Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[ClH:16].[ClH:1].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CN1CCN(Cc2ccccc2)CC1)c1ccccc1
Yield: 67 %

Procedure:
A mixture of N-benzyl-piperazine dihydrochloride (20 mmol, prepared by using the general preparation 3, yield 70%), 2-chloro-1-phenylethanone (24 mmol), K2CO3 (70 mmol) and KI(2 mmol) in 100 ml of acetone was treated according to the general preparation 2 to give N1-benzyl-N4-phenacyl piperazine dihydrochloride (67%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:11]1[C:20]2[C:15](=[C:16]([CH:21]([CH3:25])[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:22](=[O:23])[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:25]
Reactant: NCc1cccc(Cl)c1Cl
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1cccc(Cl)c1Cl)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 2,3-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI−) m/z 357 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.17 (d, J 7.8, 1H), 7.26 (t, J 7.8, 1H), 7.52 (d, J 8.1, 1H), 7.78 (t, J 7.8, 1H), 7.91 (d, J 6.5, 1H), 8.16 (d, J 8.1, 1H), 8.24 (d, J 6.4, 1H), 8.59 (d, J 6.2, 1H), 8.66 (t, J 5.8, 1H), 9.50 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][C:6]=1[F:12])(=[O:4])=[O:3].[CH3:13][O:14][C:15]([C:17]1[CH:27]=[C:26]([OH:28])[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:13][O:14][C:15]([C:17]1[CH:27]=[C:26]([O:28][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[C:6]([F:12])[CH:7]=2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16]
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)c(F)c2)c2c(c1)OC(C)(C)C2
Temperature: 80 °C
Yield: 67.6 %

Procedure:
A mixture of 2,4-difluorophenyl methyl sulfone (865 mg, 4.50 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (1.00 g, 4.50 mmol), and Cs2CO3 (2.93 g, 9.00 mmol) in DMF (2 mL) was heated to 80° C. for 2.5 h, cooled to room temperature, quenched with H2O and extracted with 3×EtOAc. The organic layers were washed with 2×H2O, dried over Na2SO4 and concentrated. The residue was purified by Biotage column chromatography with 15%-40% EtOAc in hexanes to give a white solid (1.20 g, 68% yield). 1H NMR (400 MHz, CDCl3) δ 7.82-7.95 (m, 1 H) 7.21-7.34 (m, 2 H) 6.72-6.88 (m, 2 H) 3.90 (s, 3 H) 3.22 (s, 3 H) 2.90 (s, 2 H) 1.48 (s, 6 H); LCMS for C19H19FO6S m/z 395.00 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([O:11]CC)=[O:10].C(Cl)Cl.[Li+].[OH-].Cl>CO>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1[nH]c(C)c(Cl)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
Ethyl 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 4, 7.765 g, 0.03496 mol) was dissolved in MeOH (80 ml) and DCM (10 ml) and slowly added to a 70° C. solution of 2 N LiOH (105 ml, 0.21 mol). After 2 h, the reaction mixture was cooled to room temperature and then in an ice bath, followed by acidification with 2 N HCl. The mixture was stirred at 0° C. for 1 h, and a purple solid was filtered, washed with water and lyophilized overnight to give 4.314 g (0.0222 mol, 64% yield) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:23]([O:14][C:12]1[C:11]([C:15]#[N:16])=[CH:10][C:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:13]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)[nH]c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)nc1OCc1ccccc1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To a solution of 6-(4-chlorophenyl)-5-(phenyl)-2-oxo-1,2-dihydropyridine-3-nitrile (200 mg, 0.65 mmol) from Example 1, Step B in DMF (3 mL) was added benzyl bromide (0.10 mL, 0.85 mmol) and then cesium carbonate (276 mg, 0.85 mmol). The reaction was stirred at 55° C. for 3 h and was then diluted with water and extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The products were separated by preparative TLC (30% ethyl acetate in hexanes) to give the desired higher Rf O-alkylation title product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][C:13]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]C(=O)C(C)(C)C)=[CH:18][CH:17]=3)=[C:8]2[C:7]([O:29][C@@H:30]2[O:56][C@H:55]([CH2:57][O:58]C(=O)C(C)(C)C)[C@@H:47]([O:48]C(=O)C(C)(C)C)[C@H:39]([O:40]C(=O)C(C)(C)C)[C@H:31]2[O:32]C(=O)C(C)(C)C)=[N:6]1.C[O-].[Na+]>CO>[C@@H:30]1([O:29][C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[N:5]([CH2:4][CH2:3][CH2:2][OH:1])[N:6]=2)[O:56][C@H:55]([CH2:57][OH:58])[C@@H:47]([OH:48])[C@H:39]([OH:40])[C@H:31]1[OH:32]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2nn(CCCO)c3nccc(CCc4ccc(OC(=O)C(C)(C)C)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OCCCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2c(CCc3ccc(O)cc3)ccnc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 1-(3-hydroxypropyl)-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxy-phenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (40 mg) in methanol (2 mL) was added sodium methoxide (28% methanol solution, 0.04 mL), and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (18 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[N:15][OH:16])[CH2:8][CH2:7][CH2:6]2
Reactant: NO
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCCC2=NO
Temperature: 25 °C
Yield: 77.3 %

