Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[C:11]1([NH:10][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)CCCCCBr
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Product: O=C(CCCCCBr)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromohexanoyl chloride (1.00 mL, 6.53 mmol) in THF (35 mL) at 0° C. was added dropwise a solution of aniline (0.60 mL, 6.53 mmol) and TEA (1.09 mL, 7.84 mmol) in THF (5 mL) The reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. The mixture was filtered, the solids rinsed with EtOAc, and the filtrate reduced under vacuum. The residue was partitioned between H2O (15 mL) and EtOAc (20 mL) and the layers separated. The aqueous portion was extracted with EtOAc (3×10 mL) and the organic layers combined, washed with HCl (1 N), brine, dried over MgSO4, and filtered. Concentration under reduced pressure left a brown oil which was passed through a plug of silica gel (30% EtOAc/hexanes) under aspiration. Concentration under reduced pressure left 67 as a solid (1.55 g, 5.74 mmol, 88%). TLC Rf 0.36 (25% EtOAc/hexanes); 1H-NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.57 (d, 2H), 7.27 (t, 2H), 7.01 (t, 1H), 3.53 (t, 2H), 2.30 (t, 2H), 1.81 (t, 2H), 1.63 (m, 2H), 1.42 (m, 2H); MS (ESI+) calcd for C12H16BrNO 268+270. found 269+271 [M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:24]=3)[N:19](C3CCCCO3)[N:18]=2)=[O:16])[CH:9]=1.C([SiH](CC)CC)C>C(Cl)Cl>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:24]=3)[NH:19][N:18]=2)=[O:16])[CH:9]=1
Reactant: O=C(Nc1cccnc1)c1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccnc1)c1n[nH]c2ccc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
TFA (5.0 mL) was added to a solution of N,5-di(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (CXXXIV) (0.36 g, 0.90 mmol) and triethylsilane (0.29 mL, 1.81 mmol) in DCM (5.0 mL) The solution was stirred overnight at room temperature. An additional 5.0 mL of TFA was added, and the solution was again stirred overnight. The solvents were removed, and the residue was treated with 7 N ammonia in MeOH. The solvents were again removed, and the product was purified by flash chromatography using a 12 g Thomson normal phase silica gel cartridge (100% CHCl3→5:95 MeOH[7N NH3]:CHCl3) to afford N,5-di(pyridin-3-yl)-1H-indazole-3-carboxamide (4) (0.23 g, 0.73 mmol, 82% yield) as a white solid. 1H NMR (DMSO-d6) δ ppm 14.00 (s, 1H), 10.69 (s, 1H), 9.08 (d, J=2.0 Hz, 1H), 8.93 (d, J=2.0 Hz, 1H), 8.60 (dd, J=4.8, 1.3 Hz, 1H), 8.48-8.47 (m, 1H), 8.33-8.31 (m, 2H), 8.15-8.12 (m, 1H), 7.85-7.81 (m, 2H), 7.54-7.51 (m, 1H), 7.41-7.39 (m, 1H); ESIMS found for C18H13N5O m/z 316 (M+H).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH:27]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:31][C:32]([NH:26][C@H:23]2[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][CH:12]([C:11]4[C:6]5[CH2:5][CH2:4][O:3][C:7]=5[CH:8]=[CH:9][CH:10]=4)[CH2:13][CH2:14]3)[CH2:25][CH2:24]2)=[O:33])[CH2:30][CH2:29][CH2:28]1
Reactant: O=C(O)CC1CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1CCC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (53 mg, 50%), MS (ISP) m/z=425.3 [(M+H)+], mp 196° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and 2-cyclobutyl-acetic acid.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][CH2:4][OH:5].C[C:13]([OH:22])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])CC>>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][CH2:4][O:5][C:13](=[O:22])[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCCCCCC(C)CCO
Reactant: CCCCCCC(C)(O)CC
Product: CCCCCCC(C)CCOC(=O)C1CCCCC1

