Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[CH3:28][C@H:29]1[CH2:34][NH:33][CH2:32][C@@H:31]([CH3:35])[NH:30]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>O1CCOCC1.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]>[CH3:28][C@H:29]1[NH:30][C@@H:31]([CH3:35])[CH2:32][N:33]([C:2]2[CH:3]=[C:4]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:5]=[CH:6][C:7]=2[O:8][C:9]([F:12])([F:11])[F:10])[CH2:34]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=S(=O)(Nc1ccc(OC(F)(F)F)c(Br)c1)c1ccc(-c2cccs2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2cc(NS(=O)(=O)c3ccc(-c4cccs4)cc3)ccc2OC(F)(F)F)C[C@H](C)N1

Procedure:
The product of Step 2 (162 mg, 0.34 mmol), cis-2,6-dimethyl piperazine (78 mg, 0.68 mmol), sodium tert-butoxide (169 mg, 0.68 mmol), tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.017 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (20 mg, 0.051 mmol) in dioxane (4 ml) were heated in a microwave reactor at 125° C. for 30 minutes. The reaction mixture was applied to an SCX ion exchange cartridge (Varian bond-elute) and washed with methanol and 2M ammonia in methanol. The combined basic fractions were concentrated in vacuo and the residue purified by mass directed autoprep HPLC to afford the title compound (E245). MS (ES+) m/e 512 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[N:13]/[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])/[CH:3]=1.[CH3:29][N:30]1[C:34]([SH:35])=[N:33][N:32]=[N:31]1.N1C=CC=CC=1>C1COCC1>[CH3:29][N:30]1[C:34]([S:35][C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)/[C:4](=[N:13]/[S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:19][CH:18]=3)(=[O:16])=[O:15])/[CH:3]=2)=[N:33][N:32]=[N:31]1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc21
Reactant: Cn1nnnc1S
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 99 %

Procedure:
81.6 mg 12b was dissolved in 2 ml THF. 1 ml THF solution containing 1 eq. 1-methyl-tetrazole-5-thiol and 1 eq. pyridine was added. The mixture was shaken for 30 min. The organic solvent was removed by V-10 (biotage). The residue was suspended in 10 ml water and sonicated thoroughly. The insoluble was filtered and washed with water. The solid was dried over air affording 96.5 mg (99.0%) title compound 13x.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:46][CH2:47][CH:48]([OH:60])[CH2:49][N:50]1[CH2:59][CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51]1>C(Cl)Cl>[CH2:51]1[C:52]2[C:57](=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:58][CH2:59][N:50]1[CH2:49][CH:48]([OH:60])[CH2:47][NH:46][C:12]([C:11]1[CH:10]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:17]=[CH:16][CH:15]=1)=[O:14]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
To a solution of 3-((tert-butoxycarbonyl)amino)benzoic acid (2.5 g, 10.5 mmol) in DCM (25 mL) was added EDCI (3.0 g, 15.7 mmol), HOBt (2.1 g, 15.7 mmol), Et3N (2.1 g, 21 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (2.2 g, 10.5 mmol). The mixture was stirred at 25° C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was concentrated, and the residue was purified by column chromatography to give the title product (3.2 g, 71%). LCMS (m/z): 426.3 (M+1).
