Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2][C:3]([CH3:7])([CH3:6])[C:4]#[N:5].[CH3:8][C:9]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:10]=1[O:11][CH:12]([C:15]1[NH:16][CH2:17][CH2:18][N:19]=1)[CH2:13][CH3:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:4]([C:3]([S:2][N:19]1[CH2:18][CH2:17][N:16]=[C:15]1[CH:12]([O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:9]=1[CH3:8])[CH2:13][CH3:14])([CH3:7])[CH3:6])#[N:5]
Reactant: CC(C)(C#N)SCl
Reactant: CCC(Oc1cccc(C)c1C)C1=NCCN1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC(Oc1cccc(C)c1C)C1=NCCN1SC(C)(C)C#N

Procedure:
With continuous stirring and cooling, 4.1 g of α-(chlorothio)-isobutyronitrile are added dropwise at 0° to 10° C. to a solution of 6.97 g of 2-[1-(2,3-dimethylphenoxy)-propyl]-2-imidazoline of the formula ##STR4## and 4 g of triethylamine in 80 ml of toluene. The reaction mixture is stirred for 1 hour at room temperature, then the toluene phase is washed repeatedly with water and dried. The toluene is then evaporated off, affording 1-(2-cyano-prop-2-ylthio)-2-[1-(2,3-dimethylphenoxy)-propyl]-2-imidazoline of the formula ##STR5## in the form of a yellow viscous oil with a melting point of 58°-60° C. The following compounds of the formula I can be obtained by procedures analogous to the one described in this Example: ##STR6##
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[C:12](=O)[CH2:11][CH2:10][CH2:9][C:7]=3[O:8][C:4]=2[CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>O.C(O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[C:12](=[N:22][OH:23])[CH2:11][CH2:10][CH2:9][C:7]=3[O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCCc2oc3cc(Br)ccc3c21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCCc2oc3cc(Br)ccc3c21
Temperature: 85 °C
Yield: 14.6 %

Procedure:
A mixture of the product of step A (6.80 g, 25.7 mmol), sodium acetate (3.16 g, 38.5 mmol) and hydroxylamine hydrochloride (2.67 g, 38.5 mmol) in water (28 mL) and ethanol (14 mL) was heated to 85° C. for 7 h. After cooling to 5° C., the reaction mixture was filtered. The solid obtained was washed with cold water and dried in vacuo to give 7-bromo-3,4-dihydrodibenzo[b,d]furan-1(2H)-one oxime (1.05 g, 15%) as an off-white solid: 1H NMR (DMSO-d6, 300 MHz) δ 10.95 (s, 1H), 7.88 (d, J=1.8 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.47 (dd, J=8.4, 1.8 Hz, 1H), 2.87 (t, J=6.3 Hz, 2H), 2.69 (t, J=6.3 Hz, 2H), 2.03-1.89 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[CH3:2].[C:8](=[O:13])([O:11]C)[O:9][CH3:10].[C:14](=O)=O>CO>[CH3:10][O:9][C:8](=[O:11])[O-:13].[CH2:1]([N+:3]1[CH:7]=[CH:6][N:5]([CH3:14])[CH:4]=1)[CH3:2]
Reactant: CCn1ccnc1
Reactant: O=C=O
Reactant: COC(=O)OC
Solvent: CO
Product: CC[n+]1ccn(C)c1
Product: COC(=O)[O-]
Temperature: 130 °C
Reaction time: 60 h

