Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:17][CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1)[C:3]([C:5]1[S:15][C:14]2[N:16]3[C:7](=[CH:8][N:9]=[C:10]3[CH:11]=[CH:12][CH:13]=2)[CH:6]=1)=[O:4].[ClH:31]>C(O)C>[ClH:31].[ClH:31].[CH3:1][N:2]([CH2:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:3]([C:5]1[S:15][C:14]2[N:16]3[C:7](=[CH:8][N:9]=[C:10]3[CH:11]=[CH:12][CH:13]=2)[CH:6]=1)=[O:4]
Reactant: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCO
Product: CN(CC1CCNCC1)C(=O)C1=Cc2cnc3cccc(n23)S1
Reaction time: 18 h

Procedure:
To a solution of 0.7716 g (1.8 mM) of N-methyl-N-(1-tert-butoxycarbonylpiperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide in ethanol (5 ml) was added 0.8 ml (9.6 mM) of 12N-hydrochloric acid at room temperature and the mixture was stirred for 18 hours. The solvent was then distilled off under reduced pressure, and 2 ml (24 mM) of 12N-hydrochloric acid was added to the residue. The mixture was stirred for 5 minutes, after which ethanol was added and the solvent was distilled off under reduced pressure. To the residue was further added ethanol and the ethanol, was distilled off under reduced pressure. The resulting crystals were collected by filtration and rinsed serially with ethanol, acetone, and diethyl ether to provide the title compound.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][O:13][CH:14]([O:23][CH3:24])[C:15]1[CH:16]=[C:17]([Br:22])[C:18]([CH3:21])=[N:19][CH:20]=1.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH3:24][O:23][CH:14]([O:13][CH3:12])[C:15]1[CH:16]=[C:17]([Br:22])[C:18]([CH3:21])=[N+:19]([O-:9])[CH:20]=1
Reactant: COC(OC)c1cnc(C)c(Br)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(OC)c1cc(Br)c(C)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
m-CPBA (242 mg, 1.052 mmol) was added to a suspension of 5-[bis(methyloxy)methyl]-3-bromo-2-methylpyridine (129.5 mg, 0.526 mmol) and NaHCO3 (133 mg, 1.579 mmol) in DCM (5 ml). The mixture was stirred at room temperature overnight. To the resulting white suspension was added DCM and 1N NaOH. The organic phase was extracted twice,
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:15][CH:16]([OH:19])[C:17]#[CH:18].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.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.[Cu]I>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:2]([C:18]#[C:17][CH:16]([OH:19])[CH3:15])=[CH:7][N:6]=1
Reactant: C#CC(C)O
Reactant: CCC(CC)Nc1nc(Cl)ncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(CC)Nc1nc(Cl)ncc1C#CC(C)O
Temperature: 55 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a mixture of (5-bromo-2-chloro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (0.44 g, 1.58 mmol), Pd(Ph3P)2Cl2 (0.11 g, 0.16 mmol), and CuI (0.03 g, 0.16 mmol) in DMF (14 mL) is added 3-butyn-2-ol (0.19 mL, 2.37 mmol) and triethylamine (0.44 mL, 3.16 mmol). The reaction mixture is stirred at 55° C. for 16 h, diluted with CH2Cl2, filtered through a pad of Celite, and concentrated in vacuo. Purification by flash chromatography (SiO2, EtOAc/Hexane 1:3) gave 0.23 g of 4-[2-chloro-4-(1-ethyl-propylamino)-pyrimidin-5-yl]-but-3-yn-2-ol as yellowish oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:12]4[CH2:13][C:14]5[S:15][CH:16]=[CH:17][C:18]=5[C:11]=4[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=3)=[CH:4][CH:3]=2)[CH2:30][CH2:29]1
Reactant: CN1CCNCC1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sccc3-4)cc2)CC1
Temperature: 100 °C
Yield: 39 %

Procedure:
