Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.CN(C)[CH:35]=[O:36].O>O1CCCC1>[C:8]1([N:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:2]([CH:35]=[O:36])=[CH:3][CH:4]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(CN(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(CN(c2ccccc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
In an argon atmosphere, the thus obtained N-(4-bromobenzyl)diphenylamine (440 mg, 1.30 mmol) was dissolved in tetrahydrofuran (6 mL) and cooled to −78° C. A 1.6 M n-butyl lithium hexane solution (1.3 mL, 2.0 mmol) was added thereto, and, 5 minutes thereafter, dimethylformamide (0.20 mL, 2.6 mmol) was further added thereto, followed by stirring for 5 minutes. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (9:1 hexane/ethyl acetate) to obtain 4-(N,N-diphenylaminomethyl)benzaldehyde (213 mg, 57%).
Reaction SMILES: B.[Na].C([O:5][C:6]([C:8]1[S:12][C:11]2=[CH:13][N:14]=[CH:15][N:10]2[C:9]=1[CH3:16])=O)C>C(O)C>[OH:5][CH2:6][C:8]1[S:12][C:11]2=[CH:13][N:14]=[CH:15][N:10]2[C:9]=1[CH3:16]
Reactant: CCOC(=O)c1sc2cncn2c1C
Agent: B
Agent: [Na]
Solvent: CCO
Product: Cc1c(CO)sc2cncn12
Temperature: 25 °C
Reaction time: 96 h
Yield: 98.7 %

Procedure:
A 1.56 g portion of sodium boron hydride was added to 60 ml of an ethanol solution containing 1.684 g of 2-ethoxycarbonyl-3-methylimidazo[5,1-b]thiazole, and the mixture was then stirred at room temperature for 4 days. The solvent was evaporated under reduced pressure, and water was then added thereto. The solution was extracted twice with dichloromethane, and the combined organic layer was dried over anhydrous magnesium sulfate and then filtered. Afterward, the solvent was evaporated under reduced pressure to obtain 1.33 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Br:17])[CH:11]=1.C([N-]C(C)C)(C)C.[Li+].CN([CH:29]=[O:30])C>C1COCC1>[Br:17][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([Cl:16])[CH:13]=1)[O:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([F:8])[C:4]=1[CH:29]=[O:30]
Reactant: Fc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-bromo-5-chlorophenyl 2-chloro-5-fluorophenyl ether (100 g, 298 mmol) in THF (300 mL) cooled to −78° C. over a dry ice/acetone bath was added 1.8M lithium diisopropylamide in hexanes/THF/ethylbenzene (174 mL, 313 mmol) over 10 min. The resulting mixture was stirred for 20 minutes and then treated with DMF (46.1 mL, 595 mmol). The DMF-treated mixture was then removed from the cooling bath and allowed to warm to room temperature and then left at room temperature for 1 hour. The reaction mixture was then quenched with water (1000 mL) and extracted with EtOAc (3×500 mL). The combined extracts were washed with water (500 mL), dried over MgSO4, and concentrated in vacuo. This residue was purified on a silica gel column (0-40% CH2Cl2/hexanes) to give the title product. LRMS (M−18+1)=346.7
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][C:14]3[C:19]([C:7]=2[CH2:6][CH2:5]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N+]=[N-].[BH4-].[Na+]>C1COCC1.C(O)C>[NH2:1][CH:4]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][C:14]3[C:19]([C:7]=2[CH2:6][CH2:5]1)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: [N-]=[N+]=NC1CCc2c(ccc3ccccc23)NC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: NC1CCc2c(ccc3ccccc23)NC1=O

Procedure:
A solution of 3-azido-4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2, 1-b]azepine (1.0 g, 4.0 mmol) in dry THF (20 ml) was placed under an atmosphere of nitrogen and cooled by an ice-bath. A solution of sodium borohydride (0.17 g, 4.4 mmol) in ethanol (20 ml) was added dropwise during a period of 10 minutes and the reaction mixture was heated at reflux temperature for 20 h. The volatiles were evaporated in vacuo and the residue was purified by columm chromatography on silica gel (200 g) using dichloromethane and a mixture of ethanol and 25% NH3 (aq) (9:1) (gradient 0% to 10%) as eluent. This afforded 0.30 g of 3-amino-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b]azepine.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([NH:10][CH:11]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:12]([OH:27])[C:13]([N:15]1[CH2:26][CH2:25][CH2:24][C@H:16]1[C:17]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6].[CH:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([NH:2][C@H:3]([C:8]([NH:10][C@@H:11]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:12]([OH:27])[C:13]([N:15]1[CH2:26][CH2:25][CH2:24][C@H:16]1[C:17]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)C(O)C(Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Agent: Cl