Procedure:
96 parts of 1-ethylimidazole, 135 parts of dimethyl carbonate and 192 parts of methanol were put into an autoclave made of a stainless steel equipped with a cooling condenser and mixed homogenously. After nitrogen substitution, the temperature was then raised to 130° C. while being sealed, so as to initiate a reaction. At the beginning, the pressure was approximately at 4.5 Kg/cm2, but it was gradually raised due to generation of carbon dioxide, so that the gasses were appropriately released from the upper part of the cooling condenser, adjusted at a pressure of about 7 Kg/cm2 or less. After 60 hours, they were cooled at 30° C., and the result of the reacted solution by means of 1H-NMR showed that 1-ethylimidazole was disappeared and 1-ethyl-3-methylimidazolium monomethyl carbonate was produced approximately under a quantitative theory. Into 415 parts of the resultant solution of 1-ethyl-3-methylimidazolium monomethyl carbonate, methanol and dimethyl carbonate, 205 parts of an aqueous solution of fluoroboric acid at a concentration of 42 wt % were gradually put in drops with stirring at a temperature of 25° C. over a period of about 30 minutes. As putting them in drops, bubbles of carbon dioxide were generated. Finishing the dropping and the generation of the bubbles, all the solvents were removed at a pressure of 20 Torr and at a temperature of 150° C., so as to obtain 194 parts of a transparent and colorless liquid (1). The examinations of 1H-NMR, 19F-NMR, 13C-NMR and HPLC of the liquid (1) resulted in showing that 98 mol % of 1-ethyl-3-methyl imidazolium tetrafluoroborate (which is hereinafter shortened as “EMI.BF4”), 2 mol %, in total, of 1-ethyl-3-methyl-4-carboxylate imidazolium, 1-ethyl-3-methyl-5-carboxylate imidazolium, 1-ethyl-3-methyl-4-carboxylate-5-carboxy imidazolium and 1-ethyl-3-methyl-4-carboxy-5-carboxylate imidazolium.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12]([NH:14][C:15]1([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]2=[O:35])[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)[CH2:17][CH2:16]1)=[O:13])[CH3:10].[CH:36]([C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1)=[CH2:37].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:9]([O:11][C:12]([NH:14][C:15]1([CH2:28][N:29]2[CH2:34][CH2:33][N:32]([S:44]([C:41]3[CH:42]=[CH:43][C:38]([CH:36]=[CH2:37])=[CH:39][CH:40]=3)(=[O:46])=[O:45])[CH2:31][C:30]2=[O:35])[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)[CH2:19][CH2:20]1)=[O:13])[CH3:10]
Reactant: CCOC(=O)NC1(CN2CCNCC2=O)CCN(c2ccnc(C)c2)CC1
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1ccc(S(=O)(=O)N2CCN(CC3(NC(=O)OCC)CCN(c4ccnc(C)c4)CC3)C(=O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
Triethylamine (260 mg) was added to a solution of 1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone hydrochloride (263 mg) in dichloromethane (20 ml), 4-vinylbenzenesulfonyl chloride (194 mg) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added an aqueous sodium carbonate solution, the material was extracted with dichloromethane, dried, concentrated, purified by column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1), and crystallized from diisopropyl ether to obtain the colorless crystalline title compound (157 mg).
Reaction SMILES: [CH3:1][O:2][S:3]([OH:6])(=[O:5])=[O:4].[CH2:7]([O:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13](=[NH:16])OC)[CH2:8][CH3:9].[NH3:21]>C(O)C>[CH3:1][O:2][S:3]([OH:6])(=[O:5])=[O:4].[CH2:7]([O:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH2:21])=[NH:16])[CH2:8][CH3:9]
Reactant: CCCOc1ccccc1C(=N)OC
Reactant: N
Agent: COS(=O)(=O)O
Solvent: CCO
Product: CCCOc1ccccc1C(=N)N
Reaction time: 17 h
Yield: 60 %

Procedure:
To a warm, stirred solution of 2-n-propoxybenzamide (896 g., 5.0 moles) in 1,2-dichloroethane (5 l) was added dimethyl sulfate (950 ml., 10.0 moles) over a period of about 0.5 hour. The mixture was stirred and heated under reflux for 17 hours. The solvent was removed. The residual oily solid was collected by filtration, washed with ethyl acetate and dried to give methyl 2-n-propoxybenzimidate methyl sulfate (403 g.), m.p. 79°-82°. The combined filtrate and washings were stored at 0° for 18 hours and gave a second crop (503 g.) of benzimidate, m.p. 81°-83°. A slurry of the methyl 2-n-propoxybenzimidate methyl sulfate (906 g.) in ethanol (1 l) was added to ethanol ( 4 l) which had previously been saturated with gaseous ammonia. The mixture was stored at room temperature for 17 hours. The mixture was filtered. The filtrate was evaporated to dryness to give 2-n-propoxybenzamidine methyl sulfate (872 g., 60%), m.p. 86°-88°.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.CCN=C=NCCCN(C)C.Cl.[CH:34](O)=[O:35]>C1COCC1.O>[CH:34]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])[CH:6]=2)[CH2:1]1)=[O:35]
Reactant: O=CO
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCNC3)C(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCN(C=O)C3)C(=O)O1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 73.4 %