Reaction SMILES: C(OC(=O)[N:7]([CH2:26][CH:27]1[CH2:29][CH2:28]1)[C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=2)=[O:19])=[CH:13][CH:12]=1)(C)(C)C.[ClH:31].COC1CCCC1>>[ClH:31].[CH:27]1([CH2:26][NH:7][C@@H:8]2[CH2:10][C@H:9]2[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[O:19])=[CH:13][CH:12]=2)[CH2:29][CH2:28]1
Reactant: Cn1cc(C(=O)Nc2ccc([C@@H]3C[C@H]3N(CC3CC3)C(=O)OC(C)(C)C)cc2)cn1
Agent: Cl
Solvent: COC1CCCC1
Product: Cn1cc(C(=O)Nc2ccc([C@@H]3C[C@H]3NCC3CC3)cc2)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-Butyl(cyclopropylmethyl)[trans-2-(4-{[(1-methyl-1H-pyrazol-4-yl)carbonyl]amino}phenyl)cyclopropyl]carbamate (114.8 mg) was dissolved in 4N hydrochloric acid/cyclopentyl methyl ether solution (1 mL), and the mixture was stirred at room temperature for 1.5 hr. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (51.1 mg).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:9]([O:16][CH2:17][C:18]([B-](F)(F)F)=[CH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[K+].C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:9]([O:16][CH2:17][C:18]([C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1)=[CH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=C(COCc1ccccc1)[B-](F)(F)F
Reactant: Nc1cnc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: C=C(COCc1ccccc1)c1cnc(N)cn1
Temperature: 100 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
To a solution of 5-bromopyrazin-2-amine (200 mg, 1.149 mmol) in was added potassium (3-(benzyloxy)prop-1-en-2-yl)trifluoroborate (350 mg, 1.379 mmol), PdCl2(dppf).CH2Cl2 adduct (94 mg, 0.115 mmol), Cs2CO3 (1124 mg, 3.45 mmol). Purged through Nitrogen. The reaction mixture was stirred at 100° C. in oil bath for 6 h. The reaction mixture was then partitioned between EtOAc and water, combined the organic layers and washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography to give 5-(3-(benzyloxy)prop-1-en-2-yl)pyrazin-2-amine in 61% yield. LCMS (m/z): 245.2 (MH+), 0.67 min; 1H NMR (400 MHz, CD3OD) δ ppm 8.26 (d, J=1.2 Hz, 1H), 7.96 (d, J=1.2 Hz, 1H), 7.34 (d, J=4.3 Hz, 5H), 5.91 (s, 1H), 5.44 (d, J=1.2 Hz, 1H), 4.59 (s, 2H), 4.49 (s, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[C:9]([Cl:17])[CH:8]=2)=[O:4].[OH-].[Na+].O1CCOCC1>C(OCC)(=O)C>[Cl:17][C:9]1[CH:8]=[C:7]2[C:12]([C:13](=[O:16])[C:14]([CH3:15])=[C:5]([C:3]([OH:4])=[O:2])[N:6]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1c(C)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(C(=O)O)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 150 °C
Yield: 92.6 %

Procedure:
In a sealed tube, 7-chloro-3-methyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (3.84 g, 11.7 mmol) and 1N sodium hydroxide (70 mL, 70 mmol) were added to dioxane (150 mL). The reaction mixture was heated to 150° C. overnight. The reaction mixture was poured into 500 mL ethyl acetate and extracted with 1N HCl (1×400 mL) and brine (1×100 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was triturated with diethyl ether (1×100 mL) to give 7-chloro-3-methyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid (3.40 g, 92.5% yield) as a white solid. MS calcd for C17H12ClNO3 [(M+H)+] 314, obsd. 314.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)=[CH:16][CH:15]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: COc1ccc([Mg]Br)cc1
Product: COc1ccc(-c2ccc3ccccc3c2)cc1

Procedure:
The title compound was prepared by reacting 2-bromonaphthalene (3.04 g, 14.7 mmol) with 4-methoxyphenylmagnesium bromide according to method used to prepared intermediated 10 to yield 2.89 g (89%) of a white solid: mp 114° C.; 1H NMR (CDCl3): δ 3.86 (3H, s), 7.01 (2H, d, J=9.06 Hz), 7.43–7.50 (2H, m), 7.65 (2H, d, J=8.73 Hz), 7.71 (1H, dd, J=1.84 Hz, J=8.56 Hz), 7.83–7.89 (3H, m), 7.98 (1H, d, J=0.67 Hz); MS (El) m/z 234 (M)+.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:5][CH2:4]1.C[O-].[Na+].CO.[S:29]1[CH:33]=[CH:32][C:31]([C:34]2[N:39]=[C:38]([CH:40]=O)[CH:37]=[CH:36][CH:35]=2)=[CH:30]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(Cl)(Cl)Cl.C(O)(=O)C>[ClH:1].[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15]([CH:14]=[CH:13][C:12](=[O:23])[N:11]2[CH2:10][CH2:9][N:6]2[CH2:5][CH2:4][CH:3]([NH:2][CH2:40][C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([C:31]4[CH:32]=[CH:33][S:29][CH:30]=4)[N:39]=3)[CH2:8][CH2:7]2)=[N:16][CH:17]=1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cccc(-c2ccsc2)n1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cccc(-c5ccsc5)n4)CC3)c2c1