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NCc1ccccc1
Yield: 91.5 %

Procedure:
Following a procedure similar to that described in Example 67, but using 500 mg (1.01 mmol) of 1-[3-(L-asparaginyl)amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide hydrochloride and 123 μl (1.21 mmol) of benzaldehyde, 510 mg of the title compound were obtained as a colorless powder, melting at 96°-99° C.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([OH:19])=[CH:5][C:6](=[O:18])[N:7]([O:16][CH3:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:29][N:30](C)[C:31](C1CN(C)C(=O)C=1O)=O>>[CH3:17][O:16][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)[C:6]([C:5]1[CH2:29][N:30]([CH3:31])[C:3](=[O:20])[C:4]=1[OH:19])=[O:18]
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(C)cc1)OC
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(C)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 41 %

Procedure:
2-Hydroxy-3-[methoxy-(4-methylbenzyl)-carbamoyl]-acrylic acid methyl ester (Compound 59-A) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (41% yield); mp 150–152° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.4 (3H, s, CH3), 3.16 (3H, s, NCH3), 3.78 (3H, s, OCH3), 4.21 (2H, s, NCH2), 4.91 (2H, s, NCH2), 7.22 (2H, d, J=8 Hz, aromatics), 7.28 (2H, d, J=8 Hz, aromatics), 11.7 (1H, broad s, OH). Anal. calcd for C15H18N2O4: C, 62.05; H, 6.24; N, 9.65. Found: C, 61.91; H, 6.30; N, 9.56.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)=[N:14][N:15]=2)[CH:5]=1.CO.[OH-].[Na+].Cl>O.C1COCC1>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:13]2[S:12][C:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:24])=[O:2])=[N:15][N:14]=2)=[CH:21][CH:20]=1)#[N:23]
Reactant: COC(=O)c1cccc(Cc2nnc(-c3ccc(C#N)cc3)s2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2nnc(Cc3cccc(C(=O)O)c3)s2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
Suspend 3-[5-(4-cyano-phenyl)-[1,3,4]thiadiazol-2-ylmethyl]-benzoic acid methyl ester (0.15 g, 0.45 mmol) in 10 mL of a 1:1 mixture of H2O:MeOH, add 10% aqueous solution of NaOH (0.48 mL, 1.20 mmol) and heat to 60° C. After stifling for 3 h add 5 mL of THF to the reaction mixture causing all of the solids to go into solution. Heat the mixture at 60° C. for an additional 2 h then cool to room temperature. Adjust the pH to slightly acidic by the addition of a 2N solution of HCl. Dilute the mixture with H2O and wash with CH2Cl2. Wash the combined organics with brine, dry over anhydrous sodium sulfate and concentrate to provide 0.13 g, 57% yield of 3-[5-(4-cyano-phenyl)-[1,3,4]thiadiazol-2-ylmethyl]-benzoic acid as a solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][CH:9]=O)[C:6]2[N:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]=[CH:3]1.[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][N:26]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C.C(Cl)(Cl)Cl>[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][N:26]([CH:34]3[CH2:39][CH2:38][N:37]([CH2:9][CH2:8][N:7]4[C:2](=[O:1])[CH:3]=[N:4][C:5]5[CH:14]=[CH:13][CH:12]=[N:11][C:6]4=5)[CH2:36][CH2:35]3)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: O=CCn1c(=O)cnc2cccnc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cnc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
