Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=2)=[C:18]([CH3:31])[CH:17]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CO>[CH3:31][C:18]1[CH:17]=[C:16]([CH2:14][N:10]2[CH2:11][CH2:12][CH2:13][CH:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9]2)[CH:30]=[CH:29][C:19]=1[O:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=1
Reactant: Cc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Reactant: c1ccc(C2CCCNC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CO
Product: Cc1cc(CN2CCCC(c3ccccc3)C2)ccc1Oc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 69.6 %

Procedure:
Convert 3-phenyl piperidine hydrochloride (0.652 g, 3.30 mmol) to the free base using ion exchange chromatography (methanol→2 M ammonia/methanol) and concentrate. Combine the free base with 6-(4-formyl-2-methyl-phenoxy)-nicotinonitrile (from step 1 above) (0.748 g, 3.29 mmol), sodium triacetoxyborohydride (1.05 g, 4.95 mmol), and acetic acid (0.30 mL, 5.24 mmol) in 1,2-dichloroethane (33 mL) and stir at ambient temperature. After 17 h, wash reaction mixture with saturated sodium bicarbonate (aq) (2×50 mL), dry over anhydrous magnesium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography (hexanes→2:1 hexanes:ethyl acetate) to provide 0.878 g (70%) of the title compound as a white foam: 1H NMR (CDCl3): 8.46 (d, 1H, J=2.9 Hz), 7.91 (dd, 1H, J=2.9, 8.8 Hz), 7.34-7.19 (m, 7H), 6.99 (d, 2H, J=8.8 Hz), 3.52 (s, 2H), 3.06-2.94 (m, 2H), 2.86 (tt, 1H, J=3.9, 11.7 Hz), 2.13 (s, 3H), 2.10-1.91 (m, 3H), 1.84-1.68 (m, 2H), 1.48 (dq, 1H, J=4.9, 12.2 Hz).
Reaction SMILES: C[Mg]Cl.CON(C)[C:7]([CH:9]1[CH2:13][S:12][C:11](=[O:14])[N:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:8].[C:25](O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:7]([CH:9]1[CH2:13][S:12][C:11](=[O:14])[N:10]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:8])[CH3:25]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COc1ccc(CN2C(=O)SCC2C(=O)N(C)OC)cc1
Agent: C[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)SCC2C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A dry three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with 0.805 L of a 3 M solution of methylmagnesium chloride in THF. The solution was purged with nitrogen and cooled to 0° C. In a separate flask, 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide (250.0 g, 0.805 mol) was dissolved in 1.00 L of dry THF. The resulting solution was added to the solution of methyl magnesium chloride at a rate that maintained an internal reaction temperature less than 5° C. The reaction was monitored by HPLC and was considered complete upon the disappearance of starting material. The reaction mixture was slowly added to 1.00 L of a 10% citric acid solution at a rate that maintained a temperature of less than 25° C. The mixture was diluted with 0.90 L of water. The THF was removed by distillation at atmospheric pressure. The product was extracted with 2.5 L of ethyl acetate. The organic phase was separated, concentrated to a final volume of ˜800 mL and cooled to room temperature. A suspension was formed by the addition of 16 L of n-heptane. The suspension was stirred for 30 minutes. The resulting solid was isolated by filtration and was dried in a vacuum oven at 40° C. for 12 hours. Approximately 170 g of 4-acetyl-3-(4-methoxy-benzyl)-thiazolidin-2-one was obtained (80% yield). 1H NMR (300 MHz, DMSO) δ 7.14 (d, 8.9 Hz, 2H), 6.88 (d, 8.9 Hz, 2H), 4.48 (dd, J=9.4, 2.6 Hz, 1H), 4.27 (AB, JAB=15.2 Hz, ΔvAB=267.3 Hz, 2H), 3.72 (s, 3H), 3.62 (dd, J=11.9, 10.0 Hz, 1H), 3.37 (dd, J=11.8, 2.6 Hz, 1H), 2.19 (s, 3H). 13C NMR (75 MHz, DMSO) δ 26.9, 27.9, 47.2, 55.8, 66.0, 114.7, 129.1, 130.0, 159.4, 171.7, 205.1; [α]26.5D-56.00 (c=1.39, EtOH).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[C:35]3[C:39]=2[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1Cc2c(N3CCOCC3)ccc(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCOCC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-Amino-2-methyl-4-(morpholin-4-yl)-2,3-dihydro-1H-isoindol-1-one (Compound 208A). MS (ES+): m/z 665.33 (100) [MH+]; HPLC: tR=1.07 min (UPLC, purity).
