Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:7][C:8]=1[Cl:9].[CH2:14]1[CH2:19][CH2:18][CH:17]([N:20]=[C:21]=[N:22][CH:23]2[CH2:28]CCCC2)CC1.CCN(CC)CC>>[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([N:22]2[CH2:23][CH2:28][N:20]3[CH2:17][CH2:18][CH2:19][CH2:14][C@H:21]23)=[O:13])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Br
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN2CCCC[C@@H]21
Yield: 63.5 %

Procedure:
The HBr salt of the title product of Example 4 (1.00 g, 3.3 mmol) and 3,4-dichlorophenylacetic acid (1.07 g, 5.2 mmol, 1.5 eq) and DCC (1.43 g, 6.9 mmol, 2.0 eq) were reacted by addition of Et3N (2.4 mL, 5.0 eq) to give the title compound (0.84 g, 92%) as a colorless crystalline solid. The reaction was conducted as follows. To a stirred solution of the dichlorophenylacetic acid in CH2Cl2 (100mL) was added a solution of the DCC in CH2Cl2 (100 mL) and the solution was stirred for 10 min at rt. To the precipitated complex was added the salt of the title compound of Example 4 followed by the Et3N and stirring was continued until TLC (solvent system A) indicated the reaction to be complete. The precipitated DCU was removed by filtration and the filter cake was washed with Et2O (50 mL). The filtrate was diluted with enough Et2O to render the organic layer less dense than the aqueous layer, and the organic extract was then extracted with 10% aqueous citric acid (200 mL) and discarded. The aqueous layer was washed with Et2O (2×200 mL) and the combined washings were discarded. The aqueous layer was basified by addition of excess concentrated aqueous NH3 solution and extracted with CH2Cl2 (2×200 mL). The combined organic layer was washed with water, dried (Na2SO4) and evaporated to give the desired product: mp 102.5°-103.5° C. (2-propanol); 1H-NMR (CDCl3) σ 7.39 (d, J=7.9 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.09 (d, J=2.0, 7.9 Hz, 1H), 4.67 (dd, Jgem =39 Hz, J=13 Hz, 1H), 3.81 (dd, Jgem =44, J=13 Hz, 1H), 3.68 (d, J=3.8 Hz, 2H), 2.73-3.28 (complex m, 3H), 1.98-2.48 (complex m, 3H), 1.64-1.93 (complex m, 4H), 1.32-1.48 (m, 1H); Anal (calcd for C15 H18Cl2N2O): C 57.52, H 5.79, N 8.94. Found: 57.60, H 5.76, N 8.94.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH3:11][C:12]([O:15][C:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:17])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.[I-].[Li+]>[C:22]([O:21][C:19]([N:18]([CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[C:16]([O:15][C:12]([CH3:14])([CH3:13])[CH3:11])=[O:17])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccc(C#N)cc1)C(=O)OC(C)(C)C
Yield: 83.4 %

Procedure:
4-(Bromomethyl)benzonitrile (5 g, 25.5 mmoles) and di-tert-butyliminodicarboxylate (5.54 g, 25.5 mmoles) were dissolved in anhydrous THF (50 mL) and cesium carbonate (16.62 g, 25.5 mmoles) and lithium iodide (170.5 mg, 1.275 mmoles) were added. The mixture was stirred at 70° C. for 23h and the reaction was worked up as described in Preparative Example 244, Step B above. The residue was chromatographed on a silica gel column (50×5 cm) using 5% ethyl acetate in hexane as the eluant to give 4-(di-tert-butoxycarbonylaminomethyl)benzonitrile (7.07 g, 83%): FABMS: m/z 333.2 (MH+); HRFABMS: m/z 333.1816 (MH+). Calcd. for C18H25N2O4: m/z 333.1814; δH (CDCl3) 1.45 (18H, s, —COOC(CH3)3), 4.81 (2H, s, CH2), 7.37 (2H, d, Ar—H) and 7.62 ppm (2H, d, Ar—H); δC (CDCl3) CH3: 28.1, 28.1, 28.1, 28.1, 28.1, 28.1; CH2: 49.2; CH: 127.8, 127.8, 132.3, 132.3; C, 83.2, 83.2, 111.1, 118.9, 144.1, 152.4, 152.4.