Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[S:28]1(=[O:35])(=[O:34])[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:30][CH2:31][CH2:32][CH2:33][S:28]4(=[O:35])=[O:34])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=S1(=O)CCCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 70.9 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (452 mg) described in Preparation Example 112 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (359 mg) was obtained.
Reaction SMILES: [Si]([O:18][C:19]1[CH:62]=[CH:61][C:22]([O:23][CH2:24][C@@H:25]([OH:60])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:59]=[CH:58][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH:45]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[C:46]1([CH:45]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:44][NH:43][C:41]([N:38]2[CH2:39][CH2:40][CH:35]([NH:34][C:33]3[CH:58]=[CH:59][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:60])[CH2:24][O:23][C:22]4[CH:61]=[CH:62][C:19]([OH:18])=[CH:20][CH:21]=4)=[CH:31][CH:32]=3)[CH2:36][CH2:37]2)=[O:42])[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCC(c4ccccc4)c4ccccc4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCC(c1ccccc1)c1ccccc1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 63.6 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-(2,2-diphenylethyl)-1-piperidinecarboxamide (0.20 g, 0.236 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.095 g, 0.15 mmol)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[C:9]([O:12][CH3:13])[C:8]3[C:14](=[O:21])[CH:15]=[C:16]([C:18]([OH:20])=[O:19])[O:17][C:7]=3[C:6]=2[N:5]=[C:4]([C:22]([OH:24])=[O:23])[CH:3]=1.C(=O)(O)[O-].[Na+:29].CC(C)=O>O>[Cl:1][C:2]1[C:11]2[CH:10]=[C:9]([O:12][CH3:13])[C:8]3[C:14](=[O:21])[CH:15]=[C:16]([C:18]([O-:20])=[O:19])[O:17][C:7]=3[C:6]=2[N:5]=[C:4]([C:22]([O-:24])=[O:23])[CH:3]=1.[Na+:29].[Na+:29]
Reactant: COc1cc2c(Cl)cc(C(=O)O)nc2c2oc(C(=O)O)cc(=O)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc2c(Cl)cc(C(=O)[O-])nc2c2oc(C(=O)[O-])cc(=O)c12
Yield: 46.1 %

Procedure:
The product of step (f) (0.7316 g) suspended in water was treated with sodium bicarbonate (0.45 g) and stirred until complete dissolution occurred. The solution was treated with pure acetone and cooled. The precipitated product was collected by filtration and dried under reduced pressure at 80° C. for four hours, affording (0.38 g) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:10]([CH3:12])[CH3:11].C([Li])CCC.C(OCC)C.[C:23](=[O:25])=[O:24]>O1CCCC1>[Cl:1][C:2]1[C:3]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:5]=[C:6]([Cl:8])[C:7]=1[C:23]([OH:25])=[O:24]
Reactant: O=C=O
Reactant: CC(C)Oc1ccc(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Cl)c(C(=O)O)c1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichloro-1-isopropoxybenzene (3.53 g) in tetrahydrofuran (35 ml) was added n-butyl lithium solution (1.6 Mol solution in n-hexane, 11 ml) through a syringe at -78° C. After stirring for one hour at -78° C., the mixture was poured into dry diethyl ether (50 ml) containing pulverized dry ice in a few minutes. After warming to ambient temperature, the mixture was concentrated in vacuo. The residue was partitioned between diethyl ether (50 ml) and aqueous 10% sodium. hydroxide solution (100 ml). The aqueous layer was adjusted to pH 2 with 10% hydrochloric acid. The separated oil was extracted with dichloromethane. The extract was washed with water, dried, and evaporated under reduced pressure. The residue was crystallized from n-hexane to give 2,6-dichloro-3-isopropoxybenzoic acid (3.0 g).