Procedure:
The procedure in Example XIX is followed except that 39 g. of 3-methylnonan-1-ol instead of 40 g. of 3-methylnonan-3-ol are brought into the reaction.
Reaction SMILES: N1C=CN=C1.[CH2:6]1[CH2:18][O:17][C:8]([CH3:16])([CH2:9][CH2:10][CH2:11][CH:12]([CH3:15])[CH2:13][OH:14])[O:7]1.[Si:19](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[O:14]([CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10][CH2:9][C:8]1([O:7][CH2:6][CH2:18][O:17]1)[CH3:16])[Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(CO)CCCC1(C)OCCO1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(CCCC1(C)OCCO1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Imidazole (26.5 g) is added to a solution of 6,6-ethylenedioxy-2-methyl-heptanol (33.35 g) in dimethylformamide (50 ml). A solution of t-butyldiphenylsilyl chloride (52.2 g) in dimethylformamide (200 ml) is added dropwise to the reaction mixture and allowed to stir for 3 hours at room temperature. The reaction mixtures is extracted with hexane (3X300 ml) and the combined extract is washed with brine and dried (Na2SO4). The solvent is removed in vacuo to give 1-t-butyldiphenylsiloxy-6,6-ethylenedioxy-2-methyl-heptane (75.35 g, 99.6%; nmr (CDCl3,δ), 0.91 (d, 3H, CH3CH), 1.03 [s, (CH3)3C], 1.29 (s, ##STR58## 3.47 (d, CHCH2O), 3.88 (s, OCH2CH2O), 7.2-7.8 (m, 10H, 2φ).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[O:21][C:22]([CH2:25][N:26]([CH3:28])[CH3:27])=[CH:23][CH:24]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:29])[N:3]=1.B([C:33]1[CH:44]=[CH:43][C:36]([CH2:37][C@@H:38]([C:40]([OH:42])=[O:41])[NH2:39])=[CH:35][CH:34]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:39][C@@H:38]([CH2:37][C:36]1[CH:43]=[CH:44][C:33]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[O:21][C:22]([CH2:25][N:26]([CH3:28])[CH3:27])=[CH:23][CH:24]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:29])[N:3]=2)=[CH:34][CH:35]=1)[C:40]([OH:42])=[O:41]
Reactant: CN(C)Cc1ccc(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)o1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN(C)Cc1ccc(-c2ccccc2C(Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)o1
Temperature: 150 °C
Yield: 33.1 %

Procedure:
In a microwave vial, 4-chloro-6-{1-[2-(5-dimethylaminomethyl-furan-2-yl)-phenyl]2,2,2-trifluoro-ethoxy}-pyrimidin-2-ylamine (37 mg, 0.087 mmol), 4-borono-L-phenylalanine (22 mg, 0.10 mmol), 1 ml of actonitrile and 0.7 ml of water were mixed. Then, 0.3 ml of 1N aqueous sodium carbonate was added, followed by 5 mole percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep-LC to give 16 mg of (S)-2-amino-3-[4-{2-amino-6-{1-[2-(5-dimethylaminomethyl-furan-2-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidin-4-yl)-phenyl]-propionic acid. 1H NMR (400 MHz, CD3OD) δ (ppm) 7.88(d, J=8.4 Hz, 2H), 7.71(d, J=7.6 Hz, 1H), 7.62(d, J=7.6 Hz, 1H), 7.42(m, 2H), 7.40(d, J=1.6 Hz,2H), 7.34(d, J=8.4 Hz, 1H), 6.89(q, J=3.6 Hz,2H), 6.66(s, 1H), 4.54(s, 2H), 4.20(q, J=6 Hz, 1H), 3.3(m, 1H), 3.14(m, 1H), 2.84(s, 6H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([NH:54][C@H:55]([C:58](O)=[O:59])[CH2:56][OH:57])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>ClCCl>[C:44]([NH:54][C@H:55]([C:56]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:57])[CH2:58][OH:59])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Solvent: ClCCl
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Yield: 76 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-L-serine. Yield 76%. [α]D =+20.3° (c=0.89, dichloromethane). m.p. 87-89°.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br.[NH2:18][C:19]1[N:28]=[C:27]([NH2:29])[C:26]2[C:21](=[N:22][CH:23]=[C:24]([CH2:30]Br)[N:25]=2)[N:20]=1.CO>C1COCC1>[NH2:18][C:19]1[N:28]=[C:27]([NH2:29])[C:26]2[C:21](=[N:22][CH:23]=[C:24]([CH2:30][N:15]3[C:16]4[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=4[O:8][C:9]4[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:25]=2)[N:20]=1
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(N)c2nc(CN3c4ccccc4Oc4ccccc43)cnc2n1
Reaction time: 0.17 h

