Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH:41]([Mg]Br)([CH3:43])[CH3:42].O1CCCC1>O1CCCC1.CN1CCCC1=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Fe]>[C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH:41]([CH3:43])[CH3:42])[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: CC(C)[Mg]Br
Agent: [Fe]
Agent: CC(=O)/C=C(/C)O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1cc2nc(C(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Yield: 47 %

Procedure:
To a solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26) (200 mg, 0.33 mmol) and iron (III) acetylacetonate (6 mg, 0.017 mmol) in anhydrous tetrahydrofuran/1-methyl-2-pyrrolidinone (5 mL/0.5 mL) at 0° C. was added 2.9 M in tetrahydrofuran isopropylmagnesium bromide (0.149 mL, 0.431 mmol) drop wise. The reaction was let warm to room temperature over three hours, quenched with water and extracted with ethyl acetate and concentrated. The crude reaction was purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a yellow oil (77 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H39ClNO3: 496.25. found: 496.83.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1)=[O:12].C(O)(=O)C>CCO.[Fe]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)=[O:12])[CH:4]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2Cl)cc1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc(N)ccc2Cl)cc1
Temperature: 80 °C
Yield: 85.9 %

Procedure:
A solution of ethyl (4-{[(2-chloro-5-nitrophenyl)carbonyl]amino}phenyl)acetate (2.27 g, 6.3 mmol) in EtOH (20 ml) was heated at 50° C. A 20% aqueous solution of acetic acid (10 ml) was added followed by iron (6 eq, 37.6 mmol, 2.1 g). The mixture was heated at 80° C. for 30 minutes. On cooling the mixture was filtered through celite washing with EtOH. Solvent evaporated in vacuo. Residue taken up in EtOAc and aqueous sodium bicarbonate. Layers separated, aqueous layer extracted with EtOAc (×2). Organic layers combined and washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography (Biotage SP4, 100 g silica column) eluting with 25-75% ethyl acetate in hexanes to afford the title compound as a light yellow oil (1.8 g). MS (ES+) m/z 333 [M+H]+ (C17H1735ClN2O3). 1H-NMR (400 MHz, d6-DMSO) δ 1.18 (3H, m), 3.61 (2H, s), 4.05 (2H, m), 5.47 (2H, s), 6.65 (2H, m), 7.12 (1H, d, J 8.4), 7.22 (2H, d, J 8.4), 7.64 (2H, m).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:7][C:6]=1[CH3:18])=O.[NH2:19][C:20]([NH2:22])=[S:21]>CCO>[CH3:17][O:16][CH2:15][CH2:14][CH2:13][O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:19]=[C:20]([NH2:22])[S:21][CH:2]=2)=[C:6]([CH3:18])[CH:7]=1
Reactant: COCCCOc1cc(C)c(C(=O)CBr)c(C)c1
Reactant: NC(N)=S
Solvent: CCO
Product: COCCCOc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 68.8 %

Procedure:
A reaction mixture containing 2-bromo-1-(4(3-methoxypropoxy)-2,6-dimethylphenyl)ethanone (500.0 mg, 1.6 mmol, 1.0 equiv) and thiourea (126.8 mg, 1.6 mmol, 1.0 equiv) in EtOH (10.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% EtOAc in hexanes as eluant) to provide 4-(4-(3-methoxypropoxy)-2,6-dimethylphenyl)thiazol-2-amine (328.9 mg, 1.1 mmol) as yellow solids in 71% yield: 1H NMR (CDCl3, 500 MHz) δ 9.35 (brs, 1 H), 9.00 (brs, 1 H), 6.64 (s, 2 H), 6.22 (s, 1 H), 4.04-4.05 (m, 2 H), 3.54-3.56 (m, 2 H), 3.37 (s, 3 H), 2.19 (s, 6 H), 2.03-2.06 (m, 2 H); ESI-MS m/z 293.8 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20](Cl)(=[O:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:20](=[O:29])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)CCc1ccccc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)CCc1ccccc1
Yield: 48.8 %