Procedure:
A solution of N-[[(5S)-3-[1,2,3,4-tetrahydro-6-isoquinolinyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 1, Step 6, 200 mg, 0.691 mmol) in THF is treated with EDC.HCl (172 mg, 0.899 mmol) and formic acid (34 μL, 0.899 mmol) to give a white slurry which is then diluted with H2O (approx. 2 mL) to give a homogeneous mixture. The mixture is stirred at ambient temperature for 1.25 hrs and is then diluted with H2O (10 mL) and extracted with CH2Cl2 (4×20 mL). The combined organic phase is washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure, and the crude product is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (1/99-5/95). Those fractions with an Rf=0.41 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated and the resulting glassy solid is triturated with Et2O and filtered to give 161 mg (74%) of the title compound as a white solid, mp 139-141° C. (dec.). [α]25D=−22° (c 0.92, DMSO).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)=[N:12][CH:13]=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][Si:2]([C:5]#[C:6][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:16][N:15]=2)=[N:12][CH:13]=1)([CH3:4])[CH3:3]
Reactant: Brc1ccc(-c2ccc(Br)cn2)nc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(-c2ccc(C#C[Si](C)(C)C)cn2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under dry nitrogen atmosphere, successively trimethylsilyl-acetylene (619 mg, 6.30 mmol), [Pd(PPh3)2Cl2] (112 mg, 159 μmol), CuI (54.5 mg, 286 μmol) and DIPA (4 ml) were added to a stirred suspension of 3 (500 mg, 1.59 mmol) in 30 ml THF. While the mixture was stirred for 24 hours at room temperature, its color turned black. It was stirred together with activated carbon for 20 minutes and filtered over celite. Then the solvent was removed under reduced pressure, the residue was resuspended in hexane, sonicated for 15 minutes and filtered over celite again yielding an orange solution. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica (eluent: CH2Cl2) to yield 430 mg (1.23 mmol, 78%) of pure 4 as an off-white solid. 1H NMR (CDCl3, 250 MHz): δ=8.71 (s, 2H, bpy-H), 8.33 (d, 2H, JHH=8.3 Hz, bpy-H), 7.85 (d, 2H, JHH=7.8 Hz, bpy-H), 0.27 (s, 18H, Si(CH3)3).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[O:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:29][C:30]([O:33][C:34]([NH:36][C:37]([CH3:42])([C:39](O)=[O:40])[CH3:38])=[O:35])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:42][C:37]([NH:36][C:34](=[O:35])[O:33][C:30]([CH3:32])([CH3:31])[CH3:29])([CH3:38])[C:39]([NH:19][C:16]1[CH:17]=[N:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[CH:2]([CH3:1])[CH2:3][CH2:4][O:5]3)=[CH:14][CH:15]=1)=[O:40]
Reactant: CC1CCOc2cccc(Oc3ccc(N)cn3)c21
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CCOc2cccc(Oc3ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cn3)c21
Temperature: 60 °C
Reaction time: 1 h
Yield: 161.1 %

Procedure:
In a 8 mL vial the 6-(4-methylchroman-5-yl)oxypyridin-3-amine (Intermediate 213, 22.9 mg, 0.089 mmol) was dissolved in N,N-Dimethylformamide (3 mL) to give a pale yellow solution. DIPEA (0.069 mL, 0.394 mmol), N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methylalanine (60.0 mg, 0.295 mmol) and HATU (112 mg, 0.295 mmol) were added. The reaction mixture was shaken at 60° C. for 1 hour. The reaction mixture was evaporated in vacuo and the residue was purified by flash chromatography on silica gel using a column SNAP 25 g and cyclohexane/ethyl acetate from 3:1 to 1:2 as eluents affording the title compound (63.3 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13](O)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:26]=2)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(O)=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=S)Nc1ccc(CC(=O)OCC)cc1
Yield: 31.4 %

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-4-ethylthiobutanoic acid (695.2 mg) and ethyl 4-aminophenylacetate (380 mg) were condensed in dichloromethane (30 ml) in the presence of N,N'-dicyclohexylcarbodiimide (509.5 mg). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-ethylthiobutanamide (321.5 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:52][C:53]([F:66])([F:65])[CH2:54][O:55][C:56]1[CH:64]=[CH:63][C:59]([C:60](O)=[O:61])=[CH:58][N:57]=1>C1COCC1.CCOC(C)=O>[F:66][C:53]([F:52])([F:65])[CH2:54][O:55][C:56]1[CH:64]=[CH:63][C:59]([C:60]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)=[O:61])=[CH:58][N:57]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3ccc(OCC(F)(F)F)nc3)cc2)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.3 %

