Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S)C.B(F)(F)F.CCOCC.[C:13]1([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:28][S:29]([CH:32]4[CH2:37][CH2:36][N:35](C(OCC5C=CC=CC=5)=O)[CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH:26]=3)[NH:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[C:13]1([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:28][S:29]([CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH:26]=3)[NH:21][N:20]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Nc2ccc3[nH]nc(-c4ccccc4)c3c2)CC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCS
Product: O=S(=O)(Nc1ccc2[nH]nc(-c3ccccc3)c2c1)C1CCNCC1
Temperature: 20 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
N-(3-Phenyl-1H-indazol-5-yl)piperidine-4-sulfonamide can be obtained in the following way: 1.89 g of ethanethiol, then 1.45 g of boron trifluoride etherate, are added dropwise to a solution, under argon, of 0.5 g of benzyl 4-(3-phenyl-1H-indazol-5-ylsulfamoyl)piperidine-1-carboxylate in 5 ml of dichloromethane. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours and is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in 10 ml of water, basified with 5 ml of an aqueous 32% ammonium hydroxide solution, and then extracted successively with 30 ml and 15 ml of ethyl acetate. The organic extracts are pooled, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography on a silica column (particle size 40-63 μm), eluting successively with dichloromethane/methanol (99/1; 95/5 by volume) mixtures. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue taken up in 6 ml of acetonitrile in the presence of 3S black, and dissolved under hot conditions, and the mixture is filtered under hot conditions through sintered glass and then recrystallized. The crystals are filtered off through sintered glass, washed with 2 times 0.5 ml then 1 ml of acetonitrile, partially dried and then dried under reduced pressure (3 kPa) at a temperature in the region of 50° C. 0.04 g of N-(3-phenyl-1H-indazol-5-yl)piperidine-4-sulfonamide is thus obtained in the form of a white crystalline solid melting at 230° C. (analysis: C18H20N4O2S, % calculated C, 60.65; H, 5.66; N, 15.72; O, 8.98; S, 9. % found C, 60.62; H, 5.85; N, 15.39; S, 8.72).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[C:18]([O:22][C:23](=[O:33])[N:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]1)[CH3:25])([CH3:21])([CH3:20])[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:32][C@H:29]1[CH2:30][CH2:31][C@H:26]([N:24]([CH3:25])[C:23](=[O:33])[O:22][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:27][CH2:28]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](N)CC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (335 mg, 1.07 mmol) was reacted with tert-butyl-(trans)-4-aminocyclohexyl(methyl)carbamate (366 mg, 1.61 mmol) to afford the desired product (470 mg, 87%) as an orange foam: ESI MS m/z 502 [C25H32BrN3O3+H]+.
Reaction SMILES: CC(=O)C.CCOC(C(C1(C#N)CCCC1)C#N)=O.C([O-])(=O)C.[NH4+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:34]([CH3:49])=[C:35]([C:47]#[N:48])[C:36](=[O:46])[N:37]([C:39]3[CH:44]=[CH:43][C:42](Cl)=[CH:41][CH:40]=3)[N:38]=2)=[CH:28][CH:27]=1>CCO>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:34]([CH3:49])=[C:35]([C:47]#[N:48])[C:36](=[O:46])[N:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:38]=2)=[CH:28][CH:27]=1
Reactant: Cc1c(Sc2ccc(Cl)cc2)nn(-c2ccc(Cl)cc2)c(=O)c1C#N
Agent: CC(=O)[O-]
Agent: CCOC(=O)C(C#N)C1(C#N)CCCC1
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CCO
Product: Cc1c(Sc2ccc(Cl)cc2)nn(-c2ccccc2)c(=O)c1C#N