Reaction SMILES: [CH:1]1([S:4]([C:8]2[CH:38]=[CH:37][C:11]([CH2:12][NH:13][C:14]([C:16]3[C:21](=[O:22])[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:19]([CH3:33])[N:18]([CH:34]([CH3:36])[CH3:35])[CH:17]=3)=[O:15])=[CH:10][CH:9]=2)=[N:5][C:6]#[N:7])[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:44].C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)C>[CH:1]1([S:4]([C:8]2[CH:38]=[CH:37][C:11]([CH2:12][NH:13][C:14]([C:16]3[C:21](=[O:22])[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:19]([CH3:33])[N:18]([CH:34]([CH3:36])[CH3:35])[CH:17]=3)=[O:15])=[CH:10][CH:9]=2)(=[N:5][C:6]#[N:7])=[O:44])[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(=NC#N)C3CC3)cc2)cn1C(C)C
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CCO
Product: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(=O)(=NC#N)C3CC3)cc2)cn1C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid 4-(S-cyclopropyl-N-cyanosulfinimidoyl)-benzylamide (preparation 63d, 40 mg, 74 μmol), meta-chloroperoxybenzoic acid (77%, 25 mg, 0.11 mmol) and potassium carbonate (31 mg, 0.22 mmol) in ethanol is stirred at room temperature for 1 h. Another portion of meta-chloroperoxybenzoic acid (77%, 5 mg, ai 0.02 mmol) is added and stirring is continued for 1.5 h. Saturated aqueous sodium thiosulfate solution is added, and the mixture is extracted with dichloromethane. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by preparative reversed phase HPLC (Xbridge, gradient of acetonitrile in water, 0.1% TFA). Yield: 13 mg (31% of theory); ESI mass spectrum: [M+H]+=557; r.t. HPLC: 0.65 min (X011_S03).
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]([O:20][C@H:21]([C@@H:47]1[NH:52][C@@H:51]([CH3:53])[CH:50]([OH:54])[O:49][CH2:48]1)[C@@H:22]([N:32]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.[F:62][C:63]1([CH2:69]O)[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:40]([N:32]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:22]([CH2:23][C:24]1[CH:25]=[C:26]([F:31])[CH:27]=[C:28]([F:30])[CH:29]=1)[C@H:21]([O:20][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@H:47]1[CH2:48][O:49][C@@H:50]([O:54][CH2:69][C:63]2([F:62])[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]2)[C@H:51]([CH3:53])[NH:52]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: C[C@@H]1N[C@@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)COC1O
Reactant: OCC1(F)CCCCC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1N[C@@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)CO[C@H]1OCC1(F)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
Add triphosgene (246 mg, 0.79 mmol) at room temperature to a solution of (3S,5R)-5-[(1R,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-3-methylmorpholin-2-ol (1 g, 1.75 mmol) and triethylamine (0.99 mL, 7 mmol) in anhydrous dichloromethane (17 mL). Stir for 30 min, cool to 0° C. and add (1-fluorocyclohexyl)-methanol (1.16 g, 8.75 mmol) and trimethylsilyl trifluoromethanesulfonate (TMSOTf) (0.64 mL, 3.5 mmol). Stir at 0° C. for 1 hour and at room temperature for 2 hours. Add more trimethylsilyl trifluoromethanesulfonate (0.16 mL, 0.87 mmol) and stir at room temperature for 30 min. Add 10% aqueous potassium carbonate, separate the organic layer and extract the aqueous layer with dichloromethane. Combine the organic layers, dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 20:80 hexanes:ethyl acetate), to give the title compound as a colorless oil (375 mg).
