Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:23][C:11]3=[N:12][C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:14](I)[CH:15]=[C:10]3[C:9]=2[C:24]([NH:26][CH3:27])=[O:25])=[CH:4][CH:3]=1.[B:28]([OH:33])([OH:32])B(O)O.CC([O-])=O.[K+]>CCO.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:23][C:11]3=[N:12][C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([B:28]([OH:33])[OH:32])[CH:15]=[C:10]3[C:9]=2[C:24](=[O:25])[NH:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(I)cc12
Reactant: OB(O)B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(B(O)O)cc12
Temperature: 80 °C
Reaction time: 5 h
Yield: 197.8 %

Procedure:
To a degassed solution of 2-(4-fluorophenyl)-5-iodo-N-methyl-6-(N-methylmethylsulfonamido)furo[2,3-b]pyridine-3-carboxamide (prepared according to International Patent Application Publication No. WO2011131709, 3.0 g, 6 mmol), hypodiboric acid (1.08 g, 1.2 mmol) and KOAc (1.8 g, 1.8 mmol) in EtOH (60 mL) was added Pd(OAc)2 (50 mg) and Ad2n-BuP (50 mg) under nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 5 h, concentrated in vacuo to remove EtOH. The residue was purified by column chromatography (EA:DCM=1:1˜DCM:MeOH=5:1) to afford the desired product of (2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)furo[2,3-b]pyridin-5-yl)boronic acid (1 g, yield: 40%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.53 (d, J=4.4 Hz, 1H), 8.24 (s, 1H), 8.00˜8.04 (m, 3H), 7.40 (t, J=8.8 Hz, 2H), 4.08 (br s, 1H), 3.17 (s, 3H), 3.06 (s, 3H), 2.85 (d, J=4.8 Hz, 3H). MS (M+H)+: 422.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20]Br.C([O-])([O-])=O.[K+].[K+]>>[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20][N:10]([CH2:20][C:12]1[S:11][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=1)[C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: BrCc1nc2ccccc2s1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc2sc(CN(Cc3nc4ccccc4s3)c3ccc4[nH]cnc4c3)nc2c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), (benzo[d]thiazol-2-yl)methylbromide (502 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.037 g (8.7%); 428.1 MS m/z: [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 5.22 (s, 4H); 6.96 (dd, 1H, 4J=2.4 Hz, 3J=8.9 Hz); 7.02 (br s, 1H); 7.38-7.43 (m, 3H); 7.47-7.51 (m, 2H); 7.96-7.98 (m, 2H); 8.02-8.03 (m, 3H); 12.35 (br s, 1H); HPLC (METHOD [A]): rt 14.45 min (92.1%)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].I[CH2:18][CH3:19].Cl>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:18][CH3:19])[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Reactant: CCI
Agent: Cl
Product: CCN1CCC(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and iodoethane: m.p. 158° C. (HCl). MS m/z (rel. intensity, 70 eV) 267 (M+, 20), 252 (bp), 130 (10), 115 (12), 84 (20);
Reaction SMILES: CC1C=C(O[Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])C=C(C)C=1C(C1C=CC(F)=C(C(C)C)C=1)O.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl.CCOC(C)=O.O>[CH:10]([SiH:9]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1C(O)c1ccc(F)c(C(C)C)c1
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[SiH](C(C)C)C(C)C
Reaction time: 2 h
Yield: 210.5 %

Procedure:
To a solution of (2,6-dimethyl-4-triisopropylsilanyloxy-phenyl)-(4-fluoro-3-iso-propyl-phenyl)-methanol (520 mg, 1.08 mmol) in CH2Cl2 (10 mL)was added TFA (1.53 M, 0.7 mL) followed by triethylsilane (0.6 mL, 3.77 mmol) at r.t. After stirring for 2 h, the reaction mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was further extracted with EtOAc. The combined organic layers were washed with Sat. NaHCO3, water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, hexanes) to provide 3,5-dichloro-4-(4′-fluoro-3′-iso-propyl-benzyl)-phenoxy]-triisopropylsilane as a colorless liquid (360 mg, 72%): 1H NMR (300 MHz, CDCl3): δ 7.11 (m, 1H), 6.91 (m, 4H), 4.21 (s, 2H), 3.19 (m, 1H), 1.24 (m, 3H), 1.17 (m, 24H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes; Rf=0.68.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:16])([CH3:15])[CH2:4][CH2:5][CH2:6][C:7]([CH3:14])=[CH:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:12].[C:17](=O)([O-:20])[O:18][CH3:19].[H-].[Na+].Cl>CN(C)C=O>[CH3:1][O:2][C:3]([CH3:16])([CH3:15])[CH2:4][CH2:5][CH2:6][C:7]([CH3:14])=[CH:8][CH2:9][CH2:10][C:11](=[O:13])[CH2:12][C:17]([O:18][CH3:19])=[O:20]
Reactant: COC(=O)[O-]
Reactant: COC(C)(C)CCCC(C)=CCCC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)CCC=C(C)CCCC(C)(C)OC
Temperature: 40 °C
Reaction time: 6 h