Procedure:
The reaction of 1.8 g (5.9 mmol) of 1-[(4-chlorophenyl)thio]-1-[phenyl)hydmzono]-2-propanone, 1.5 ml of ethylcyano acetate and 750 mg of ammonium acetate as in Example 22, yielded1.29 g of 6-[(4-chlorophenyl)thio]- 2,3-dihydro-2-(4-chlorophenyl)5-methyl-3-oxo-4-pyridazinecarbonitrile, mp 180°-182° C. (EtOH).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)C(=O)c1ccccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In an argon atmosphere, a mixture of 6.55 g (39.7 mmol) of 15, 10.9 g (79.3 mmol) of K2CO3, 1.0 g (5.94 mmol) of KI and 80 mL of anhydrous DMF was stirred for 10 min at room temperature. After that 7.52 g (59.5 mmol) of benzyl chloride was added in one portion. The resulting mixture was stirred for 2 hr at 70° C. and then evaporated to dryness. To the residue, 70 mL of water and 30 mL of dichloromethane were added. The organic layer was separated, and the aqueous layer was washed by 2×50 mL of dichloromethane. The combined organic extract was dried over Na2SO4 and then evaporated to dryness. The residue was washed by 50 mL of cold ether and dried in vacuum. Yield 9.71 g (96%) of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10](OCC)=[O:11])[C:4]([CH3:9])([CH3:8])[CH:5]=[CH:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C(OCC)C>[CH3:1][C:2]1[CH:3]([CH2:10][OH:11])[C:4]([CH3:8])([CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1C(C)=CC=CC1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC1=CC=CC(C)(C)C1CO
Reaction time: 4 h
Yield: 86.3 %

Procedure:
(Not Shown) A solution of ethyl 2,6,6-trimethyl-2,4-cyclohexadiene-1-carboxylate III (9.09 g, 0.0468 mol) in anhydrous diethyl ether (100 mL) was slowly added to a suspension of LiAlH4 (3.75 g, 0.099 mol) in diethyl ether (200 mL) at 0° C. The mixture was stirred for 4 h and monitored by thin layer chromatography (TLC). Water (4.0 mL) was carefully added, followed by 15% NaOH (4.0 mL) and water (12 mL). The white precipitate was filtered and rinsed with warm EtOAc (100 mL). EtOAc (100 mL) was added and the combined organic layer was washed with water (3×50 mL), brine (3×50 mL), dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (hexanes:EtOAc 4:1) to give 6.15 g (87% yield) of pure 2,6,6-trimethyl-2,4-cyclohexadiene-1-methanol; IR (neat) 3340 (--OH), 2958 (CH aliph.), 1467 (C=C), 1442, 1375, 1357, 1049, 1012 cm-1 ;1H-NMR (CDCl3 ; 400 MHz) δ (ppm): 5.76 (m, 1 H, H3), 5.69 (m, 1 H, H2), 5.36 (d, 9.4 Hz, 1 H, H4), 3.73 (m, 2 H, --CH2OH), 1.85 (s, 3 H, --CH3, ring), 1.77 (t, J=4.1 Hz, 1 H, OH), 1.55 (t, J=5.0 Hz, 1 H, CH ring), 1.14 (s, 3 H, gem CH3), 1.02 (s, 3 H, gem CH3); 13C-NMR (CDCl3 ; 100 MHz) δ (ppm): 2 diastereomers: 136.6, 135.2, 135.0, 122.3, 120.7, 120.3, 118.8, 63.1, 61.7, 61.6, 60.3, 52.2, 50.9, 33.7, 28.1, 26.9, 25.4, 24.1, 22.5, 21.2.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([C:9]#[N:10])[S:8][C:4]=2[CH:3]=1.N[C@@H:14]([C:17]([OH:19])=[O:18])[CH2:15][SH:16]>>[CH2:15]1[S:16]/[C:9](=[C:7]2/[N:6]=[C:5]3[C:4]([S:8]/2)=[CH:3][C:2](=[O:1])[CH:12]=[CH:11]3)/[NH:10][C@H:14]1[C:17]([OH:19])=[O:18]
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: N[C@H](CS)C(=O)O
Product: O=C1C=Cc2n/c(=C3\N[C@@H](C(=O)O)CS3)sc2=C1