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([Si](C)(C)C)=[C:6]([F:21])[C:7]([F:20])=[C:8]([C:10](=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:9]=1.Br[CH:27]([C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1)[CH2:28][CH2:29][CH3:30]>CN(C=O)C.[Na+].[Cl-]>[Br:3][C:4]1[CH:5]=[C:6]([F:21])[C:7]([F:20])=[C:8]([C:10](=[O:19])[CH:11]([CH:27]([C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=2)[CH2:28][CH2:29][CH3:30])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:9]=1
Reactant: CCCC(Br)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: C[Si](C)(C)c1c(Br)cc(C(=O)Cc2ccc(Cl)cc2)c(F)c1F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(c1ccc(C(=O)OC(C)(C)C)cc1)C(C(=O)c1cc(Br)cc(F)c1F)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60 wt % in mineral oil, 0.129 g, 3.23 mmol) in DMF (5 mL) at 0° C. was add a solution of the product from Step D (0.900 g, 2.15 mmol) in DMF (2 mL). The suspension was stirred for 30 minutes, then a solution of tert-butyl 4-(1-bromobutyl)benzoate (0.742 g, 2.37 mmol) in DMF (2 mL) was added. The mixture was stirred at 0° C. for two hours then diluted with saturated NaCl (aq, 50 mL), then the product was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with water then saturated NaCl (aq), dried over MgSO4, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-50% toluene/hexanes to afford racemic mixtures of both diastereomers of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH2:24][C:25]([OH:27])=O)[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:10]=1.[CH3:36][NH:37][CH3:38].C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH2:24][C:25]([N:37]([CH3:38])[CH3:36])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:10]=1
Reactant: CNC
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(CC(=O)O)c3)cc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(CC(=O)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of {3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid (100 mg, 0.19 mmol), dimethylamine (2 N solution in THF, 0.19 mL, 0.38 mmol), diisopropylethylamine (49 mg, 0.38 mmol) in THF was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluromiumhexafluorophosphate (110 mg, 0.29 mmol). The resulting suspension was heated to 60° C. with stirring till the 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluromiumhexafluorophosphate completely dissolved. The THF was evaporated and the residue was used in the next step reaction without further purification. MS: m/z 517 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH3:17])[C:5]([O:14][CH3:15])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[CH3:13].I[CH2:19][CH2:20][CH2:21][CH:22]([N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])[CH3:23].C(N(CC)CC)C>C(OCCO)C.C(=O)(O)[O-].[Na+]>[CH3:15][O:14][C:5]1[C:4]([O:16][CH3:17])=[CH:3][C:2]([NH:1][CH2:19][CH2:20][CH2:21][CH:22]([N:24]2[C:25](=[O:34])[C:26]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]3[C:28]2=[O:29])[CH3:23])=[C:11]2[C:6]=1[C:7]([CH3:13])=[CH:8][C:9]([CH3:12])=[N:10]2
Reactant: COc1cc(N)c2nc(C)cc(C)c2c1OC
Reactant: CC(CCCI)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCCO
Product: COc1cc(NCCCC(C)N2C(=O)c3ccccc3C2=O)c2nc(C)cc(C)c2c1OC
Temperature: 135 °C
Yield: 33 %

Procedure:
A solution of 8-amino-5,6-dimethoxy-2,4-dimethylquinoline (20.0 g, 86 mmole), 1-iodo-4-phthalimidopentane (38.4 g, 112 mmole) and triethylamine (11.3 g, 112 mmole) in 2-ethoxyethanol (230 ml) was heated at reflux (135° C.) for 5 hr. After cooling, the solution was diluted with 5% aqueous sodium bicarbonate (0.5 l) and then extracted with methylene chloride (2× 250 ml). The combined extracts were washed with water (2× 250 ml) and brine (100 ml) and then dried (potassium carbonate). Filtration, then evaporation of the solvents, afforded a black tar. The tar was chromatographed over silica gel (0.7 kg) with benzene. The orange-brown material eluting first from the column was crystallized from ethanol (10% solution), affording 12.7 g (33%) of the title compound as orange plates, mp 141°-144°. Further recrystallization of a small amount gave an analytical sample with mp 144.5°-146.5°; the analysis was satisfactory after drying at 110° (the analysis corresponded to a hemihydrate after drying at 78°).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][O:34][C:35]1[CH:67]=[CH:66][C:38]([C:39]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:56]=[C:55]4[C:51]([CH2:52][N:53]([C@@H:58]([CH:63]([CH3:65])[CH3:64])[C:59]([O:61]C)=[O:60])[C:54]4=[O:57])=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)=[O:40])=[CH:37][CH:36]=1>>[CH3:33][O:34][C:35]1[CH:36]=[CH:37][C:38]([C:39]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([C:48]3[CH:56]=[C:55]4[C:51]([CH2:52][N:53]([C@@H:58]([CH:63]([CH3:64])[CH3:65])[C:59]([OH:61])=[O:60])[C:54]4=[O:57])=[CH:50][CH:49]=3)=[CH:46][CH:47]=2)=[O:40])=[CH:66][CH:67]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)cc1
Yield: 89 %

Procedure:
The compound of example 104 was prepared analogous to compound of example 98 by hydrolysis of compound of example 103.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:17][C:18]1[C:23]([F:24])=[C:22]([N:25]([CH3:34])[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:28])[CH3:27])[C:21]([F:35])=[C:20](F)[N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][N:38]1[CH2:42][CH2:41][N:40]=[C:39]1[C:43]1[CH:44]=[C:45]([OH:49])[CH:46]=[CH:47][CH:48]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:17][C:18]1[C:23]([F:24])=[C:22]([N:25]([CH3:34])[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:27])[CH3:28])[C:21]([F:35])=[C:20]([O:49][C:45]2[CH:46]=[CH:47][CH:48]=[C:43]([C:39]3[N:38]([CH3:37])[CH2:42][CH2:41][N:40]=3)[CH:44]=2)[N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)N(C)c1c(F)c(F)nc(Oc2cc(C#N)ccc2OCc2ccccc2)c1F
Reactant: CN1CCN=C1c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)N(C)c1c(F)c(Oc2cccc(C3=NCCN3C)c2)nc(Oc2cc(C#N)ccc2OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of 4-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonyl-1-methylethyl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile (2.4 g, 4.5 mmol) in DMSO (50 mL) was added 3-((1-methyl)imidazolin-2-yl)phenol (0.8 g, 4.5 mmol) and cesium carbonate (1.9 g, 5.8 mmol). The resultant mixture was stirred at 35° C. After 13 hours, the mixture was then cooled to ambient temperature and poured into 200 mL of water and 200 mL of ethyl acetate. The aqueous layer was separated and extracted with 100 mL of ethyl acetate. The combined organic extracts were washed with 0.5 M aqueous KOH solution (200 mL) then brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford 4-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonyl-1-methylethyl)amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)-oxy]benzonitrile as a solid foam: NMR (CDCl3) 7.4-7.0 (m, 12), 5.0 (s, 2), 4.2 (q, 2), 3.9 (t, 2), 3.5 (t, 2), 3.1 (s, 3), 2.8 (s, 3), 1.6 (s, 6), 1.3 (t, 3) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]=O.P([O-])([O-])([O-])=O.[NH4+].[NH4+].[NH4+].[N+:22](CCC)([O-])=O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]#[N:22]