Reaction SMILES: [H-].[Na+].ClC1C=CC([C:8](=O)[CH2:9][NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=CC=1.CI.[O:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1.CN(C)C=O>>[Cl:20][C:18]1[CH:17]=[CH:16][C:42]([C:43](=[O:39])[CH2:8][CH2:9][NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:12]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:41][CH:40]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1c(NCC(=O)c2ccc(Cl)cc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1c(NCCC(=O)c2ccc(Cl)cc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Suspend sodium hydride (160 mg of a 60% dispersion, 4 mmol) in anhydrous tetrahydrofuran/dimethylformamide (3 mL/2:1) and cool to 0° C. under a nitrogen atmosphere. Add 3-[(p-chlorophenacyl)amino]-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole (2 g, 3.9 mmol) in tetrahydrofuran/dimethylformamide (10 mL/2:1) dropwise to the suspension. Stir at 0° C. for 30 minutes. Add methyl iodide (0.137 mL, 2.2 mmol) and stir for 30 minutes at 0° C. Warm the reaction to room temperature and after 4 hours quench with water (20 mL). Extract with ethyl acetate (20 mL), wash with saturated sodium chloride, dry over magnesium sulfate, filter and concentrate in vacuo to yield the title compound.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[CH2:4][C:5]([OH:7])=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:32](O)[CH:33]=[CH2:34]>CC#N.CCOC(C)=O>[CH3:2][N:3]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[CH2:4][C:5]([O:7][CH2:34][CH:33]=[CH2:32])=[O:6]
Reactant: CN(CC(=O)O)Cc1ccc(NS(C)(=O)=O)cc1
Reactant: C=CCO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOC(=O)CN(C)Cc1ccc(NS(C)(=O)=O)cc1
Temperature: 75 °C
Yield: 88 %

Procedure:
A mixture of 2-(methyl(4-(methylsulfonamido)benzyl)amino)acetic acid hydrochloride (1.054 g, 3.41 mmol), CDI (1.107 g, 6.83 mmol), and TEA (0.952 ml, 6.83 mmol) in CH3CN (80 ml) was heated at 75° C. for 3 hours. The solvent was evaporated; the residue was dissolved in prop-2-en-1-ol (30 ml, 439 mmol) and heated at 75° C. for 1 hour. The mixture was diluted with EtOAc and washed several times with NH4Cl sat. sol. The organic phase was dried over Na2SO4, the solvent was removed, and the residue was filtered on SCX cartridge (DCM/MeOH 1/1; conc.aq.NH4OH/MeOH 1/9). The basic fraction was evaporated to dryness to give allyl 2-(methyl(4-(methylsulfonamido)benzyl)-amino)acetate as a brown oil (0.942 g, 3.02 mmol, 88% yield, MS/ESI+ 313.2 [MH]+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=O)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:32][CH:33]([CH3:36])[CH2:34][OH:35].CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl.CN(C=O)C>[OH:35][CH2:34][CH:33]([NH:32][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([C:18]2[CH:19]=[C:14]([NH:13][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])[N:12]=3)[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=2)[CH:21]=1)[CH3:36]
Reactant: CC(N)CO
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(CO)NC(=O)c1cccc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 15.2 %

Procedure:
A mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (50 mg, 0.121 mmol), 2-aminopropan-1-ol (10 mg, 0.133 mmol), 1-methyl-1H-imidazole (40 mg, 0.484 mmol) and EDCI (92 mg, 0.484 mmol) in dichloromethane (10 mL) and DMF (0.2 mL) was stirred at room temperature for 20 h then extracted with ethyl acetate (50 mL) and washed with water (2×2 mL), then brine (2×2 mL). After drying and concentration, the residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, methanol:dichloromethane=1:50) and further purified by Prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 45% acetonitrile/55% water (0.1% TFA, v/v) in a linear fashion over 9 min) to afford N-(1-hydroxypropan-2-yl)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (8.7 mg, 14%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.91 (s, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.17-8.00 (m, 4 h), 7.65 (t, 1H, J=7.8 Hz), 7.58-7.55 (m, 1H), 6.40 (d, 1H, J=7.5 Hz), 6.28 (d, 1H, J=8.4 Hz), 4.25-4.21 (m, 2H), 3.71-3.58 (m, 3H), 3.54-3.48 (m, 1H), 2.19-2.07 (m, 3H), 1.81 (brs, 1H), 1.29 (d, 3H, J=6.3 Hz), 1.19 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 472, tR=1.654 min, HPLC: 99.36% at 214 nm, 98.85% at 254 nm, tR=5.697 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21]1[C:25](I)=[C:24]([CH:27]2[CH2:30][CH:29]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28]2)[O:23][N:22]=1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]1(B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21]1[C:25]([CH:36]2[CH2:38][CH2:37]2)=[C:24]([CH:27]2[CH2:30][CH:29]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28]2)[O:23][N:22]=1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: CC(C)(C)CC1CC(c2onc(C(CCCOCc3ccccc3)CC(=O)OC(C)(C)C)c2I)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)CC1CC(c2onc(C(CCCOCc3ccccc3)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
tert-Butyl 6-benzyloxy-3-{5-[3-(2,2-dimethylpropyl)cyclobutyl]-4-iodoisoxazole-3-yl}hexanoate (4.20 g), 2-cyclopropyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.34 g), tripotassium phosphate (5.92 g), DMF (90 mL) and water (10 mL) were mixed. The mixture was degassed by bubbling argon gas. To the mixture was added PdCl2(PPh3)2 (734 mg). The mixture was stirred at 80° C. for 1 hr. To the reaction mixture was added ethyl acetate, and then the mixture was filtered. The aqueous layer was removed, and the organic layer was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/25) to give the title compound (980 mg). A mixture of the title compound and impurities thereof (1.24 g) was also obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:16])CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][F:16])[N:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCc1cccc(Br)n1
Solvent: ClCCl
Product: FCc1cccc(Br)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A solution of (6-bromopyridin-2-yl)methanol (5 g, 27 mmol) in dry DCM (60 mL) was added dropwise at −78° C. to a cooled solution of DAST (13 g, 80 mmol) in dry DCM (50 mL). The reaction mixture was stirred 1 h at −78° C. then 1 h at room temperature. To complete the reaction, an additional 5 mL of DAST were slowly added at −60° C. and the reaction mixture was kept overnight at room temperature. The reaction was quenched with water and the organic layer extracted with DCM, dried over MgSO4 and evaporated. Purification over silicagel chromatography (prepacked 85 g silicagel column, Cyclohexane/AcOEt:90/10 as eluent) to afford 4.50 g of 2-bromo-6-(fluoromethyl)pyridine (Yield: 89%) as pale yellow oil which crystallized at 0° C.
Reaction SMILES: C([O:3][P:4](Cl)[O:5]CC)C.[CH2:9]([Mg]Cl)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(OCC)C>[CH2:9]([PH:4](=[O:3])[OH:5])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cl[Mg]CCc1ccccc1
Reactant: CCOP(Cl)OCC
Solvent: O
Solvent: CCOCC
Product: O=[PH](O)CCc1ccccc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
Diethylchlorophosphite (15.6 g,0.1 mol) in 100 mL of dry diethyl ether was cooled to 5° C. under an atmosphere of nitrogen. Phenethylmagnesium chloride (100 mL, 0.1 mol, 1.0 M in THF) was added dropwise over 2 hours while maintaining a temperature between 0-10° C. A thick white slurry formed and stirred at room temperature overnight. The mixture was filtered under a nitrogen atmosphere and the filtrate evaporated under reduced pressure to give a clear and colorless liquid. The liquid was stirred as 15 mL of water was added followed by 0.5 mL of concentrated hydrlochloric acid. An exothermic reaction was observed and stirring continued for 15 minutes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO4) and evaporated. The clear liquid was brought up in sodium hydroxide (40 mL, 2.0 M NaOH), stirred for 1 hour and washed once with diethyl ether. The aqueous layer was acidified to pH 1.0 with concentrated hydrochloric acid and extracted with ethyl acetate. The organics were combined, dried (MgSO4) and evaporated to give phenethylphosphinic acid (1,R=CH2CH2Ph, R1=H)(9.8 g, 58%) as a clear light yellow oil.