A mixture of the corresponding 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.7 g, 1.5 mmol), 1-Methyl-piperazine (0.2 g, 3 mmol), Cs2CO3 (2 M, 1.5 mL), Xantphos (180 mg, 0.06 mmol) and Pd(OAc)2 (70 mg, 0.06 mmol) in toluene/ethanol (1:1, 10 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give 6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 39% yield.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.COC(=O)[C:31]1C=CC(OCC2C(C3C=CC(Cl)=CC=3)=NOC=2C)=[N:33][CH:32]=1.C(N)C>>[CH2:32]([NH:33][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:18])([F:19])[F:20])=[N:6][CH:5]=1)[CH3:31]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Agent: CCN
Product: CCNC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1

Procedure:
As described for example 117, 6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.26 mmol), 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (144 mg, 0.4 mmol) was converted, using ethylamine (2 M in THF) instead of 2,2,2-trifluoroethylamine, to the title compound (80 mg, 77 which was obtained as a white solid. MS: m/e=392.3 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[C:14]4[C:19]([CH2:20][C:8]=3[C:7]=2[CH:6]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C.O.[OH-].[Na+]>FC(F)(F)C(O)=O>[C:1]([C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C@@H:9]3[C:14]4[C:19]([CH2:20][C@@H:8]3[C:7]=2[CH:6]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2[nH]c3c(c2c1)Cc1ccccc1-3
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)c1ccc2c(c1)[C@H]1Cc3ccccc3[C@H]1N2
Reaction time: 8 h

Procedure:
A solution of 5,10-dihydro-8-tert-butylindeno[1,2-b]indole (0.57 g, 2.2 mM) in trifluoroacetic acid (5 cm3) was stirred rapidly, and triethylsilane (0.7 cm3, 2 eq ) added in one portion. The reaction was stirred overnight, poured into water (10 cm3) and neutralised by the addition of sodium hydroxide. The product was extracted into diethyl ether (2×5 cm3), and the combined extracts were washed with water, dried (Na2SO4) and evaporated to yield a pink solid. This was washed with cold petroleum ether (60°-80° C.), and then crystallised from petrol to yield a colourless solid. Yield: 0.47 g, 81% M.p. 103°-105° C.; 1H NMR (CDCl3) δ: 7.4-6.9 (6H, m), 6.58 (1H, d, J=8 Hz), 5.25 (1H, d, J=8.5 Hz), 4.15 (2H, br.m), 3.5 (1H, dd, J=16.0 and 9 Hz), 3.2 (1H, d, J=16 Hz), 1.2 (9H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24](O)=[O:25])[N:21]=2)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O[NH:52][C:53](=[NH:55])[CH3:54]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]3[O:25][N:55]=[C:53]([CH3:54])[N:52]=3)[N:21]=2)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Reactant: CC(=N)NO
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(CCc2csc(Nc3ncc(Br)cc3OCc3ccccc3)n2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
To a mixture of 3-(2-(3-(benzyloxy)-5-bromopyridin-2-ylamino)thiazol-4-yl)propanoic acid (0.200 g, 0.461 mmol), N,N-diisopropylethylamine (0.0882 ml, 0.507 mmol) in DMF (5 mL) at ambient temperature was added N-((dimethylamino)fluoromethylene)-N-methylmethanaminium hexafluorophosphate(V) (0.122 g, 0.461 mmol). The mixture was stirred for 30 minutes at ambient temperature, and then N-hydroxyacetamidine (0.0375 g, 0.507 mmol) was added in one portion. The reaction mixture was heated at 110° C. overnight and then cooled to ambient temperature. Ethyl acetate was added and the organic layer was washed with water. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a residue that was purified on a silica gel column, eluting with 40% EtOAc/Hexanes. The isolated material was recrystallized from EtOAc/Hexanes and dried under high vacuum to afford 3-(benzyloxy)-5-bromo-N-(4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)thiazol-2-yl)pyridin-2-amine (0.110 g, 50% yield) as a tan solid. 1H NMR (DMSO-d6) δ 2.30 (s, 3H), 3.05 (t, J=7.6 Hz, 2H), 3.26 (t, J=7.6 Hz, 2H), 5.29 (s, 2H), 6.73 (s, 1H), 7.35 (t, J=7.2 Hz, 1H), 7.42 (t, J=7.2 Hz, 2H), 7.58 (s, 1H), 7.60 (s, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H), 10.32 (s, 1H); Mass Spectrum (apci) 472 (M+H).
