Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[ClH:18].C(N([C:24]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][C:33]2([C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=3)[CH2:39][CH2:38][CH2:37][CH2:36][N:35]([C:40](=[O:47])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:34]2)[CH2:26][CH2:25]1)C)(=O)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[OH2:4].[ClH:54].[C:40]([N:35]1[CH2:36][CH2:37][CH2:38][CH2:39][C:33]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=2)([CH2:32][CH2:31][CH2:30][N:8]2[CH2:7][CH2:6][C:5]([C:3]([N:2]([CH3:17])[CH3:1])=[O:4])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][CH2:9]2)[CH2:34]1)(=[O:47])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1.[C:40]([N:35]1[CH2:36][CH2:37][CH2:38][CH2:39][C:33]([CH2:32][CH2:31][CH2:30][N:27]2[CH2:28][CH2:29][C:24]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:3]([N:2]([CH3:17])[CH3:1])=[O:4])[CH2:25][CH2:26]2)([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=2)[CH2:34]1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[ClH:18]
Reactant: CN(C)C(=O)C1(c2ccccc2)CCNCC1
Reactant: CC(=O)N(C)C1(c2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCCN(C(=O)c3ccccc3)C2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN(C)C(=O)C1(c2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCCN(C(=O)c3ccccc3)C2)CC1
Product: O
Yield: 80.2 %

Procedure:
This compound is prepared by the procedure described in step D of EXAMPLE 13, starting from 0.69 g of 4-(N,N-dimethylaminocarbonyl)-4-phenyl-piperidine, 1.2 g of the compound obtained in step C of EXAMPLE 13 and 1.2 g of K2CO3 in 20 ml of a DMF/acetonitrile mixture (50/50; v/v). This gives 0.65 g of the expected product, m.p.=150° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[CH:7][NH:6][C:5]2=O.P(Cl)(Cl)([Cl:21])=O.C(N(C(C)C)C(C)C)C>>[Cl:21][C:5]1[C:4]2[C:9](=[CH:10][C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(N3CCOCC3)c(F)cc12
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc2c(Cl)ncnc2cc1N1CCOCC1
Yield: 123.3 %

Procedure:
5.0 g (0.02 mol) of 6-fluoro-7-morpholin-4-yl-3H-quinazolin-4-one were suspended in 37.0 ml (0.04 mol) of phosphoryl chloride at room temperature, 3.4 ml (0.02 mol) of N-ethyldiisopropylamine were subsequently added, and the mixture was heated under reflux for 2 h. Conventional work-up gave 6.6 g of 4-chloro-6-fluoro-7-morpholin-4-ylquinazoline.
Reaction SMILES: [Li]CCCC.[O:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[F:11][CH:12]([F:33])[C:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:16]([CH:27]=[O:28])=[C:15]([C:29]([F:32])([F:31])[F:30])[N:14]=1.Cl>CCCCCC.CCOCC.O>[F:33][CH:12]([F:11])[C:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:16]([CH:27]([C:7]2[O:6][CH:10]=[CH:9][CH:8]=2)[OH:28])=[C:15]([C:29]([F:32])([F:30])[F:31])[N:14]=1
Reactant: c1ccoc1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C=O)c1CC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(O)c2ccco2)c1CC(C)C
Temperature: -6 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To 2.5N n-BuLi in hexane (30 mL) cooled to 0° C. was added in a slow stream furan (7 g, 0.1 mol) in anhydrous ether (60 mL). The mixture was heated at reflux for 3 h under a nitrogen atmosphere and then cooled to -6° C. A solution of methyl 2- (difluoromethyl)-5-formyl-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (6 g, 17.6 mmol) in anhydrous ether (20 mL) was added dropwise and stirring was continued for 2 h. The mixture was then poured into iced water, acidified with conc. HCl and extracted with methylene chloride. The extract was washed with water and brine, dried (MgSO4), and conc. The oily residue was purified by chromatography with 10% ethyl acetate/cyclohexane to yield 4.4 g of methyl 2-(difluoromethyl)-5-(2-furanylhydroxymethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate as an orange oil, a 61% yield. nD25 1.4863.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:23]=[N:24][C:25]([O:28]C)=[CH:26][CH:27]=5)[CH:19]=[C:18]([CH3:30])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Si](I)(C)(C)C.CO>CC#N>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([CH3:30])[CH:19]=[C:20]([C:22]5[CH:27]=[CH:26][C:25](=[O:28])[NH:24][CH:23]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)n2)cn1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CO
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(-c2ccc(=O)[nH]c2)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (180 mg, 0.45 mmol) in CH3CN (7 mL) was added TMSI (130 uL, 0.90 mmol) dropwise at 20° C. The reaction was stirred at 50° C. for 30 min. MeOH (1.0 mL) was added and the solution was evaporated to dryness. The residue was re-dissolved in DCM-EtOAc (1:3) before it was washed with NaHSO3 (2×) and brine. The organics were dried over MgSO4 and evaporated to dryness. The crude material was purified by HPLC to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(4-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 387.2. found 388.1 (M+1)+. Retention time 1.35 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([OH:22])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:28](I)[CH3:29]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22][CH2:28][CH3:29])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: O=C(NC12CCC(C(=O)O)(CC1)CC2)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C12CCC(NC(=O)OCc3ccccc3)(CC1)CC2
Temperature: 55 °C
Reaction time: 5 h

