Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH3:24][O:25][C:26](=[O:44])[C@@H:27]([NH2:43])[CH:28]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1>>[CH3:24][O:25][C:26](=[O:44])[C@@H:27]([NH:43][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:14]=1[NH:13][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:11])=[O:12])[CH:28]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1
Reactant: COC(=O)[C@@H](N)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Product: COC(=O)[C@@H](NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 84 %

Procedure:
The title compound (49 mg, 84%) was prepared from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid (EXAMPLE 101, Part D) and (S)-2-amino-3,3-bis-(4-chloro-phenyl)-propionic acid methyl ester (EXAMPLE 106, Part H) as in Example 1, Part C. 1H NMR (500 MHz, CDCl3): 11.16 (s, 1H), 8.36 (dd, J=7.0, 1.0, 1H), 8.23 (dd, J=8.8, 1.0, 1H), 8.03 (d, J=1.6, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.32-7.27 (m, 4H), 7.24 (dd, J=8.2, 1.6, 1H), 7.21-7.15 (m, 4H), 6.71 (d, J=8.3, 1H), 6.22 (br d, J=8.8, 1H), 5.48 (t, J=8.5, 1H), 4.48 (d, J=8.3, 1H), 3.62 (s, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:4][CH2:5][Cl:6]
Reactant: Oc1ccccc1
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCCl)Oc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 58.2 %

Procedure:
To a solution of chloromethyl chloroformate (1 g, 7.8 mmol) in DCM (40 mL) was added a mixture of phenol (0.73 g, 7.8 mmol) and pyridine (750 μL, 9.3 mmol) in DCM (10 mL) at −20° C. over 20 min. The reaction was stirred at 0° C. for 4 h, then at rt for another 1 h. The mixture was washed with 1N HCl solution (50 mL), followed by brine (50 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=100/1) to give the title compound as colorless oil (847 mg, 58.2%). The title compound was characterized by 1H NMR as shown below:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.[C:24]([OH:28])(=O)[CH2:25][OH:26].CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[N:40][NH:41]3)O1>>[NH:41]1[C:42]2[C:38](=[C:37]([C:2]3[N:3]=[C:4]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([NH:17][C:24](=[O:28])[CH2:25][OH:26])[CH:14]=[CH:15][CH:16]=5)=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:44][CH:43]=2)[CH:39]=[N:40]1
Reactant: O=C(O)CO
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: O=C(CO)Nc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (40 mg) was reacted with glycolic acid via General Procedure I to give N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxyacetamine. 47 mg of the crude N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxyacetamine was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 3 mg of 139. MS (Q1) 487 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].[CH3:12][O:13][C:14]([C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1)=[O:15].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[CH2:6]([N:5]([CH2:4][C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[F:1])[C:27](=[O:28])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][C:17]2[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=2[C:14]([O:13][CH3:12])=[O:15])=[CH:21][CH:22]=1)[CH3:7]
Reactant: COC(=O)c1ccccc1OCc1ccc(CC(=O)O)cc1
Reactant: CCNCc1ccccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(Cc1ccccc1F)C(=O)Cc1ccc(COc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
N-(2-Fluorobenzyl)ethanamine (0.077 g, 0.500 mmol) was dissolved in DMF (10 ml), (4-{[2-(methoxycarbonyl)phenoxy]methyl}phenyl)acetic acid (0.150 g, 0.500 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.176 g, 0.549 mmol) and N-ethyl-N,N-diisopropylamine (0.136 g, 1.049 mmol) was added. The solution was stirred overnight at room temperature. EtOAc (20 ml) was added and the organic phase was washed with two portions of Na2CO3 (2×20 ml, aq). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.146 g of methyl 2-[(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethyl}benzyl)oxy]benzoate (yield 67.1%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[S:11])[CH3:2].Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:10]1=[S:11])[CH3:2]
Reactant: CCc1ccccc1N=C=S
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1ccccc1N1C(=O)CN(C)C1=S
Yield: 87.4 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 16.3 g of 2-ethylphenyl-isothiocyanate, 15.3 g of sarcosine ethyl ester hydrochloride, 20.2 g of triethyl amine, and 300 mL of chloroform. The title compound (20.4 g) was obtained as an off-white solid, m.p. 135°-137° C. Anal. Calcd. for C12H14N2OS: C, 61.51; H, 6.02; N, 11.96. Found: C, 61.11; H, 5.92; N, 11.71. Mass spectrum (EI, M.+) m/z 234.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[S-2:12].[Na+].[Na+].I[CH2:16][CH2:17][CH2:18][CH3:19]>CN(C)C=O>[CH2:16]([S:12][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1])[CH2:17][CH2:18][CH3:19]
Reactant: [S-2]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CCCCI
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCSc1ccc([N+](=O)[O-])cc1Cl