To 0.13 g of (3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde, a solution of 0.23 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate in 4 mL of dichloromethane, 38 μL of acetic acid and 0.21 g of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 3 hours. Chloroform and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=100:0 to 90:10 to obtain 0.24 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown oily substance.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1.[CH3:21][C:22]1([CH3:37])[CH2:27][CH:26]([N:28]2[CH2:32][CH2:31][N:30]([C:33](Cl)=[O:34])[C:29]2=[O:36])[CH2:25][CH2:24][O:23]1>C(Cl)Cl>[CH3:21][C:22]1([CH3:37])[CH2:27][CH:26]([N:28]2[CH2:32][CH2:31][N:30]([C:33]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([O:13][C:11]4[CH:10]=[CH:9][N:8]=[C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)[CH:12]=4)=[CH:19][N:18]=3)=[O:34])[C:29]2=[O:36])[CH2:25][CH2:24][O:23]1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Reactant: CC1(C)CC(N2CCN(C(=O)Cl)C2=O)CCO1
Solvent: ClCCl
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOC(C)(C)C5)C4=O)nc3)ccn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A 0° C. solution of Example A2 (0.060 g, 0.224 mmol) and TEA (0.094 mL, 0.673 mmol) in DCM (1 mL) was treated with a solution of crude 3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoimidazolidine-1-carbonyl chloride (0.088 g, 0.337 mmol) in DCM (1 mL). The mixture was warmed to RT, stirred for 0.5 h, then concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide as an off-white solid (74 mg, 67%). 1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 8.21 (m, 1 H), 8.05 (m, 1 H), 7.96 (d, J=0.7 Hz, 1 H), 7.72 (dd, J=9.0, 2.9 Hz, 1 H), 7.23 (d, J=2.4 Hz, 1 H), 6.68 (dd, J=5.7, 2.4 Hz, 1 H), 4.04 (m, 1 H), 3.84 (s, 3 H), 3.84-3.75 (m, 2 H), 3.70-3.59 (m, 2 H), 3.46-3.39 (m, 2 H), 1.60-1.47 (m, 4 H), 1.18 (d, J=15.1 Hz, 6 H); MS (ESI) m/z: 492.2 (M+H+).
Reaction SMILES: C(O[CH:5]1[O:34][C@H:33]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[BrH:44].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OC(C)C)(C)C>[CH2:8]([O:7][C@@H:6]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:24]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:33]([CH2:35][O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[O:34][C@@H:5]1[Br:44])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Br
Reactant: CC(=O)OC1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)OC(C)C
Product: Br[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
2,3,4,6-Tetra-O-benzyl-D-galactopyranosyl acetate (79.8 g) was dissolved in a mixed solution of toluene (160 mL) and isopropyl ether (520 mL) and then cooled to −10-0° C. To the solution was added a solution containing 2.0 equivalent amount of HBr in isopropyl ether (2.8 mmol/mL, about 100 mL). After the reaction solution was stirred at −10-0° C. for about 90 minutes, a 5% aqueous solution of sodium hydrogencarbonate was poured thereto and stirred to neutralize the excess HBr. The whole of the solution was transferred to a separatory funnel to cause separation into an aqueous layer and an organic layer. The aqueous layer obtained was discarded and the organic layer was washed with a 10% aqueous solution of sodium chloride twice. The organic layer was concentrated under reduced pressure, thereby giving a syrup product of 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl bromide (Gal-Br).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([CH3:28])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CC(O)=O.C(O[Na])(C)=O.C=O.[BH3-]C#N.[Na+]>Cl.O1CCOCC1>[CH3:28][C:16]1[S:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH3:6])[CH2:13][CH2:12]2)=[N:18][C:17]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1ccc(C(=O)O)cc1
Agent: C=O
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1sc(N2CCN(C)CC2)nc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
4-[4-(4-Carboxyphenyl)-5-methylthiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.421 mmol) was dissolved in 4M HCl in 1,4-dioxane, and stirred at room temperature for 1 h. The solvent was then removed in vacuo, and the residue 4-(5-methyl-2-piperazin-1-yl-thiazol-4-yl)-benzoic acid was suspended in methanol (10 mL) and treated with AcOH/AcONa buffer (pH ˜5.5, 5 mL), and formaldehyde (0.547 mmol). The reaction mixture was stirred at room temperature for 1 h, then treated with NaCNBH3 (0.547 mmol) and stirred at room temperature overnight. The solvent was then removed under vacuum, and the residue was purified by column chromatography to afford the title compound (0.403 mmol, 95%).