Procedure:
4-Benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxylic acid (56.0 g) was dissolved in N,N-dimethylformamide (1000 mL). To this solution, sodium bicarbonate (46.6 g) and then ethyl iodide (22.2 mL) were added and the mixture was stirred at 50 to 60° C. for 5 hours. Subsequently, additional sodium bicarbonate (46.6 g) and ethyl iodide (22.2 mL) were added and the mixture was stirred for additional 3 hours. The insoluble materials in the mixture were filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (700 mL) and the solution was washed with water, dried over anhydrous sodium sulfate, and dried under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant:hexane:ethyl acetate=2:1→ethyl acetate) to give ethyl 4-benzyloxycarbonylamino-bicyclo[2.2.2]octane-1-carboxylate (56.8 g).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].CS[C:17]1[NH:18][CH2:19][C:20]([CH3:27])([CH3:26])[CH2:21][C:22]=1[N+:23]([O-:25])=[O:24]>>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[NH:18][CH2:19][C:20]([CH3:27])([CH3:26])[CH2:21][C:22]=2[N+:23]([O-:25])=[O:24])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CSC1=C([N+](=O)[O-])CC(C)(C)CN1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Product: CC1(C)CNC(NCCSCc2csc(NC(=N)N)n2)=C([N+](=O)[O-])C1

Procedure:
The title compound is prepared from 2-(2-guanidino-4-thiazolylmethylthio)ethylamine and 2-methylthio-3-nitro-5,5-dimethyl-1,4,5,6-tetrahydropyridine by a process analogous to that of Example 1.
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([OH:21])=O)=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:40][O:41][C:42]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[C:45]([O:51][CH3:52])[C:43]=1[NH2:44].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:13]1[N:17]=[N:16][C:15]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([NH:44][C:43]2[C:45]([O:51][CH3:52])=[CH:46][C:47]([O:49][CH3:50])=[CH:48][C:42]=2[O:41][CH3:40])=[O:21])=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCn1nnc(C(C(=O)O)c2ccccc2)n1
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCn1nnc(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound obtained in (d) above (6.58 g; 17.6 mmoles) was dissolved in tetrahydrofuran (50 mL), treated with carbonyldiimidazole (3.1 g; 19.1 mmoles), and stirred for 1 hour at room temperature under an atmosphere of N2 . A solution of 2,4,6-trimethoxyaniline (3.2 g; 17.6 mmoles/50 mL THF) was then added in one portion and the solution was stirred at room temperature for overnight. Ethyl acetate (150 mL) was then added as well as aqueous HCl (1N). The layers were separated and the organic portion was washed with NaOH (1N), brine, and then dried over MgSO4. The drying agent was filtered and the filtrate concentrated in vacuo leaving a lavender colored solid which was purified by silica gel chromatography using chloroform (95%)/methanol (5%) as the eluent. Yield: 6.7 g (70%), mp 119°-120° C.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[C:24](Cl)(=[O:26])[CH3:25].C(N(CC)CC)C>C(Cl)Cl>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([C:2]2([NH:1][C:24](=[O:26])[CH3:25])[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:12])=[C:14]([O:22][CH3:23])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: COc1cc(C(C)C)ccc1C1(N)C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(C)C)ccc1C1(NC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62251.7 %