Reactant: CCC[N+](=O)[O-]
Reactant: O=Cc1c[nH]c2c(Br)cc(Cl)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: N#Cc1c[nH]c2c(Br)cc(Cl)cc12
Yield: 54.5 %

Procedure:
A mixture of 7-bromo-5-chloro-1H-indole-3-carbaldehyde (0.80 g, 3.09 mmol), Ammonium phosphate, dibasic (1.269 mL, 15.47 mmol), and 1-nitropropane (0.276 mL, 3.09 mmol) in Acetic Acid (20 mL) was heated at reflux. The solvent was evaporated, the residue was taken up in aqueous sodium bicarbonate (300 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with 20%-25% ethyl acetate/hexanes to give 7-bromo-5-chloro-1H-indole-3-carbonitrile (0.43 g, 1.683 mmol, 54.4% yield) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.27 (bs, 1H), 7.79 (s, 1H), 7.72 (d, J=1.8 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H). LC/MS (HPLC method 4): tR=3.12 min, 255.01(MH)+.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4](O)=[O:5].S(Cl)([Cl:17])=O>CN(C=O)C.C1C=CC=CC=1>[CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([Cl:17])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(C)(C)CC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cc1ccc(C(C)(C)CC(=O)Cl)cc1
Temperature: 25 °C
Yield: 107.4 %

Procedure:
A solution containing 3-methyl-3-(4-methylphenyl)butyric acid (8.5 g, 44.2 mmol) and anhydrous DMF (5 drops) in anhydrous benzene (110 mL) was refluxed under nitrogen as thionyl chloride (8.1 mL, 110 mmol)was added dropwise under nitrogen. The solution was refluxed an additional 15 h after complete addition of thionyl chloride. The dark brownish reaction mixture was allowed to cool to room temperature and concentrated under vacuum. TLC analysis of the crude material showed complete disappearance of the starting material. Presence of DMF was evident from the proton NMR. The crude material, 3-methyl-3-(4-methylphenyl)butyric acid chloride (305) (about 10 g), thus obtained was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[CH2:15][O:14][C:13]2[CH:16]=[C:17]3[C:21](=[CH:22][C:12]1=2)[CH2:20][CH2:19][O:18]3.N1C2C(=CC=CC=2)[C:25]2([C:35]3=CC4OCOC=4[CH:42]=[C:34]3[O:33][CH2:32]2)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:42][C@H:34]1[CH2:35][CH2:25][CH2:32][O:33]1)[C:8](=[O:11])[C:7]12[CH2:15][O:14][C:13]2[CH:16]=[C:17]3[C:21](=[CH:22][C:12]1=2)[CH2:20][CH2:19][O:18]3
Reactant: O=C1Nc2c(F)cccc2C12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Product: O=C1N(C[C@H]2CCCO2)c2c(F)cccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 7′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 7′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (28%) as a colorless solid: mp 169-170° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ7.35-7.32 (m, 1H), 7.15-7.01 (m, 2H), 6.56 (d, J=28.1 Hz, 1H), 6.41 (d, J=2.9 Hz, 1H), 4.78-4.67 (m, 2H), 4.52-4.46 (m, 2H), 4.30-3.93 (m, 3H), 3.82-3.93 (m, 2H), 2.99-2.91 (m, 2H), 2.06-1.58 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ176.7, 156.8, 156.7, 154.3, 142.9, 142.7, 136.1, 136.0, 132.8, 131.5, 131.3, 128.7 (2C), 123.3 (2C), 122.7, 121.9, 121.8, 109.7, 109.6, 109.5, 104.5, 104.4, 92.4, 79.5, 75.6, 75.4, 67.1, 67.0, 57.2, 43.8, 43.7, 28.5, 28.4, 28.1, 25.0, 24.9.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.Cl.[NH:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([OH:30])[CH2:25]1.C(N(CC)CC)C>C(#N)C>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([OH:30])[CH2:25]1)[CH:11]=[CH:10]2