Procedure:
Stock solutions of the benzothiazole compounds 3016, 3019, 3026, 3806, 3814, 3820, 3821, 3833, 3835, 3866, and 3868 were made at 50 mM in DMSO. One picomole of each P450 enzyme (Supersomes™, BD Bioscience) was incubated with 50 mM of each of the compounds in a 50 μl, reaction in KPO4 buffer pH 7.4 (25 mM KPO4 for CYP2C9, 50 mM KPO4 for CYP2B6, -2C8, -2C19, -4F2, -4F3A and -4F3B, 100 mM KPO4 for CYP1A1, -1A2, -1B1, -2D6, -2E1, -3A5, -3A7, -2J2, -4F12, -19 and minus P450 control, 200 mM KPO4 for CYP3A4) or 100 mM Tris-HCl, pH 7.5 (for CYP2A6, -2C18 and -4A11). Reactions were initiated by adding an NADPH regenerating system (final concentrations of the regenerating system components in the assay were: 1.3 mM NADP+, 3.3 mM glucose-6-phosphate, 3.3 mM MgCl2, 0.4 U/mL glucose-6-phosphate dehydrogenase and 0.05 mM sodium citrate). Reactions were incubated for 30 minutes at 37° C. After incubation, 50 μl, of P450-Glo™ luciferin detection reagent (available from Promega Corp.) supplemented with 6.6 mM D-cysteine was added to each reaction, allowed to incubate at room temperature for 20 minutes, and luminescence was detected on a Veritas luminometer. FIGS. 14-25 demonstrate that the benzothiazole compounds can also be used to detect CYP450 enzyme activity as light output in this assay scheme. Each compound was active with one or more P450 enzymes and the profile of P450 activity varied across the panel of enzymes depending on the compound structure. The light output specific to a given P450 enzyme can be due to oxidation of the benzothiazole compound by the P450 enzyme to yield 6-hydroxybenzo[d]thiazole-2-carbonitrile (a benzothiazole derivative). The 6-hydroxybenzo-[d]thiazole-2-carbonitrile can then react with D-cysteine to form a D-luciferin derivative that in turns reacts with luciferase in the luciferin detection reagent to generate light in proportion to the amount of D-luciferin present.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([C:5](=[O:22])[CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[OH:21])[CH2:3]1.[CH2:23]1[CH2:36]OC23OCCOC2([C@]2(CC[C@H]4[C@@H](CC=C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:24]1>>[CH2:36]1[CH2:23][O:24][C:5]2([CH:4]3[C@:17]([CH3:20])([CH2:18][CH2:19][C@H:2]([OH:1])[CH2:3]3)[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C@@H:11]([OH:21])[CH2:10][CH2:9]4)[CH2:6]2)[O:22]1
Reactant: C[C@]12CCCCC1=CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CC[C@H]3[C@@H](CC(=O)C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Product: C[C@]12CC[C@H]3[C@@H](CC4(OCCO4)C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Yield: 70 %

Procedure:
6,6-Ethylendioxyandrostane-3β,17β-diol was prepared in 70% yield from 3β,17β-dihydroxyandrostan-6-one by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-5-androstene (Prepn. 5). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness to give 6,6-ethylendioxyandrostane-3β,17β-diol. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.45 (d, 1H), 4.41 (d, 1H), 3.90-3.57 (m, 4H), 3.41 (m, 1H), 3.29 (m, 1H), 1.87-0.53 (m, 20H), 0.84 (s, 3H), 0.60 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:25])[N:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:7]([CH:13]([NH:15][CH3:16])[CH3:14])=[N:8]2.[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:15]([CH:13]([C:7]2[N:6]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C:5](=[O:25])[C:4]3[C:9](=[CH:10][CH:11]=[CH:12][C:3]=3[O:2][CH3:1])[N:8]=2)[CH3:14])[CH3:16])(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CNC(C)c1nc2cccc(OC)c2c(=O)n1-c1ccc(OC)cc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(-n2c(C(C)N(C)S(=O)(=O)c3ccc(C(C)(C)C)cc3)nc3cccc(OC)c3c2=O)cc1