Procedure:
2-Amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.10 g, 0.32 mmol) was dissolved in methylene chloride (4 ml). This solution was added with acetyl chloride (0.05 ml, 0.70 mmol), followed by stirring at room temperature for 15 min, and added with triethylamine (0.12 ml, 0.86 mmol), and stirred for 6 hrs. After the reaction mixture was extracted with methylene chloride (50 ml×3), the organic layer was purified using column chromatography (45% ethylacetate in hexane) to afford the title compound (70 g, 62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9]C(OC)=O)=[CH:4][C:3]=1[NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>O>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18]
Reactant: CCOC(=O)Nc1cc(OC(=O)OC)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Nc1cc(O)c(Cl)cc1F
Temperature: 25 °C

Procedure:
The resulting ethyl N-(2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl)carbamate (45.2 g, 155 mmol) was reacted with potassium carbonate (21.4 g, 155 mmol) and water (100 ml) for 2 hours while heating under refluxing. After completion of the reaction, the mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue was made acidic by adding 1N hydrochloric acid (300 ml), and extracted with ethyl acetate (100 ml×3 times). The organic layer was washed with water, dried, the solvent was distilled off under reduced pressure, and the precipitated solid was isolated by filtration. The solid was recrystallized from chloroformhexane to obtain ethyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate as white crystals (35.2 g, 974 yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[F:18])=[O:22])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1ccc(-c2cc3c(cc2Cl)CCO3)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2cc3c(cc2Cl)CCO3)cn1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a solution of 5-(5-chloro-2,3-dihydrobenzo[3,4-b]furan-6-yl)-2-pyridylamine (151) (15 mg, 0.06 mmol) in 1 ml DCM was added 2-fluorobenzoyl chloride (11 μl, 0.088 mmol) followed by addition of DIEA (52 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (120 μl) at r.t. for 2 h and before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished N-[5-(5-chloro(2,3-dihydrobenzo[3,4-b]furan-6-yl))(2-pyridyl)](2-fluorophenyl)carboxamide (153) (14.7 mg, yield: 66.4%, purity>90%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CN(C)P(N(C)C)(N(C)C)=O>[CH2:26]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C#N)cc1
Temperature: 120 °C

Procedure:
p-Aminobenzonitrile (11.8 g., 0.1 mole) and 1-bromohexadecane (15.25 g., 0.05 mole) are dissolved in hexamethylphosphoramide (200 ml.) and heated under nitrogen in an oil bath maintained at 120° C. for 22 hours. The reaction mixture is cooled to room-temperature, and water (50 ml.) is added gradually. The mixtue is then chilled in an ice-bath. The precipitate separated is filtered, washed thoroughly with water and dried. It is then washed repeatedly with hexane and dried, providing 14.2 g. of a pale brownish yellow granular solid as a homogeneous product. Recrystallization from ether-hexane affords p-hexadecylaminobenzonitrile as pale yellow prisms, m.p. 63°-64° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:18][CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[C:5]([C:21]([OH:23])=O)[CH:4]=1.C(N(CC)CC)C.C1(P([N:45]=[N+:46]=[N-:47])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C>[CH3:1][O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:18][CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[C:5]([C:21]([N:45]=[N+:46]=[N-:47])=[O:23])[CH:4]=1
Reactant: COc1cccc2c1C(=O)c1c(OC)cc(C(=O)O)cc1C2=O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc2c1C(=O)c1c(OC)cc(C(=O)N=[N+]=[N-])cc1C2=O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
9,10-Dihydro-4,5-dimethoxy-9,10-dioxoanthracene-2-carboxylic acid (10 g) was suspended in dry DMF (130 ml) and cooled to 0° C. Triethylamine (3.89 g) was then carefully added, followed by a solution of diphenylphosphoryl azide (10.57 g) in dry DMF (20 ml). A yellow precipitate was generated during 12 hours stirring at room temperature. The precipitate was collected by filtration and washed with saturated sodium bicarbonate solution (1×100 ml) and water (5×100 ml). Drying in vacuo over silica gel yielded 9,10-dihydro-4,5-dimethoxy-9,10-dioxoanthracene-2-carbonyl azide as a signal yellow powder. Decomposition point: 139° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]([NH2:19])=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22]([C:26](O)=[O:27])[CH:21]=1>ClCCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:29][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]([NH2:19])=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1)=[O:27]
Reactant: Cc1cccc(C(=O)O)c1
Reactant: NC(=O)n1c(-c2ccc(N)cc2)cc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=O)Nc2ccc(-c3cc4ccccc4n3C(N)=O)cc2)c1
Temperature: 60 °C