Procedure:
A solution of 6-methoxy-3,4-dihydronaphthalen-1(2H)-one (5 g, 28.4 mmol), hydroxylamine hydrochloride (2.366 g, 34.0 mmol) and sodium acetate (2.79 g, 34.0 mmol) in anhydrous methanol (20 mL) was heated at 80° C. (oil bath temp.) for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Next, 75 mL of water was added to the resulting solid and the contents were triturated and filtered. The solid was washed with addition water (2×50 mL), toluene (50 mL) and then dried for 80 h to yield 4.2 g of the oxime as a white solid. A second crop of additional product (1.1 g of pink solid) was obtained from the mother liquor. 1H NMR (400 MHz, CDCl3) δ ppm 1.83-1.91 (m, 2H) 2.70-2.83 (m, 4H) 3.81 (s, 3H) 6.66 (d, J=2.76 Hz, 1H) 6.77 (dd, J=8.78, 2.76 Hz, 1H) 7.83 (d, J=8.78 Hz, 1H) 8.32 (br. s., 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][OH:14])=[CH:7]2)([O-:3])=[O:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH:13]=[O:14])=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]c(CO)cc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Yield: 57.4 %

Procedure:
A solution of crude (5-nitro-1H-indol-2-yl)methanol (3.60 g, 18.7 mmol) in chloroform (200 mL) was heated at 50° C. with manganese dioxide (20 g, 0.23 mol) for 3 h. The reaction mixture was then filtered through Celite and concentrated to give 5-nitro-1H-indole-2-carbaldehyde (904) (2.04 g, 57% through two steps). 1H NMR δ [(CD3)2SO] 12.64 (br, 1H), 9.96 (s, 1H), 8.83 (d, J=2.3 HZ, 1H), 8.18 (dd, J=9.0 Hz, 2.3 Hz, 1H), 7.69 (d, J=0.7 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[C:12]1[CH:17]=[CH:16][N:15]2[N:18]=[C:19]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:20]([C:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])=[C:14]2[C:13]=1[F:39].CC1C=CC(C(O)=O)=CC=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1>[C:26]([O:25][C:24]([N:23]([CH3:31])[C:21]([C:20]1[C:19]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)=[N:18][N:15]2[CH:16]=[CH:17][C:12]([C:3]3[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=3[CH3:1])[C:6]([OH:8])=[O:7])=[C:13]([F:39])[C:14]=12)=[O:22])=[O:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: CN(C(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(F)cc2)nn2ccc(Cl)c(F)c12
Agent: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-c1ccn2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1F
Temperature: 95 °C
Reaction time: 18 h

