Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.O>[CH3:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[O:1][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][C:9]2=[O:11]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1cc(C)ccc1O
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)C(=O)CC(c1ccccc1)O2
Yield: 34 %

Procedure:
A mixture of 1-(2-hydroxy-5-methyl-phenyl)-ethanone (15 g, 0.10 mol), benzaldehyde (10.6 g, 0.10 mol) and borax (38 g, 0.10 mol) in ethanol (90 mL) and H2O (150 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ether. The ether was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-methyl-2-phenyl-chroman-4-one (8.1 g, 34%). 1H-NMR (CDCl3): 2.32 (s, 3H), 2.86 (d, 1H), 3.06 (t, 1H), 5.44 (d, 1H), 6.96 (d, 1H), 7.38 (d, 1H), 7.44 (m, 5H), 7.71 (s, 1H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH:12]([CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][N:6]=2)=[O:26])=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Cl)cc2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(CO)cn1)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 16.6 %

Procedure:
A solution of 6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester (prepared as in Example 31(B)(c), 83.3 mg, 0.21 mmol) in tetrahydrofuran (2.1 mL) was added to a cooled (0° C.) slurry of lithium aluminum hydride (12.0 mg, 0.32 mmol) in tetrahydrofuran (1.54 mL). The reaction mixture was stirred at 0° C. for 2.5 h. The reaction was then quenched by the dropwise addition of water (25 mL). The reaction was further diluted with water and was then extracted with ethyl acetate (3×35 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-propionamide (12.5 mg, 16.1%) as a white solid: mp 60-62° C.; EI-HRMS m/e calcd for C20H23ClN2O2(M+) 358.1448, found 358.1443.
Reaction SMILES: [CH2:1]([C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@@H:5]([C:16]([OH:18])=[O:17])[NH:4]1)[CH3:2].C([C@H]1C2NC3C(=CC=CC=3)C=2C[C@H](C(OC)=O)N1)C.[OH-].[Na+]>CO>[CH2:1]([C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@H:5]([C:16]([OH:18])=[O:17])[NH:4]1)[CH3:2]
Reactant: CC[C@@H]1N[C@H](C(=O)O)Cc2c1[nH]c1ccccc21
Agent: CC[C@@H]1N[C@@H](C(=O)OC)Cc2c1[nH]c1ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@@H]1N[C@@H](C(=O)O)Cc2c1[nH]c1ccccc21

Procedure:
In the same manner as described above (1) using methyl (1RS,3SR)-trans-1-ethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (2.58 g), 1N NaOH (15 ml) and methanol (30 ml), there is obtained the title compound (1.50 g, 61.4%) as colorless needles, m.p. 242°-243° C. (recrystallized from aqueous methanol).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[C:5]([NH:6][CH3:7])=[C:4]([N+:15]([O-])=O)[CH:3]=1.[CH2:18]([N:20]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[CH:22]=[C:21]1[CH:29]=O)[CH3:19].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O.ClCCl>[Br:1][C:2]1[CH:9]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[C:5]2[N:6]([CH3:7])[C:29]([C:21]3[N:20]([CH2:18][CH3:19])[C:24]4=[N:25][CH:26]=[CH:27][CH:28]=[C:23]4[CH:22]=3)=[N:15][C:4]=2[CH:3]=1
Reactant: CNc1c(OC(F)(F)F)cc(Br)cc1[N+](=O)[O-]
Reactant: CCn1c(C=O)cc2cccnc21
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCn1c(-c2nc3cc(Br)cc(OC(F)(F)F)c3n2C)cc2cccnc21
Temperature: 80 °C
Reaction time: 17 h
Yield: 32.9 %

Procedure:
To a solution of 4-bromo-N-methyl-2-nitro-6-(trifluoromethoxy)aniline (1.368 g, 4.34 mmol) and 1-ethyl-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (0.756 g, 4.34 mmol) in ethanol (20 mL) was added sodium dithionite (2.67 g, 13.03 mmol) in water (10 mL). The mixture was flushed with nitrogen and then heated to 80° C. with stirring for 17 h. LCMS showed ˜52% conversion to the desired product with no starting material remaining. The reaction mixture was partitioned between aqueous hydrochloric acid (0.25 M, 100 mL) and extracted with dichloromethane (3×100 mL). The organics were combined, dried using a hydrophobic frit and evaporated under vacuum to give the crude product as a yellow solid. The sample was loaded in dichloromethane and purified by column chromatography on silica (100 g) using a gradient of 0-30% cyclohexane-ethyl acetate. The appropriate fractions were combined and evaporated in vacuo to give the required product (628 mg, 33%) as a yellow gum which solidified.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH2:11][N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[O:26])=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>CN(C=O)C.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]>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[N:13]4[CH:14]=[N:15][CH:16]=[C:12]4[CH2:11][N:10]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:9]3=[O:26])=[CH:4][CH:3]=2)=[CH:38][CH:37]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1ccc(CN2Cc3cncn3C(c3ccc(Br)cc3)C2=O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3cncn3C(c3ccc(-c4ccc(Cl)cc4)cc3)C2=O)cc1
Temperature: 95 °C