Procedure:
A mixture of 900 mg of the product from Step B, 1 ml of methyl carbonate and 15 ml of dimethylformamide was heated to 40° C. and 360 mg of sodium hydride in a 50% oil suspension were added thereto portion wise and the mixture was stirred for 6 hours at room temperature. The mixture was poured into an aqueous hydrochloric acid solution and was extracted with petroleum ether (b.p.= 40°-75° C.). The extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed over silica and was eluted with a 7-3 petroleum ether-ethyl ether mixture to obtain 374 mg of methyl 11-methoxy-7,11-dimethyl-3-oxo-6-dodecenoate in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[O:34][CH3:35])=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:33][O:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([O:34][CH3:35])[C:26]=1[O:25][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4c(OC)cccc4OC)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4c(OC)cccc4OC)cc3)c2cc1OC
Temperature: 0 °C
Yield: 79.8 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(2,6-dimethoxyphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:29]=[CH:28][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]4[C:26]5[CH2:25][CH2:24][NH:23][CH2:22][C:21]=5[S:20][C:19]=4[CH3:27])[CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C=O.[C:32]([BH3-])#N.[Na+]>C(O)C>[CH3:27][C:19]1[S:20][C:21]2[CH2:22][N:23]([CH3:32])[CH2:24][CH2:25][C:26]=2[C:18]=1[CH2:17][CH2:16][N:13]1[CH2:14][CH2:15][CH:10]([C:7]2[C:6]3[CH:28]=[CH:29][C:3]([F:2])=[CH:4][C:5]=3[O:9][N:8]=2)[CH2:11][CH2:12]1
Reactant: [BH3-]C#N
Reactant: Cc1sc2c(c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCNC2
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1sc2c(c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCN(C)C2
Temperature: 25 °C

Procedure:
To a solution of 0.5 g of 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine hydrochloride in ethanol was added 0.3 ml of 37% formaldehyde solution and the mixture was stirred at room temperature for an hour. To the mixture was added 0.2 g of sodium cyanoborohydride, the mixture was stirred for an hour, and then concentrated. To the residue was added water and extracted with chloroform. The extract was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography and recrystallized from isopropyl ether to give 2,6-dimethyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine 1/2hydrate as white crystals, m.p. 100°-103° C.
Reaction SMILES: C(OC([N:8]([C:25]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22](=[O:24])[NH2:23])=[CH:12][CH:11]=1)=O)(C)(C)C.Cl>CO>[C:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:25]2[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:15][CH:14]=1)(=[O:24])[NH2:23]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2C(N)=O)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCc1ccc(-c2ccccc2C(N)=O)cc1
Yield: 71.3 %

