Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([CH2:63][CH:64]([S:81][S:82][CH:83]([CH3:85])[CH3:84])[CH2:65][C@H:66]([NH:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:67](OCC#N)=[O:68])=[N+:61]=[N-:62]>O.O1CCCC1>[N:60]([CH2:63][CH:64]([S:81][S:82][CH:83]([CH3:85])[CH3:84])[CH2:65][C@@H:66]([NH:73][C:74]([O:76][C:77]([CH3:78])([CH3:79])[CH3:80])=[O:75])[C:67]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:68])=[N+:61]=[N-:62]
Reactant: CC(C)SSC(CN=[N+]=[N-])C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)SSC(CN=[N+]=[N-])C[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 40.8 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h, 43.6 mg, 0.069 mmol) in water (0.3 mL) and a solution of (2S)-cyanomethyl 5-azido-2-((tert-butoxycarbonyl)amino)-4-(isopropyldisulfanyl)pentanoate (Compound 45) (83 mg, 0.206 mmol) in tetrahydrofuran (0.2 mL) were added to buffer A (12 mL), and the mixture was stirred at room temperature for 55 minutes. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-azido-2-((tert-butoxycarbonyl)amino)-4-(isopropyldisulfanyl)pentanoate (Compound 46) (27.7 mg, 41%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[CH:4][CH:3]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:22])=[CH:18][N:17]=2)=[CH:6][CH:7]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: NN1CCOCC1
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NN2CCOCC2)cn1
Yield: 76 %

Procedure:
As described for example 10b, 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (68 mg, 0.21 mmol) was converted, using N-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (65 mg, 76%) which was obtained as a white solid. MS: m/e=413.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Br-].[CH:10]1([Zn+])[CH2:14][CH2:13][CH2:12][CH2:11]1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: [Zn+]C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Product: Brc1cccc(C2CCCC2)n1

Procedure:
To 2,6-dibromopyridine (5.9 g, 25 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.4 g, 1.2 mmol) was added cyclopentylzinc bromide (50 ml, 0.5 M solution in tetrahydrofuran) and the mixture heated at reflux for 18 h. The reaction was diluted with ethyl acetate and washed with water. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated in vacuo to give an oil. The crude product was chromatographed on silica, eluting on a gradient from 1 to 5% methanol in dichloromethane, to give 2-bromo-6-cyclopentylpyridine (3.25 g) as a white solid: δH (400 MHz, CDCl3) 1.60-1.90 (6H, m), 2.09 (2H, m), 3.17 (1H, m), 7.12 (1H, d, J 7.4), 7.28 (1H, d, J 7.4), 7.44 (1H, t, J 7.2); m/z (ES+) 226:228 (1:1) (M++H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH:25]4[CH2:29][CH2:28][CH2:27]C4)[CH2:21][CH2:20]3)=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].ClCC(N1CCN(C2CCC2)CC1)=[O:33]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]([N:19]3[CH2:20][CH2:21][N:22]([CH:25]4[CH2:27][CH2:28][CH2:29]4)[CH2:23][CH2:24]3)=[O:18])[CH2:12][C:11]2=[O:33])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N2CCN(CC(=O)N3CCN(C4CCCC4)CC3)CC2)cc1
Reactant: O=C(CCl)N1CCN(C2CCC2)CC1
Product: CC(=O)c1ccc(N2CCN(CC(=O)N3CCN(C4CCC4)CC3)CC2=O)cc1

