Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([SH:9])[N:4]([CH2:10][CH2:11][CH3:12])[C:3]1=[O:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>CN(C)C=O.ClCCl.[Ti](Cl)(Cl)(Cl)Cl.O>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][S:9][C:5]=2[N:4]([CH2:10][CH2:11][CH3:12])[C:3]1=[O:13]
Reactant: CCCn1c(S)cc(=O)n(C)c1=O
Reactant: CCOC(=O)C(=O)CBr
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)n(C)c(=O)c2c(C(=O)OCC)csc21
Reaction time: 0.17 h

Procedure:
The product of step b) (6.95 g) in dry dimethylformamide (100 ml) was added potassium carbonate (2.4 g) and stirred for 10 min. Ethyl bromopyruvate (5 ml) was added and was stirred under nitrogen at room temperature for 2 h. The reaction was poured into water (1 L), acidified (2M HCl) and extracted with ethyl acetate. The organic extracts were washed with brine (100 ml). Drying and evaporation afforded an oil. The oil was dissolved in dichloromethane (100 ml) and cooled in ice whilst stirring. Titanium tetrachloride (7.58 ml) was added and stirring continued under nitrogen for 2 h. The reaction was poured into water (1 L) and extracted with dichloromethane. The organics were dried and evaporated in vacuo. The residue was purified by chromatography (SiO2/ethyl acetate-dichloromethane 0-8%) to afford the subtitle compound as an orange oil, 4.64 g. δ 1HCDCl3 1.02 (3H, t), 1.83 (2H, sextet), 3.42 (3H, s), 3.95 (2H, t), 4.41 (2H, q), 7.30 (1H, s). MS (APCI) 297.1 (M++H)
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].C(N(CC)CC)C.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24].O>C1COCC1>[O:9]=[C:8]1[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3](=[O:14])[CH:2]1[NH:1][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)C(=O)Cl
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NC1C(=O)Nc2ccccc2NC1=O
Temperature: 1.5 °C
Reaction time: 3.5 h
Yield: 76.8 %

Procedure:
Stir 3-amino-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (10.0 g, 52.3 mmol) as a tan colored slurry in THF (300 mL) at 0-3° C. under nitrogen. Add triethylamine (8.00 mL, 57.0 mmol) in one portion. Add dropwise isobutyryl chloride (6.00 mL, 57.0 mmol) keeping the temperature below 3° C. Stir the resulting light yellow colored slurry at 0-3° C. for 3.5 hours until complete reaction by HPLC. Add deionized water (450 mL) over 15-20 minutes, keeping the pot temperature below 10° C. After stirring at 0-10° C. for 1.5 hours, isolate the product by filtration, rinse with cold (0-3° C.) 2:1/Water:THF (50 mL), then water (50 mL). Dry the solid in a vacuum oven at 50° C. to afford 10.5 g (77%) of the title compound: 1H NMR (500 MHz, DMSO-d6) δ 10.7 (s, 2H), 8.15 (d, 1H), 7.2 (m, 4H), 4.7 (d, 1H), 2.75 (m, 1H), 1.0 (s, 6H).
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2)[CH3:2].[C:16]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)#[N:17].C(N(CC)CC)C.C(#N)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C>[C:16]([C:18]1[CH:23]=[C:22]([N:7]2[CH:6]=[N:5][C:4]3[C:8]2=[N:9][C:10]([C:12]([F:14])([F:15])[F:13])=[N:11][C:3]=3[CH2:1][CH3:2])[CH:21]=[CH:20][CH:19]=1)#[N:17]
Reactant: CCc1nc(C(F)(F)F)nc2nc[nH]c12
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1nc(C(F)(F)F)nc2c1ncn2-c1cccc(C#N)c1
Temperature: 52.5 °C
Reaction time: 18 h
Yield: 18.9 %