Procedure:
A mixture of the compound (2.8 g) obtained in Example (54b) in methanol (15 ml) and 1N-HCl (6 ml) was heated for 2 hours under reflux. After removal of the solvent, the residue was made alkaline with an aqueous solution of NaHCO3, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel, and the product was recrystallized from ethyl acetate--hexane to afford yellow needles (1.6 g, 73%).
Reaction SMILES: [F:1][C:2]1[C:11]2[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)[CH:9]=[C:8]3[C:24](=[O:34])[N:25]([C:27]4(I)[CH:32]=[CH:31][CH:30]=[CH:29][CH2:28]4)[N:26]=[C:7]3[C:6]=2[C:5]([F:35])=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC.[NH:54]1[CH:58]=[CH:57][CH:56]=[N:55]1>CS(C)=O.O.[Cu]I>[F:1][C:2]1[C:11]2[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)[CH:9]=[C:8]3[C:24](=[O:34])[N:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[N:54]4[CH:58]=[CH:57][CH:56]=[N:55]4)[N:26]=[C:7]3[C:6]=2[C:5]([F:35])=[CH:4][CH:3]=1
Reactant: c1cn[nH]c1
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3c(F)ccc(F)c3c-2nn1C1(I)C=CC=CC1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3c(F)ccc(F)c3c-2nn1-c1ccccc1-n1cccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6,9-Difluoro-2-(1-iodophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one [(Example 53), 36 mg, 0.062 mmol], potassium phosphate (40 mg, 0.19 mmol, 3 equiv), (±)-trans-N,N′-bismethyl-1,2-cyclohexane diamine (7.1 mg, 0.050 mmol, 0.8 equiv), copper(I) iodide (4.7 mg, 0.025 mmol, 0.4 equiv) and pyrazole (8.5 mg, 0.12 mmol, 2 equiv) were combined in dimethylsulfoxide (0.9 mL) and water (0.1 mL). The mixture was sparged under a nitrogen atmosphere, the vessel was sealed and placed into an preheated oil bath at 130° C. for 3 hours. The mixture was cooled to ambient temperature, poured into water (10 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (20:80 to 95:5; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid). The appropriate fractions were poured into sodium bicarbonate (50 mL, aqueous saturated) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 8.96 (1H, s), 8.46 (1H, d, J=2.6 Hz), 7.81 (2H, d, J=8.7 Hz), 7.76-7.68 (3H, m), 7.64-7.47 (5H, m), 7.40 (1H, td, J=8.9, 3.5 Hz), 7.30 (2H, d, J=8.6 Hz), 6.53 (1H, dd, J=2.4, 2.0 Hz), 6.34 (1H, dd, J=2.4, 1.9 Hz), 5.75 (2H, d, J=3.1 Hz) ppm; high resolution mass spectrometry (ES+) m/z 520.1697 [(M+H)+; calculated for C29H19F2N7O: 520.1692].
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][NH:11][NH2:12]>C(O)C>[Br:1][C:2]1[C:3]([CH:8]=[N:12][NH:11][CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNN
Reactant: O=Cc1ncccc1Br
Solvent: CCO
Product: CNN=Cc1ncccc1Br
Temperature: 80 °C
Yield: 99.1 %

Procedure:
3-bromo-2-formylpyridine (5 g, 26.88 mmol) and methylhydrazine (1.70 mL, 32.25 mmol) are dissolved in ethanol (10 mL) and heated at 80° C. for 2 h. Volatiles are removed under reduced pressure and the residue is re-evaporated several times to give N-[1-(3-Bromo-pyridin-2-yl)-methylidene]-N′-methyl-hydrazine (5.70 g, 99%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH:5]=[CH2:6])[CH3:2].[CH2:8](O)[CH2:9]CC.C(OC(=O)C=C)C.C(O)C>C1(C=CC(O)=CC=1)O.[C-]#N.[K+]>[C:4]([O:3][CH2:1][CH2:2][CH2:8][CH3:9])(=[O:7])[CH:5]=[CH2:6]
Reactant: CCCCO
Reactant: C=CC(=O)OCC
Agent: Oc1ccc(O)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Product: C=CC(=O)OCCCC
Reaction time: 4.5 h
Yield: 96.7 %

Procedure:
500 g of ethylacrylate (5 mole), 92.5 g of n-butanol (1.25 mole) and 0.148 g of hydroquinone (250 ppm) are added to a 1 liter round-bottomed flask. By conducting air through by way of a 1 m vigreux column, the azeotrope is dehydrated. After cooling of the contents of the flask to 60° to 70° C., 6 g of potassium cyanide (1%) are added, and the ethylacrylate/ethanol-azeotrope is distilled-off at 77° C. at the head of the column. After 4 to 5 hours, the trans-esterification is completed. After cooling down of the flask, the potassium cyanide is filtered off and the filter residue is washed out with a little ethyl acrylate. The filtrate is processed by fractional distillation. 155 g of n-butyl acrylate = 97% are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:15])=[O:7]
Reactant: COc1cccc(C(=O)O)c1C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1cccc(C(=O)Cl)c1C
Yield: 86.2 %