Procedure:
NaH (60% oil suspension containing 51 mg, 2.0 mmol) was added to a stirred solution of phenoxazine (147 mg, 0.784 mmol) in dry THF (10 mL) at 0° C. under N2. After 10 min. 2,4-diamino-6-bromomethylpteridine hydrobromide (100 mg, 0.392 mmol) was added and the reaction mixture was allowed to come to room temperature and left to stir for 2 days. The excess NaH was decomposed with MeOH (1 mL), and the mixture was concentrated to dryness by rotary evaporation. Flash chromatography on silica gel yielded the title compound, N-[(2,4-diaminopteridin-6-yl)methyl]phenoxazine, as a brown solid; yield 47 mg (34%); mp >250° C. dec. Anal. Calcd. for C19H15N7O0.4H2O: C, 62.60; H, 4.37. Found: C, 62.84; H, 4.10.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1N.N([O-])=O.[Na+].C(O)C>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(F)cc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
A mixture of 2-bromo-4-fluoro-6-nitrophenylamine (55 g, 234 mmol) in 50% sulphuric acid (500 mL) was cooled to 0° C. then treated dropwise with a solution of sodium nitrite (22.6 g, 328 mmol) in water (100 mL) keeping the internal temperature <5° C. Following the addition of the sodium nitrite the reaction was stirred at <5° C. for 1 h. Ethanol (75 mL) was then added followed by ferrous sulfate heptahydrate (32.5 g, 117 mmol) and the reaction stirred at ambient temperature for 2 h. The reaction was diluted with water (1 L) and extracted with dichloromethane (2×500 mL). The organics were combined, washed with saturated aqueous sodium hydrogencarbonate, water and brine, then dried for 1 h over anhydrous magnesium sulfate containing decolorizing charcoal (5 g). Filtration through glass micro-fibre filter paper (Whatman GF/A) and evaporation to dryness gave an oil which on standing furnished 1-bromo-3-fluoro-5-nitrobenzene as colourless crystals (50 g, 97%): δH (360 MHz, CDCl3) 7.61 (1H, ddd, J 8, 2 and 2), 7.90 (1H, ddd, J 8, 2 and 2), 8.20-8.23 (1H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)/[C:7]1=[O:23])=[O:5])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[N:32][C:33]([O:35][Si](C)(C)C)=[CH2:34])[CH:28]=[CH:29][CH:30]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C@:8]2([C@@H:16]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:35][C:33](=[O:34])[NH:32][C@H:31]2[C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=2)[C:7]1=[O:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C(=O)/C(=C\C2CCCCC2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)[C@]2(c3ccc(Cl)cc31)[C@@H](C1CCCCC1)CC(=O)N[C@H]2c1cccc(Cl)c1
Yield: 32 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-cyclohexylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.40 g, 1.20 mmol) was reacted with 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b, in toluene to give racemic ((2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclohexyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow oil (Yield 0.2 g, 32%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[CH:10]=[C:9]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:8]=[N:7]1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[CH:10]=[C:9]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:13]=2[CH3:23])[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)cn1
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)Cn1cc(Sc2c(C)n(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)cn1

Procedure:
Prepared according to the procedure described in Example 9, Step 4, using the following starting materials: [4-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-pyrazol-1-yl]-acetic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[C:8](=[O:14])[NH:9][C:10]([SH:13])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:17]O>[H-].[Na+]>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[C:8](=[O:14])[NH:9][C:10]([S:13][CH3:17])=[N:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=c1[nH]c(S)ncc1Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CSc1ncc(Oc2ccc(Cl)cc2)c(=O)[nH]1
Temperature: 60 °C
Yield: 88 %

Procedure:
Idomethane (Aldrich) (2.8 mL. 45 mmoles) was added to a solution of 5-(4-chlorophenoxy)-2-(mercapto)pyrimidine-4(3H)-one (10.24 g, 40 mmoles) in methanol (52 mL) and 1.0 N aqueous sodium hydride (40 mL). The resultant mixture was stirred at ambient temperature for 5.5 hours, then heated at 60° C. for 30 minutes. The mixture was spin evaporated in vacuo to give a solid, which was triturated with ice-water and then collected by suction filtration. Half of the light brown solid was recrystallized from ethyl acetate and half from ethanol to give 7.06 g (88% yield) of 5-(4-chlorophenoxy)-2(methylmercapto)pyrimidin-4-(3H)-one as a fluffy off-white solid, mp 232-233° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7](=[O:13])[CH2:8][NH:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=[CH:3]1.[Br:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:14][CH2:15][CH2:16][CH2:17][N:9]1[CH2:8][C:7](=[O:13])[C:6]2[N:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[S:10]1(=[O:12])=[O:11]
Reactant: BrCCCBr
Reactant: Cn1ccc2c1C(=O)CNS2(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1ccc2c1C(=O)CN(CCCBr)S2(=O)=O
Yield: 34.1 %