Procedure:
The intermediate obtained from step 2 is reacted with 1-(chloroacetyl)-4-cyclobutylpiperazine as in Example 1D, step 3 to give the title compound. LC-MS (M+1): 399.21.
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].I[CH2:15][CH3:16].[Cl-].[NH4+]>CN(C=O)C.O>[CH2:15]([N:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1)[CH3:16]
Reactant: CCI
Reactant: O=Cc1ccnc2[nH]ccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ccc2c(C=O)ccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (0.413 g, 2.83 mmol) in 5 mL of DMF under an atmosphere of nitrogen was added sodium hydride (74.6 mg, 3.11 mmol). After 5 min, iodoethane (0.529 g, 3.39 mmol) was added. After 30 min, the reaction was treated with saturated aqueous ammonium chloride, diluted with water, and extracted 2× with dichloromethane. The combined organic solution was washed 3× with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-25% ethyl acetate in hexanes to provide 1-ethyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 175.2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC.COC(C)(C)C>[CH:15]([C@H:12]1[CH2:13][CH2:14][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)=[CH:1][CH2:3][CH2:4][CH3:5]
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCC=C[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 3.6 g of butyltriphenylphosphonium bromide in 40 ml of t-butyl methyl ether was placed at room temperature while gassing with argon in a sulphonation flask provided with a thermometer, a mechanical stirrer, a dropping funnel and a solid substance addition tube, treated with 1.01 g of potassium t-butylate and stirred at room temperature for a further 1 hour. The deep orange, heterogeneous reaction mixture was subsequently cooled to -60° C. and treated within 15 minutes with a solution of 1.28 g of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde in 10 ml of t-butyl methyl ether. The reaction mixture was stirred for a further 60 minutes while warming slowly to -30° C., then poured into 100 ml of water and extracted three times with 50 ml of diethyl ether each time. The organic phases were washed once with 50 ml of water, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (3.45 g) on silica gel with ethyl acetate/petroleum ether (vol. 3:97 ) gave 1.52 g (99%) of p-[trans-4-(1-pentenyl)cyclohexyl]benzonitrile (trans-1-pentenyl/cis-1-pentenyl ratio about 5:95) as a colourless oil: Rf-value (ethyl acetate/petroleum ether, vol. 3:97) 0.19.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([C:2]2[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccc(Br)o1
Product: O=Cc1ccc(-c2ccccc2)o1
Yield: 101.9 %

Procedure:
The title compound (2.0 g, 95%) was prepared from 5-bromo-2-furaldehyde (2.0 g, 11.4 mmol) and phenylboronic acid (1.5 g, 12 mmol) using the procedure of Example 159, step 1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([CH:11]([O:16][CH3:17])[C:12](OC)=[O:13])[CH:9]=[CH:10][C:2]1=2.O.[NH2:19][NH2:20]>CCO>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([CH:11]([O:16][CH3:17])[C:12]([NH:19][NH2:20])=[O:13])[CH:9]=[CH:10][C:2]1=2
Reactant: COC(=O)C(OC)c1ccc2c(c1)OCCO2
Reactant: NN
Solvent: O
Solvent: CCO
Product: COC(C(=O)NN)c1ccc2c(c1)OCCO2
Temperature: 90 °C
Reaction time: 24 h
Yield: 80.3 %

Procedure:
To a stirred solution of methyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methoxyacetate (18.3 mmol) in anhydrous EtOH (150 mL) was added hydrazine hydrate (73.2 mmol, 4 eq) and heated to 90° C. Stirring was then continued for 24 hours. The reaction mixture was then cooled and the solvents removed under reduced pressure. The crude oil was diluted with EtOAc and washed with H2O and the organic phase dried over Na2SO4, filtered, and the solvents removed under reduced pressure to yield a yellow oil (3.5 g) that was used without further purification.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].C(O[CH:14]=[C:15]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[C:16](=O)[C:17]([F:20])([F:19])[F:18])C>CO>[CH:23]([C:22]([C:15]1[C:16]([C:17]([F:18])([F:19])[F:20])=[N:9][CH:8]=[N:10][CH:14]=1)=[O:26])([CH3:25])[CH3:24]
Reactant: N=CN
Reactant: CCOC=C(C(=O)C(C)C)C(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)C(=O)c1cncnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.9 %

Procedure:
46 g (0.85 mol) of sodium methoxide was dissolved in 700 ml of methanol, and 76 g (0.73 mol) of formamidine acetate was added, followed by stirring at room temperature for 15 minutes. Then, 146 g (0.61 mol) of 3-ethoxymethylene-1,1,1-trifluoro-5-methyl-2,4-hexanedione was added under cooling with ice, followed by heating and refluxing for further 2 hours. The solvent was distilled off under reduced pressure, and 1,000 ml of ice water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (developing solvent/n-hexane:ethyl acetate=6:1) to obtain 89 g (yield: 67%) of 5-isopropylcarbonyl-4-trifluoromethylpyrimidine as slightly yellow liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:11][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH2:1])[CH:10]=2)=[N:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccc(N)c(N)c2)nc1