Procedure:
To a solution of the title compound of Example 21, 5-(4-bromo-phenyl)-7-(4-methoxy-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one (0.125 g, 0.30 mmol) in DMF (2 mL) is added potassium phosphate (0.129 g, 0.61 mmol) and 4-chlorophenyl boronic acid (0.057 g, 0.36 mmol) followed by [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) (0.025 g, 10 mol %). The reaction mixture is degassed, purged with nitrogen then heated at 95° C. for 5 h. The reaction mixture is partitioned between water and EtOAc. The combined organic phases are washed with brine, dried (anhydrous sodium sulfate) and concentrated. The residue is subjected to flash chromatography (silica) eluting with EtOAc: MeOH:NH4OH (90:10:1) to give 5-(4′-chlorobiphenyl-4-yl)-7-(4-methoxy-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one which is dissolved in diethyl ether and treated with HCl(g)-MeOH and the precipitated product, 5-(4′-chlorobiphenyl-4-yl)-7-(4-methoxy-benzyl)-7,8-dihydro-imidazo[1,5-a]pyrazin-6-one hydrochloride is collected by filtration and dried: m.p. 270-273° C.; 1H-NMR (DMSO-d8) δ 9.19 (1H, s), 7.73 (5H, m), 7.54 (2H, d, J=8.3), 7.37 (2H, d, J=8.3), 7.22 (2H, d, J=8.6), 6.90 (2H, d, J=8.6), 6.49 (1H, s), 4.67 (4H, m), 3.73 (3H, s); 13C-NMR (DMSO-d6) 163.0, 158.8, 139.6, 137.9, 134.4, 133.9, 132.7, 129.4, 128.9, 128.5, 127.6, 127.4, 124.7, 115.3, 114.0, 60.8, 55.0, 48.9; e/z (ES) 444 (M+1, 100%); calculated for C26H22N3O2Cl HCl, C, 65.01; H, 4.83; N, 8.75. found C, 64.64; H, 4.78; N, 8.74.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9]/[CH:10]=[C:11]2\[C:12](=[O:23])[NH:13][C:14](=[O:22])[C:15]3[C:20]\2=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]=1[NH:24][C:25](=[O:30])/[C:26](/[CH3:29])=[CH:27]/C.NC1C=CC([CH2:36][NH:37]/[CH:38]=C2\C(=O)NC(=O)C3C\2=CC(I)=CC=3)=CC=1O[Si](C(C)C)(C(C)C)C(C)C.CN(CC(=C)C(O)=O)C>>[CH3:36][N:37]([CH2:29][C:26](=[CH2:27])[C:25]([NH:24][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][NH:9]/[CH:10]=[C:11]2\[C:12](=[O:23])[NH:13][C:14](=[O:22])[C:15]3[C:20]\2=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)=[CH:7][C:2]=1[OH:1])=[O:30])[CH3:38]
Reactant: C/C=C(\C)C(=O)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Reactant: CC(C)[Si](Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)ccc1N)(C(C)C)C(C)C
Agent: C=C(CN(C)C)C(=O)O
Product: C=C(CN(C)C)C(=O)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O