Procedure:
To a stirred suspension of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (1.5 g) in THF (75 ml) were added sequentially N-methylmorpholine (1.78 ml), HBTU (3.07 g) and 6-(2,2,2-trifluoroethoxy)nicotinic acid (1.63 g) and the mixture was stirred at room temperature for 17 h. The suspension was diluted with EtOAc and washed sequentially with 0.5 M aq. HCl, sat. aq. NaHCO3 and saturated brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by recrystallisation from heptane/EtOAc (1:1) to give (S)-tert-butyl 2-(4-(6-(2,2,2-trifluoroethoxy)nicotinamido)phenyl)morpholine-4-carboxylate (2.11 g, 81%) as a white solid. MS (ISP): 482.1 ([M+H]+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:16][S:17][CH:18]2[CH2:23][CH2:22][CH:21]([C:24]#[N:25])[CH2:20][CH2:19]2)[CH2:15][CH2:14]1.[CH:26]1([CH:29]=[O:30])[CH2:28][CH2:27]1>C1COCC1>[CH:26]1([CH:29]([OH:30])[C:21]2([C:24]#[N:25])[CH2:22][CH2:23][CH:18]([S:17][CH2:16][CH:13]3[CH2:14][CH2:15]3)[CH2:19][CH2:20]2)[CH2:28][CH2:27]1
Reactant: N#CC1CCC(SCC2CC2)CC1
Reactant: O=CC1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CC1(C(O)C2CC2)CCC(SCC2CC2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a stirred solution of diisopropylamine (1.59 ml; 11.3 mmol) in THF (10 ml) at 0° C. was added dropwise butyl lithium (2.5 M in hexanes; 4.51 ml; 11.3 mmol). The mixture was stirred at 0° C. for 15 minutes then cooled to −78° C. A solution of 4-cyclopropylmethylsulfanyl-cyclohexanecarbonitrile (2 g; 10.2 mmol) in THF (10 ml) was added dropwise. On complete addition, the mixture was stirred at −78° C. for 30 minutes. Cyclopropanecarboxaldehyde (0.91 ml; 12.2 mmol) was added dropwise and the mixture was allowed to warm slowly to room temperature and stir for 64 hours. The mixture was quenched with brine (50 ml) and extracted with EtOAc (2×75 ml). The combined organics were washed with saturated sodium hydrogen carbonate solution (50 ml) and brine (50 ml), dried (MgSO4) and evaporated in vacuo to give an orange oil. The crude product was chromatographed on silica eluted with 25-30% EtOAc in hexane to give the product as an orange oil (1.9339 g). 1H NMR (400 MHz, DMSO): δ 5.29 (1H, d, J 4.9), 2.76 (1H, dd, J 4.9, 7.8), 2.68-2.58 (1H, m), 2.15-2.11 (1H, m), 2.04-1.98 (4H, m), 1.56-1.38 (4H, m), 0.98-0.88 (2H, m), 0.52-0.48 (3H, m), 0.45-0.37 (1H, m), 0.34-0.28 (2H, m), 0.19-0.17 (2H, m). m/z=266 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:4][CH2:5][OH:6].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[S:17]([O:6][CH2:5][CH2:4][CH:3]([CH2:2][O:1][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])[CH2:7][CH2:8][CH2:9][O:10][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: OCCCC(CO)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCC(CCOS(=O)(=O)c2ccc(C)cc2)COS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a solution of 3-hydroxymethylhexane-1,6-diol (4 g, 0.027 mol) in pyridine (80 mL) stirred in an ice bath was added para-toluenesulphonyl chloride (16.9 g, 0.09 mol) in one portion. The mixture was allowed to warm to ambient temperature. After 48 hours the reaction was worked up using DCM (100 mL) which was washed with 1N HCl (2×100 mL). The organic layer was dried and concentrated to yield a very viscous, sticky oil which was analysed by NMR. This confirmed the desired material had been formed in a yield of 60% (9.9 g). The material was used without further purification.
Reaction SMILES: C[N:2](C)C=O.[CH:6]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.[OH-].[K+].NOS(O)(=O)=O>O>[CH:15]1[C:16]2[N:17]([NH2:2])[C:18]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)C=O
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nn1c2ccccc2c2ccccc21