Procedure:
2-Nitro-4-hydroxyaniline was reacted with 2-chloro-5-nitropyridine and K2CO3 in DMF at rt, followed by hydrogenation over Pd/C in MeOH, afforded the title compound; MS m/e 217 (M+1).
Reaction SMILES: [C:1]1([OH:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH2:10]1[O:13][CH:11]1[CH3:12].C(N(CC)CC)C>>[CH3:10][CH:11]([OH:13])[CH2:12][O:9][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: CC1CO1
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(OCC(C)O)c1
Temperature: 110 °C
Yield: 88.5 %

Procedure:
A 500 ml three-necked flask was charged with 51.88 g (425 mmol) of 3,5-xylenol, 29.6 g (510 mmol) of propylene oxide and 4.25 g (42 mmol) of triethylamine, and the resultant mixture was refluxed under heat at 90° C. for 1 hour and at 110° C. for 4 hours. The reaction product was recrystallized from hexane to give 1-methyl-2-(3,5-dimethylphenoxy)ethanol.
Reaction SMILES: O[C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])([CH:4]=[CH2:5])[CH3:3].C(OCC)C.P(Br)(Br)[Br:23].C(=O)(O)[O-].[Na+]>O.N1C=CC=CC=1>[CH2:5]([Br:23])[CH:4]=[C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:3]
Reactant: BrP(Br)Br
Reactant: C=CC(C)(O)CCC=C(C)CCC=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCBr
Reaction time: 12 h
Yield: 240.4 %

Procedure:
Following the procedure reported by G. Pala et al. in Helv. Chim. Acta., 53, 1827- 1832 (1970), a mixture of 666 g of nerolidol (cis:trans= 40:60 ), 2,000 ml of diethyl ether and 20 ml of pyridine was cooled at -5° - -10° C. Thereto, 300 g of phosphorus tribromide was added dropwise slowly at the same temperature. Thereafter, the reaction was completed by further stirring of the mixture for 12 hours at the same temperature. The reaction mixture was poured into water and neutralized with sodium bicarbonate. The ether layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off in vacuo at room temperature to give 760 g of farnesyl bromide which showed orange color and irritating odor. As this substance was relatively unstable, it was brought to the following reaction without further purification or kept in a cold place.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[NH2:19])=[CH:12][CH:11]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[NH:19][C:24]2=[O:26])=[CH:12][CH:11]=1
Reactant: Cc1cccc(Oc2ccc(NC(=O)C(C)(C)N)cc2)c1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cccc(Oc2ccc(N3C(=O)NC(C)(C)C3=O)cc2)c1C
Reaction time: 0.08 h
Yield: 207.4 %

Procedure:
N1-{4-[(2,3-dimethylphenyl)oxy]phenyl}-2-methylalaninamide (Intermediate 76, 68 mg) was solved in 2 mL of ethyl acetate under nitrogen atmosphere. TEA (0.070 mL, 0.50 mmol) was added followed by a solution of triphosgene (33.8 mg, 0.11 mmol) in 1.0 mL of ethyl acetate. After stirring for 5 minutes, DMAP (13.9 mg, 0.11 mmol) was added and the reaction mixture was stirred at room temperature for 10 minutes. After quenching with a saturated solution of NaHCO3, the mixture was extracted two times with ethyl acetate, and the collected organic were dried over sodium sulphate, filtered and evaporated. The residue obtained was purified by silica gel chromatography eluting with a gradient cHex/EtOAc from 100/0 to 0/100. This afforded the title compound (74 mg).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:36][CH:33]5[CH2:35][CH2:34]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h
Yield: 54 %