Reaction SMILES: [C:1]([Cl:5])(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OC[CH2:27][S:28]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]1[N:45]=[CH:44][N:43]=[C:42]([O:46][CH:47]3[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]3)[CH:41]=1)[CH2:35][CH2:34]2)(=[O:30])=[O:29]>ClCCl>[Cl:5][CH2:1][CH2:27][S:28]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]1[N:45]=[CH:44][N:43]=[C:42]([O:46][CH:47]3[CH2:48][CH2:49][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:51][CH2:52]3)[CH:41]=1)[CH2:35][CH2:34]2)(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(=O)(=O)CCO)ccc43)ncn2)CC1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(=O)(=O)CCCl)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
Carbon tetrachloride (58 μL, 0.601 mmol) and triphenylphosphine (52 mg, 0.198 mmol) were added to a dichloromethane (5 mL) solution of the tert-butyl 4-[(6-{5-[(2-hydroxyethyl)sulfonyl]indolin-1-yl}pyrimidin-4-yl)oxy]piperidine-1-carboxylate (49.9 mg, 0.0990 mmol) produced in Example 84, and the mixture was stirred overnight at room temperature. From the reaction solution, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-7:3, V/V) to obtain the title compound as white foam (32.3 mg, yield: 62%).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[N:5]([CH3:14])[C:6](=[O:13])[N:7]2[CH3:12].[F-].[Cs+].[CH2:18](B1OC(C)(C)C(C)(C)O1)[CH:19]=[CH2:20]>O1CCOCC1.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>[CH2:20]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[N:5]([CH3:14])[C:6](=[O:13])[N:7]2[CH3:12])[CH:19]=[CH2:18]
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Reactant: Cn1c(=O)c2c(I)cccc2n(C)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: C=CCc1cccc2c1c(=O)n(C)c(=O)n2C
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a stirred solution of Step 4 intermediate (40 g, 126 mmol) in 1,4-dioxane (1.3 lit) was added cesium fluoride (38.3 g, 252 mmol) and allylboronic acid pinacol ester (42.5 ml, 225 mmol) under nitrogen atmosphere and the mixture was degassed for 10 min. Tetrakis(triphenylphosphine)palladium(0) (14.46 g, 12 mmol) catalyst was added and the mixture was stirred at 100° C. for 20 h under nitrogen atmosphere. The mixture was diluted with water (500 ml) and extracted with ethyl acetate (3×500 ml). The combined extracts were concentrated and the residue obtained was purified by silica gel column chromatography to give 26.5 g of the product as an off-white solid; 1H NMR (δ ppm, CDCl3, 300 MHz): 7.54 (t, J=7.8, 1H); 7.08 (t, J=6.9, 2H); 6.18-6.00 (m, 1H); 5.06-4.95 (m, 2H); 4.04 (d, J=6.3, 2H); 3.60 (s, 3H); 3.45 (s, 3H). MS (m/z): 231.37 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[CH:10]([O:26][CH2:27][CH3:28])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]1[O:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:33][C:32]=1[CH2:42][C:43](O)=[O:44].C(Cl)Cl>CCCCCCC.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:29])[CH:10]([O:26][CH2:27][CH3:28])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:43](=[O:44])[CH2:42][C:32]2[N:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:35][C:31]=2[CH3:30])=[C:14]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1CC(=O)O