Procedure:
To 3-methoxy-2-methylbenzoic acid (454 g, 2.73 tool) in 1300 mL chloroform containing 20 g dimethyl formamide at 65° C., thionyl chloride (390 g) was added dropwise over 6 hours, whereupon the solvent was removed by evaporation at a reduced pressure. The residue (512 g) was distilled at 110° C. at 1-2 mm Hg to give 3-methoxy-2-methylbenzoyl chloride (435 g. 85%).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]1([CH2:19][CH2:20][SH:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:1](=[O:12])([S:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: SCCc1ccccc1
Product: CCCCCCC/C=C/C(=O)SCCc1ccccc1

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 2-phenylethanethiol as starting materials to give the aimed compound.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([N:11]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][C:8]([CH:28]([NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH3:29])=[N:7][C:6]=12.B(O)O.[F:40][C:41]1[CH:42]=[C:43]2[C:48](=[CH:49][CH:50]=1)[N:47]=[CH:46][CH:45]=[CH:44]2.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>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].O.O1CCOCC1>[F:40][C:41]1[CH:42]=[C:43]2[C:48](=[CH:49][CH:50]=1)[N:47]=[CH:46][C:45]([C:2]1[CH:3]=[N:4][N:5]3[C:10]([N:11]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][C:8]([CH:28]([NH:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH3:29])=[N:7][C:6]=13)=[CH:44]2
Reactant: CC(NC1CCOCC1)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(I)c2n1
Reactant: Fc1ccc2ncccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(NC1CCOCC1)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Temperature: 100 °C
Yield: 60 %

Procedure:
To 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, 0.21 mmol) was added 6-fluoroquinoline boronate (0.11 g, 0.42 mmol), K2CO3 (87 mg, 0.63 mmol), PdCl2(dppf).CH2Cl2 (18 mg, 0.02 mmol), dioxane (4 ml) and H2O (1 ml). The resulting mixture was heated at 100° C. for 2 hours, at which time LC/MS analysis confirmed full consumption of starting material. On cooling, the solvent was rotoevaporated, and the crude was redissolved in DCM (40 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-(6-fluoroquinolin-3-yl)-5-(1-(tetrahydro-2H-pyran-4-ylamino)ethyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (84 mg, 60%).
Reaction SMILES: [C:1]([C:5]1[C:6]([C:18](Cl)=[O:19])=[N:7][C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([Cl:16])[CH:11]=[C:10]([Cl:17])[CH:9]=2)([O:3]C)=O.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[NH:29][NH2:30]>O1CCCC1>[Cl:17][C:10]1[CH:11]=[C:12]([Cl:16])[C:13]2[C:14](=[O:15])[C:5]3[C:1](=[O:3])[N:29]([C:23]4[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=4[CH3:21])[N:30]=[C:18]([OH:19])[C:6]=3[NH:7][C:8]=2[CH:9]=1
Reactant: COC(=O)c1c(C(=O)Cl)nc2cc(Cl)cc(Cl)c2c1O
Reactant: Cc1ccc(NN)c(C)c1
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(O)c3[nH]c4cc(Cl)cc(Cl)c4c(=O)c3c2=O)c(C)c1

Procedure:
3-Carbomethoxy-5,7-dichloro-4-hydroxyquinoline-2-carbonyl chloride (3.65 g,11.0 mM) was dissolved in tetrahydrofuran (274 mL) and added dropwise to a cooled (0° C.) solution of 2,4-dimethylphenylhydrazine (3.13 g, 23.0 mM) in tetrahydrofuran (172 mL) with stirring. A brown/red suspensionslowly formed and the resulting mixture was stirred at 0° C. for 30 min. The reaction was quenched by adding cold water (223 mL) followed by 1N HCl (669 mL). The resulting mixture was stirred for 1 hr and then filtered to separate the precipitated solids. The collected solids were washed with water and then ether to provide, after air drying, the title compound (3.60 g, 76%) as a white powder; MS(CI): 434 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:12]=[C:11]([C:13]3[N:14]=[CH:15][O:16][CH:17]=3)[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:9]=2)[CH:3]=1.[OH-].[NH4+:27]>C(O)CO.O1CCOCC1.[Cl-].[Na+].O.[Cu-]=O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:10]1[C:11]([C:13]2[N:14]=[CH:15][O:16][CH:17]=2)=[N:12][C:8]([C:4]2[CH:3]=[C:2]([NH2:27])[CH:7]=[CH:6][N:5]=2)=[N:9]1
Reactant: Fc1ccccc1Cn1nc(-c2cc(Br)ccn2)nc1-c1cocn1
Reactant: [NH4+]
Agent: O=[Cu-]
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCO
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccnc(-c2nc(-c3cocn3)n(Cc3ccccc3F)n2)c1
Temperature: 100 °C
Yield: 41.2 %