Procedure:
Using the method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.2 g, 0.78 mmol) was reacted with hydrocinnamoyl chloride (0.11 mL, 0.74 mmol) to provide 0.14 g of N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-phenylpropanamide as a white solid, m.p. 148-150° C. 1H NMR (500 MHz, DMSO-d6) δ8.19 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.82 (t, J=6.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 2H), 7.15 (m, 3H), 6.66 (broad s, 2H), 4.58 (t, J=7.0 Hz, 2H), 3.06 (q, J=6.0 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H), 2.31 (t, J=7.0 Hz, 2H), 1.79 (quintet, J=7.0 Hz, 2H), 1.40 (t, J=7.0 Hz, 2H); MS (EI) m/e 387.2067 (387.2059 calcd for C23H25N5O).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br>>[N:1]1([CH:2]2[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: BrCCCCCBr
Reactant: NC1CCC(O)CC1
Product: OC1CCC(N2CCCCC2)CC1

Procedure:
Prepared from 4-amino-cyclohexanol and 1,5-dibromopentane.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([N:26]1CCOCC1)[CH3:25].ClC(OCC(C)C)=O.[Cl-].C([NH3+])C>O1CCCC1.CN(C)C=O>[CH2:24]([NH:26][C:18](=[O:20])[C@@H:17]1[CH2:21][CH2:22][CH2:23][N:16]1[C:14](=[O:15])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:25]
Reactant: CCN1CCOCC1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CC[NH3+]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 59.6 %

Procedure:
32 g (0.1 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline were dissolved in 250 ml of dry tetrahydrofuran and the solution was cooled to -10° C. 12.7 ml (0.1 mol) of N-ethylmorpholine and 13.1 ml (0.1 mol) of isobutyl chloroformate were then added and the solution was stirred at -10° C. for 20 minutes. To this mixture was then added a further 12.7 ml of N-ethylmorpholine followed by a solution of 8.15 g (0.1 mol) of ethylammonium chloride in 50 ml of dimethylformamide. The solution was stirred for 1 hour at 0° C. then left for 16 hours at room temperature. The solvents were removed by evaporation and the residue was triturated with 450 ml of ethyl acetate and washed successively with 200 ml of 1-N hydrochloric acid, 200 ml of water and 200 ml of 5% sodium bicarbonate solution. After drying over sodium sulphate and filtration, the solvent was removed by evaporation. The resulting oil crystallised slowly from ethyl acetate ether to yield 20.7 g of N-benzyloxycarbonyl-L-alanyl-L-proline ethylamide of melting point 110°-113° C. Evaporation of the mother liquors followed by treatment with ethyl acetate/ether gave a further crop of 1.2 g of melting point 107°-110° C.; total yield 68% [α]D20 =-96.0° (c=1.04% in methanol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted with 0.390 g. of caprylic acid chloride as in Example 1. The 0.671 g. of yellowish crystals obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.586 g. of colorless crytals which are recrystallized from acetone-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl octanoate obtained melts at 77.5°-77.9° and is liquid crystalline (monotrope) upon cooling to 74.1°. UV (EtOH): ε 272 = 26500.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([OH:13])(=[O:12])/[CH:9]=[CH:10]/[CH3:11]>C1(C)C=CC=CC=1>[C:2]1([NH:1][CH:10]([CH3:11])[CH2:9][C:8]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C=C/C(=O)O
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: CC(CC(=O)O)Nc1ccccc1
Yield: 60.7 %

