Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[N+:27]([O-:41])([O:29][CH2:30][C@H:31]([O:37][N+:38]([O-:40])=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35]O)=[O:28].CCN=C=NCCCN(C)C.C(OC(=O)C)(=O)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([O:10][CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]([O:37][N+:38]([O-:40])=[O:39])[CH2:30][O:29][N+:27]([O-:41])=[O:28])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C(=C(\C(=O)O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Reactant: O=[N+]([O-])OC[C@@H](CCCCO)O[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)OC/C(=C(\C(=O)OCCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Yield: 63.6 %

Procedure:
A solution of 3 g of (2Z)-4-(acetyloxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid, 1.7 g of (2R)-6-hydroxyhexane-1,2-diyl dinitrate, 10 mmol of DMAP and 10 mmol of EDCI was stirred in 40 mL of dichloromethane at rt for 2 h. Then, acetic anhydride (0.5 mL) was added and the mixture was filtered through a pad of silica gel and washed with EtOAc, evaporated, purified by flash chromatography (15-50% EtOAc/hexane) to afford 2.8 g of the desired compound as a white solid. 1H NMR (acetone-d6, 500 MHz): δ 7.79 (d, 2H), 7.45 (d, 2H), 7.21-7.16 (m, 1H), 7.13-7.08 (m, 2H), 5.52-5.44 (m, 1H), 5.21 (s, 1H), 4.98 (dd, 1H), 4.72 (dd, 1H), 4.29 (t, 2H), 3.09 (s, 3H), 1.92 (s, 3H), 1.89-1.74 (m, 4H), 1.60-1.48 (m 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH2:13]([N:25]([CH2:27][CH2:28]O)[CH3:26])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:13]([N:25]([CH2:27][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8](=[O:12])[O:9][C:10]=2[CH:11]=1)[CH3:26])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: CCCCCCCCCCCCN(C)CCO
Product: CCCCCCCCCCCCN(C)CCOc1ccc2ccc(=O)oc2c1
Yield: 46.7 %

Procedure:
7-Hydroxycoumarin (6.0 g, 37.0 mmol) and 2-[N-dodecyl-N-methylamino] ethanol (9.0 g, 37.0 mmol) were reacted by the general procedure as described in example 1 and afforded the title compound (6.7 g, 47%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]([F:20])[F:19])=[CH:12][CH:11]=2)[CH:3]=1.[Li][CH2:22]CCC.C[Si](C)(C)[O:28][C@@H:29]1[C@@H:34]([O:35][Si](C)(C)C)[C@H:33]([O:40][Si](C)(C)C)[C@@H:32]([CH2:45][O:46][Si](C)(C)C)[O:31][C:30]1=[O:51].CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>CC(OC)(C)C.CCCCCC.CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C@@:30]2([O:51][CH3:22])[C@H:29]([OH:28])[C@@H:34]([OH:35])[C@H:33]([OH:40])[C@@H:32]([CH2:45][OH:46])[O:31]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]([F:20])[F:19])=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: FC(F)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: [Li]CCCC
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CCCCCC
Solvent: CO
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: -78 °C
Yield: 14.4 %

Procedure:
Under Ar protection, 4-bromo-1-chloro-2-[[4-(2,2-difluoroethoxy)phenyl]methyl]benzene 12p (26.5 g, 73.3 mmol), MTBE (266 mL) and n-hexane (133 mL) were added into a 1 L reaction flask, stirred uniformly and cooled to −78° C., followed by dropwise addition of 2.4 M nBuLi (52 mL, 124.6 mmol) in 30 minutes. After stirring for 50 minutes at −78° C., a mixed solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-one 2f (55 g, 117.3 mmol) in MTBE and n-hexane (60 mL:30 mL) was added within 20 minutes at −78° C. before the reaction mixture was stirred for 4 hours at −78° C. Thereafter, 130 mL methanol were added before stirring for 20 minutes. Then the reaction mixture was warmed to room temperature and stirred for 16 hours after methanesulfonic acid (25 g, 256.55 mmol) was added. 500 mL saturated sodium bicarbonate were added to the reaction mixture, stirred for 1 hour and partitioned. The aqueous phase was extracted with MTBE (100 mL×2) and the organic extract was combined, concentrated and purified by column chromatography (eluant: dichloromethane: methanol=100:1˜10:1) to obtain the title compound (2S,3R,4S,5S,6R)-2-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 12e (5 g, pale yellow solid), yield: 10%. MS m/z (ESI): 492.46 [M+18].
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Br:19][CH2:20][C:21](Br)=[O:22].N1C=CC=CC=1>>[CH3:7][O:6][C:4](=[O:5])[CH2:3][C@H:2]([O:1][C:21](=[O:22])[CH2:20][Br:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Br)CBr
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Solvent: c1ccncc1
Product: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)CBr
Yield: 89.8 %