Procedure:
A mixture of 6-ethyl-2-trifluoromethylpurine (86 mg, 0.40 mmol), 3-cyanophenylboronic acid (103 mg, 0.70 mmol), copper (II) acetate (72 mg, 0.4 mmol), triethylamine (202 mg, 2.0 mmoL), anhydrous acetonitrile (5 ml) and molecular sieves (˜10 pellets) was stirred at 50-55° C. for 18 hours. Ethyl acetate (20 ml) was added and the solid was filtered off. The filtrate was washed with 20 ml of 5% aqueous sodium bicarbonate, concentrated under vacuum, and purified by chromatography over SiO2 (ethyl acetate/hexane 1:3) to give 24 mg of 9-(3-cyanophenyl)-6-ethyl-2-trifluoromethylpurine (yield 19%). 1H NMR (300 MHz, CDCl3) δ 8.50 (s, 1H), 8.11 (m, 2H), 7.82(m, 2H), 3.35 (q, J=7.5 Hz, 2H), 1.50 (t, J=7.5 Hz, 3H). [ESMS m/z (318.4 (M+H)+)]
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:61]([O:68][C:69]1[CH:74]=[CH:73][C:72]([C:75]2[O:79][N:78]=[C:77]([C:80](O)=[O:81])[CH:76]=2)=[CH:71][CH:70]=1)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>CN(C=O)C.O>[O:20]=[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]1)[CH2:18][NH:17][C:80]([C:77]1[CH:76]=[C:75]([C:72]2[CH:71]=[CH:70][C:69]([O:68][CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:74][CH:73]=2)[O:79][N:78]=1)=[O:81]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccc(OCc3ccccc3)cc2)on1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 47.6 %

Procedure:
DIPEA (65.5 mg, 0.51 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt (87 mg, 0.20 mmol) in DMF (1 mL). HOBT (27 mg, 0.20 mmol) and EDCI.HCl (38 mg, 0.20 mmol) were then added at room temperature. After 2 minutes, 5-(4-benzyloxyphenyl)-isoxazole-3-carboxylic acid (50 mg, 0.17 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water (20 mL) was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. the resulting residue was purified by column chromatography (using silica gel 60-120 mesh and 2.5% methanol in chloroform as eluent) to afford 48 mg (48% yield) of 5-(4-benzyloxy-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 83.69%, HPLC Purity: 99.66%, 1H NMR (DMSO-d6): δ 8.6 (t, 1H), 8.0-7.8 (m, 3H), 7.8-7.7 (d, 1H), 7.7 (d, 1H), 7.6-7.5 (m, 1H), 7.4 (m, 4H), 7.3-7.2 (s, 1H), 7.2 (d, 2H), 5.0 (s, 2H), 4.3-4.2 (dd, 2H), 3.8-3.7 (m, 2H), 3.6 (m, 2H), 3.4 (m, 2H), 3.2-3.1 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[N:14]=[CH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)=[CH:18][CH:17]=3)=[O:11])=[CH:5][CH:4]=1.[C:28]([O-])([O-])=O.[Cs+].[Cs+].CI>O1CCOCC1.CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[N:14]=[CH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[CH:18][CH:17]=3)=[O:11])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CC(=O)Nc2cc3cc(-c4cn[nH]c4)ccc3cn2)cc1
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Solvent: CI
Product: COc1ccc(CC(=O)Nc2cc3cc(-c4cnn(C)c4)ccc3cn2)cc1
Temperature: 70 °C