Reaction SMILES: C[O:2]C1C=CC(C(O)=O)=CC=1[N+]([O-])=O.ON1C(=O)CCC1=O.[CH:23]1([N:29]=[C:30]=[N:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[CH:32]1([NH:31][C:30]([NH:29][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:2])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
1.97 g (10 mmoles) of 4-methoxy-3-nitrobenzoic acid was dissolved in 50 ml of acetonitrile. 1.15 g (10 mmoles) N-hydroxysuccinimide was added with agitation. Finally 2.063 g (10 mmoles) of N,N′-dicyclohexylcarbodiimide were added and the mixture agitated. After 2 hours at approx. 20° C. a precipitate of dicyclohexyl-urea had formed. The solution was filtered through a Gooch 3G funnel. The formation of ester was determined by t.l.c. of the filtrate (CHCl3/MeOH=9:1, v/v). Observation under U.V. revealed the ester as a dark spot of Rf approx. 0.9. After evaporation of the acetonitrile a whitish-yellow powder remained in the flask. The powder was redissolved in 50 ml of hot isopropanol. Approximately 2 spatula-tips activated charcoal were added and the solution was boiled in a boiling water-bath for about 5 minutes. The boiling solution was quickly poured through a sintered glass filter (G4, previously heated by a passage of hot isopropanol) into a hot flask. The solution was allowed to cool down overnight. White, needle-like crystals were formed (m.p. approx. 145-152° C.) having the expected t.l.c. properties.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[N:36]=[CH:35][C:34]3[C:29](=[C:30]([F:41])[CH:31]=[C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:33]=3)[C:28]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[N:23]([CH3:24])[N:22]=[N:21][CH:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:37]([C:32]1[CH:33]=[C:34]2[C:29](=[C:30]([F:41])[CH:31]=1)[C:28](=[O:42])[N:27]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[N:23]([CH3:24])[N:22]=[N:21][CH:20]=4)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:36]=[CH:35]2)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cnnn3C)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cn1nncc1Nc1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cn(C)c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
A mixture of 154c (85 mg, 0.15 mmol) and lithium hydroxide (36 mg, 1.5 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted diluted with water (5 mL). It was then with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford the title compound (11 mg, 16%) as a white solid. MS-ESI: [M+H]+ 531.4. 1H NMR (500 MHz, DMSO-d6) δ 8.54-8.53 (m, 2H), 8.03 (s, 1H), 7.91 (d, J=1.5 Hz, 1H), 7.80-7.76 (m, 1H), 7.75 (s, 1H), 7.55 (d, J=2.5 Hz, 1H), 7.52 (d, J=5.0 Hz, 1H), 6.89 (d, J=2.5 Hz, 1H), 5.04 (t, J=5.0 Hz, 1H), 4.34 (d, J=5.0 Hz, 2H), 3.88 (s, 3H), 3.63 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1CCCC1=O>[C:12]([NH:8][NH:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNC(=O)c1cccc(Br)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(NNC(=O)c1cccc(Br)c1)c1ccccc1
Yield: 96 %

Procedure:
Next, 5.0 grams (23 mmol) of the 3-bromobenzoylhydrazine obtained in (i) were placed into a 300 mL, three-neck flask, 10 mL of N-methyl-2-pyrrolidone was added thereto, and the mixture was stirred. A mixed solution of 10 mL of N-methyl-2-pyrrolidone and 3.2 mL (28 mmol) of benzoyl chloride were dripped into this mixture through a 50 mL dropping funnel. After completion of the dripping, the mixture was heated and stirred at 80° C. for 3 hours, and the contents of the flask were reacted together. After the reaction was completed, a solid was precipitated out with the addition of water to the reaction solution. A solid was obtained by suction filtration of the precipitate solid. The obtained solid was washed with approximately 1 L of water and removed by suction filtration. After the suction-filtered solid was washed with methanol and a solid was removed by suction filtration, 7.1 grams of a white-colored solid, which was the objective of the synthesis process, were obtained at a yield of 96%.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:5]2[N:4]=1.O1CCCC1.CO.[Br:25]N1C(=O)CCC1=O>>[Br:25][C:9]1[CH:10]=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:5]2[C:6]=1[CH:7]=[N:8][C:3]([S:2][CH3:1])=[N:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ncc2ccc(-c3ccccc3)n2n1
Solvent: C1CCOC1
Solvent: CO