Reaction SMILES: [CH2:1]1COCC1.Cl.[F:7][C:8]1[CH:9]=[C:10]([N+:27]([O-:29])=[O:28])[C:11]([C:18](=[O:26])[CH2:19][C:20]2[N:24]=[CH:23][N:22](C)[N:21]=2)=[C:12]([CH:17]=1)[C:13](OC)=[O:14]>CCCCCCC>[F:7][C:8]1[CH:17]=[C:12]2[C:11](/[C:18](=[CH:19]/[C:20]3[N:21]([CH3:1])[N:22]=[CH:23][N:24]=3)/[O:26][C:13]2=[O:14])=[C:10]([N+:27]([O-:29])=[O:28])[CH:9]=1
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C(=O)Cc1ncn(C)n1
Reactant: C1CCOC1
Agent: Cl
Solvent: CCCCCCC
Product: Cn1ncnc1/C=C1\OC(=O)c2cc(F)cc([N+](=O)[O-])c21

Procedure:
An alternative workup procedure to that illustrated in Example 2A follows. Instead of evaporating the reaction mixture to dryness, it was condensed to 2 volumes, followed by solvent exchange with 12 volumes of THF, and then 12 volumes of heptane. The slurry mixture was concentrated to 2 volumes and filtered to give the product. As such, 1.8 kilograms of (Z)-6-fluoro-3-((1-methyl-1H-1,2,4-triazol-3-yl)methylene)-4-nitroisobenzofuran-1(3H)-one (3) gave 2.15 kilograms (yield 96.4%) of the product methyl 5-fluoro-2-(2-(1-methyl-1H-1,2,4-triazole-3-yl)acetyl)-3-nitrobenzoate hydrochloride (4).
Reaction SMILES: ClCCl.O=C1CCC(=O)N1[O:11][C:12]([O:14][CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=O.OCC(C)(C)C(OC)=O.[C:32]1([C@H:42]([N:44]([CH2:52][C@@H:53]2[C@@H:57]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH2:56][NH:55][CH2:54]2)[C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH3:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>C(N(CC)CC)C>[C:47]([O:46][C:45]([N:44]([CH2:52][C@@H:53]1[C@@H:57]([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:56][N:55]([C:12]([O:14][CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[O:11])[CH2:54]1)[C@@H:42]([C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)[CH3:43])=[O:51])([CH3:49])([CH3:50])[CH3:48]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)C(C)(C)COC(=O)ON1C(=O)CCC1=O
Agent: COC(=O)C(C)(C)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)COC(=O)N1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Temperature: 25 °C

Procedure:
A 2 ml dichloromethane solution of methyl 3-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)-2,2-dimethylpropionate prepared from 136 mg of methyl 3-hydroxy-2,2-dimethylpropionate in the same manner as in Reference Example 46 was added to 5 ml dichloromethane solution of 235 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate and 0.21 ml of triethylamine. After 12Hours of stirring at room temperature, the reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (hexane-ethyl acetate) to obtain 227 mg of 3-methoxy-2,2-dimethyl-3-oxopropyl (3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidine-1-carboxylate as a colorless amorphous substance.
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][CH:10]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:2][C:3]([OH:5])=O.[CH3:23][O:24][NH:25][CH3:26].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]([C:6]([O:8][CH2:9][CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])[CH2:2][C:3]([N:25]([O:24][CH3:23])[CH3:26])=[O:5]
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h

Procedure:
Fmoc-Gly-OH, 1 g (3.36 mmol), 361.0 mg (3.70 mmol) of CH3ONHCH3 and 447.3 mg (3.53 mmol) of HOBt were dissolved in DMF. Under ice cooling, 677 mg (3.53 mmol) of WSCI.HCl and 1.94 mL (11.1 mmol) of DIEA were added to the solution, followed by stirring overnight. After the reaction solution was concentrated, 10% aqueous citric acid solution was added and the precipitated solid was extracted with AcOEt. The organic layer was washed with 10% aqueous citric acid solution, 5% NaHCO3 aqueous solution and satd. sodium chloride aqueous solution, and dried over anhydrous Na2SO4. The oily Fmoc-Gly-N(CH3)OCH3 product obtained by concentrating the solvent was dissolved in THF. Under ice cooling, 332 mg (0.726 mmol) of LiAlH4 was added by small portions to the solution over 15 minutes. After stirring at 0° C. for 30 minutes, 150 mL of diethyl ether and 150 mL of 20% citric acid aqueous solution were sequentially added to the reaction solution, which was then vigorously stirred for an hour. The organic layers were collected and the aqueous layer was again extracted with 150 mL of diethyl ether. The pooled organic layer was washed sequentially with 5% NaHCO3 aqueous solution, water, 10% citric acid aqueous solution, water and then satd. sodium chloride aqueous solution, and dried over anhydrous Na2SO4. The organic layer obtained was concentrated to give Fmoc-Gly-al as an oily substance.