Reactant: O[C@@H]1CCCNC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CCC[C@@H](O)C3)ccc12
Temperature: 120 °C
Yield: 58.7 %

Procedure:
N-(2,6-Dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (1 g), (3R)-3-piperidinol hydrochloride (0.424 g) and triethylamine (1.2 mL) were placed into a 10 mL microwave vial followed by the addition of acetonitrile (3 mL). The vial was sealed and heated at 120° C. in a single mode microwave for 45 minutes. On cooling a solid crystallised from the reaction mixture which was filtered and washed with acetonitrile (10 mL) to afford the sub-title compound (0.7 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:19]>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl

Procedure:
Reaction of commercially-available 2-chloro-3,5-dinitrobenzoic acid (X) with SOCl2 gave 2-chloro-3,5-dinitrobenzoyl chloride (XI: Z=Cl), which was quenched with ammonia to give 2-chloro-3,5-dinitrobenzamide (XI: Z=NH2). A solution of this amide (1.00 g, 4.07 mmol) and Et3N (1.42 g, 10 mmol) in ρ-dioxane (30 mL) was 0356 treated with N,N-bis(2-chloroethyl)amine hydrochloride (1.45 g, 8.14 mmol) at 50° C. for 18 h. The mixture was then poured into water and extracted with EtOAc to give an oil, which was chromatographed on silica gel. Elution with EtOAc/petroleum ether (1:1) gave 2-[N,N-bis(2-chloroethyl)amino]-3,5-dinitrobenzramide (19) (Ie: R=CONH2) (1.15 g, 80%), mp (CHCl3 /petroleum ether) 123°-124° C. 1H NMR (CD3SOCD3) δ8.70 (d, J=2.7 Hz, 1 H, H-4), 8.49 (d, J=2.7 Hz, 1 H, H-6), 7.68, 7.35 (2xbr, 2H, CONH2), 3.80, 3.61 (2.xt, J=6.9 Hz, y 8H. NCH2CU2Cl). 13C NMR δ167.94 (CONH2), 147.27 (C-2), 147.2 0. 142.84 (C-3,5), 137.70 (C-1), 128.40, 123.24 (C-4:6), 55.84 (CH2N), 42.28 ) (CH2CI). Anal. (C11H12Cl2,N4O5) C,H,N,Cl.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH3:2].CCN(C(C)C)C(C)C.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[O:29][CH2:30][C:31](Cl)=[O:32])[CH3:24]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:31](=[O:32])[CH2:30][O:29][C:28]2[CH:34]=[CH:35][CH:36]=[C:26]([O:25][CH2:23][CH3:24])[CH:27]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCOc1cccc(OCC(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cccc(OCC(=O)Nc2ccc(OCC)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A 1 L 3-neck flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with aniline 46a (9.57 g, 52.6 mmol) and CH2Cl2 (200 mL). The resultant solution was cooled in an ice bath and iPr2NEt (20.4 g, 27.5 mL, 158 mmol) was added followed by acid chloride 47a (14.1 g, 65.7 mmol) in CH2Cl2 (120 mL) over 30 min. The mixture stirred at rt overnight. The red solution was diluted with CH2Cl2 (250 mL) and was washed with saturated aqueous NH4Cl (200 mL), saturated NaHCO3 (200 mL), and brine (200 mL). The organic phase was filtered through phase separation paper and concentrated in vacuo to an orange solid. The solid was triturated with EtOH (75 mL), filtered, pressed with a rubber dam, and rinsed with EtOH (3×20 mL). The solid dried to give 14.3 g of 48a as a yellow solid (80%). 1H NMR (300 MHz, CDCl3): δ 11.36 (s, 1H), 8.78 (d, 1H), 7.72 (d, 1H), 7.30-7.20 (m, 2H), 6.67-6.59 (m, 3H), 4.66 (s, 2H), 4.09 (qt, 2H), 4.07 (qt, 2H), 1.44 (t, 3H), 1.42 (t, 3H) ppm. HPLC analysis (0:10:90 H2O:A1:MeOH) showed a purity of 98% with a retention time of 4.8 min.