Procedure:
To the solution of 2-(4-Methoxy-phenyl)-N-[6-(1H-pyrazol-4-yl)-isoquinolin-3-yl]-acetamide (30.00 mg, 0.08 mmol) in 2 mL of dioxane was added Cs2CO3 (59.80 mg, 0.18 mmol) and CH3I (13.10 mg, 0.09 mmol). The mixture was heated at 70° C. for 72 hrs. Evaporation of the solvent gave the crude product which was re-dissolved in DMSO and purified by HPLC to give the title compound as a crystalline solid product (7.5 mg, 24.0%). 1H NMR (DMSO-d6, 400 MHz): δ 3.68 (2H, s), 3.73 (3H, s), 3.89 (3H, s), 6.89 (2H, d, J=8.5 Hz), 7.30 (2H, d, J=8.5 Hz), 7.75 (1H, dd, J=8.5, 1.5 Hz), 7.97-8.06 (2H, m), 8.08 (1H, s), 8.37 (2H, d, J=16.6 Hz), 9.03 (1H, s), 10.70 (1H, s). 13CNMR (DMSO-d6, 100 MHz): δ 42.19, 55.03, 106.31, 113.77, 120.33, 121.25, 123.88, 124.41, 127.88, 128.18, 128.9, 130.16, 134.93, 136.86, 137.86, 147.56, 150.80, 158.06, 170.78. HRMS: m/z 373.1660, calc. 373.1659. MS m/z, (APCI); 373.1 [(M+1)+100].
Reaction SMILES: [O:1]=[C:2]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])/[CH:3]=[CH:4]/[C:5]1[O:6][C:7]([CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:8][C:9](=[O:22])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C([BH-](CC)CC)C.[Li+]>O1CCCC1>[OH:1][CH:2]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])/[CH:3]=[CH:4]/[C:5]1[O:6][C:7]([CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:27])([CH3:28])[CH3:29])=[CH:8][C:9](=[O:22])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCCCCC(=O)/C=C/c1oc(COC(=O)C(C)(C)C)cc(=O)c1OCCCCCC(=O)OCC
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC(O)/C=C/c1oc(COC(=O)C(C)(C)C)cc(=O)c1OCCCCCC(=O)OCC
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To a solution, cooled under nitrogen to -78°, of 0.715 g (1.45 mmol) of 2-(3-oxo-trans-1-octenyl)-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone in 10 ml of tetrahydrofuran was added dropwise keeping the internal temperature at -70° to -75°, 1.7 ml (1.7 mmole) of lithium triethylborohydride. After being stirred for an additional 30 min the cold reaction was quenched by the addition of 5 drops of 40% aqueous acetic acid and then partially concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed successively with aqueous sodium bicarbonate and brine solution. The organic solution was dried over magnesium sulfate and evaporated to give an oil. Chromatographic purification on silica gel eluting with ether furnished 0.290 g (40%) of 2-[(3RS)-3-hydroxy-trans-1-octenyl]-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone. NMR (CDCl3): δ0.90 (3H, t, J=4.5 Hz), 2.31 (2H, t, J=6 Hz), 4.88 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[CH:3]=1.Cl[C:10]1[C:11]2[C:18]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[CH:17][N:16]([CH3:27])[C:12]=2[N:13]=[CH:14][N:15]=1.FC(F)(F)C(O)=O>C(OCC)C>[NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:10]2[C:11]3[C:18]([C:19]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:20])=[CH:17][N:16]([CH3:27])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(N)c1
Reactant: Cn1cc(C(=O)c2ccccc2)c2c(Cl)ncnc21
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C(=O)c2ccccc2)c2c(Nc3cccc(N)c3)ncnc21

Procedure:
(4-((3-aminophenyl)amino)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone was synthesized according to general procedure A step 2 using 1,3-diaminobenzene and (4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone. A white solid was obtained. M.p: 170-173° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.53 (s, 1H), 8.12 (s, 1H), 8.06 (s, 1H), 7.86 (d, J=6.6 Hz, 2H), 7.71 (d, J=4.3 Hz, 2H), 7.68 (d, J=4.3 Hz, 2H), 7.43 (d, J=7.8 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H), 6.95 (d, J=5.8 Hz, 1H), 6.69 (s, 1H), 6.57 (d, J=1.9 Hz, 1H), 3.68 (s, 3H); LCMS [M+H]: 344; Calc. C20H17N5O.1.6 trifluoroacetic acid.0.1 diethyl ether: C, 53.16; H, 3.70; N, 13.13. Found C, 50.79; H, 3.73; N, 12.93.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]=2[CH:15]=1.[Cl:16][C:17]1[CH:28]=[CH:27][C:20]2[NH:21][C:22]([CH2:24][NH:25][CH3:26])=[N:23][C:19]=2[CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[Cl:16][C:17]1[CH:28]=[CH:27][C:20]2[NH:21][C:22]([CH2:24][N:25]([CH3:26])[C:12](=[O:14])[CH2:11][N:7]3[C:6]4[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[S:9][C:8]3=[O:10])=[N:23][C:19]=2[CH:18]=1
Reactant: CNCc1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)Cn1c(=O)sc2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1nc2cc(Cl)ccc2[nH]1)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a mixture of (5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetic acid (300 mg), 1-(5-chloro-1H-benzimidazol-2-yl)-N-methylmethanamine (265 mg) and DMF (20 mL) were added TEA (687 μL), HOBt (200 mg), and WSC.HCl (283 mg), followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with water, a saturated aqueous NaHCO3 solution, and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. The obtained solid was washed with EtOAc to obtain N-[(5-chloro-1H-benzimidazol-2-yl)methyl]-2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-methylacetamide (339 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:13]#[N:14])=[CH:6][CH:5]=1.Br[C:23]1[CH:24]=[N:25][CH:26]=[N:27][CH:28]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])([C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)[C:13]#[N:14])=[CH:8][CH:9]=1
Reactant: N#CC(CCc1ccc(Cl)cc1)c1ccccc1F
Reactant: Brc1cncnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(CCc1ccc(Cl)cc1)(c1cncnc1)c1ccccc1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A 1 L 4-neck flask under a nitrogen atmosphere was charged with 4.4 g. of 60% sodium hydride (1.1 equiv., 0.11 moles), and washed with hexanes, in 75 ml. DMF. Then over 30 minutes, 27.3 g. of 4-(4-chlorophenyl)-2-(2-fluorophenyl)butanenitrile (1.0 equiv., 0.10 moles) in 110 ml. DMF was added dropwise to the base causing an exotherm to 30° C. After the addition was complete, the reaction mixture was stirred for 30 minutes. Over 5 minutes 17.5 g. of 5-bromopyrimidine (1.1 equiv., 0.11 moles) in 75 ml. DMF was added to the reaction mixture which was heated at 50° C. and monitored by GLC analysis. The reaction was quenched after 2 hours by the addition of 350 ml. water and extracted with 600 ml. ethyl acetate. The organic phase was washed with three 300 ml. portions of water, the organic phase dried over anhydrous magnesium sulfate, and then concentrated in vacuo at 50° C. to give 34.2 grams oil which solidified..The solid was with triturated with 75 ml. isopropanol, filtered, and dried to give 16.5 g. white solid (47.0% yield), m.p.=86° C.-88° C.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:46][C:47]([S:50][C:51]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([CH3:49])[CH3:48])[CH2:12][CH2:13][N:14]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:15][C:16]([CH3:38])([S:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:17])C(=O)C2=CC=CC=C12.C(O)C.O.O.NN>C1COCC1>[C:42]([O:41][C:39]([N:14]([CH2:15][C:16]([CH3:38])([S:18][C:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:17])[CH2:13][CH2:12][N:11]([CH2:46][C:47]([S:50][C:51]([C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)([CH3:49])[CH3:48])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH2:5])=[O:40])([CH3:43])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N(CCN(CCCCCN1C(=O)c2ccccc2C1=O)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N(CCN(CCCCCN)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 68 %