Reactant: CCOC(Cc1ccc(O)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3-(3-benzyl-4-hydroxy-phenyl)-2-ethoxy-propionic acid benzyl ester (45 mg, 0.11 mol) and (5-methyl-2-phenyl-oxazol-4-yl)-acetic acid (25 mg, 0.11 mmol) in dry DCM (2.0 mL) first DMAP (2.8 mg, 0.02 mmol) and then EDCxHCl (26.5 mg, 0.13 mmol) was added and the mixture was stirred under nitrogen atmosphere at room temperature for 17 h. The solvent was removed under vacuo and the product was isolated out of the remaining oil by column chromatography using n-heptane/EtOAc (4:1) as the eluent. The title compound was obtained as an oil (56.1 mg, 82.6%). 1H NMR (400 MHz, CDCl3): δ 7.95 (m, 2H), 7.40 (m, 2H), 7.32 (m, 2H), 7.25 (m, 2H), 6.98-67.20 (m, 10H), 5.08, (d, 2H), 3.97 (t, 1H), 3.85 (s, 2H), 3.70 (s, 2H), 3.55 (m, 1H), 3.28 (m, 1H), 2.93 (d, 2H), 2.32 (s, 3H), 1.1 (t, 3H).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCOCC1>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:17]1[O:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])[C:11]=2[C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3OC)c(-c3ccc(OC)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(-c3ccccc3OC)oc3ncnc(NCCCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 55 mg (0.12 mmol) 6-{[6-(2-methoxyphenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester in 2.5 ml dioxan and add 0.5 ml 1 N sodium hydroxide solution. Stir for 16 h at RT, then add 0.5 ml 1 N hydrochloric acid and 6 ml ethyl acetate. Separate the organic phase, dry over sodium sulphate, filter and concentrate by evaporation. 42 mg (77% of theor.) of the target compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([F:11])[C:5]=1[F:12].Cl.[CH3:15][NH:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([N:16]([CH3:17])[CH3:15])=[C:6]([F:11])[C:5]=1[F:12]
Reactant: CNC
Reactant: COC(=O)c1ccc(F)c(F)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)c(F)c1F
Temperature: 55 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
To a stirred solution of 4.28 g (22.5 mmol) 2.3.4-Trifluoro-benzoic acid methyl ester (Apollo) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 5 h at 55° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 5a was obtained in 69% yield (3.34 g, 15.5 mmol).
Reaction SMILES: [CH3:1][CH:2]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:3][CH2:4]OC1C=CC=CC=1.[BrH:18]>C(Cl)(Cl)Cl>[BrH:18].[CH3:1][CH:2]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:3][CH2:4][Br:18]
Reactant: CC(CCOc1ccccc1)N1CCCCC1
Agent: Br
Solvent: ClC(Cl)Cl
Product: CC(CCBr)N1CCCCC1
Yield: 75 %

Procedure:
5 g of the 1-(1-methyl-3-phenoxypropyl)piperidine thus obtained was reacted with 30 ml of 40% hydrobromic acid at 150° C for 7 hours with stirring. The reaction solution was cooled and added with 20 ml of chloroform. Then, the hydrobromic acid layer was separated from the chloroform layer. The hydrobromic acid was removed under reduced pressure and the residue was recrystallized from 5 ml of ethyl alcohol to give 4.84 g of 1-(1-methyl-3-bromopropyl)piperidine hydrobromide in a yield of 75%.