Procedure:
A solution of 3-chloro-4-fluoro-nitrobenzene (5.0 g) and sodium sulfide (2.5 g) in N,N-dimethylformamide (30 mL) is stirred at room temperature for 1 hour and then treated with 1-iodobutane (12.6 g). The solvent is then removed under reduced pressure and the resulting residue is treated with ethyl acetate and hexanes to precipitate the inorganic salts. The solids are removed by filtration and the filtrate is reduced under reduced pressure. The resulting residue is then passed through hydrous magnesium silicate using dichloromethane as the eluent to provide the desired compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[OH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH:28]=[C:27]([CH:29]=O)[CH:26]=[N:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:45]CCCl>>[ClH:45].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:15][CH2:16][N:17]([CH2:29][C:27]4[CH:26]=[N:25][N:24]([CH2:23][CH2:22][CH2:21][OH:20])[CH:28]=4)[CH2:18][CH2:19]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: ClCCCl
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: O=Cc1cnn(CCCO)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cl
Product: OCCCn1cc(CN2CCN(c3nccnc3-c3ccc(F)cc3)CC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
Dissolve 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.150 g, 0.581 mmol) in DCE (5 mL). Add 1-(3-hydroxy-propyl)-1H-pyrazole-4-carbaldehyde (0.107 g, 0.697 mmol) followed by sodium triacetoxyborohydride (0.185 g, 0.872 mmol) and stir at room temperature for 18 hr. Purify via SCX chromatography, followed by silica gel chromatography (0:100 hexanes:ethyl acetate then 10:90 methanol:ethyl acetate), followed by reverse phase chromatography, SCX chromatography and silica gel chromatography (100:0 to 0:100 hexanes:ethyl acetate then 10:90 methanol:ethyl acetate to 20:80 methanol:ethyl acetate), to give the free base of the title compound (103 mg, 45%). Dissolve the free base (0.099 g, 0.251 mmol) in methanol and add a solution of ammonium chloride (0.013 g, 0.251 mmol) in a minimal volume of methanol. Shake for 18 hr. at ambient temperature and concentrate to give the title compound (105 mg, 97%). MS (ES): m/z=397 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(Cl)(Cl)Cl>[CH2:31]([O:30][C:28]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][CH2:17][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:16]=2)[CH2:20][CH2:21]1)=[O:29])[CH3:32]
Reactant: c1ccc(-c2cc(CCC3CCNCC3)c3ccccc3n2)cc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(CCc2cc(-c3ccccc3)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 104.4 %

Procedure:
A solution of 15.6 g of 2-phenyl-4-[2-(4-piperidyl)ethyl] quinoline, prepared as indicated in Example 16, in 200 ml of chloroform is treated with stirring with 200 ml of a 1 N aqueous solution of sodium hydroxide. Then 21.7 g of ethyl chloroformate are added, drop by drop, and the suspension obtained is stirred for 17 hours at the ambient temperature. After separation, the organic phase is washed with water, dried over magnesium sulphate, then evaporated under reduced pressure. 20 g of 4-[2-(1-ethoxycarbonyl-4-piperidyl)-ethyl]-2-phenyl-quinoline in the form of an oil are obtained.
Reaction SMILES: CC([O-:5])(C)C.[K+].[CH2:7]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)[CH:8]=[CH2:9].O.[CH2:20]1[CH2:24][O:23][CH2:22][CH2:21]1>>[CH2:7]([O:10][C:11]1[CH:18]=[CH:17][C:14](/[CH:15]=[CH:21]/[C:22]([O:23][CH2:24][CH3:20])=[O:5])=[CH:13][CH:12]=1)[CH:8]=[CH2:9]
Reactant: C=CCOc1ccc(C=O)cc1
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: C=CCOc1ccc(/C=C/C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
t-BuOK (4.57 g, 40.7 mmol) was added in small portions to a solution of triethyl phosphonoacetate (8.10 mL, 40.7 mmol) and 4-(allyloxy)benzaldehyde (Intermediate D, 6.00 g, 37.0 mmol) in THF (100 mL) cooled at 0° C., leading to the formation of a viscous mixture. After 30 min, water (20 mL) was added and the solvent was removed by rotatory evaporation. The crude residue was dissolved in EtOAc (100 mL) and washed with water (2×100 mL); the organic layer was dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (7% EtOAc/Hexanes), affording 7.76 g of (E)-ethyl 3-(4-(allyloxy)phenyl)acrylate [Rf=0.4 (10% EtOAc/Hexanes), colorless oil, 90% yield].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH:11][C:12]3[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:9]=[CH:10][C:2]1=2.O=[C:20]([C:26](OCC)=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:12]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:18]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]3=[O:27])[CH:9]=[CH:10][C:2]1=2
Reactant: Nc1ccccc1Nc1ccc2c(c1)OCCO2
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc2ccccc2n(-c2ccc3c(c2)OCCO3)c1=O
Yield: 62.2 %