Procedure:
A mixture of aniline (3.0 g, 32 mmol) and crotonic acid (2.0 g, 23 mmol) in toluene (20 mL ) was heated at reflux for 18 h. Removal of solvent and chromatography (silica gel, EtOAc/hexane, 9/1 ) of the crude material afforded 2.5 g (61%) of 3-phenylaminobutanoic acid. The acid was treated with PPA (20 mL ) at 110° C. for 6 h and the reaction mixture was poured into ice water (50 mL) and then was neutralized with Na2 CO3 to pH 7. Extraction with EtOAc (3×60 mL) followed by chromatography (silica gel, EtOAc/hexane, 4/6) afforded 1.0 g (44%) of 1,2,3,4-tetrahydro-2-methyl-4-quinolinone (structure 59A of Scheme XLVIII, where R1 =R3 =H, R2 =methyl) as a yellow solid. The quinolinone was treated with di-tert-butyl dicarbonate (2.2 g, 10 mmol) and DMAP (0.84 g, 6.8 mmol) in THF (15 mL) for 16 h followed by chromatography (silica gel, EtOAc/hexane, 2/8) to afford 1.1 g (68%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinone as a yellow oil. Data for 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinone: 1H NMR (400 MHz, CDCl3) 7.99 (d,J=7.5, 1H), 7.78 (d,J=7.5, 1H), 7.50 (t, J=7.5, 1H), 7.12(t,J=7.5, 1H), 5.10(m, 1H), 3.04(dd,J=17.3, 5.8, 1H), 2.57(dd,J=17.3, 1.7, 1 H), 1.56 (s, 9 H), 1.22 (d,J=6.9, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.[H][H]>CO.[Pd]>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[C:6]#[N:7]
Reactant: [H][H]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(O)c(N)c1
Yield: 100.2 %

Procedure:
A solution of 4-hydroxy-3-nitrobenzonitrile (10 g, 61 mmol) in MeOH (200 mL) was treated with hydrogen gas through a balloon in the presence of 5% Pd on active carbon (0.5 g) at room temperature for 24 hours. The mixture was filtered, and the filtrate was concentrated to give the product (8.2 g, 100%).
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:19][CH2:20][CH2:21][C:22]4[NH:23][C:24]5[C:29]([CH:30]=4)=[CH:28][C:27]([CH2:31][C:32]([O:34]C)=[O:33])=[CH:26][CH:25]=5)=[C:15]([CH2:16][CH2:17][CH3:18])[C:10]=3[O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO.[Li+].[OH-].C(OCC)(=O)C>[C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:19][CH2:20][CH2:21][C:22]4[NH:23][C:24]5[C:29]([CH:30]=4)=[CH:28][C:27]([CH2:31][C:32]([OH:34])=[O:33])=[CH:26][CH:25]=5)=[C:15]([CH2:16][CH2:17][CH3:18])[C:10]=3[O:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCc1c(OCCc2cc3cc(CC(=O)OC)ccc3[nH]2)ccc2c(-c3ccccc3)coc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1c(OCCc2cc3cc(CC(=O)O)ccc3[nH]2)ccc2c(-c3ccccc3)coc12
Yield: 0.1 %

Procedure:
A solution of 18.6 mg (39.8 mmol) of methyl 2-(2-(3-phenyl-7-propylbenzofuran-6-yloxy)-ethyl)-indole-5-acetate in ca. 2.0 ml of methanol and 1 M aqueous LiOH (79.6 uL) was heated at 60° C. for 16 hours. The mixture was diluted with ethyl acetate and acidified to pH 5-6 with 1 M HCl, washed with water (2 times), brine (1 time) and dried over sodium sulfate and concentrated to afford 11.6 mg of the title compound. (mp=129-130° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][C:13]([OH:15])=O.Cl.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([C:13](=[O:15])[CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:27][CH2:26]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1ccc2[nH]cc(CCC(=O)O)c2c1
Agent: Cl
Product: COc1ccccc1N1CCN(C(=O)CCc2c[nH]c3ccc(C)cc23)CC1

Procedure:
Prepared from 5-methyl-1H-indole-3-propanoic acid (Description 24) and-(2-methoxyphenyl)piperazine hydrochloride according to the method of Description 25. 1H NMR (360 MHz, CDCl3) δ7.89 (1H, br s), 7.40 (1H, s), 7.24 (1H, d, J 8.3 Hz), 7.04-7.00 (3H, m), 6.94-6.81 (3H, m), 3.86 (3H, s), 3.81 (2H, t, J 5.0 Hz), 3.53 (2H, t, J 5.0 Hz), 3.13 (2H, t, J 7.6 Hz), 2.96 (2H, t, J 5.0 Hz), 2.80 (2H, t, J 5.0 Hz), 2.77-2.73 (2H, m), and 2.46 (3H, s).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:24]([O:27][C:28]1[N:33]=[C:32]2[S:34][C:35]([NH2:37])=[N:36][C:31]2=[CH:30][CH:29]=1)([CH3:26])[CH3:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([NH:37][C:35]3[S:34][C:32]4[C:31]([N:36]=3)=[CH:30][CH:29]=[C:28]([O:27][CH:24]([CH3:26])[CH3:25])[N:33]=4)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)Oc1ccc2nc(N)sc2n1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2nc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)sc2n1
Yield: 38.9 %