Procedure:
To a rapidly-stirred slurry of 1.29 g (4.99 mmol) methyl (R)-3-hydroxytetradecanoate and 0.45 ml (5.2 mmol) bromoacetyl bromide in 25 ml hexanes at 0° C. in a flame-dried flask under N2 was added 0.42 ml (5.2 mmol)pyridine all at once. The mixture was removed from the cold bath for 30 min. The mixture was suction filtered through celite, washing with 75 ml ether. The filtrate was washed with 2×100 ml H2O and with 50 ml 10% NaHCO3. The ether was dried over MgSO4 and removed by rotary evaporation, giving 1.70 g (90%) crude (R)-3-[(bromoacetyl)oxy]tetradecanoic acid methyl ester as a yellow oil. Analytically pure samples could be prepared by subjecting the oil to radial chromatography, eluting with CH2Cl2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH:9]1[CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][S:37]([CH3:36])(=[O:39])=[O:38])[CH:9]1[CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1CCNC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution containing 112 (1.68 g, 4.60 mmol) and DIPEA (0.71 g, 5.53 mmol) in DCM (20 mL) was cooled to 0° C. MsCl (0.52 g, 4.60 mmol) was added. After 1 h, the reaction mixture was diluted with EtOAc and washed successively with dilute aqueous HCl, brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 to 1:3 hexanes/EtOAc) to afford 2.6 g (quant.) of 113.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[Cu][C:18]#[N:19]>CN1CCCC1>[N:12]1([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:18]#[N:19])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH3:11])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: N#C[Cu]
Reactant: CCCC(c1ccc(Br)cc1)n1ccnc1
Agent: CN1CCCC1
Product: CCCC(c1ccc(C#N)cc1)n1ccnc1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
2.79 g of 1-[1-(4-bromophenyl)-butyl]-imidazole and 1.8 g of copper(I) cyanide are heated in 5 ml of N-methylpyrrolidine for 4 hours at 180° C. under a protecting gas atmosphere (argon). After cooling, it is precipitated in 50 ml of ammonia solution, stirred for 15 more minutes at room temperature and extracted with ethyl acetate. After concentration by evaporation in a vacuum 1.95 g of dark oil is obtained. This oil is distilled on a bulb tube in a vacuum; boiling point 200°-215° C./0.05 mbar. The resulting distillate is recrystallized from ethanol/petroleum ether. 1.54 g of 4-[1-(1-imidazolyl)-butyl]-benzonitrile with a melting point of 63°-71° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].IC.[C:13](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:13])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cc(C)c(Br)c(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
To a 0° C. solution of 4-bromo-3,5-dimethylphenol (1.00 g, 4.98 mmol) in DMF (10.0 mL) was added iodomethane (1.41 g, 9.96 mmol) and potassium carbonate (1.37 g, 9.96 mmol). The mixture was stirred for 5 h at room temperature. The mixture was poured into water and extracted with ethyl acetate (15 ml*3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to give 2-bromo-5-methoxy-1,3-dimethylbenzene (1.00 g) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.57 (s, 2H), 3.69 (s, 3H), 2.31 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)=[O:12])=[CH:7][CH:6]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[O:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)Cc1ccc(C(=O)c2ccc(O)cc2)cc1
Temperature: 0 °C
Yield: 90.4 %