Procedure:
To a stirring suspension of 4-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)oxazole (I-54, 1 eq) and copper(I) oxide (0.2 eq) in ethylene glycol-dioxane (approx. 4:1) in a sealed tube was added ammonium hydroxide (30 eq). The resultant reaction mixture was heated at 100° C. for 12 hr. The reaction was cooled to room temperature and treated with brine and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated and purified using SiO2 chromatography (DCM/CAN/MeOH) to afford 2-(1-(2-fluorobenzyl)-5-(oxazol-4-yl)-1H-1,2,4-triazol-3-yl)pyridin-4-amine in 41.2% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:27][C:28](=[O:31])[CH2:29][CH3:30])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](O)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[O:23])[C:17]1=[O:26])[CH2:27][C:28](=[O:31])[CH2:29][CH3:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CCC(=O)CN([C@H]1CCN([C@@H](C)C(=O)O)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)CN([C@H]1CCN([C@@H](C)C(=O)N2CCOCC2)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](2-oxobutyl)amino]-2-oxopyrrolidin-1-yl}propanoic acid [Intermediate 25] (0.035 g) in DCM (2 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.044 g), HOBT (0.031 g) and triethylamine (0.064 ml) and the mixture was stirred at room temperature for 30 min. Morpholine (0.02 ml) was added and the resultant mixture stirred at room temperature for 16 h. The mixture was partitioned between DCM and water. The aqueous layer was re-extracted with DCM and the combined, dried (over magnesium sulphate) organic extracts were concentrated under reduced pressure. The residue was purified using mass directed preparative h.p.l.c. to give the title compound (0.008 g) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[N:35]=[C:34]([C:36]([OH:38])=[O:37])[C:33]([C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][O:46][C:47]5[CH:52]=[CH:51][CH:50]=[C:49]([NH:53]C(OC(C)(C)C)=O)[CH:48]=5)[CH:40]=4)=[CH:32][CH:31]=3)[CH:28]=2)[CH2:23][CH2:22][CH2:21]1)=[O:19]>C(Cl)Cl>[NH2:53][C:49]1[CH:48]=[C:47]([CH:52]=[CH:51][CH:50]=1)[O:46][CH2:45][C:41]1[CH:40]=[C:39]([C:33]2[C:34]([C:36]([OH:38])=[O:37])=[N:35][C:30]([C:27]3[CH:28]=[C:29]4[C:24]([CH2:23][CH2:22][CH2:21][N:20]4[C:18](=[O:19])[NH:17][C:9]4[S:8][C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=5[N:10]=4)=[CH:25][CH:26]=3)=[CH:31][CH:32]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(OCc2cccc(-c3ccc(-c4ccc5c(c4)N(C(=O)Nc4nc6ccccc6s4)CCC5)nc3C(=O)O)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(OCc2cccc(-c3ccc(-c4ccc5c(c4)N(C(=O)Nc4nc6ccccc6s4)CCC5)nc3C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The title compound 3-(3-((3-aminophenoxy)methyl)phenyl)-6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)picolinic acid (34) was prepared by the following procedure: Trifluoroacetic acid (0.5 mL) was added to a solution of 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-(3-((3-(tert-butoxycarbonylamino)phenoxy)methyl)phenyl)picolinic acid (34E) (0.016 g, 0.022 mmol) in anhydrous DCM (0.75 mL). The reaction mixture was stirred at rt for 1.5 hours, concentrated under reduced pressure, and the crude material triturated in diethyl ether to provide the desired product 3-(3-((3-aminophenoxy)methyl)phenyl)-6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)picolinic acid (34): 1H NMR (300 MHz, DMSO) δ 8.43 (1H, s, br), 8.08 (1H, d), 7.99 (1H, d), 7.85-7.77 (2H, m), 7.67 (1H, s), 7.55-7.41 (4H, m), 7.37 (1H, t), 7.31 (1H, d), 7.22 (1H, t), 7.12 (1H, t), 6.59-7.50 (2H, m), 6.47 (1H, d), 5.11 (2H, s), 3.97 (2H, t), 2.84 (2H, t), 1.96 (2H, m). MS (ESI(+)) m/z 628.1 (M+H).