Procedure:
A 250 mL single-necked round-bottomed flask, equipped with stir bar and reflux condenser, was charged with 9-phthalimido-N1 -(t-butoxycarbonyl)-N1, N4 -bis[2-methyl-2-(triphenylmethylthio)propyl ]-1,4-diazanonane (5.50 g, 5.319.43 mmol) in 25 mL of THF. To this was added 100 mL ethanol and 5 mL water. The addition of water caused the starting material to precipitate out of solution. Hydrazine hydrate (1.2 mL, 24.7 mmol, 466 mole %) was added, and the reaction heated at reflux for two days. The reaction mixture was concentrated and partitioned between 100 mL each of water and 0.25M K2CO3. The organic layer was separated and washed once with brine (75 mL), dried over Na2SO4 and concentrated to a solid foam. Purification of the crude product by low-pressure liquid chromatography (100 g SiO2, CHCl3 →5% methanol in CHCl3, the column pre-treated with 200 mL 2% triethylamine in CHCl3) afforded 3.27 g of pure N1 -(t-butoxycarbonyl)-N1,N4 -bis [2-methyl-2-(triphenylmethylthio)propyl ]-1,4,10-triazadecane as a yellow foam (68% yield). Chemical analysis of the purified product confirmed its identity as follows:
Reaction SMILES: [OH-].[Na+].O.CO.C([C@@:9]1([OH:28])[C@@H:13]([CH:14](C(=O)C)[OH:15])[O:12][C@@H:11]([N:19]2[CH:26]=[C:25]([F:27])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:10]1)(=O)C>C(O)(=O)C>[F:27][C:25]1[C:23](=[O:24])[NH:22][C:20](=[O:21])[N:19]([CH:26]=1)[C@@H:11]1[O:12][C@H:13]([CH2:14][OH:15])[C@@H:9]([OH:28])[CH2:10]1
Reactant: CC(=O)C(O)[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@]1(O)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reaction time: 3.5 h
Yield: 78.7 %