Procedure:
3-(3-(tert-butoxycarbonyl)methyl)carbamoyl)-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid. To a degassed solution containing tert-butyl 5-chloro-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate (0.10 g, 0.24 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.078 g, 0.30 mmol), sodium carbonate (0.075 g, 0.71 mmol), dioxane (2.0 mL) and water (0.40 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.008 g, 0.007 mmol). The mixture was stirred at 95° C. for 18 h. The solution was cooled to room temperature, filtered to remove solids and adjusted to below pH 4 with 1 N aqueous hydrochloric acid (2.0 mL). Water was added (10 mL) and the aqueous portion was extracted with ethyl acetate (2×15 mL). The combined organic portions were washed with brine (20 mL) and dried over magnesium sulfate. The mixture was filtered and concentrated to afford 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid as a residue which was used without further purification. LCMS retention time: 2.467 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire C18, 5 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 522 (MH+).
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][C:22]3[N:31]=[C:30]4[C:25]([CH2:26][CH2:27][C:28](=[O:32])[NH:29]4)=[CH:24][CH:23]=3)[CH2:13][CH2:12]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl>C1COCC1.CCOCC.[Ni]>[C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[N:31]=[C:30]4[C:25]([CH2:26][CH2:27][C:28](=[O:32])[NH:29]4)=[CH:24][CH:23]=3)[CH2:13][CH2:12]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2ccc(C=CCCCN3CCN(c4cccc5c4CCCC5)CC3)nc2N1
Agent: [Ni]
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CCc2ccc(CCCCCN3CCN(c4cccc5c4CCCC5)CC3)nc2N1
Yield: 69.4 %

Procedure:
7-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.225 g, 0.523 mmol) was hydrogenated using Ra—Ni (0.25 g) in THF for 16 hours. The reaction was filtered and concentrated to give a foam. This was dissolved in Et2O and 1M HCl in Et2O (1 equiv) was added. The precipitate was filtered and dried to give the title compound as a white solid (0.157 g, 70%). MS: APCI: M+1: 433.4 (Exact Mass: 432.29).
Reaction SMILES: C1(CO[C@H]2[C@H](OCC3C=CC=CC=3)[C@@H](COCC3C=CC=CC=3)O[C@@H]2C=O)C=CC=CC=1.P([O-])(OCC)OCC.[O-]CC.[Na+].[CH2:45]([O:47][P:48]([O:82][CH2:83][CH3:84])([CH:50]([OH:81])[C@@H:51]1[O:71][C@H:70]([CH2:72][O:73][CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)[C@@H:61]([O:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C@@H:52]1[O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:49])[CH3:46].C(N(CC)C(C)C)(C)C.[CH3:94][Si:95]([CH3:102])([CH3:101])[CH2:96][CH2:97][O:98][CH2:99]Cl>ClCCl>[CH2:45]([O:47][P:48]([O:82][CH2:83][CH3:84])([CH:50]([O:81][CH2:99][O:98][CH2:97][CH2:96][Si:95]([CH3:102])([CH3:101])[CH3:94])[C@H:51]1[O:71][C@H:70]([CH2:72][O:73][CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)[C@@H:61]([O:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C@@H:52]1[O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:49])[CH3:46]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOP(=O)(OCC)C(O)[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CCOP([O-])OCC
Agent: CC[O-]
Agent: O=C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(OCC)C(OCOCC[Si](C)(C)C)[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