Procedure:
A mixture of methyl(4-{[4-(methyloxy)phenyl]carbonyl}phenyl)acetate (151) (1.00 g, 3.52 mmol) and AlCl3 (1.90 g, 14.07 mmol) were refluxed in benzene (40 mL) for 1 h and then cooled to 0° C. in an ice bath. Water (35 mL) was added slowly, and the mixture was extracted with ether (2×50 mL, each contained 15 mL of EtOAc). The combined ethereal extract washed with water, brine, and dried over Na2SO4. Concentration gave light brown oil, which was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 45% EtOAc:hexanes to afford 0.86 g (90%) of compound 152 as colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.71 (s, 2H), 3.72 (s, 3H), 5.63 (br s, 1H), 6.89 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.6 Hz, 2H), 8.24 (d, J=7.9 Hz, 1H). LCMS (ESI): m/z 271 (M+H)+, 269 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].B.C[OH:45]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=4)[C:38]([NH2:39])=[O:45])[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Reactant: CO
Agent: B
Agent: [Br-]
Solvent: ClCCl
Product: NC(=O)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
To a solution of N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-cyano-phenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (0.50 g, 0.87 mmol) in dichloromethane (DCM) (10 mL) at −78° C. was added a solution of borane tribromide (BBr3) (1.74 mL, 1.0 M in DCM). The mixture was stirred at −78° C. for 0.5 hour, then room temperature for one hour. The mixture was then cooled to −78° C. and methanol (1 mL) was added. The resulting mixture was stirred at room temperature overnight. Solvent was removed in vaco, the residue was treated with a 1:1 mixture of dichloromethane and water (50 mL). Organic layer was separated, dried over sodium sulfate and concentrated. Product was purified by flash chromatography on silica gel eluting with 5% methanol in dichloromethane to afford 0.019 g (4%) of the title compound as a yellow solid. M.p.=168-170° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.70 (br. s, 1H), 8.10 (s, 1H), 8.10 (d, J=4.8 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.94-7.80 (m, 1 H), 7.77-7.65 (m, 4H), 7.53 (t, J=8.0 Hz, 1H), 7.42 (d, J=4.4 Hz, 1H), 7.25-7.13 (m, 2H), 7.15 (d, J=7.2 Hz, 1H), 6.34 (d, J=5.6 Hz, 1H), 3.92 (bs, 1H), 3.73 (d, J=8.4 Hz, 1H), 3.48 (d, J=11.2 Hz, 1H), 2.48-2.43 (m, 1H), 2.35 (t, J=10.8 Hz, 1H), 1.90-1.82 (m, 2H), 1.59-1.56 (m, 1H), 1.39-1.34 (m, 1H). LCMS: 595 [M+H].
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].C(#N)C>CN(C)C=O>[CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[N:6]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)CN1C(=O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A mixture of 6.66 g of 3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-2H-1,4-benzoxazine, 5.51 g of ethyl bromoacetate, 4.5.6 g of potassium carbonate and 20 ml of acetonitrile was refluxed under heating for 2.5 hours. Then, 10 ml of N,N-dimethylformamide was added and the mixture was stirred at 80° C. for 2 hours. To this mixture was added 2-80 g of ethyl bromoacetate. After an hour of stirring at 80° C., 2.28 g of potassium carbonate was added and the mixture was further stirred at 80° C. for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was chromatographed on a silica gel column, elution being carried out with hexane-ethyl acetate (10:.1). The crystals from the eluate were recrystallized from ethyl acetate-hexane to give 7.4 g of ethyl (3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-2H1,4 -benzoxazin-4-yl)acetate. This compound has the following physicochemical properties.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[CH2:8]=[O:9].[Cl:10][Si](C)(C)C>C1COCC1>[Cl:10][CH2:2][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:8]1=[O:9]
Reactant: C[Si](C)(C)Cl
Reactant: C=O
Reactant: O=C1CCCCN1
Solvent: C1CCOC1
Product: O=C1CCCCN1CCl