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH2:21][CH:20]([CH2:25][C:26](OC)=[O:27])[CH2:19][CH2:18]3)=[CH:9][CH:8]=1>C1COCC1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>[C:7]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH2:21][CH:20]([CH2:25][CH2:26][OH:27])[CH2:19][CH2:18]3)=[CH:11][CH:12]=1
Reactant: COC(=O)CC1CCc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCC1CCc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a suspension of lithium aluminum hydride (4.71 g) in THF (200 ml) was added a solution of methyl 6-(4-biphenylyl)methoxy-2-tetralinacetate (24.0 g) in THF (50 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr and diluted with saturated aqueous Rochelle salt. The precipitate was filtered off and the filtrate was concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the titled compound (22.1 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:19])=[C:7]([CH:18]=1)[O:8][CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17].[C-:20]#[N:21].[Na+]>CN(C=O)C>[CH3:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[CH2:9][O:8][C:7]1[CH:18]=[C:3]([CH2:2][C:20]#[N:21])[CH:4]=[CH:5][C:6]=1[F:19]
Reactant: Cc1cccc(C)c1COc1cc(CCl)ccc1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1COc1cc(CC#N)ccc1F
Temperature: 100 °C

Procedure:
To a stirred solution of 2-((5-(chloromethyl)-2-fluorophenoxy)methyl)-1,3-dimethylbenzene (Step C, 4 g, 14.3 mmol), KI (0.33 g) in DMF (30 ml) was added NaCN (1.02 g, 20.8 mmol). The reaction mixture was heated at 100° C. for 4 hours, concentrated, diluted with EtOAc and washed with water (2×), dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hexane:methylene chloride, 1:1) to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[S:10](Cl)(=[O:13])(=[O:12])[NH2:11]>C(Cl)Cl>[NH2:11][S:10]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])(=[O:13])=[O:12]
Reactant: O=C1CCCN1CCO
Reactant: NS(=O)(=O)Cl
Solvent: ClCCl
Product: NS(=O)(=O)OCCN1CCCC1=O
Reaction time: 2 h
Yield: 66.3 %

Procedure:
A solution of 6.5 g (0.05 mole) of 1-(2-hydroxyethyl)-2-pyrrolidone (Fluka) in 100 ml of methylene chloride was treated with 5.8 g (0.05 mole) of sulfamoyl chloride. The solution was stirred for 2 hr, then concentrated under vacuum. The residue was crystallized twice from 2-propanol to give 6.9 g (66%) of the title compound as white crystals, mp 110°-112° C. The compound was noted to be slightly hygroscopic.
Reaction SMILES: [C:1]([N:5]1[C:14](=[O:15])[C:13]2[C:8](=[N+:9]([O-])[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=2)[C:6]1=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[C:1]([N:5]1[C:14](=[O:15])[C:13]2[C:8](=[N:9][C:10]([Cl:22])=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=2)[C:6]1=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)N1C(=O)c2cc([N+](=O)[O-])c[n+]([O-])c2C1=O
Product: CC(C)(C)N1C(=O)c2cc([N+](=O)[O-])c(Cl)nc2C1=O

Procedure:
100 ml of phosphoryl chloride were treated with 7.5 g (0.028 mol) of N-tert-butyl-5-nitropyridine-2,3-dicarboximide-1-oxide at 60° C. and in portions in the course of 2 minutes with stirring and the mixture was stirred under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was taken up in methylene chloride and the solution was stirred into ice-water. The organic phase was extracted in succession with water, saturated sodium hydrogencarbonate and sodium chloride solution and dried. After filtering off with suction through neutral alumina, it was concentrated and the residue was stirred with ether and ether/pentane, filtered off with suction and dried. 4.49 g (56% of theory) of the title compound of m.p. 100°-104° C. were obtained (active compound Example 1.019).