Procedure:
In a similar manner as described above in Paragraph A, 5-methoxy-3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one, as prepared above in Example 5, was condensed with 4-tert-butylbenzenesulfonyl chloride to yield 4-tert-butyl-N-{1-[5-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide; MS (ESI) 536 (MH+).
Reaction SMILES: C1(C)C(C)=CC=CC=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]([N:24]=[CH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)C2C=CC=CC=2)[CH:14]=[CH:15][CH:16]=1.[C:32]1(=[O:38])[O:37][C:35](=[O:36])[CH2:34][CH2:33]1>CCOCC>[CH2:25]([N:24]1[C:35](=[O:36])[CH2:34][CH:33]([C:32]([OH:37])=[O:38])[CH:17]1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1cccc(C(N=Cc2ccccc2)c2ccccc2)c1
Reactant: O=C1CCC(=O)O1
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: COc1cccc(C2C(C(=O)O)CC(=O)N2Cc2ccccc2)c1

Procedure:
To 450 ml. of xylene was added 143.3 gm of 3-methoxyphenylbenzylidenebenzylamine and 63.9 gm. of succinic anhydride. The solution was refluxed for 15 hours, cooled and extracted with saturated sodium bicarbonate solution. After washing the basic solution with ether, the aqueous phase was acidified with concentrated hydrochloric acid to provide a white gum. The gum was dissolved in ether, dried (Na2SO4), filtered and concentrated in vacuo to a semi-solid which was titurated with anhydrous ethyl ether and the resultant solid removed by filtration and discarded. Concentration in vacuo provided 18.5 g of the desired product as a gum.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH2:34]([NH:36][CH:37]1[CH2:40][NH:39][CH2:38]1)[CH3:35].CN1CCCC1>C(O)C>[CH2:34]([NH:36][CH:37]1[CH2:40][N:39]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:38]1)[CH3:35]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CCNC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CCNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
To 310 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-(ethylamino)azetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 15 minutes. After adding 1 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 107 mg of the title compound as a colorless powder.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:15]([OH:19])(=[O:18])[CH:16]=[CH2:17].Cl>C1COCC1>[C:1]1([S:7][CH2:17][CH2:16][C:15]([OH:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)O
Reactant: Sc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)CCSc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a solution of thiophenol (8.87 g, 80.6 mmol) in THF (20 ml) and triethylamine (8.6 g, 11.9 ml, 85 mmol) was added dropwise, with ice cooling, acrylic acid (5.8 g, 5.5 ml, 81 mmol). The reaction mixture was stirred at 0° C. for 1 h and then at RT overnight, acidified with 2N hydrochloric acid and extracted with diethyl ether (2×100 ml). The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. The desired 3-phenylsulfanylpropionic acid product (13.67 g, 93% of theory) was obtained as a white solid (m.p. 51-54° C.)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[CH:10][O:9][C:8]=12.[Li]CCCC.[Cl:17]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:17][C:10]1[O:9][C:8]2=[C:3]([O:2][CH3:1])[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COc1nccc2ccoc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nccc2cc(Cl)oc12
Temperature: -15 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A 0.13 M solution of 7-methoxyfuro[2,3-c]pyridine (250 mg, 1.7 mmol) in THF stirred at −78° C. under an atmosphere of nitrogen was treated with n-BuLi (1.6M in hexanes, 450 uL, 5.2 mmol) dropwise over 30 sec. The mixture was warmed gradually to −15° C. over a period of 7 to 10 min. After 1 h at −15° C., the mixture was cooled to −65° C. and was treated with a 0.26 M solution of hexachloroethane (473 mg, 2 mmol) in THF by dropwise addition over 3 min. After stirring at −65° C. for 15 min, the mixture was allowed to gradually warm to rt. After the mixture was allowed to stir overnight, it was quenched with water (5 mL) and extracted with EtOAc (3×15 ml). The combined organic layers were washed brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (5 to 30%) in hexanes to afford the title compound (266 mg, 87%) as an amber oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.99-4.08 (m, 3H) 7.13 (s, 1H) 7.25 (d, J=5.31 Hz, 1H) 7.95 (d, J=5.31 Hz, 1H). LCMS (M+H)+=184.
Reaction SMILES: C([NH:4][C:5]1[CH:20]=[CH:19][N:8]([C@@H:9]2[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:10]2[O:11][CH3:12])[C:7](=[O:21])[N:6]=1)(=O)C.COC1C=CC(C(Cl)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>N1C=CC=CC=1>[CH3:12][O:11][C@@H:10]1[C@H:13]([OH:14])[C@@H:15]([CH2:16][OH:17])[O:18][C@H:9]1[N:8]1[CH:19]=[CH:20][C:5]([NH2:4])=[N:6][C:7]1=[O:21]
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(C)=O)nc1=O
Agent: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Yield: 65 %