Procedure:
5.0 g (21 mmol) of N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzene-1,2-diamine and 3.9 g (22 mmol) of diethyl ketomalonate were dissolved in toluene (60 ml), and the solution was heated to reflux for 12 hours while removing water using a Dean-Stark apparatus. The reaction solution was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (developing solvent: ethyl acetate:hexane=2:3) to obtain 4.6 g (yield: 63%) of ethyl 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate as a milky yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12]C(OC)=O)[N:8]=[C:7]([CH3:17])[CH:6]=[CH:5]2.[CH3:18][Mg+].[Br-].CC[O:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][C:24]([CH3:25])([OH:23])[CH3:18])[N:8]=[C:7]([CH3:17])[CH:6]=[CH:5]2
Reactant: CCOCC
Reactant: C[Mg+]
Reactant: COC(=O)Cc1cc2nc(C)ccc2cc1F
Agent: [Br-]
Solvent: Cc1ccccc1
Product: Cc1ccc2cc(F)c(CC(C)(C)O)cc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
To a stirred solution of methyl 2-(6-fluoro-2-methylquinolin-7-yl)acetate (0.650 g, 2.79 mmol) in toluene (14 mL) was added dropwise a solution of MeMgBr in ether (3.0 M, 2.79 mL, 8.36 mmol) at 0° C. under nitrogen. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction was quenched by the addition of saturated aqueous NH4Cl solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:2 hexanes/EtOAc) to give 1-(6-fluoro-2-methylquinolin-7-yl)-2-methylpropan-2-ol (0.202 g, 31%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[C:19]([CH2:29][C:30](O)=[O:31])=[CH:20][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)(=[O:11])=[O:10])[O:4][N:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[C:50]([NH2:54])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl.CCOC(C)=O>[CH3:51][C:50]([NH:54][C:30](=[O:31])[CH2:29][C:19]1[C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:9]([N:8]([C:5]2[O:4][N:3]=[C:2]([CH3:1])[C:6]=2[CH3:7])[CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])(=[O:11])=[O:10])=[CH:23][CH:22]=[C:21]([C:24]2[O:25][CH:26]=[CH:27][N:28]=2)[CH:20]=1)([CH3:53])[CH3:52]
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CC(=O)O
Reactant: CC(C)(C)N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CC(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the title compound of Step (C) (85 mg, 0.16 mmol) and 0.004 ml DMF in 1.6 ml CH2Cl2, oxalyl chloride (2M in CH2Cl2, 0.20 ml, 0.40 mmol) was added. The mixture was stirred at room temperature for 0.5 hr and concentrated. To the residue, 2 ml CH2Cl2 and tert-butylamine (t-BuNH2, 69 mg, 0.94 mmol) were added. The reaction was stirred at room temperature overnight, diluted with EtOAc, washed with H2O and brine, dried and concentrated. The residue was chromatographed on silica gel using 1:2 hexane/EtOAc to afford the title compound of this step (45 mg, 48%) as a colorless gum.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[CH2:10]O.C(Br)(Br)(Br)[Br:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)[Cl:37]>>[ClH:37].[Br:13][CH2:10][C:2]1[O:1][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: ClCCl
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc2cnccc2o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: BrCc1cc2cnccc2o1
Product: Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred suspension of furo[3,2-c]pyridin-2-ylmethanol (Preparation 4, 1.47 g, 9.9 mmol) in anhydrous CH2Cl2 (60 mL) was treated with CBr4 (4.90 g, 14.8 mmol). The mixture was cooled down to 0° C., before being treated with PPh3 (3.88 g, 14.8 mmol). After 2 h at 20° C., the reaction was filtered, then the filtrate was diluted with CH2Cl2 (50 mL), before being washed with saturated aqueous NaHCO3 (2×50 mL) and H2O (50 mL). The CH2Cl2 solution was extracted with 2 M HCl (3×50 mL), then the combined HCl extracts were evaporated to furnish the title compound: m/z (ES+)=211.9, 213.9 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.F[C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][N:30]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:17][C:16]=1[C:14]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([CH:4]2[CH2:5][CH2:6][N:1]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][N:30]=3)[CH2:2][CH2:3]2)=[CH:12][CH:11]=1)=[O:15]
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(C2CCNCC2)cc1
Reactant: O=C(O)c1ccc(F)nc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(C2CCN(c3ccc(C(=O)O)cn3)CC2)cc1
Temperature: 175 °C
Yield: 50.8 %