In accordance with Flowchart C, 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose 4 is reacted with diethyl phosphite and sodium ethoxide under argon, giving [lR(and/or IS)]-2,5-anhydro-1-C-(diethoxyphosphinyl)-3,4,6-tris-O-(phenylmethyl)-D-glucitol 21, which is reacted with N,N-diisopropylethylamine and 2-(trimethylsilyl)ethoxymethyl chloride in dry dichloromethane under argon at reflux, giving [1R-(and/or 1S)]-2,5-anhydro-1-C-(diethoxyphosphinyl)-3,4,6-tris-O-(phenylmethyl)-1-O-[[2-(trimethylsilyl)ethoxy]methyl]-D-mannitol 22. Compound 22 is hydrogenated in methanol over palladium hydroxide on carbon, giving [lR(and/or lS)]-2,5-anhydro-1-C-(diethoxyphosphi8nyl)-1-O-[[2-(trimethylsilyl)ethoxy]methyl]-D-mannitol 23 which is then reacted with diphenyl chlorophosphate in pyridine at ice bath temperature, giving [1R(and/or 1S)]-2,5-anhydro-1-C-(diethoxyphosphinyl)-1-0-[[2-(trimethylsilyl)ethoxy]methyl]-D-mannitol, 6-(diphenyl phosphate) 24. Compound 24 is reacted with boron trifluoride etherate in anhydrous acetonitrile under argon, giving [1R(and/or 1S)]-2,5-anhydro-1-C-(diethoxyphosphinyl)-D-mannitol, 6-(diphenyl phosphate) 25 which is then reacted with bromotrimethylsilane in deuterated chloroform under argon, giving [1R(and/or 1S)]-2,5-anhydro-1-C-phosphono-D-mannitol, 6-(diphenyl phosphate) 26 which is hydrogenated in methanol over platinum oxide, giving [1R(and/or 1S)]-2,5-anhydro-1-C-phosphono-D-mannitol, 6-(dihydrogen phosphate) 27. ##STR12##
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:7]([CH2:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:38]I>CN(C)C=O>[CH3:38][O:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:7]([CH2:20][CH2:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of 4-hydroxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (300 mg, 0.6 mmol, 1 eq) in anhydrous N,N-dimethylformamide (3 m) was treated with sodium hydride (60% in mineral oil, 26 mg, 0.66 mmol, 1.1 eq). The resulting mixture was stirred for thirty minutes at room temperature. Methyl iodide (94 mg, 0.66 mmol, 1 eq) was added to the reaction and the resulting mixture was stirred for two hours at room temperature. The reaction was quenched with the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (2×10 ml), then brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by flash column chromatography to yield the title product as a crystalline product in 50% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=[C:13](N)[CH:12]=2)=[CH:7][CH:6]=1.[Cl-:25].[Li+].N(OCCC(C)C)=O>C(#N)C.[Cu](Cl)Cl>[Cl:25][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=2)[N:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:14]=1
Reactant: COCOc1ccc(-c2cc(N)nn2-c2ccc(OC)cc2)cc1
Reactant: [Cl-]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Agent: [Li+]
Solvent: CC#N
Product: COCOc1ccc(-c2cc(Cl)nn2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-[4-(methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-amine obtained by Example 20-2 (3.79 g), lithium chloride (2.47 g), and copper (II) chloride (3.13 g) in acetonitrile (60 ml) was stirred at room temperature for 10 min. To this mixture was added isoamyl nitrite (2.73 g), and the mixture was stirred at room temperature for 1 hr.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([S:18]([NH:21][CH3:22])(=[O:20])=[O:19])[N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([OH:9])=O.[NH2:23][CH2:24][C:25]1[C:26]([F:42])=[C:27]([O:32][C:33]2[CH:34]=[C:35]([CH:38]=[C:39]([Cl:41])[CH:40]=2)[C:36]#[N:37])[C:28]([Cl:31])=[CH:29][CH:30]=1>>[Cl:1][C:2]1[N:3]=[C:4]([S:18]([NH:21][CH3:22])(=[O:19])=[O:20])[NH:5][C:6]=1[C:7]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([O:32][C:33]2[CH:34]=[C:35]([C:36]#[N:37])[CH:38]=[C:39]([Cl:41])[CH:40]=2)[C:26]=1[F:42])=[O:9]
Reactant: CNS(=O)(=O)c1nc(Cl)c(C(=O)O)n1COCC[Si](C)(C)C
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Product: CNS(=O)(=O)c1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Yield: 53.2 %