Procedure:
To the solution of 2-(4-amino-phenyl)-indole-1-carboxylic acid amide (125.5 mg, 0.5 mmol, 1 eq) and m-toluic acid (68.8 mg, 0.5 mmol, 1 eq) in anhydrous DCE (4 mL) was added DMAP (12.2 mg, 0.2 eq) and EDC (115.2 mg, 1.2 eq). The reaction mixture was heated at 60° C. for 1.5 hours. It was then cooled to room temperature, diluted with ethyl acetate, washed subsequently with aqueous NH4Cl, saturated aqueous NaHCO3, brine, and lastly dried with anhydrous sodium sulfate. The upper liquor was decanted, concentrated, and the solid residue was treated with EtOAC-Hex(2:1) with stirring. 2-{4-[(3-methylbenzoyl)amino]phenyl}-1H-indole-1-carboxamide was obtained as slightly brown solid upon filtration in amount of 165 mg (89%).
Reaction SMILES: C([O:3][P:4]([CH:9]=[CH:10][C:11]1([N:26]=[N+:27]=[N-:28])[CH:15]([OH:16])[CH:14]([OH:17])[CH:13]([N:18]2[CH:23]=[CH:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[O:12]1)(=[O:8])[O:5]CC)C.N1C(C)=CC=CC=1C.C[Si](Br)(C)C>CC#N>[N:26]([C:11]1([CH:10]=[CH:9][P:4](=[O:3])([OH:8])[OH:5])[CH:15]([OH:16])[CH:14]([OH:17])[CH:13]([N:18]2[CH:23]=[CH:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[O:12]1)=[N+:27]=[N-:28]
Reactant: CCOP(=O)(C=CC1(N=[N+]=[N-])OC(n2ccc(=O)[nH]c2=O)C(O)C1O)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: [N-]=[N+]=NC1(C=CP(=O)(O)O)OC(n2ccc(=O)[nH]c2=O)C(O)C1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Compound 48.5 (119 mg, 0.28 mmol) was dissolved in 2.6 mL CH3CN, treated with 2,6-lutidine (0.1 mL) and TMSBr (0.2 mL). The mixture was stirred at rt for 2 h and concentrated under reduced pressure. The residue was coevaporated with saturated NH4OH three times and the residue was subjected to a reverse phase HPLC to give compound 48.6 (100 mg, 92% yield). 1H NMR (D2O, 300 MHz) 7.45 (d, J=8.1 Hz, 1H), 6.22 (app d, J=8.7 Hz, 1H), 6.16 (app d, J=5.7 Hz, 1H), 5.85 (d, J=3.0 Hz, 1H), 5.71 (d, J=8.1 Hz, 1H), 4.31 (m, 1H), 4.24 (m, 1H); 31P NMR (D2O 121.4 MHz) 7.3; MS (ESI) m/z 359 [M−2H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].C1COCC1.C(Cl)(=O)C([Cl:26])=O>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8]([Cl:26])=[O:9])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)O)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)Cl)c1