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]3[CH2:23][N:22]([C:24]([O:26]C(C)(C)C)=O)[C@H:21]([CH2:31][O:32][C:33](=[O:43])[NH:34][C:35]4[CH:40]=[CH:39][C:38]([CH2:41][CH3:42])=[CH:37][CH:36]=4)[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl.CCN(C(C)C)C(C)C.[Cl:54][C:55]1[CH:64]=[CH:63][CH:62]=[CH:61][C:56]=1[CH2:57][N:58]=C=O>CO>[CH2:41]([C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:33](=[O:43])[O:32][CH2:31][C@@H:21]2[CH2:20][C@@H:19]([NH2:18])[CH2:23][N:22]2[C:24](=[O:26])[NH:58][CH2:57][C:56]2[CH:61]=[CH:62][CH:63]=[CH:64][C:55]=2[Cl:54])=[CH:40][CH:39]=1)[CH3:42]
Reactant: CCc1ccc(NC(=O)OC[C@@H]2C[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)CN2C(=O)OC(C)(C)C)cc1
Reactant: O=C=NCc1ccccc1Cl
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(NC(=O)OC[C@@H]2C[C@@H](N)CN2C(=O)NCc2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of crude (2S,4R)-tert-butyl 4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-((4-ethylphenylcarbamoyloxy)methyl)pyrrolidine-1-carboxylate in MeOH was added HCl (4 N in dioxane). The reaction was stirred at rt for 1 h and concentrated. The residue was dissolved in THF (10 mL). To this solution were added DIEA (469 μL, 2.7 mmol) and 2-chlorobenzylisocyanate. The mixture was stirred at rt for 1 h and concentrated. The residue was dissolved in 10 ml of 20% piperidine in DCM. The reaction mixture was stirred at rt for 15 min, concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give ((2S,4R)-4-amino-1-(2-chlorobenzylcarbamoyl)pyrrolidin-2-yl)methyl 4-ethylphenylcarbamate (210 mg, 53% for 4 steps). LRMS (M+H+) m/z 431.1.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@:8]([CH2:27][O:28]C(=O)C)([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@H:6]1[N:32]1[CH:40]=[N:39][C:38]2[C:33]1=[N:34][CH:35]=[N:36][C:37]=2[NH:41][C:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=O)C.C[O-].[Na+].Cl>CO>[CH2:11]([O:10][C@@H:9]1[C@@:8]([CH2:27][OH:28])([CH2:18][O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:7][C@@H:6]([N:32]2[CH:40]=[N:39][C:38]3[C:33]2=[N:34][CH:35]=[N:36][C:37]=3[NH:41][C:42](=[O:49])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C@@H:5]1[OH:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@](CO)(COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1O)c1ccccc1
Reaction time: 2 h

Procedure:
To a stirred solution of nucleoside 58 (4.18 g, 6.28 mmol) in methanol (50 cm3) was added sodium methoxide (0.75 g, 13.8 mmol) at 0° C. The reaction mixture was stirred for 2 h, and ice was added. The mixture was neutralised using a 20% aqueous solution of HCl. Extraction was performed using dichloromethane (3×75 cm3), the organic phase was separated, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (98.5:1.5, v/v), as eluent to give nucleoside 59 as a white solid material (2.68 g, 73%). δH (CDCl3) 9.42 (1H, br s, NH), 8.58 (1H, s, H-8), 8.16 (1H, s, 2-H), 7.96 (2H, d, J 7.2 Bz), 7.52-7.08 (13H, m, Bn, Bz), 6.18 (1H, d, J 2.5, 1′-H), 4.85-4.38 (4H, m, Bn, 2′-H, 3′-H), 4.33 (2H, s, Bn) 3.09 (1H, d, J 11.9, 1″-Ha), 3.71 (1H, d, J 11.8, 1″-Hb), 3.50-3.39 (2H, m, 5-H). δC (CDCl3) 164.98 (NHCO), 152.19 (C-6), 151.00 (C-2), 149.34 (C-4), 142.28 (C-8), 137.32, 137.25, 133.46, 132.70, 128.69, 128.49, 128.40, 128.11, 128.03, 127.94, 127.83, 127.62, (Bz, Bn), 122.92 (C-5), 90.94, 88.75 (C-1′, C-4′), 77.65, 74.08, 73.44, 73.20, 71.12, 62.39 (C-1″, C-5′, C-2′, C-3′, 2×Bn). FAB-MS m/z 582 [M+N]+. Found: C, 65.6; H, 5.5; N, 11.7; C32H31N5O6 requires C, 66.1; H, 5.4; N, 12.0%.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[CH2:5]([O:7][P:8]([O:12]CC)[O:9][CH2:10][CH3:11])[CH3:6]>>[Br:1][CH2:2][CH2:3][P:8](=[O:12])([O:9][CH2:10][CH3:11])[O:7][CH2:5][CH3:6]
Reactant: CCOP(OCC)OCC
Reactant: BrCCBr
Product: CCOP(=O)(CCBr)OCC
Temperature: 65 °C
Yield: 95 %

Procedure:
1,2-dibromoethane (69 ml, 0.8 mol) was poured into a two-necked 150 mL round-bottom flask. Triethylphosphite (34.3 ml, 0.2 mol) was added under stirring and the mixture was then refluxed for 2 hours. The excess of 1,2-dibromoethane was removed by rotary evaporation under gentle warming at 60-70° C. The residue was distilled under reduced pressure (2 mmHg, 95-105° C. or 1 mmHg, 75° C.). Yield 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11]N(C)C.[C-:15]#[N:16].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:15]#[N:16]
Reactant: [C-]#N
Reactant: CN(C)Cc1c[nH]c2ccc(Cl)cc12
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1c[nH]c2ccc(Cl)cc12
Temperature: 140 °C
Yield: 62.1 %

Procedure:
A solution of aqueous formaldehyde (37%, 2.95 mL, 66.0 mmol) and dimethylamine (40%, 5.30 mL, 66.0 mmol) in 20 mL EtOH was cooled to 0° C. 5-Chloroindole (4.0 g, 26.4 mmol) was dissolved in a HOAc:EtOH mixture (1:1, 40 mL) and added dropwise to the reaction mixture. After stirring at this temperature for 2 h, the mixture was allowed to warm to room temperature and stir overnight. The mixture was added to a sat'd solution of NaHCO3. 1 N NaOH was added until the pH was between 9-10. The resulting mixture was extracted with CH2Cl2 (3×). The organics were combined and washed with a sat'd aq. NaCl, dried over MgSO4, filtered and concentrated in vacuo to give 4.65 g (85%) of 5-chloro-3-[(dimethylamino)methyl]indole as a yellow powder. Without further purification, 5-chloro-3-[(dimethylamino)methyl]indole (4.65 g, 22.4 mmol) was dissolved in dimethylformamide (80 mL) at room temperature with stirring. To this was added KCN (2.18 g, 33.5 mmol) in H2O (10 mL). The mixture was warmed to 140° C. and stirred for 14 h. H2O was added and the mixture was extracted with EtOAc (2×). The organics were combined and washed with sat'd brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by SiO2 flash chromatography (3:2, Heptane: EtOAc) to give 2.65 g (63%) of 5-chloroindole-3-acetonitrile. 1H NMR (DMSO-d6, 300 MHz) δ11.30 (br s, 1H), 7.63 (s, 1H), 7.42-7.38 (m, 2H), 7.05 (d, J=6.0 Hz, 1H), 5.70 (s, 2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[Cl:34][C:35]1[CH:36]=[C:37]([CH2:41][C:42](O)=[O:43])[CH:38]=[CH:39][CH:40]=1.Cl.CN(C)CCCN=C=NCC>CC#N>[Cl:34][C:35]1[CH:36]=[C:37]([CH2:41][C:42]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:43])[CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1cccc(Cl)c1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 3-chloro-phenylacetic acid (0.41 g, 2.4 mmol) were added. The reaction was then added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol) and was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 30% EtOAc in CH2Cl2 for 10 min, then increase to 60% EtOAc in CH2Cl2 over 20 min) to afford 2-(3-chloro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide as a white solid (0.73 g, 76%): mp, 185-187° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.2 min. (99%); 1H NMR (DMSO-d6): δ 2.03-2.08 (m, 1H), 2.52-2.63 (m, 2H), 2.86-2.91 (m, 1H), 3.56 (s, 2H), 4.73 (d, J=6.0 Hz, 2H), 5.12-5.18 (dd, J=5, 13 Hz, 1H), 7.23-7.82 (m, 7H), 8.70 (t, J=6 Hz, 1H), 11.13 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 30.90, 37.87, 41.53, 48.83, 121.93, 126.40, 127.15, 127.82, 128.94, 130.04, 131.52, 132.74, 133.25, 134.66, 138.54, 139.01, 166.88, 167.41, 169.77, 170.03, 172.73. Anal Calcd for C22H18ClN3O5: C, 60.08; H, 4.12; N, 9.55; Cl, 8.06. Found: C, 59.92; H, 3.85; N, 9.55; Cl, 8.37.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[N:16][N:15]([CH3:18])[C:14](=[O:19])[CH:13]=2)=[CH:8][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:18][N:15]1[C:14](=[O:19])[CH:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:7][CH:8]=2)[CH:17]=[N:16]1
Reactant: C1CCNCC1
Reactant: Cn1ncc(-c2ccc(OCCCCl)cc2)cc1=O
Product: Cn1ncc(-c2ccc(OCCCN3CCCCC3)cc2)cc1=O

Procedure:
This compound was prepared as the hydrochloride salt using 5-[4-(3-chloropropoxy)-phenyl]-2-methyl-2H-pyridazin-3-one and piperidine using the procedure described in Example 91 Step 5; Mp 253-4° C.; MS m/z 328 (M+H).