Procedure:
The title compound is prepared in accordance with the procedures set forth in Moreira, R. et al., Tet. Lett. , (1994), 35, 7107–7110. Thus, a mixture of 2-piperidinone (1.0 g, 10.09 mmol) and paraformaldehyde (500 mg) is refluxed in anhydrous THF (30 mL) and chlorotrimethylsilane (30 mL) overnight under N2. Concentrate the solvent under vacuum to give N-(chloromethyl)-2-piperidone as an oil (1.30 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]([NH2:14])[CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29]([C:35]3[N:36]=[C:37]4[C:43]([C:44](O)=[O:45])=[CH:42][N:41]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[C:38]4=[N:39][CH:40]=3)=[N:30][N:31]2[CH3:34])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]([NH:14][C:44]([C:43]2[C:37]3[C:38](=[N:39][CH:40]=[C:35]([C:29]4[C:28]5[C:32](=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=5)[N:31]([CH3:34])[N:30]=4)[N:36]=3)[N:41]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH:42]=2)=[O:45])[CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(N)C1CN(C(=O)OC(C)(C)C)C1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a solution of 3-(1-amino-ethyl)-azetidine-1-carboxylic acid tert-butyl ester (crude from step 3, 63 mg, 0.31 mmol) in DMF (2 mL) were added N,N-diisopropylethylamine (69 μL, 0.39 mmol), 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.26 mmol), and HATU (110 mg, 0.29 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 30% to 60% EtOAc/hexanes to afford 158 mg (94%) of 3-(1-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-azetidine-1-carboxylic acid tert-butyl ester as a white foam. 1H NMR (CDCl3, 300 MHz): δ (ppm) 9.23 (s, 1H), 8.36 (t, J=4.3 Hz, 2H), 8.18 (d, J=9.1 Hz, 1H), 7.52 (s, 1H), 7.24-7.29 (m, 1H), 5.73 (s, 2H), 4.57-4.68 (m, 1H), 4.18 (s, 3H), 3.87-4.08 (m, 3H), 3.79 (dd, J=8.7, 6.0 Hz, 1H), 3.55-3.65 (m, 2H), 2.73 (br. s., 1H), 1.39 (s, 9H), 1.36 (d, J=6.8 Hz, 6H), 0.89-1.01 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(O)CCCCC1.CC(C)([O-])C.[Na+].[OH:21][C:22]1[CH:27]=[C:26]([Cl:28])[N:25]=[N:24][C:23]=1Cl.Cl>C1(C)C=CC=CC=1.O>[Cl:28][C:26]1[N:25]=[N:24][C:23]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:22]([OH:21])[CH:27]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: OC1CCCCC1
Product: Oc1cc(Cl)nnc1Oc1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 29.2 %

Procedure:
A mixture of 25.0 g (266 mmol) of phenol and 30.0 g of cyclohexanol was charged, and 25.5 g (266 mmol) of sodium t-butoxide was added to the mixture over one hour, and then stirred at 70° C. for 30 minutes. The resultant solution was cooled to 40° C., and then 8.94 g (purity: 98%; 153.1 mmol) of 4-hydroxy-3,6-dichloropyridazine was added to the cooled solution. Then, the resultant mixture was heated from 40° C. to 140° C. to effect a reaction for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 100 g of pure water and 100 g of toluene were added to the cooled mixture, and stirred for 30 minutes. Then, 41.7 g (400 mmol) of a 35% aqueous hydrochloric acid solution was added dropwise to the resultant mixture, and an organic phase containing phenol added in an excess amount was separated. 287 g of toluene was added to the resultant aqueous phase, and stirred at room temperature for 30 minutes, and then an organic phase was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-phenoxy-4-pyridazinol was added dropwise to a 35% aqueous hydrochloric acid solution at 0° C. to deposit solids, followed by filtration. The resultant solids were washed with pure water and dried under a reduced pressure, and dissolved in an organic solvent and quantitatively determined by an HPLC area percentage method, which showed that 9.94 g of 6-chloro-3-phenoxy-4-pyridazinol (yield: 84.0%) was obtained.
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([NH:15][C:16](=[NH:19])[NH:17][CH3:18])=[O:14])[CH3:3].[CH3:20]N(C(OC)OC)C.Cl.CO>CC#N.O>[ClH:1].[CH2:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:2][CH3:3])[C:5]=1[N:12]1[CH:18]=[N:17][C:16]([NH:19][CH3:20])=[N:15][C:13]1=[O:14])[CH3:11]
Reactant: COC(OC)N(C)C
Reactant: CCc1cccc(CC)c1NC(=O)NC(=N)NC
Agent: Cl
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CCc1cccc(CC)c1-n1cnc(NC)nc1=O
Yield: 46.6 %