Procedure:
Into 250 ml of dimethylformamide was dissolved 25 g of carbazole. This solution was cooled with an ice-salt bath and 42 g of potassium hydroxide was added portionwise. To this mixture was added hydroxylamine-O-sulfonic acid. After two hours the mixture was stirred with water and extracted with ethyl acetate. The organic extracts were washed with water and brine. After filtering the solvent was evaporated and the residue was eluted with 25% dichloromethane in hexane on a silica column to yield 9.5 g of a mixture of carbazole and 9H-carbazol-9-amine.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][OH:13]>O>[Cl:1][C:2]1[C:3]([O:13][CH3:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CO
Solvent: O
Product: COc1ncc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5,6-Dichloro-nicotinic acid (1.00 g, 5.21 mmol) is added to a solution of Na (252 mg, 10.9 mmol) in methanol (50 mL). The mixture is refluxed overnight before another portion of Na (252 mg, 10.9 mmol) is added. Refluxing is continued for 2 h. The mixture is cooled to rt, diluted with water and concentrated. The remaining solid is dissolved in water and the solution is neutralised by adding 2 N aq. HCl. The resulting suspension is extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered, concentrated and dried to give 5-chloro-6-methoxy-nicotinic acid (976 mg) as a white solid; LC-MS: tR=0.77 min; [M+1]+=189.90; 1H NMR (D6-DMSO): δ 4.03 (s, 3H), 8.22 (d, J=1.8 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H).
Reaction SMILES: C(OC(=O)[CH2:5][CH2:6][C:7]1[C:12]([C:13]([O:15]C)=O)=[CH:11][N:10]=[CH:9][CH:8]=1)C.[H-].[Na+].CO>O1CCCC1>[CH:11]1[C:12]2[C:13](=[O:15])[CH2:5][CH2:6][C:7]=2[CH:8]=[CH:9][N:10]=1
Reactant: CCOC(=O)CCc1ccncc1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCc2ccncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
A solution of methyl 4-(3-ethoxy-3-oxopropyl)nicotinate (4.80 g, 20.2 mmol) in tetrahydrofuran (100 mL) was added to a suspension of 60% sodium hydride (3.73 g, 93.3 mmol) in tetrahydrofuran (50 mL) at room temperature. Methanol (100 μL) was added to the mixture at room temperature, and the mixture was heated under reflux for 4 hr. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was added to 12M hydrochloric acid (50 mL) at 0° C., and the mixture was stirred at 110° C. for 30 min. The mixture was alkalified with sodium hydrogen carbonate, the insoluble material was filtered off, and the filtrate was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane to give the title compound (1.57 g, yield 58%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:2]2[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: OB(O)c1ccccc1
Product: O=C(O)c1ncc(-c2ccccc2)cn1

Procedure:
Conducting the operations similar to those of Production Example 14 using 5-bromopyrimidine-2-carboxylic acid and phenylboronic acid, the title compound was obtained as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([C:27](=[O:39])[C:28]([P:31](=[O:38])([O:35]CC)[O:32]CC)([F:30])[F:29])=[CH:26][C:4]=2[N:3]=1.[Si](I)(C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([C:27](=[O:39])[C:28]([P:31](=[O:32])([OH:35])[OH:38])([F:29])[F:30])=[CH:26][C:4]=2[N:3]=1
Reactant: CCOP(=O)(OCC)C(F)(F)C(=O)c1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: COc1ccc(CCc2cnc3c(N)nc4cc(C(=O)C(F)(F)P(=O)(O)O)ccc4c3c2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-oxoethylphosphonate (2-4) (1.0 equiv.) in DCM (0.05 M) at 0° C. was added TMSI (5.0 equiv.). The reaction was warmed to room temperature over 2 hours, and more TMSI was added (2.5 equiv.). The reaction was stirred for another 30 minutes, and then quenched with small amounts of water. The DCM was removed by evaporation, and then added DMSO/water. The mixture was adjusted to pH 9 and directly purified on RP-HPLC using a C18 column, eluting with 10-40% 95:5 (MeCN/5 mM NH4OAc) in 10 mM NH4OAc (pH 9) gradient. The fractions containing the product were combined and concentrated in vacuo to give 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-oxoethylphosphonic acid (9) as a solid. 1H NMR (Dimethylsulfoxide-d6): δ 8.82 (s, 1H), 8.5 (br, 1H), 8.44 (s, 1H), 8.2 (br, 1H), 7.98 (d, 1H, J=8.2 Hz), 7.2 (br, 2H), 7.05 (d, 1H, J=8.3 Hz), 6.73 (s, 1H), 6.67 (d, 1H, J=8.3 Hz), 3.70 (s, 3H), 2.99-2.87 (m, 4H), 2.25 (s, 3H). LRMS [M+H]=502.2