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a suspension of 0.14 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride in 5 mL of methanol, 0.14 g of a 28% sodium methoxide/methanol solution, 46 mg of 6-(3-thienyl)pyridine-2-carbaldehyde, 0.10 g of molecular sieves 3 A, 28 μL of acetic acid and 15 mg of sodium cyanoborohydride were added at room temperature, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, 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 basic silica gel column chromatography using an eluent of chloroform:methanol=30:1. To a solution of the resultant residue in 2 mL of ethyl acetate, 2 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution was added, and the mixture was stirred at room temperature for 30 minutes. The solid was filtered off to obtain 97 mg of 7-methoxy-1-(2-(4-(((6-(3-thienyl)pyridin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one hydrochloride as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([CH3:25])[C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[N:9]2)=[CH:4][C:3]=1[CH2:27][N:28]([C:32]1[CH:44]=[CH:43][C:35]([C:36]([O:38]C(C)(C)C)=O)=[CH:34][CH:33]=1)[CH2:29][C:30]#[CH:31].[NH2:45][CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl.FC(F)(F)C(O)=O.CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([CH3:25])[C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[N:9]2)=[CH:4][C:3]=1[CH2:27][N:28]([C:32]1[CH:44]=[CH:43][C:35]([C:36]([NH:45][CH2:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)=[O:38])=[CH:34][CH:33]=1)[CH2:29][C:30]#[CH:31]
Reactant: NCc1cccnc1
Reactant: C#CCN(Cc1cc2c(=O)n(C)c(CN3CCN(c4ccccc4)CC3)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C#CCN(Cc1cc2c(=O)n(C)c(CN3CCN(c4ccccc4)CC3)nc2cc1Cl)c1ccc(C(=O)NCc2cccnc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of tert-butyl 4-[N-[7-chloro-3-methyl-4-oxo-2-(4-phenylpiperazin-1-yl)methyl-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.140 g, 0.23 mmol) (Preparation Example 22) in dichloromethane (1.7 ml) and trifluoroacetic acid (2.3 ml) was stirred at room temperature for 55 min with protection from the light. The trifluoroacetic acid was then removed in vacuo, and the residue was treated with dichloromethane/toluene, concentrated in vacuo, and dried in vacuo over P2O5 (0.182 g). This was dissolved in anhydrous DMF (2 ml) under argon. The solution was placed in an ice-bath and then a solution of 3-(aminomethyl)pyridine (0.037 g, 0.34 mmol) in anhydrous DMF (0.2 ml) was added followed by PyBOP® (0.125 g, 0.24 mmol), and finally diisopropylethylamine (0.178 g, 1.38 mmol). The solution was stirred at 0° C. for 5 min, then the ice-bath was removed and stirring was continued under argon for 3 h. The clear solution was then partitioned between ethyl acetate (150 ml) and saturated aqueous sodium bicarbonate (100 ml). The organic layer was washed with more saturated aqueous sodium bicarbonate (100 ml), brine (100 ml), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography, on gradient elution with methanol in dichloromethane (2 to 5%), afforded a white solid which was reprecipitated from dichloromethane/hexanes (0.104 g, 71%), mp 214-216° C. 1H-NMR (DMSO-d6) 2.76 (br s) and 3.11 (br s) (8H, N(CH2CH2)2), 3.20 (s, 1H, C≡CH), 3.63 (s, 3H, N3-Me), 3.70 (s, 2H, 2-CH2), 4.37 (s, 2H, CH2C≡C), 4.45 (d, J 5.7 Hz, 2H, CONHCH2), 4.78 (s, 2H, 6-CH2), 6.74 (t obscured, 1H), 6.90 (d, J=8.6 Hz, 2H), and 7.20 (t, J=8.20 Hz, 2H) (C6H5—N(CH2CH2)2N—), 6.76 (d, J=8.7 Hz, 2H, 3,5′-ArH), 7.32 (dd, J=4.6, 7.8 Hz, 1H, pyr 5-H), 7.68 (d, J=7.7 Hz, pyr 4-H), 7.75 (d, J=8.6 Hz, 2H, 2′,6′-ArH), 7.83, 7.93 (2×s, 2H, 5-H, 8-H), 8.43 (d, J=4.7 Hz, pyr 6-H), 8.52 (s, 1H, pyr 2-H), 8.76 (t, J=5.8 Hz, 1H, CONH).