Product: CSc1ncc2c(Br)cc(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Into a 30 mL vial, 2-Methylsulfanyl-7-phenyl-pyrrolo[2,1-f][1,2,4]triazine (0.295 g, 0.00122 mol), Tetrahydrofuran (10 mL, 0.1 mol) and Methanol (5 mL, 0.1 mol) were added. N-Bromosuccinimide (0.239 g, 0.00134 mol) was added over 10 minutes. The reaction was stirred at room temperature overnight. The solvent was removed under vacuum. The solid was partitioned with water, filtered and washed with water to give a yellow solid. The solid was dried under vacuum over night to give 5-Bromo-2-methylsulfanyl-7-phenyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (0.34 g, 87%). NMR 1H (DSMO-d6)-8.93 (s, 1H), 8.19 (d, 2H, J=7.61 Hz), 7.61 (s, 1H), 7.53 (t, 2H, J=8.60 Hz), 7.42 (t, 1H, J=7.37), 2.58 (s, 3H)
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=O)[CH:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH3:16])=[CH:9][CH:8]=1>CO>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH3:16])=[CH:9][CH:8]=1
Reactant: CC(C(=O)Nc1ccc(Br)cc1)N1CCCC1
Solvent: CO
Solvent: C1CCOC1
Product: CC(CNc1ccc(Br)cc1)N1CCCC1
Reaction time: 8 h

Procedure:
A 1M solution of BH3 in tetrahydrofuran (10 ml, 10 mmol) was added dropwise to N-(4-bromo-phenyl)-2-pyrrolidin-1-yl-propionamide (0.44 g, 1.48 mmol) and the solution was stirred overnight at reflux then subsequently hydrolysed by slow addition of excess of methanol and refluxing for a further 2 hours. The reaction mixture was loaded onto an SCX cartridge, which was washed with methanol and the product subsequently eluted with 2M ammonia in methanol. Removal of all solvents under rotary evaporation gave the desired product. Yield: 0.04 g, 10%. LCMS method: 2, RT: 3.07 min; MI: 283-285 [M+1].
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][N:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=O)=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52][CH2:51][NH:50]1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[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][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]([N:50]2[CH2:51][CH2:52][C:53]3[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:49]2)=[O:24])=[CH:25][CH:26]=1
Reactant: COc1cc2ncnc(Oc3ccc(OCC(=O)O)cc3)c2cc1OC
Reactant: c1ccc2c(c1)CCNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(OCC(=O)N4CCc5ccccc5C4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
2-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]phenoxy}acetic acid (100 mg), WSC.HCl (81 mg), and HOBT.H2O (57 mg) were dissolved in chloroform (3 ml) to prepare a solution. 1,2,3,4-Tetrahydro-isoquinoline (45 mg) was then added to the solution, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (39 mg, yield 30%).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[S:5][C:6](C2C=CC(OC)=CC=2)=[C:7](C2C=CC(OC)=CC=2)[N:8]=1.C(=O)([O-])O.[Na+].Cl.CN(C)CCCN=C=NCC.C(OC([N:49]1[CH:53]([C:54](O)=[O:55])[CH2:52][S:51][CH2:50]1)=O)(C)(C)C>CN(C)C=O.O.ClCCl>[ClH:1].[S:51]1[CH2:52][CH:53]([C:54]([NH:2][CH2:3][C:4]2[S:5][CH:6]=[CH:7][N:8]=2)=[O:55])[NH:49][CH2:50]1
Reactant: COc1ccc(-c2nc(CN)sc2-c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CSCC1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1nccs1)C1CSCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
2-Aminomethyl-4,5-bis(4-methoxyphenyl)thiazole hydrochloride (1.20 g) was added to a mixture of dichloromethane and saturated aqueous sodium hydrogencarbonate, and was extracted with dichloromethane. The separated organic layer was washed with water, and brine, and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and resulting residue was dissolved in dimethylformamide (25 ml). To the reaction mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.71 g) and 3-(tert-butyloxycarbonyl)-4-thiazolidinylcarboxylic acid (0.77 g), and stirred at ambient temperature for 2 hours. The mixture was poured into water, and extracted with ethyl acetate. The separated organic layer was washed with saturated aqueous sodium hydrogencarbonate, water, and brine, and dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate was evaporated in vacuo. The residue was subjected to column chromatography on silica gel (50 g) and eluted with a mixture of methanol and chloroform. The fractions containing the object compound were combined and evaporated in vacuo. The resulting residue (oil-compound) (1.10 g) was dissolved with dichloromethane (20 ml), and stirred at 2° C. To the reaction mixture was added 1,4-dioxan solution of 4N hydrogen chloride (10 ml), and stirred at ambient temperature for 1 hour. The resulting residue was evaporated in vacuo. The residue was added iso-propyl ether (50 ml) and stirred at 2° C. for 3 hours. The resulting precipitate was collected by filtration and washed with iso-propyl ether, to give 4-methoxyphenyl)-2-(4-thiazolidinylcarbonylaminomethyl)thiazole hydrochloride (0.45 g).