Procedure:
4-chloro-2-[(methylamino)sulfonyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.12 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.040 g, 0.13 mmol) were employed using a procedure similar to that described herein to provide the title compound (0.034 g, 54%) as a white solid after deprotection and purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% formic acid). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.55 (s, 1H), 7.40 (s, 2H), 7.27 (s, 1H), 7.24 (s, 1H), 4.63 (s, 2H), 2.70 (s, 3 H). ES-LCMS: m/z 532.1, 534.1, 536.0 (M+1).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH2:14][CH2:15][O:16][CH3:17])[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][S:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.O>CC#N>[CH3:17][O:16][CH2:15][CH2:14][N:4]1[C:5](=[O:13])[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([S:20][CH3:19])=[CH:22][CH:23]=2)[C:3]1=[O:18]
Reactant: CSc1ccc(N)cc1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O
Solvent: O
Solvent: CC#N
Product: COCCN1C(=O)C(Nc2ccc(SC)cc2)=C(c2ccccc2)C1=O
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 51.1 %

Procedure:
3-Chloro-1-(2-methoxyethyl)-4-phenyl-1H-pyrrole-2,5-dione (0.26 mmol, 70 mg) and 4-(methylthio)aniline (0.53 mmol, 73 mg) was dissolved in dry CH3CN (2 mL) and the reaction mixture was sequentially subjected to microwave heating single node 140° C. for, 10 min, 140° C. for 10 min, and 140° C. for 20 min. 0.3 mL Water was added and the reaction mixture was purified using HPLC (57% 0.1M ammonium acetate buffer: 43% CH3CN→100% CH3CN, 20 mL/min) to give 49 mg (50%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.22 (bs, 1H), 7.19-7.10 (m, 3H), 7.06-7.00 (m, 2H), 6.95-6.90 (m, 2H), 6.58-6.53 (m, 2H), 3.82 (t, J=5.6 Hz, 2H), 3.63 (t, J=5.6 Hz, 2H), 3.38 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[F:13][C:14]1[CH:15]=[C:16]([CH:35]=[CH:36][CH:37]=1)[CH2:17][NH:18][C:19]([C:21]1[S:22][C:23]([N:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]2=[O:34])=[CH:24][C:25]=1[CH3:26])=[O:20]>>[Si:6]([O:5][CH2:4][CH2:3][CH2:2][O:33][C:30]1[CH:31]=[CH:32][N:27]([C:23]2[S:22][C:21]([C:19]([NH:18][CH2:17][C:16]3[CH:35]=[CH:36][CH:37]=[C:14]([F:13])[CH:15]=3)=[O:20])=[C:25]([CH3:26])[CH:24]=2)[C:28](=[O:34])[CH:29]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: Cc1cc(-n2ccc(O)cc2=O)sc1C(=O)NCc1cccc(F)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Product: Cc1cc(-n2ccc(OCCCO[Si](C)(C)C(C)(C)C)cc2=O)sc1C(=O)NCc1cccc(F)c1

Procedure:
Following the procedure as described in Example 9, making variations only as required to use (3-bromopropoxy)(tert-butyl)dimethylsilane in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-(3-fluorobenzyl)-5-(4-hydroxy-2-oxopyridin-1(2H)-yl)-3-methylthiophene-2-carboxamide, the title compound was obtained as a yellowish viscous oil in quantitative yield: 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=7.8 Hz, 1H), 7.35-7.27 (m, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.05 (d, J=9.6 Hz, 1H), 7.00-6.94 (m, 1H), 6.85 (s, 1H), 6.19 (t, J=5.8 Hz, 1H), 6.07 (dd, J=7.8, 2.7 Hz, 1H), 5.98 (d, J=2.7 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 4.07 (t, J=6.0 Hz, 2H), 3.77 (t, J=6.0 Hz, 2H), 3.52 (t, J=6.0 Hz, 2H), 2.54 (s, 3H), 0.88 (s, 9H), 0.04 (s, 6H); MS (ES+) m/z 531.5 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[N:11]3[C:15]([C:16](=O)[C:8]4[C:9]=2[C:4]([CH:5]=[CH:6][N:7]=4)=[CH:3][CH:2]=1)=[CH:14][CH:13]=[CH:12]3.Cl.[NH2:19][OH:20].O>N1C=CC=CC=1>[OH:20][N:19]=[C:16]1[C:8]2[C:9]3[C:4]([CH:5]=[CH:6][N:7]=2)=[CH:3][CH:2]=[CH:1][C:10]=3[N:11]2[C:15]1=[CH:14][CH:13]=[CH:12]2
Reactant: NO
Reactant: O=c1c2nccc3cccc(c32)n2cccc12
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: ON=c1c2nccc3cccc(c32)n2cccc12
Yield: 90.9 %

Procedure:
A solution of 7H-indolizino[5,6,7-ij]isoquinolin-7-one (28 g.) and hydroxylamine hydrochloride (28 g.) in pyridine (560 cc.) is maintained at the boiling point, with stirring. The brown solution thus obtained is poured into water (3.92 liters). After stirring for 3 hours, the mustard yellow crystals obtained are filtered off and then washed copiously with water. After drying, 7-hydroxyimino-7H-indolizino[5,6,7-ij]isoquinoline (27.2 g.), melting at 254° C. with decomposition, is obtained. After recrystallisation from a mixture of water and pyridine (6- 5 by volume), the pure product melts at 258° C. with decomposition.