Reaction SMILES: [H-].[Na+].[CH3:3]O.[Br:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=1.CI>CN(C)C=O>[Br:5][C:6]1[C:11]([O:12][CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CO
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccnc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, 60% oil sodium hydride (605 mg, 15.1 mmol) was added in portions to methanol (10 ml) under ice cooling. Twenty minutes later, a dimethylformamide (20 ml) solution of 2-bromo-3-hydroxypyridine (2.5 g, 14.4 mmol) was added to the resulting mixture. The reaction mixture was distilled under reduced pressure to remove methanol and to the residue was added methyl iodide (0.94 ml, 15.1 mmol). The mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [N+](C1C=CC(CBr)=CC=1)([O-])=O.[CH2:12]([O:19][CH2:20][C@H:21]([C@H:33]([C@@H:35]([C@@H:37]([CH2:49][O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[O:38]CC1C=CC([N+]([O-])=O)=CC=1)[OH:36])[OH:34])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Ag]=O>[CH2:12]([O:19][CH2:20][C@H:21]([C@H:33]([C@@H:35]([C@@H:37]([CH2:49][O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[OH:38])[OH:36])[OH:34])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(CO[C@H](COCc2ccccc2)[C@@H](O)[C@H](O)[C@@H](COCc2ccccc2)OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=[Ag]
Agent: O=[N+]([O-])c1ccc(CBr)cc1
Product: O=[N+]([O-])c1ccc(CO[C@H](COCc2ccccc2)[C@@H](O)[C@H](O)[C@H](O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 1,6-di-O-benzyl-3,4-O-isopropylidene-D-mannitol, obtained as in example 2, (402 mg, 1 mmol) in toluene (10 mL) was added freshly prepared silver oxide (464 mg, 2 mmol) and 4-nitrobenzylbromide (648 mg, 3 mmol). The suspension was stirred at room temperature overnight. More silver oxide (464 mg, 2 mmol) was added and the reaction was refluxed for 24 h. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 50% EtOAc in hexane to yield 60% of 1,6-di-O-benzyl-2-O-(4-nitrobenzyl)-D-mannitol and 12% of 1,6-di-O-benzyl-2,5-di-O-(4-nitrobenzyl)-D-mannitol.
Reaction SMILES: FC1C=CC(C2[C:13](=[O:14])[C:12]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]4[C:26]5[N:27]([CH:46]=[CH:47][N:48]=5)[N:28]=[C:29]([NH:31][C@H:32]5[CH2:37][CH2:36][C@H:35]([NH:38]C(=O)OC(C)(C)C)[CH2:34][CH2:33]5)[CH:30]=4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:10]=[CH:9]2)=CC=1.[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>C(Cl)Cl>[NH2:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([NH:31][C:29]2[CH:30]=[C:25]([NH:24][C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:15]([C:12]4[C:13](=[O:14])[N:17]([C:18]5[CH:19]=[CH:20][C:50]([F:55])=[CH:51][CH:23]=5)[CH:9]=[CH:10][CH:11]=4)=[O:16])=[CH:23][CH:22]=3)[C:26]3[N:27]([CH:46]=[CH:47][N:48]=3)[N:28]=2)[CH2:37][CH2:36]1.[C:51]([OH:53])([C:50]([F:55])([F:54])[F:49])=[O:52]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(Nc3ccc(NC(=O)C4=CC=CC(c5ccc(F)cc5)C4=O)cc3)c3nccn3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3)c3nccn3n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a 50 ml round bottom flask added tert-butyl(trans)-4-(8-(4-(5-(4-fluorophenyl)-6-oxocyclohexa-1,3-dienecarboxamido)phenylamino)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate (0.025 g, 0.04 mmol) from 1e and 20% trifloroacetic acid in methylene chloride (4 ml). The reaction was allowed to stir at room temperature for 5 min. The reaction was then concentrated in vacuo and diluted with methanol and purified via HPLC (20-100% methanol gradient), which provided the titled compound as a TFA salt (0.007 g). 1H NMR (400 MHz, MeOD) δ ppm 12.11 (1H, s), 8.68 (1H, dd, J=7.38, 2.29 Hz), 7.87-8.13 (2H, m), 7.71-7.88 (3H, m), 7.41-7.63 (2H, m), 7.33 (4H, t, J=8.65 Hz), 6.65-6.82 (1H, m), 6.43 (1H, s), 3.54-3.88 (1H, m), 2.96-3.17 (1H, m), 2.23 (2H, m), 2.08 (2H, m), 1.44-1.68 (2H, m), 1.17-1.43 (2H, m). LC/MS, m/e 553 (M+1). HPLC Rt, 2.14 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.