Procedure:
A mixture of 5-methyl-2-phenyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (181 mg, 0.5 mmol) and 6-fluoronicotinic acid (113 mg, 0.8 mmol) in dioxane (2 mL) containing diisopropylethylamine (0.5 mL, 2.7 mmol) was heated in a microwave at 175° C. for 30 minutes. The mixture was evaporated and extracted with ethyl acetate and aqueous citric acid solution. The organic layer was dried over sodium sulfate and solvents were evaporated. The residue was triturated with ethyl acetate and filtered to give a pale pink solid as 4-{4-[(5-methyl-2-phenyl-oxazole-4-carbonyl)-amino]-phenyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (122.5 mg). LC-MS for C28H26N4O4 (m/e) calcd 482, obsd 483 (M+H). 1H-NMR is consistent with the desired structure.
Reaction SMILES: C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O.C([O:23][C:24]1[CH:51]=[CH:50][C:49]([C:52]2[CH:56]=[CH:55][O:54][CH:53]=2)=[CH:48][C:25]=1[C:26]([NH:28][C:29]1[CH:41]=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:39]=[CH:38][C:30]=1[C:31]([O:33]C(C)(C)C)=[O:32])=[O:27])C1C=CC=CC=1>>[O:54]1[CH:55]=[CH:56][C:52]([C:49]2[CH:50]=[CH:51][C:24]([OH:23])=[C:25]([CH:48]=2)[C:26]([NH:28][C:29]2[CH:41]=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:39]=[CH:38][C:30]=2[C:31]([OH:33])=[O:32])=[O:27])=[CH:53]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccoc2)ccc1OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(-c2ccoc2)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 19.5 %

Procedure:
Thioanisole (1.6 mL) and trifluoroacetic acid (5.2 mL) were added to tert-butyl 2-(2-(benzyloxy)-5-(furan-3-yl)benzamido)-4-phenylbenzoate (0.14 g), followed by stirring at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and dioxane was added to the residue. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the residue. The solid substance was collected by filtration to obtain 0.020 g of 2-(5-(furan-3-yl)-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:25][Cl:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[ClH:26].[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][NH:10][CH2:25][CH2:24][CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: ClCCC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: c1ccccc1
Product: Cl
Product: c1ccc(C(CCNCCC(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Yield: 31.3 %

Procedure:
A mixture of 3,3-diphenylpropylamine (4.9 g) and 3,3-diphenyl-1-chloropropane (5.0 g) in xylene (10 ml) was heated at 120° to 130°C for 4 hours. After cooling, a small amount of benzene was added to the reaction mixture and then the mixture was filtered to remove 3,3-diphenylpropylamine hydrochloride. The filtrate was washed with 5 % hydrochloric acid and water in order. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crystalline residue was recrystallized from methanol to give bis(3,3-diphenylpropyl)amine hydrochloride (3.0 g.). M.P. 192° to 194°C.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:46]=[C:47]([N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[CH2:48][NH:49][C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:53]=1)=[O:51]>CN(C=O)C.O>[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:12]=1[C:13]([N:67]1[CH2:66][CH2:65][N:64]([C:47](=[O:46])[CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)=[O:51])[CH2:69][CH2:68]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)ccc2Cl)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2-chloro-5-trifluoromethyl-benzoic acid (57.8 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 63 mg (42.1% yield) of biphenyl-4-carboxylicacid {2-[4-(2-chloro-5-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 97.5%, 1H NMR: (DMSO) δ 8.7 (s, 1H), 8.0-7.9 (t, 3H), 7.9-7.7 (m, 6H), 7.54-7.38 (m, 3H), 4.2 (dd, 2H), 3.8-3.6 (m, 4H), 3.6-3.4 (m, 2H), 3.2 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:14]=1[NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:13]=1[Cl:12])=[O:9]
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1cc(Cl)ccc1Cl)c1cc(Cl)ccc1O
Yield: 10.8 %

Procedure:
Using 5-chlorosalicylic acid and 2,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.