stirred for 10 min. The reaction mixture was poured into a water (4 mL), extracted with ethyl acetate (2×10 mL), dried (Na2SO4) and purified by chromatography to give 3.2 mg (50% yield) of 1-tert-butyl-3-(3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-6-hydroxy-2,2-dimethylhexyl)urea. MS found: (M+H)+=455.
Reaction SMILES: [NH2:1][C@H:2]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.CCN(CC)CC.[NH:36]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[C@H:37]([C:42]([NH:44][C@H:45]([C:50](O)=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(O)(=O)C>[NH:36]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[C@H:37]([C:42]([NH:44][C@H:45]([C:50]([NH:1][C@H:2]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:51])[CH2:46][CH:47]([CH3:48])[CH3:49])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40]
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 93.6 %

Procedure:
A solution of H-Lys(Z)-OBzl.HCl (20.35 g, 50 mmol) in DMF (50.0 g) was treated with Et3N (5.26 g, 51 mmol) at 25 to 30° C. Boc-Leu-Leu-OH (17.57 g, 51 mmol) and HOBt (1.08 g, 8 mmol) were added followed by an additional portion of DMF (7.0 g). A solution of DCC (11.35 g, 55 mmol) in DMF (25.0 g) was added dropwise over a period of 30 min at 20° C. The reaction mixture was stirred for 4 h and the temperature was allowed to rise (to ca. 34° C.). Acetic acid (0.2 g) was added, the resulting suspension was filtered and the filter cake was rinsed with DMF (15.0 g). Acetone (126.0 g) was added to the filtrate, followed by two portions of H2O (66.5 g, 89.5 g-30 min apart). The resulting precipitate was filtered and the filter cake was washed with acetone (53.0 g) and H2O (212.0 g). The crude solid was triturated with a mixture of acetone (100 g) and H2O (400 g), filtered, washed with H2O and dried in vacuo at 40° C. to give Boc-Leu-Leu-Lys(Z)-OBzl (32.6 g, 93.4%).