Reaction SMILES: O[CH2:2][C:3]1([C:19]2[C:28]([OH:29])=[CH:27][C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[CH:20]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:4]1=[O:18].OC1C=C2C(CCC2)=CC=1C1(CO)C2C(=CC=CC=2)N(CC(OCC)=O)C1=O>>[O:18]=[C:4]1[C:3]2([CH2:2][O:29][C:28]3[CH:27]=[C:26]4[C:21](=[CH:20][C:19]2=3)[CH2:22][CH2:23][CH2:24][CH2:25]4)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)CCCC3)c2ccccc21
Agent: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)CCC3)c2ccccc21
Product: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCCC4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 1.45, and making non-critical variations using ethyl [3-(hydroxymethyl)-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate to replace ethyl [3-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (24% in three steps): 1H NMR (300 MHz, CDCl3) δ 7.29 (td, 1H), 7.19 (d, 1H), 7.07 (t, 1H), 6.79 (d, 1H), 6.66 (s, 1H), 6.51 (s, 1H), 4.91 (d, 1H), 4.67 (d, 1H), 4.52 (ABq, 2H), 4.24 (q, 2H), 2.77-2.51 (m, 4H), 1.77-1.64 (m, 4H), 1.29 (t, 3H); MS (ES+) m/z 378 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][CH:8]([C:10]2[CH:15]=[C:14]([N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:13]3[N:33]=[CH:34][CH:35]=[C:12]3[N:11]=2)[CH3:9])[CH2:3][CH2:2]1.C1C(=O)N([I:43])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[I:43][C:35]1[CH:34]=[N:33][N:13]2[C:14]([N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:22])[CH3:23])=[CH:15][C:10]([CH:8]([NH:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH3:9])=[N:11][C:12]=12
Reactant: O=C1CCC(=O)N1I
Reactant: CC(NC1CCOCC1)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2nccc2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CC(NC1CCOCC1)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(I)c2n1
Reaction time: 0.17 h
Yield: 67.5 %

Procedure:
To a solution of 5-(1-(tetrahydro-2H-pyran-4-ylamino)ethyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.17 g, 0.32 mmol) in acetonitrile (15 ml) at 0° C. was added NIS (78 mg, 0.35 mmol) and stirring continued for 10 minutes. LC/MS showed no starting material (M.W=521) remaining. Saturated sodium thiosulfate solution (˜0.5 ml) was added and stirring continued for 5 minutes. After the acetonitrile was rotoevaporated, the aqueous phase was extracted with DCM (25 ml), washed with water (1×5 ml), brine (1×5 ml), dried over MgSO4. Solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with MeOH/EtOAC (0-20%) gave desired product, 3-iodo-5-(1-(tetrahydro-2H-pyran-4-ylamino)ethyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.14 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([OH:21])=O)=[CH:14][CH:13]=1)=[O:11].[CH:23]([NH2:26])([CH3:25])[CH3:24].O>O1CCCC1>[CH:23]([NH:26][C:19](=[O:21])[CH:18]([C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[NH:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[CH:17][CH:16]=1)[CH3:22])([CH3:25])[CH3:24]
Reactant: CC(C(=O)O)c1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Reactant: CC(C)N
Solvent: O
Solvent: C1CCOC1
Product: CC(C)NC(=O)C(C)c1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
3.38 g of 2-[4-(2,3-dichlorophenylcarbamoyl)phenyl]-propionic acid was dissolved in 30 ml of anhydrous tetrahydrofuran. While cooling the solution with ice water, 2.43 g of N,N'-carbonyldiimidazole was added thereto, and the mixture was stirred for 30 minutes. Thereafter, 0.59 g of isopropylamine was added thereto. The mixture was returned to room temperature and stirred for 5 hours. After completion of the reaction, the reaction solution was poured into 200 ml of water, and the resulting crystals were collected by filtration, washed with water and dried, and then recrystallized from toluene to obtain 3.30 g of desired N-isopropyl-2-[4-(2,3-dichlorophenylcarbamoyl)-phenyl]-propionamide. The yield was 87%, and the melting point of this compound was from 203° to 204° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[NH:16][CH:15]=[N:14][N:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[S:29][C:28]([CH2:30][CH:31]([C:37](=O)[CH2:38][CH2:39][CH3:40])[C:32](OCC)=[O:33])=[CH:27][CH:26]=1)#[N:18].N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>Cl>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([N:11]3[C:32](=[O:33])[C:31]([CH2:30][C:28]4[S:29][C:25]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[C:17]#[N:18])=[CH:26][CH:27]=4)=[C:37]([CH2:38][CH2:39][CH3:40])[N:13]4[N:14]=[CH:15][N:16]=[C:12]34)[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)s1)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