Procedure:
Following the acetylation and desilylation procedure employed for the preparation of (2E)-N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]-2-methylbut-2-enamide, (4Z)-4-[({4-amino-3-[(triisopropylsilyl)oxy]benzyl}amino)methylene]-6-iodoisoquinoline-1,3(2H,4H)-dione (65 mg, 0.11 mmol) is reacted with acid chloride derived from 2-dimethylaminomethyl acrylic acid (Wissner, A.; Overbeek, E.; Reich, M. F.; Floyd, M. B.; Johnson, B. D.; Mamuya, N.; Rosfjord, E. C.; Discafani, C.; Davis, R.; Shi, X.; Rabindran, S. K.; et al. J. Med. Chem. 46; 1; 2003; 49-63, 0.18 g, 1.1 mmol). Following desilylation and precipitation, 2-[(dimethylamino)methyl]-N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]acrylamide is obtained as a solid (19 mg, 32%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:14])[CH2:10][CH2:11][CH2:12]O>ClCCCl.C(Cl)(Cl)Cl.CC(O)C.F[Sb-](F)(F)(F)(F)F.[Ag+].[Pt](Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:10][CH2:11][CH2:12][O:14]1
Reactant: OCCCC(O)c1ccc(F)cc1Br
Agent: Cl[Pt]Cl
Agent: [Ag+]
Agent: F[Sb-](F)(F)(F)(F)F
Solvent: CC(C)O
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: Fc1ccc(C2CCCO2)c(Br)c1
Temperature: 110 °C
Yield: 77.3 %

Procedure:
Combine 1-(2-bromo-4-fluoro-phenyl)-butane-1,4-diol (1 g, 3.8 mmol), silver (I)hexafluoroantimonate (131 mg, 0.4 mmol), platinum(II) chloride (40 mg, 0.2 mmol) in 1,2-dichloroethane (10 mL) in a pressure tube. Seal the tube and heat the mixture overnight at 110° C. Dilute the mixture with chloroform-IPA (3:1, 100 mL). Wash the organic phase with aqueous saturated sodium chloride and water. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (20% ethyl acetate in hexane) to give the title compound as a pale yellow oil (0.72 g, 77%).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:21](Cl)[C:22]#[CH:23]>O.CN(C)C=O>[CH2:23]([O:12][C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[N:4][N:3]=[N:2]2)=[N:11][CH:10]=1)[C:22]#[CH:21]
Reactant: Oc1ccc(-n2cnnn2)nc1
Reactant: C#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1ccc(-n2cnnn2)nc1
Temperature: 80 °C

Procedure:
To a flask under N2 fitted with a reflux condenser was added 6-tetrazol-1-yl-pyridin-3-ol (2.25 g, 13.7 mmol) and N,N-dimethylformamide (8.2 mL). Potassium carbonate (3.79 g, 27.4 mmol, 2 eq.), potassium iodide (0.143 g, 0.86 mmol, 0.06 eq.) and propargyl chloride (1.98 mL, 17.9 mmol, 1.3 eq.) were added and heated at 80° C. for three hours. The reaction was cooled to room temperature and 10 mL of water was added to affect precipitation. The solid was filtered off, washed with water and dried overnight. The expected product was used in the next step without further purification. 1H NMR (DMSO-d6): δ 10.08 (1H, s), 8.36 (1H, d, J=3.0 Hz), 8.01 (1H, d, J=9 Hz), 7.79 (1H, dd, J=3.0, 9.0 Hz), 5.01 (2H, s), 3.71 (1H, s).
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1)=O.[CH:16]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)C.[BH4-].[Na+]>O>[CH:16]1([NH:23][CH2:1][C:3]2[CH:15]=[CH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6][C:5]=3[CH:4]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Reactant: NC1CCCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc2c(c1)Cc1cc(CNC3CCCCCC3)ccc1-2
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
2-Formylfluorene (2.27 g, 11.7 mmol) and cycloheptylamine (1.39 g, 12.3 mmol) were heated together at 120° C. for 14 hrs. After cooling, the reaction mixture was distilled under reduced pressure. Then, ethanol (30 ml) and sodium borohydride (0.44 g, 11.7 mmol) were added to the residue and the mixture was stirred for 0.5 hr. The mixture was then diluted with water (100 ml) and extracted with chloroform (80 ml×2 times). The organic layer was dried over anhydrous magnesiumsulfate. The solvent was then distilled off under reduced pressure to give 3.15 g of a pale yellow solid residue.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][NH2:19]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:19][CH3:18])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CNc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 4-bromo-1-fluoro-2-nitrobenzene (6 g, 27.27 mmol) in dichloromethane (100 ml) was added potassium carbonate (7.5 g, 54.27 mmol). This was followed by the addition of CH3NH2 (20 ml, 33% aqueous), which was added dropwise with stirring at room temperature. The resulting solution was stirred for 2 h at room temperature, extracted with dichloromethane (2×200 ml), and the organic layers combined and concentrated under vacuum to afford 4-bromo-N-methyl-2-nitroaniline as a red solid (6.1 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Reactant: COc1ccc(CBr)cc1
Product: COc1ccc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)cc1
Yield: 35 %