Procedure:
The compound of example A82 was obtained by similar method described in example A75 using (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 14) (0.100 g,0.29 mmol), 5-iso-propoxy-thiazolo[5,4-b]pyridin-2-ylamine (0.067 g, 0.32 mmol), HOBt (0.047 g, 0.35 mmol), and EDCI (0.067 g, 0.35 mmol), N-methyl morpholine (0.065 g, 0.58 mmol) in DMF (5 mL) to provide the title compound (0.060 g).
Reaction SMILES: Br[C:2]1[C:3]([C:24]#[N:25])=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[N:20][CH:19]=2)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:8]=1.[Br-].[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[CH2:37][Zn+].O1CCCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[CH2:37][C:2]1[C:3]([C:24]#[N:25])=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[N:20][CH:19]=2)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:8]=1
Reactant: [Zn+]Cc1ccc2ccccc2c1
Reactant: N#Cc1c(-c2ccnnc2)sc(-c2ncn(C3CCCCO3)n2)c1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccnnc2)sc(-c2ncn(C3CCCCO3)n2)c1Cc1ccc2ccccc2c1
Temperature: 70 °C
Yield: 72 %

Procedure:
Bis(tri-t-butylphosphine)palladium(0) (4.92 mg, 0.00963 mmol), 4-bromo-2-pyridazin-4-yl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile (0.0402 g, 0.0963 mmol), 2-naphthylmethylzinc bromide in tetrahydrofuran (0.50M, 0.578 mL, 0.289 mmol) and tetrahydrofuran (4.0 mL, 49 mmol) were added to a microwave tube. The tube was sealed under a nitrogen atmosphere and heated at 70° C. for 2 h then cooled to rt. The mixture was concentrated in vacuo and the residue was purified by chromatography on a silica gel column eluting with 0-100% EtOAc in hexane to afford a solid product (0.0332 g, yield 72%). LCMS: (AA) ES+, 479. 1H NMR (300 MHz, d4-methanol) δ: 9.63 (s, 1H), 9.28-9.35 (m, 1H), 8.68 (s, 1H), 8.13-8.15 (m, 1H), 7.69-8.00 (m, 4H), 7.37-7.48 (m, 3H), 5.62-5.66 (m, 1H), 3.94-4.08 (m, 1H), 3.69-3.80 (m, 1H), 3.30 (s, 2H), 2.07-2.22 (m, 1H), 1.95-2.07 (m, 2H), 1.61-1.79 (m, 3H).
Reaction SMILES: N12CCCN=C1CCCCC2.[C:12]([OH:16])(=[O:15])[C:13]#[CH:14].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>C(Cl)Cl>[C:12]([O:16][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)(=[O:15])[C:13]#[CH:14]
Reactant: C#CC(=O)O
Reactant: COc1ccc(CCl)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C#CC(=O)OCc1ccc(OC)cc1
Reaction time: 2 h

Procedure:
64 ml (0.43 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to a solution of 26.4 ml (0.43 mol) of propiolic acid in 400 ml of methylene chloride at 25°, where required while cooling with ice. The mixture was stirred at 25° for 2 hours, then 56 ml (415 mmol) of 4-methoxybenzyl chloride were added and the mixture was finally stirred at 25° for a further 2 days. The reaction mixture was washed in succession with 200 ml of saturated sodium hydrogen carbonate solution and twice with 200 ml of water each time. The organic phase was dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent hexane/ethyl acetate 9:1). There was obtained 4-methoxybenzyl propiolate as a colorless oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([O:10][CH2:11][C:12]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH3:9])[CH:5]=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1.C[Si](C)(C)[C:37]([F:40])([F:39])[F:38].[F-].[K+].CN1CCCC1=O>CN(C)C=O.[Cu]I>[C:25]1([C:12]2([CH2:11][O:10][CH:8]([C:6]3[CH:5]=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=[C:2]([C:37]([F:40])([F:39])[F:38])[N:7]=3)[CH3:9])[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc(Br)n1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)n1
Temperature: 110 °C
Yield: 18 %