Procedure:
A mixture of 0.070 g (0.16 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.013 g (0.23 mmole) of cyclopropylamine, 0.074 g (0.19 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.195 mL (1.1 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethate-methanol (gradient 100:0-60:40) to give 0.042 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-cyclopropyl-3-methoxy-benzamide (I-26) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:15]=[C:14]([OH:16])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[OH:17])[CH3:2].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Br:30].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:15]=[C:14]([O:16][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Br:30])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[O:17][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Br:30])[CH3:2]
Reactant: BrCCCCCCCCCCBr
Reactant: CCOC(=O)c1cc(O)c(C(=O)OCC)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(OCCCCCCCCCCBr)c(C(=O)OCC)cc1OCCCCCCCCCCBr

Procedure:
25.4 g (0.1 mol) diethyl-2,5-dihydroxyterephthalate, 450 g (1.5 mol) 1,10-dibromodecane, 138 g (1.0 mol) K2CO3 and 200 mg NaI in 200 ml acetone are heated under reflux for 28 hours until the originally yellow suspension has decolorized. After distilling off the solvent, the reaction mixture is extracted twice with diethyl ether (2×250 ml), and insoluble salts are filtered off. The filtrate is washed twice with 200 ml water and dried over Na2SO4. The solvent is then distilled off. The colourless, solid residue is washed twice with petroleum ether and then recrystallized from petroleum ether.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:10]([O-])=[O:11])=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:6][NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:10][OH:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@H](CO)Cc1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-(pyridin-2-yl)propanoate (1.05 g, 3.96 mmol) in THF (20 mL) was added LAH (2 M in THF, 4.0 mL, 8.0 mmol) at 0° C. The resulting solution was stirred at 0° C. for 30 min and heated to reflux for 2 h. The reaction mixture was cooled and quenched with water (0.32 mL), NaOH (3 N, 0.32 mL), and water (0.96 mL). The resulting suspension was stirred at RT for 30 min. The mixture was filtered and the filtrate was concentrate to give (S)-2-(methylamino)-3-(pyridin-2-yl)propan-1-ol (510 mg, crude), which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CO>C(#N)C.ClCCl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Clc1ccnc2ccc(I)cc12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc3ccc(I)cc23)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
The mixture of 4-chloro-6-iodo-quinoline (217.5 mg, 1 mmol, prepared by similar procedure to example 1e), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.75 mmol), and 1-tert-butyl-2,2,4,4-pentakis(dimethylamino)-2λ5, 4λ5-catenadi(phosphazene) in tetrahdyrofuran (2M, 0.75 ml, 1.5 mmol) in acetonitrile (3.5 ml) was stirred at 100° C. for 30 min in microwave instrument (Personal Chemistry). After cooling the reaction, the solvent was evaporated, followed by addition of water, some of sodium carbonate saturated solution. The resulting solution was extracted with dimethylene chloride three times. The combined organic layer was dried over the brain, sodium sulfate, then evaporated to give a reddish gel. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-3% methanol in dichloromethane for 30 min) afforded 4-(6-iodo-quinolin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (262.5 mg, 77%) as A light yellow solid. LC-MS m/e 455 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1.[I:21]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[C:11]([I:21])[N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(-c2cncc(F)c2)s1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1sc(-c2cncc(F)c2)nc1I
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84.1 %

Procedure:
To a solution of tert-butyl 2-(5-fluoropyridin-3-yl)thiazol-5-ylcarbamate (1.50 g, 5.08 mmol) in acetonitrile (50 mL) at 0° C. was added N-iodosuccinimide (2.40 g, 10.67 mmol). The mixture was stirred at 0° C. for 5 min and diluted with ethyl acetate and water. The organic phase was separated and rinsed with brine, dried over MgSO4 and concentrated in vacuo to give a dark solid. This solid was passed through a bed of silica gel (100g) eluting with 10% ether in hexanes (600 mL) to give tert-butyl 2-(5-fluoropyridin-3-yl)-4-iodothiazol-5-ylcarbamate as a pale yellow solid (1.80 g, 84% yield): mp 148-149° C.; 1H NMR (300 MHz, CDCl3) δ 8.87 (t, J=1.5 Hz, 1H), 8.47 (d, J=2.7 Hz, 1H), 7.93 (ddd, J=9.0, 2.5, 1.9 Hz, 1H), 7.08 (s, 1H), 1.57 (s, 9H). ESIMS m/z 422.1 (M+1), 420.2 (M-1),