Procedure:
In accordance with the present invention, DMT CAc -2'-OMe-3'-cyanoethylphosphoramidite ("CAc 2'-OMe phosphoramidite") of the formula ##STR4## was synthesized as depicted in Scheme I. Cytidine (1) was quantitatively converted to 2 by a selective acetylation procedure [Bhat, U. et al., Nucleoside aid Nucleotides (1989) 8, 179-183)]. N4 -Acetylcytidine 2 was reacted with 1,3-dichloro- 1,1,3,3-tetraisopropyldisiloxane to give N4 -acetyl-3,5'-O-tetraisopropyldisiloxane-1,3-diyl-cytidine (3) in 90% yield. Treatment of 3 with excess MeI/Ag2O [Inoue, H. et al., Nucleic Acids Research (1987) 15, 6131-6148] in dry benzene at room temperature afforded 60% of the 2'-O-methyl derivative (4) after column chromatography. Removal of the silyl groups using Bu4NF in THF at room temperature gave N4 -acetyl-2'-O-methyl cytidine (5) in 42% yield after work up according to literature procedure [Chattopadhyaya, J. et al., Acta Chem. Scand. (1986) B40, 826-830]. The compound 5 was tritylated with 1.2 equivalents of 4,4'-dimethoxytrityl chloride in pyridine at 5° C. for 20 hours to yield the DMT-2'-O-methylcytidine derivative 6 in 65% yield. Phosphorylation of 6 with 2 equivalents of β-cyanoethyl N,N-diisopropylmonochlorophosphoramidite [Sinha, N. D. et al., Nucleic Acids Research (1984) 12, 4539-4537] in tetrahydrofuran in the presence of 4 equivalents of N,N,N-diisopropylethylamine afforded 60% yield of 5'-DMT-N4 -acetyl-2'-O-methylcytidine-3'-phosphoramidite 7. ##STR5##
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:8]=1[NH2:9].C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:9][C:8]1[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:7]=1[CH3:6])=[O:4]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C)c1NC(=O)CCl
Reaction time: 20 h

Procedure:
Chloroacetyl chloride (4.0 g) in methylene chloride (25 ml) was cooled via an ice bath to 0° C. A solution of 2,6-dimethylaniline (4.25 g) and triethylamine (5 ml) in methylene chloride (25 ml) was added dropwise over 1 hour and the resulting solution stirred and allowed to come to room temperature for a 20 hour period. 10% Hydrochloric acid was added and the layers were separated. The organic layer was washed with 1N hydrochloric acid and water, dried over sodium sulfate, filtered and the solvent removed to give a solid which was recrystallized from benzene. The structure was confirmed by NMR.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[N:4]=1)#[N:2].C(O)(C(F)(F)F)=[O:21]>>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]([OH:15])=[O:14])[N:4]=1)(=[O:21])[NH2:2]
Reactant: CC(C)(C)OC(=O)Cn1nc(C#N)c2ccncc21
Reactant: O=C(O)C(F)(F)F
Product: NC(=O)c1nn(CC(=O)O)c2cnccc12