Procedure:
To a suspension of 22.8 g (80.0 mmol) of 1-(2,6-diethylphenyl)-3-methylamidinourea hydrochloride in CH3CN (100 ml) were added 19.1 g (160.0 mmol) of DMF-DMA and the reaction mixture was heated at reflux for 3 hours. The CH3CN was removed under reduced pressure and the residue partitioned between CHCl3 and H2O. The layers were separated and the aqueous layer extracted with CHCl3 (1×100). The combined CHCl3 extracts were washed with H2O (1×100 ml), dried (MgSO4) and concentrated under reduced pressure to give an off-white solid, which by NMR confirmed the desired free base. The solution was dissolved in H2O and acidified with HCl/MeOH and the MeOH removed under reduced pressure to give an off-white solid which was crystallized from CH3CN to give after vacuum drying over the weekend (105° C., house vacuum) 16.7 g (71%) of crude product. The material was recrystallized from CH3CN (a hot filtration was necessary to remove some undissolved solid) to give 11.0 g (47%) of desired product as a white crystalline solid:
Reaction SMILES: [C:1](=[O:6])([O:3][CH2:4][CH3:5])[NH2:2].B(F)(F)F.CCOCC.[CH3:16][C:17]([CH3:31])=[CH:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30]>C1(C)C=CC=CC=1>[CH2:4]([O:3][C:1](=[O:6])[NH:2][C:17]([CH3:31])([CH3:16])[CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])[CH3:5]
Reactant: CC(C)=CCN1C(=O)c2ccccc2C1=O
Reactant: CCOC(N)=O
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)NC(C)(C)CCN1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 32.9 %

Procedure:
34.2 g of ethyl carbamate are put in the solution in the toluene, 22 mL of BF3.Et2O are added and heating is performed for 1 h 30 mins at 70° C. 11 g of 2-(3-methylbut-2-en-1-yl)-1H-isoindole-1,3-dione are added and heating with reflux is performed for 12 h. After returning to RT, the mixture is dry evaporated and then taken up in an H2O/AcOEt mixture. The organic phase is decanted, washed with a solution saturated with NaCl and then dried on magnesium sulfate. The crude is purified by flash chromatography on silica gel (CH2Cl2/MeOH, 99/1). 5.12 g (yield=31%) of ethyl[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1,1-dimethylpropyl]-carbamate are obtained as a brown powder used as such.
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][CH:13]=O.BrC[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][CH2:13][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CBr
Reactant: O=CNc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1nc2ccccc2s1
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To the suspension of 0.2 g (5 mmol) 60% sodium hydride in 5 ml dimethylformamide in small portions 0.89 g (5 mmol) 1,3-benzothiazol-2-ylformamide, then after 30 minutes of stirring, dropwise the solution of 0.92 g (5.5 mmol) ethyl bromoacetate in 2 ml dimethylformamide are added and the mixture is stirred at room temperature for 4 hours. The reaction mixture is poured onto ice-water mixture, the precipitated crystals are filtered off. 0.85 g title compound is obtained. LC/MS[MH+]=237 (C11H12N2O2S 236.294). The mixture of N2-1,3-benzothiazol-2-yl-N1-{3-[(3,4-dichlorobenzyl)(methyl)amino]propyl}glicinamide 0.68 g (2.88 mmol) ethyl N-1,3-benzothiazol-2-ylglicinate and 0.81 g (2.88 mmol) N-(3,4-dichlorobenzyl)-N-(methyl)propane-1,3-diamine is heated at 100° C. for 2 hours. The crude melt is purified by column chromatography using chloroform-methanol 19:1 mixture as eluent. 500 mg title compound is obtained as crystals.