Procedure:
A suspension of 500 mg (2.5 mmol) of Compound 13, 2.5 g (12.5 mmol) of 1,3-dibromopropane and 690 mg (5 mmol) of potassium carbonate in 25 ml of acetone was refluxed for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: ethyl acetate/methylene chloride=1/40), whereby 274 mg of the title compound were obtained (yield: 34%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[F:9][C:10]([F:25])([F:24])[C:11]1[CH:12]=[C:13]([C:17]2[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1>>[F:25][C:10]([F:9])([F:24])[C:11]1[CH:12]=[C:13]([C:17]2[O:21][C:20]([CH:22]=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[OH:8])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(-c2cccc(C(F)(F)F)c2)o1
Reactant: Nc1ccccc1O
Product: Oc1ccccc1N=Cc1ccc(-c2cccc(C(F)(F)F)c2)o1

Procedure:
Using 2-Aminophenol and 5-(3-(trifluoromethyl)phenyl)furan-2-carbaldehyde, 3.44 g of 2-{[5-(3-(trifluoromethyl)phenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 86%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C[O:18][C:19]([C:21]1[N:22]=[CH:23][C:24]2[C:29]([C:30]=1[OH:31])=[CH:28][CH:27]=[C:26]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:25]=2)=O.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:16])[CH:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][NH:9][C:19]([C:21]1[N:22]=[CH:23][C:24]2[C:29]([C:30]=1[OH:31])=[CH:28][CH:27]=[C:26]([O:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:25]=2)=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C(CN)c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)C(CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)c1ccccc1
Temperature: 150 °C
Yield: 76.2 %

Procedure:
A mixture of 3-amino-2-phenyl-propionic acid tert-butyl ester (90 mg), 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (40 mg) and DBU (0.030 mL) in DMA (1 mL) was heated in an oil bath (150° C.) for 1.5 h. The reaction mixture was then partitioned between EtOAc and diluted HCl solution, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulfate solution, filtered, concentrated and silica gel column purified to give desired product as brown solid (50 mg). LC-MS ESI+: 485 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]([OH:37])[CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[N:26]=[C:25]([C:27]5[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=5)[O:24][N:23]=4)[CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[CH3:40]I.O>C1(C)C=CC=CC=1>[CH3:40][O:37][CH:13]([CH2:14][N:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[O:24][N:23]=2)[CH2:19][CH2:20]1)[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1
Reactant: CI
Reactant: Cc1nc2cc(OCC(O)CN3CCN(Cc4noc(-c5ccc(C(F)(F)F)cc5)n4)CC3)ccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(COc1ccc2sc(C)nc2c1)CN1CCN(Cc2noc(-c3ccc(C(F)(F)F)cc3)n2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 3-(2-methylbenzothiazol-5-yloxy)-1-[4-({5-[4-(trifluoromethyl)phenyl]-(1,2,4-oxadiazol-3-yl)}methyl)piperazinyl]propan-2-ol (0.10 g) in toluene (6 ml) was added to a suspension of sodium hydride (0.09 g) in toluene (2 ml) at 0° C. The mixture was stirred at 100° C. for 2 hours, then cooled to 0° C. Methyl iodide (0.14 ml) was then added, and the mixture stirred overnight at room temperature. After slow addition of water the mixture was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, and the solvent removed under reduced pressure. The residue was purified by flash chromatography (3% methanol in methylene chloride), to provide 5-{2-methoxy-3-[4-({5-[4-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)}methyl)piperazinyl]propoxy}-2-methylbenzothiazole (0.0075 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]1([NH:31][CH2:32][C:33]2[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]([O:41][CH3:42])[CH:34]=2)[CH2:30][CH2:29]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][C:33]2[CH:34]=[C:35]([O:41][CH3:42])[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=2)=[O:26])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(CNC2CC2)cc(OC)c1
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: COc1cc(CN(C(=O)CN(c2cccc(N(C)C)c2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)cc(OC)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with cyclopropyl-(3,5-dimethoxy-benzyl)-amine
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:7][C:6](=[O:8])[C:5]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=1.CCN(CC)CC.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([NH:1][CH2:2][C:3]1[NH:7][C:6](=[O:8])[C:5]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(CN)NC2=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC1=NC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1
Reaction time: 0.33 h
Yield: 87 %

Procedure:
tert-Butyl 2-(aminomethyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (1E) in CH2Cl2 (150 mg, 0.05 M), prepared by the procedure of Example 1, was added Et3N and acetyl chloride at −45° C. The reaction was complete after 20 minutes at −30° C. as determined by LCMS analysis, and then partitioned between ethyl acetate and water. The organics were subsequently washed with NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was passed thorough a pad of silica to afford the tert-butyl 2-(acetamidomethyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (2A, 87%).