Reaction SMILES: [B-](F)(F)(F)F.[CH3:6][CH2:7][O+](CC)CC.[CH3:13][O:14][C:15]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18]>C(Cl)Cl>[CH3:13][O:14][C:15]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](=[NH:19])[O:18][CH2:6][CH3:7]
Reactant: CC[O+](CC)CC
Reactant: COc1c(C)cccc1C(N)=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=N)c1cccc(C)c1OC
Reaction time: 72 h

Procedure:
A solution of triethyloxonium borofluoride (23 g.) in anhydrous methylene chloride (60 ml.) was added to a solution of 2-methoxy-3-methylbenzamide [19.7 g; prepared as described in French Patent M.21] in anhydrous methylene chloride (200 ml.). The mixture was kept at room temperature for 3 days, concentrated to about 120 ml. and diluted with anhydrous diethyl ether (300 ml.). The solid which separated was filtered off and washed with anhydrous diethyl ether to give ethyl 2-methoxy-3-methylbenzimidate borofluoride (28.7 g.), m.p. 93°-96° C., which was pure enough for use in the next stage of the synthesis. An aliquot was recrystallised from a mixture of anhydrous methylene chloride and anhydrous diethyl ether to give pure ethyl 2-methoxy-3-methylbenzimidate borofluoride, m.p. 102°-104° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][S:12](=[O:17])(=[O:16])[NH:13][CH2:14][CH3:15])[C:8]([CH3:18])=[CH:7][C:6]=1[S:19]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:4])([CH3:3])[CH3:2].[OH:30][C:31]1[CH2:32][C:33]([CH2:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([NH:58]C(=O)[O-])=[CH:54][CH:53]=2)([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([NH:46]C(=O)[O-])=[CH:42][CH:41]=2)[O:34][C:35](=[O:37])[CH:36]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[C:1]([C:5]1[C:6]([S:19][C:36]2[C:35](=[O:37])[O:34][C:33]([CH2:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]([NH2:46])=[CH:44][CH:45]=3)([CH2:50][CH2:51][C:52]3[CH:53]=[CH:54][C:55]([NH2:58])=[CH:56][CH:57]=3)[CH2:32][C:31]=2[OH:30])=[CH:7][C:8]([CH3:18])=[C:9]([O:11][S:12](=[O:16])(=[O:17])[NH:13][CH2:14][CH3:15])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])Nc1ccc(CCC2(CCc3ccc(NC(=O)[O-])cc3)CC(O)=CC(=O)O2)cc1
Reactant: CCNS(=O)(=O)Oc1cc(C(C)(C)C)c(SS(=O)(=O)c2ccc(C)cc2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNS(=O)(=O)Oc1cc(C(C)(C)C)c(SC2=C(O)CC(CCc3ccc(N)cc3)(CCc3ccc(N)cc3)OC2=O)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer were added toluene-4-thiosulfonic acid S-(2-tert-butyl-4-ethylsulfamoyloxy-5-methyl-phenyl) ester (prepared in Example VVV; 0.218 g, 0.470 mmol), (1,1-dimethylethyl)[(3,6-dihydro-4-hydroxy-6-oxo-2H-pyran-2,2-diyl)bis[2,1-ethanediyl-(4, 1 -phenylene)]-biscarbamate (prepared in Example OO; 0.200 g, 0.380 mmol), K2CO3 (0.260 g, 1.88 mmol), and DMF (8 mL), as described in General Method 9. The reaction was stirred at room temperature for 3 hours and then worked up in the usual fashion. The residue was submitted to flash chromatography (100% EtOAc). The product form chromatography was taken up in EtOAc, triturated with hexane, filtered, and then taken up in CH2Cl2 (20 mL). Gaseous HCl was bubbled into this solution for 30 minutes. The solids that formed were filtered, washed with Et2O and dried under high vacuum to yield the title compound, m.p. 194° C. 1H NMR (DMSO-d6) δ 1.14 (t, 3 H), 1.49 (s, 9 H), 1.88 (s, 3 H), 2.09 (br m, 4 H), 2.70 (br m, 4 H), 3.12 (s, 2 H) 3.13 (m, 2 H), 6.79 (s, 1 H), 7.11 (s, 1 H), 7.27 (d, 4 H), 7.33 (d, 4 H), 8.40 (t, 1 H).