Procedure:
A solution of 15.55 g (0.389 mol) of sodium hydroxide in 200 ml of ino-exchanged water was mixed with 500 ml of methanol and cooled with ice. Then 42.18 g (0.128 mol) of 2'-deoxy-3',5'-diacetyl-5-fluorouridine (R is CH3 in the general formula (I)) was added to the solution under stirring, and stirring was continued at room temperature for 3.5 hr. As a result the reaction liquid became a clear solution. Then 20 g of acetic acid was added to the reaction liquid for neutralization, and the liquid was concentrated under reduced pressure. The solid residue was dissolved by adding 500 ml of water, followed by addition of 100 ml of a cation-exchange resin (IR 120-B), and the solution was left to stand for 1 hr. Then the resin was filtered out, and the addition of the cation-exchange resin and the subsequent treatment were repeated. After that the filtrate was concentrated and dried under reduced pressure. As the result a white solid was obtained. This solid product was recrystallized from ethanol to thereby obtain 24.80 g (yield 78.9%) of 2'-deoxy-5-fluorouridine. The melting point of this product was 149.5°-150.5° C., and the specific rotary power [α]D25 was +37.3° (C=1.06, H2O).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][NH2:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([O:45][CH3:46])[CH:39]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>CN(C=O)C>[N+:1]([C:4]1[C:5]([N:10]2[C:21](=[O:20])[NH:22][C:23]([CH:24]([C:38]3[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([O:45][CH3:46])[CH:39]=3)[NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[N:36]=[C:35]([CH3:37])[O:34][N:33]=4)=[CH:28][CH:27]=3)=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNc1ncccc1[N+](=O)[O-]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(C)nc(OC)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccc3[N+](=O)[O-])c(=O)[nH]2)cc(C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.4 %

Procedure:
After adding 32 mg of (3-nitropyridin-2-yl)hydrazine [CAS No. 15367-16-5] and 29 μl of triethylamine to a solution of 90 mg of {2-(2-methoxy-6-methylpyridin-4-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 3 ml of DMF, the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 2 ml of a methanol:THF=1:1 mixed solvent. After adding 42 μl of acetic acid and 64 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 4 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 2-(3-nitropyridin-2-yl)-5-{(2-methoxy-6-methylpyridin-4-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2,4-dihydro-[1,2,4]triazol-3-one (30 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]#[C:10][C:11]2[CH:12]=[N:13][C:14]([NH:17][CH3:18])=[CH:15][CH:16]=2)=[C:7]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([F:28])[CH:20]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(#N)C>[CH2:1]([C:3]1[C:8]([C:9]#[C:10][C:11]2[CH:12]=[N:13][C:14]([NH:17][CH3:18])=[CH:15][CH:16]=2)=[C:7]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:24])=[C:21]([F:28])[CH:20]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1nccc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(NC)nc1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nccc(-c2ccc(C(=O)N3CCN(C)CC3)c(F)c2)c1C#Cc1ccc(NC)nc1

Procedure:
The title compound is synthesized according to general procedure GP5 starting from 100 mg (0.27 mmol) 4-[2-Ethyl-3-(6-methylamino-pyridin-3-ylethynyl)-pyridin-4-yl]-2-fluoro-benzoic acid (A-46) using 50 μL (0.45 mmoL) N-methyl piperazine, 101 mg (0.27 mmol) HATU and 50 μL (0.29 mmol) DIPEA in 1.5 mL DMF. After completion of the reaction, the reaction mixture is filtered and the product is isolated from the obtained solution by RP-HPLC using a H2O/ACN-gradient. Yield: 70 mg (58%).
Reaction SMILES: [Mg].II.[Br:4][C:5]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][C:6]=1[CH2:7]Br.[CH3:15][CH2:16][O:17]CC>>[Br:4][C:5]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][C:6]=1[CH2:7][CH2:15][CH2:16][OH:17]
Reactant: CCOCC
Reactant: CSc1ccc(Br)c(CBr)c1
Agent: II
Agent: [Mg]
Product: CSc1ccc(Br)c(CCCO)c1
Reaction time: 2 h

Procedure:
To a suspension of 25.0 g of magnesium ribbon in a solution of 0.5 g of iodine in 550 ml of anhydrous ether is added 5 ml of a solution of 296.0 g of 2-bromo-5-(methylthio)benzyl bromide in 250 ml of anhydrous ether. The reaction is initiated by gentle heating, and the remainder of the solution is then added dropwise so as to maintain a reflux. Subsequently, the mixture is heated and stirred under reflux for one hour, and then cooled to 10°. A stream of nitrogen gas that has been bubbled through a reservoir containing 48.0 g of ethylene oxide is introduced into the reaction mixture. The addition of the ethylene oxide requires two hours. The mixture is subsequently stirred as it warms to room temperature, is stirred for four hours at room temperature, and then hydrolyzed by pouring on a mixture of 1 kg of ice and 55.0 g of ammonium chloride. Extraction with ether, followed by conventional workup of the ether solution, yield 210.0 g of 3-(2 -bromo-5-(methylthio)phenyl)-1-propanol, bp, about 125°-127° (0.6mm).