Reaction SMILES: [P:1]([O:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[CH2:23][O:24][Si](C(C)(C)C)(C)C)[CH:16]=[CH:15][CH:14]=1)([O:7][CH2:8][CH:9]=[CH2:10])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1.CCCCCC>[P:1]([O:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[CH2:23][OH:24])[CH:16]=[CH:15][CH:14]=1)([O:7][CH2:8][CH:9]=[CH2:10])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2]
Reactant: C=CCOP(=O)(OCC=C)OCc1cccc2cccc(CO[Si](C)(C)C(C)(C)C)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCOP(=O)(OCC=C)OCc1cccc2cccc(CO)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of diallyl [8-[(tert-butyldimethylsilyl)oxymethyl]-1-naphthyl]methyl phosphate (5.01 g, 10.8 mmol) obtained from Example 25-(1) in tetrahydrofuran (50 ml) was added tetrabutylammonium fluoride (1 mol/l tetrahydrofuran solution; 13.5 ml, 13.5 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added and the product was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to give an oily residue. The residue was subjected to chromatography on a silica gel (75 g) column (eluent; ethyl acetate:hexane=3:1˜4:1) to afford the title compound (2.22 g, 59% yield) as a colorless oil.
Reaction SMILES: O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:22](=[C:26]1[C:31](=[O:32])[O:30][C:29]([CH3:34])([CH3:33])[O:28][C:27]1=[O:35])[CH:23]([CH3:25])[CH3:24]>O.ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:23]([C@H:22]([CH:26]1[C:27](=[O:35])[O:28][C:29]([CH3:33])([CH3:34])[O:30][C:31]1=[O:32])[C:21]#[C:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:25])[CH3:24]
Reactant: CC(C)C=C1C(=O)OC(C)(C)OC1=O
Reactant: C#Cc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@@H](C#Cc1ccccc1)C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Yield: 94.6 %

Procedure:
A solution of copper (II) acetate monohydrate (5.0 mg, 0.025 mmol) in water (0.2 ml) was treated with sodium (L)-ascorbate (10 mg, 0.050 mmol), the mixture was stirred until the mixture was turned bright orange (3 min). Subsequently, (R,M)-3-{[4-(2-diphenylphosphanyl-7-methoxy-naphthalen-1-yl)-phthalazin-1-ylamino]-phenyl-methyl}-pentan-3-ol (1st diastereomer, 16.5 mg, 0.025 mmol) and phenylacetylene (0.275 ml, 2.5 mmol) were added, the resulting mixture was stirred for 10 min at 23° C., cooled to 0° C., stirred for 5 min and treated with 5-isobutylidene-2,2-dimethyl-1,3-dioxane-4,6-dione (50 mg, 0.25 mmol). The reaction mixture was stirred vigorously at 0° C. for 14 hrs, diluted with dichloromethane (2 ml) and subjected directly to flash chromatography on silica gel (hexane/EtOAc 3:1) to give 71 mg of the pure title compound as a white solid. (yield: 94%)