Procedure:
Tert-butyl 4-((1-(6-bromo-4-(trifluoromethyl)pyridin-2-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (100 mg, 0.18 mmol), trimethyl(trifluoromethyl)silane (70 mg, 0.46 mmol), potassium fluoride (70 mg, 1.2 mmol) and Copper(I) Iodide (100 mg, 0.525 mmol) were combined in dry dimethylformamide (1 mL) and dry N-Methyl-2-pyrrolidinone (1 mL) in a sealed tube. The mixture was heated to 110° C. for 2 hours. After cooling the reaction mixture was quenched with the addition of ammonia hydroxide (6M, 15 mL). The reaction was diluted with ether, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting oil was redissolved in methanol (2 mL) and treated with HCl (g) for 30 seconds. The solvent was evaporated and preparatory HPLC afforded 14 mg (15%) of desired product as the TFA salt. 1H-NMR (CD3OD, 400 MHz) δ 7.92 (s, 1H), 7.24-7.57 (m, 6H), 4.54 (q, 1H), 3.91 (d, 1H), 3.57 (m, 1H), 2.82-3.03 (m, 2H), 2.51-2.77 (m, 2H), 2.34-2.48 (m, 2H), 2.03-2.22 (m, 2H), 1.38 (d, 3H). LC: Tr=1.785 min, HPLC Method 1. Mass spec.: 433.35 (MH)+.
Reaction SMILES: [F:1][C:2]1[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2>C1COCC1.CO.[C].[Pd]>[F:1][C:2]1[C:3]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: COC(=O)/C=C/c1c(F)cc2nn(C)cc2c1C(=O)OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCc1c(F)cc2nn(C)cc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.4 %

Procedure:
To a solution of methyl 6-fluoro-5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-2-methyl-2H-indazole-4-carboxylate (430 mg, 21.47 mmol) in THF/methanol (5 mL/5 mL) was added palladium-carbon powder (86 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (407 mg, yield 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]1[CH2:31][C@@H:30]([NH2:32])[C@H:29]([NH2:33])[CH2:28][CH2:27]1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:32][CH:30]1[CH2:31][CH2:26][CH2:27][CH2:28][CH:29]1[NH2:33])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: NC1CCCCC1NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), (-)-R,R-1,2-diaminocyclohexane (0.314 g, 2.75 mmol), triethylamine (0.306 g, 3.06 mmol) and benzene (30 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-aminocyclohexyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.110 g, 8.4% yield).
Reaction SMILES: [OH-].[K+].[NH:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[CH2:10]([O:17][CH2:18]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(C(C)=O)C(C)C.COCCOCCN(CCOCCOC)CCOCCOC>[CH2:10]([O:17][CH2:18][N:5]1[C:6](=[O:8])[CH2:7][NH:3][C:4]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCOCc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=C1CNC(=O)N1COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
In 5 ml of methyl isobutyl ketone were suspended 216 mg (3.85 mmoles) of potassium hydroxide and 73 mg (0.226 mmoles) of tris[2-(2-methoxyethoxy)ethyl]-amine followed by addition of 900 mg (8.99 mmoles) of imidazolidine-2,4-dione, and the mixture was stirred at room temperature for 10 minutes. Then, 704 mg (4.50 mmoles) of benzyloxymethyl chloride was added dropwise at 0° C. and the mixture was stirred at room temperature for 3 hours. To this reaction mixture was added water and the organic layer was separated and washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel chromatography (eluent: hexane:ethyl acetate =1:1) to give 687 mg (3.12 mmoles) of 3-benzyloxymethylimidazolidine-2,4-dione. Yield 70% (based on benzyloxymethyl chloride) 1H-NMR, δ(CDCl3): 3.90 (2H, s), 4.60 (2H, s), 5.05 (2H, s), 6.00-6.20 (1H, brs, -NH), 7.20-7.45 (5H, m)