Procedure:
To a solution of tert-butyl 2-(3-cyano-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (663 mg, 2.40 mmol) in TFA (6 mL) was subjected to microwave irradiation at 140° C. for 90 min. The reaction mixture was concentrated in vacuo, the residual solid was suspended in MeOH and volatiles were removed again in vacuo. MS: 221.0 [M+H]+; tR (HPLC conditions d): 0.23 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=3)=[C:11]([CH3:24])[CH:10]=2)[N:5]=1.[CH3:25][N:26]1[CH2:31][CH2:30][C:29]2([C:42]3[C:34](=[CH:35][C:36]4[CH2:37][CH2:38][NH:39][C:40]=4[CH:41]=3)[O:33][CH2:32]2)[CH2:28][CH2:27]1>>[CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:39]4[C:40]5[CH:41]=[C:42]6[C:29]7([CH2:32][O:33][C:34]6=[CH:35][C:36]=5[CH2:37][CH2:38]4)[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]7)=[O:22])=[CH:17][CH:16]=3)=[C:11]([CH3:24])[CH:10]=2)[N:5]=1
Reactant: COCc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: COCc1nc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)no1
Yield: 62 %

Procedure:
The title compound was prepared from 4'-(5-methoxymethyl-1,2,4-oxadiazol-3-yl)-2'-methylbiphenyl-4-carboxylic acid (D112) and 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8) using a similar procedure as described in Example 1. This afforded the title compound as a pale yellow solid (62%), which was converted to its hydrochloride salt to give an off white solid m.p. 247-251° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[N:10]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:9](=[O:24])[NH:8][C:5]2=[N:6][CH:7]=1.[F:25]C(F)(F)C(O)=O>ClCCl>[F:25][N:6]1[CH:7]=[CH:2][CH:3]=[C:4]2[N:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:9](=[O:24])[NH:8][CH:5]12
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncc(F)cc32)CC1
Solvent: ClCCl
Product: O=C1NC2C(=CC=CN2F)N1C1CCNCC1

Procedure:
tert-Butyl 4-(6-fluoro-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (340 mg, 1.01 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was added. After 2h, the reation was concentrated, diluted with dichlormethane (5 mL) and a solution of 1N hydrochloric acid in 1,4-dioxane (2 mL) was added at room temperature. Concentration afforded the title compound (302 mg). MS 237.2 (M+1) 1H NMR (500 MHz, CDODl3) δ 7.92 (br s, 1H), 7.70 (dd, 1H), 4.60 (m, 1H), 3.60 (s, 2H), 3.25 (dd, 2H), 2.70 (m, 2H), 2.10 (d, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:25]=[CH:24][C:16]([C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:20]([N:19]([CH2:22][CH3:23])[C:17](=[O:18])[C:16]1[CH:24]=[CH:25][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:14][CH:15]=1)[CH3:21]
Reactant: CCN(CC)C(=O)c1ccc(CCCCOCCCCCCBr)cc1
Reactant: NCc1ccccc1
Product: CCN(CC)C(=O)c1ccc(CCCCOCCCCCCNCc2ccccc2)cc1
Yield: 76.5 %

Procedure:
4-[4-[(6-Bromohexyl)oxy]butyl]-N,N-diethybenzamide (6.0 g) and benzylamine (9.36 g) were stirred under nitrogen at 120° for 30 mins. Excess benzylamine was removed by distillation under reduced pressure. The residual solid was dissolved in ethyl acetate (100 ml) and washed with 8% aqueous sodium bicarbonate (100 ml). The ethyl acetate solution was dried and evaporated to give a yellow oil which was purified by FCC eluting System B (95:5:1) to give the title compound as a yellow oil (4.88 g), t.l.c. (System B 95:5:1) Rf 0.15.