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-(bromomethyl)-4-methoxybenzene. Yield 35%, colorless gel (195 mg, 35%). 1H NMR (DMSO-d6, 400 MHz): . s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 3.71 (s, 3H), 4.48 (s, 2H), 5.18 (s, 2H) 6.87 (d, J=8.8 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.80 (s, 1H), 8.18 (s, 1H). MS 424 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an 1050 of 0.11 μM.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:22][C:23]1[CH:24]=[C:25]([C:33]([OH:35])=O)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:32])[CH3:31].O[NH:37]/[C:38](=[N:55]\[H])/[C:39]1[CH:47]=[C:46]2[C:42]([C:43]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:44][NH:45]2)=[CH:41][CH:40]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:22][C:23]1[CH:24]=[C:25]([C:33]2[O:35][N:55]=[C:38]([C:39]3[CH:47]=[C:46]4[C:42]([C:43]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:44][NH:45]4)=[CH:41][CH:40]=3)[N:37]=2)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:31])[CH3:32]
Reactant: CC(C)Oc1ncc(C(=O)O)cc1F
Reactant: [H]/N=C(\NO)c1ccc2c(CCC(=O)OCC)c[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4cnc(OC(C)C)c(F)c4)n3)ccc12
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
EDCI (385 mg) and HOBT (330 mg) were added to a solution of 5-fluoro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (200 mg) in THF (5 mL) at RT. The resulting solution was stirred for 30 mins. Ethyl 3-{6-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D107) (413 mg) in THF (5 mL) was added and the reaction mixture was stirred at RT for 2 hours. TBAF (1.1 g) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 2 hours. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography (15% EtOAc in hexane) to afford ethyl 3-[6-(5-{5-fluoro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D110) (60 mg) as a pale yellow solid. MS (ES): C23H23FN4O4 requires 438; found 439.2 (M+H+).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([Cl:4])[CH:17]=[CH:16][C:15]=1[OH:20])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: Cc1ccccc1
Product: Oc1ccc(Cl)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sulfuryl chloride (0.965 ml) was added to a stirred solution of 2-(benzyloxy)phenol (2.0 g) in dry toluene (20 ml) at 0° C. The mixture was warmed to RT and stirred overnight then cooled to 0° C. and quenched with ice-water before extracting with ethylacetate. The organics were dried, evaporated under reduced pressure and the residue purified by chromatography on silica eluting with DCM/isohexane (1:1). Yield 1.5 g
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][S:2]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)(=[O:4])=[O:3]
Reactant: OCCCCCCCOC1CCCCO1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.32 ml of methanesulfonyl chloride dissolved in 10 ml of benzene was added dropwise, whilst ice-cooling, to a solution of 4.32 g of 7-(tetrahydropyran-2-yloxy)-1-heptanol and 5.56 ml of triethylamine dissolved in 80 ml of benzene. The mixture was stirred at room temperature for 1 hour, after which it was washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give 5.86 g of 7-(tetrahydropyran-2-yloxy)heptyl methanesulfonate, as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:21])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][CH:10]=1)[CH3:7])=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.CS(O)(=O)=O.[CH3:38][NH:39][C:40]([N:42]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=1)[NH2:43])=[O:41].N1C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:43][N:42]([CH2:44][C:45]2[CH:46]=[CH:47][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:49][CH:50]=2)[C:40]([NH:39][CH3:38])=[O:41])=[O:20])=[CH:13][CH:14]=1)[CH3:21])=[O:5])[CH3:2]
Reactant: CNC(=O)N(N)Cc1ccc(C(C)(C)C)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)NN(Cc2ccc(C(C)(C)C)cc2)C(=O)NC)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