Procedure:
3,5-Diacetoxybenzoic acid (15 g, 63 mM) was suspended in dichloromethane (100 mls), THF(20 mls) with oxalyl chloride (7.34 mls, 69.3 mM) and DMF(2–3 drops) added. The resultant mixture was stirred for three hours at ambient temperature in a flask fitted with a gas bubbler. This gave a pale brown solution. After concentration ‘in vacuo’ the residue was triturated with diethyl ether. This gave a colourless solid, 3,5-diacetoxybenzoyl chloride (15.95 g) which was used for the next stage without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C@H:13]([OH:16])[CH2:14][OH:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([Sn](=O)CCCC)CCC.[C:29]1([CH3:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:35]([O:15][CH2:14][C@H:13]([C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=1)[OH:16])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1ccccc1
Reactant: OC[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCCC[Sn](=O)CCCC
Product: O[C@H](COCc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
(S)-1-(3,5-Bis(trifluoromethyl)phenyl)ethan-1,2-diol (11.45 g) and di-n-butyltin oxide (10.40 g) were dissolved in toluene (200 ml) and refluxed in a Dean and Stark apparatus for 16 hours. The toluene was removed under reduced pressure, cesium fluoride (12.70 g) suspended in N,N-dimethylformamide (200 ml) was added and the reaction stirred for 1 hour. The reaction was diluted with water and filtered through Hyflo™ before concentrating under reduced pressure and extracting into ethyl acetate. The organic phase was dried (brine, MgSO4) and concentrated under reduced pressure to give a crude brown oil. This was purified on silica eluting with 20% ethyl acetate/iso-hexane to afford the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[I:13]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[C:9]([I:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: COc1ccc(C(C)(C)C)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COc1ccc(C(C)(C)C)cc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-tert-butyl-4-methoxybenzene (0.10 g, 0.61 mmol) in MeOH (2 mL) was added to a mixture of silver sulfate (0.19 g, 0.61 mmol) and iodine (0.154 g, 0.61 mmol) in MeOH (1 mL). The mixture was stirred at room temperature for 1 h. The mixture was filtered. The filtrate was concentrated. The title compound was obtained. 1H NMR (CDCl3, 500 MHz): δ 7.82 (d, J=2.5 Hz, 1H), 7.36 (dd, J=8.5, 2.5 Hz, 1H), 6.80 (d, J=8.5 Hz, 1H), 1.35 (s, 9H).
Reaction SMILES: CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[OH:22].F[C:24]1[CH:25]=[CH:26][C:27]([N+:33]([O-:35])=[O:34])=[C:28]([CH:32]=1)[C:29]([NH2:31])=[O:30]>O>[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:13]=1[O:22][C:24]1[CH:25]=[CH:26][C:27]([N+:33]([O-:35])=[O:34])=[C:28]([CH:32]=1)[C:29]([NH2:31])=[O:30]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.9 %

Procedure:
To a 100 ml flask fitted with a magnetic stirrer and drying tube is added dimethyl sulfoxide (50 ml), anhydrous potassium carbonate (3.6 g, 0.026 mole) and 2-chloro-4-trifluoromethylphenol (4.8 L g, 0.024 mole). This mixture is stirred at room temperature overnight. 5-Fluoro-2-nitrobenzamide (4.5 g, 0.024 mole) is added rapidly and the reaction mixture stirred at room temperature for 24 hours. The reaction mixture is poured into water (300 ml) and triturated with carbon tetrachloride (50 ml). The water and carbon tetrachloride insoluble solid is collected by filtration and dried under vacuum to afford 1.2 g of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzamide, mp 139°-43° C. Anal. Calcd. for C14H8ClF3N2O4 : C, 46.62; H, 2.23; Cl, 9.83; N, 7.76. Found: C, 45.77; H, 2.30; Cl, 10.62; N, 7.91.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.[CH2:37]([NH2:43])[C:38]1[O:42][CH:41]=[CH:40][CH:39]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:43][CH2:37][C:38]1[O:42][CH:41]=[CH:40][CH:39]=1)=[O:25]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: NCc1ccco1
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2ccco2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with furfurylamine.