A mixture of N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (1.10 g), ethyl 2-{[5-(2-cyanophenyl)thiophen-2-yl]methyl}-3-oxohexanoate (3.30 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) and N,N-diethylaniline (20 mL) was stirred at 180° C. overnight. The mixture was allowed to cool and poured into 1 M hydrochloric acid (50 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (0.85 g, 34%).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[O:16]=[C:17]1[C:22]2=[CH:23][NH:24][C:25]([CH:26]=O)=[C:21]2[CH2:20][CH2:19][O:18]1>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:25]1[NH:24][CH:23]=[C:22]2[C:17](=[O:16])[O:18][CH2:19][CH2:20][C:21]=12)(=[O:5])=[O:4]
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCOC3=O)C(=O)N2
Yield: 79.1 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (0.2 g, 0.88 mmol) was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde (1.2 eq, 0.18 g) to give 0.26 g (79%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+]>CO>[CH3:1][C:2]([CH3:21])([CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(C)(C)CCNS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CCNS(=O)(=O)c1ccccc1)CC(=O)O
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl 3,3-dimethyl-5-(benzenesulphonamido)pentanoate (4.4 g, 14.1 mmol), methanol (30 ml) and 2N NaOH (20 ml) was stirred for 5 hours at 60° C. The methanol was then evaporated, the aqueous phase was acidified (diluted HCl) and the oily acid was extracted with methylene chloride. After drying over sodium sulphate the solvent was removed. Yield: 4.0 g (100 % of theory), oily product, nD20 =1.5250.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH:14]=[CH2:15])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH3:15])[CH3:2]
Reactant: C=CCc1ccccc1OCC(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccccc1OCC(=O)OCC
Yield: 97.5 %

Procedure:
A solution of (2-allyl-phenoxy)-acetic acid ethyl ester (5.8 g, 26.3 mmol) in ethanol (200 mL) was treated with 5% Pd/C (59 mg) and hydrogen at ambient temperature for overnight. The mixture was filtered and concentrated to give the title compound (5.7 g, 98%). 1H NMR (400 MHz, CDCl3) • 7.16˜7.10 (m, 2H), 6.94˜6.89 (m, 1H), 6.71 (d, J=8.1 Hz, 1H), 4.53 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 2.65 (t, J=7.7 Hz, 2H), 1.71˜1.60 (m, 2H), 1.29 (t, J=7.0 Hz, 2H), 0.96 (t, J=7.0 Hz, 3H); MS (ES) m/e 406.18 (M++1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:40]=[CH:39][C:16]([O:17][CH2:18][C:19]2[CH:38]=[CH:37][CH:36]=[CH:35][C:20]=2[O:21][CH:22]([C:30]([O:32]CC)=[O:31])[CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])=[CH:15][CH:14]=1.[OH-].[Na+]>O1CCOCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]2[CH:38]=[CH:37][CH:36]=[CH:35][C:20]=2[O:21][CH:22]([C:30]([OH:32])=[O:31])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:39][CH:40]=1
Reactant: CCOC(=O)CCC(Oc1ccccc1COc1ccc(OCc2ccc3ccccc3n2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCC(Oc1ccccc1COc1ccc(OCc2ccc3ccccc3n2)cc1)C(=O)O

Procedure:
The crude product is purified by column chromatography to give ethyl 4-(2-(4-((quinolin-2-yl)methyloxy)phenoxymethyl)phenoxy)-4-carbethoxybutyrate. The ester is treated with 1N NaOH solution (30 mL) in dioxane overnight. The reaction mixture is then acidified, and purified by flash chromatography which gives 4-(2-(4-((quinolin-2-yl)methyloxy)phenoxymethyl)phenoxy)-4-carboxybutyric acid.