4-[4-(1-Ethoxycarbonyl-1-methyl-ethoxy)-phenyl] butyric acid (0.89 g, 3.02 mmol) was dissolved in ethyl acetate (10 mL). Oxalyl chloride (316 μL, 3.62 mmol) was added to this solution dropwise in the presence of a catalytic amount of N,N-dimethylformamide (17 μL, 0.24 mmol). Completion of acid chloride formation was verified by HPLC. The solution was then concentrated to remove excess oxalyl chloride and then redissolved in ethyl acetate (7 mL). This solution was then added dropwise to a suspension of N-Methyl-1-(4-t-butylphenylmethyl)hydrazine carboxamide methanesulfonate (1.02 g, 3.07 mmol) and pyridine (256 μL, 6.14 mmol) in ethyl acetate (10 mL) at 0° C. After stirring at 0° C. for 3 h, an additional charge of pyridine (256 μL, 6.14 mmol) was added and the solution was stirred at 0° C. for 1 h. The solution was warmed to rt and washed with 1N HCl (2×10 mL) and then with 5% aq. NaHCO3 (2×10 mL). The organic layer was dried (MgSO4), filtered and concentrated to an orange oil. Column chromatography (SiO2, ethyl acetate) afforded the title compound as a clear oil (1.06 g, 68%): 1H NMR (DMSO-d6, 60° C.) δ 9.50 (s, 1H), 7.29 (d, 2H, J=8 Hz), 7.16 (d, 2H, J=8 Hz), 7.01 (d, 2H, J=8 Hz), 6.71 (d, 2H, J=8 Hz), 6.27 (br s, 1H), 4.52 (br s, 2H), 4.15 (q, J=7 Hz), 2.58 (d, 3H, J=4 Hz), 2.44 (t, 2H, J=7 Hz ), 2.07 (t, 2H, J=7 Hz ), 1.72 (quint, 2H, J=7 Hz), 1.48 (s, 6H), 1.25 (s, 9H), (1.17 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ 174.0, 172.0, 158.7, 153.8, 149.9, 135.9, 129.7, 128.7, 125.6, 119.5, 79.2, 61.6, 50.8, 34.8, 34.4, 33.4, 31.8, 27.7, 27.1, 25.7, 14.6.; IR (CHCl3) 3009, 2966, 1671, 1509, 1211 cm−1; Anal. Calcd. for C29H41N3O5: C, 68.08; H, 8.08; N, 8.21. Found:,C, 67.70; H, 7.86; N, 8.11.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][N:4]1[CH2:16][CH2:17][CH:18]=O.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:27]=[CH:26][C:25]([C@:28]23[CH2:33][C@H:32]2[CH2:31][NH:30][CH2:29]3)=[CH:24][CH:23]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClC(Cl)C.CO>[ClH:1].[ClH:1].[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[C:7](=[O:9])[NH:8][C:3](=[O:2])[N:4]([CH2:16][CH2:17][CH2:18][N:30]3[CH2:31][C@H:32]4[C@:28]([C:25]5[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:35])[F:34])=[CH:27][CH:26]=5)([CH2:33]4)[CH2:29]3)[CH:5]=2)[N:11]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: O=CCCn1cc(-c2cccnn2)c(=O)[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1-c1cccnn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
A solution of 3-(2,4-dioxo-5-pyridazin-3-yl-3,4-dihydro-2H-pyrimidin-1-yl)-propionaldehyde hydrochloride (Prep123, 100 mg, 0.35 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 80 mg, 0.35 mmol), and AcOH (21 mg, 0.35 mmol) in dichloroethane-MeOH (1-1, 4 ml) was cooled to 0° C. NaBH(AcO)3 (83 mg, 0.39 mmol) was added portionwise. The mixture was stirred at 0° C. for further one hour and then basified with 1N NaOH. The product was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The residue was redissolved in DCM and stirred for 72 hours in the presence of PS-isocyanate (300 mg). The mixture was filtered and the solvent evaporated. The crude was triturated with diethyl ether to give 20 mg the free base of title compound (12% yield).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13]>C1(C)C=CC=CC=1>[N+:12]([C:15]1[CH:16]=[C:17](/[CH:18]=[N:9]/[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=2)[CH:20]=[CH:21][CH:22]=1)([O-:14])=[O:13]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(/C=N/c2ccc(C(F)(F)F)cc2)c1
Yield: 100.2 %

Procedure:
A mixture of 4-trifluoromethyl-phenylamine (10.0 g, 62.06 mmol) and 3-Nitro-benzaldehyde (9.3 g, 62.06 mmol) in toluene was heated to reflux for 5 h with a Dean-stark trap. After evaporation of the toluene, the reaction mixture was heated for another 1 h at this temperature to afford 18.3 g of [1-(3-nitro-phenyl)-meth-(E)-ylidene]-(4-trifluoromethyl-phenyl)-amine. The mixture was used in next step without further purification.