Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2[NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](C(OC(C)(C)C)=O)[N:34]=[CH:33]2.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CS(C)=O>[C:23]1([C:19]2[CH:18]=[C:17]([C:10]3[N:9]=[C:8]([NH:29][C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[NH:35][N:34]=[CH:33]5)[C:7]4[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)[CH:6]=4)[N:11]=3)[CH:22]=[CH:21][CH:20]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN1CCOCC1
Temperature: 85 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
To a mixture of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.25 g, 0.40 mmole) in DMSO (2 mL) was added morpholine (1.32 g, 1.33 mL, 15.2 mmole) and the reaction was stirred at 85° C. for 48 h. The mixture was poured onto ice-water and the crude product was filtered. The product was then dissolved in a mixture of CH2Cl2 and CH3OH and the solution was concentrated in vacuo. The residue was purified via preparative TLC (SiO2, 10% CH2Cl2/CH3OH) to give 2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-morpholinoethoxy)quinazolin-4-amine (0.131 g, 0.20 mmole, 50%). MS 572.2 (M+). HPLC retention time 5.27 mins.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH2:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+].[C:22](O)(=[O:24])[CH3:23]>C(O)C.[OH-].[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][C:12]([O:24][CH2:22][CH3:23])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=C(COC1CCN(C(C)=O)CC1)c1ccccc1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(C)(COC1CCN(C(C)=O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Acetyl-4-(2-phenylallyloxy)piperidine (7.0 g.) (prepared as in Example BB) in ethanol (10 ml.) was added to a stirred suspension of mercuric acetate (9.2 g.) in ethanol (50 ml.) at room temperature. The mixture was stirred at room temperature for one hour then cooled to 0° C. Sodium hydroxide solution (20 ml., 5 N) followed by sodium borohydride (1.03 g.) in sodium hydroxide solution (20 ml., 5 N) were added to the stirred suspension and after 10 minutes glacial acetic acid was added to pH 6. The suspension was filtered, the filtrate concentrated and the residue partitioned between chloroform and water. The organic layer was dried (Na2SO4) and the solvent evaporated in vacuo. Gas-liquid chromatographic (GLC) analysis of the product indicated incomplete conversion to the desired product therefore the oxymercuration process was repeated as above to give N-acetyl-4-(2-ethoxy-2-phenyl-n-propoxy)piperidine (7.4 g.), 84% pure by GLC. The product in ethanol (100 ml.) and sodium hydroxide solution (30 ml.) was heated under reflux for 11 hours. The organic solvent was evaporated and the aqueous solution was extracted with chloroform (3×30 ml.). The combined chloroform extracts were dried (Na2SO4) and the solvent evaporated in vacuo to give 4-(2-ethoxy-2-phenyl-n-propoxy)piperidine as an oil (3.8 g.). A sample was converted to the oxalate salt which was recrystallized twice from ethyl acetate then acetone and had an m.p. of 126°-127° C.
Reaction SMILES: C([NH:4][CH:5]([C:11]([O:13]CC)=[O:12])[C:6](OCC)=O)(=O)C.[O-]CC.[Na+].[Na].BrC[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[NH2:4][CH:5]([CH2:6][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]([OH:13])=[O:12]
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: NC(CCCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Diethyl acetamidomalonate (220 g) in 1 L of absolute ethanol was added to a stirred solution of sodium ethoxide in ethanol, prepared by dissolving sodium (24 g) in absolute ethanol (500 mL), under nitrogen. The reaction mixture was refluxed under nitrogen for 30 minutes, then 1-bromo-3-phenylpropane (200g) was added. The reaction mixture was refluxed overnight, cooled to ambient temperature, filtered, and the solvent was removed under vacuum. Concentrated HCl (800 mL) was added to the residue, and the reaction mixture was refluxed for 14 hours. The cooled aqueous solution was washed with ether, and the residual ether in the aqueous phase was removed by bubbling nitrogen through the solution. The pH of the aqueous phase was adjusted to pH 7-8 by the addition of ammonium hydroxide. The title compound was collected by filtration, air dried and recrystallized from ethanol-water (150 g) m.p. 255-257° C. MS m/z: 194 (M+H)+.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[O:18][CH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC>[CH2:1]=[C:20]1[CH2:21][CH2:22][CH2:23][CH:19]1[O:18][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[O:7][CH3:6])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(OC)c(OC2CCCC2=O)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1CCCC1Oc1cc(C(=O)OC)ccc1OC
Temperature: -40 °C

Procedure:
28.5 g of methyltriphenylphosphonium bromide are suspended under nitrogen in 300 ml of anhydrous THF and the mixture is cooled to -40° C. 50 ml of n-butyllithium (1.6M) in n-hexane are then added dropwise with stirring. After stirring at -20° to -10° for 30 min, a solution of 20 g of methyl 4-methoxy-3-(2-oxocyclopentyloxy)benzoate in 100 ml of abs. THF is added dropwise. The mixture is then allowed to warm to RT and is stirred for a further 1 h. It is poured onto water and extracted with ethyl acetate. The oil which remains after concentrating the organic phase is chromatographed on a silica gel column using ethyl acetate/petroleum ether (4:6). The chromatographically pure fractions are combined, concentrated and dried in a high vacuum. 12.7 g of the title compound are obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH2:16][CH2:15][CH2:14][NH:13][C:12]=23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCCl>[C:30]([N:13]1[CH2:14][CH2:15][CH2:16][N:11]2[N:10]=[C:9]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:12]12)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(-c2c(-c3ccncc3)nn3c2NCCC3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)N1CCCn2nc(-c3ccncc3)c(-c3ccc(F)cc3)c21

Procedure:
A mixture of 3-(4-fluorophenyl)-2-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (100 mg), triethylamine (0.4 ml) and acetic anhydride (0.2 ml) in dry 1,2-dichloroethane (3 ml) was refluxed for 2 days. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in dichloromethane and the solution was washed with an aqueous saturated sodium bicarbonate solution and brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from diisopropyl ether to give 4-acetyl-3-(4-fluorophenyl)-2-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (60 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:22])[C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:28]=1)[CH3:19]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: CCOC(=O)c1cccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)c1
Yield: 50.9 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (2.25 g, 10.0 mmol) was converted, using 3-ethoxycarbonylphenylboronic acid (2.89 g, 15 mmol), instead of 4-fluorophenylboronic acid, which after purification by chromatography (SiO2, heptane:ethyl acetate=50:50) afforded the title compound (1.9 g, 52%) which was obtained as a light yellow solid. MS: m/e=374.1[M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:5]=[C:4]([C:12]([O:14]C)=[O:13])[CH:3]=1.[OH-].[K+].CO.ClCCl>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[N:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cc(Br)cc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6.09 g of dimethyl 4-bromopyridine-2,6-dicarboxylate, 1.08 g of potassium hydroxide, 200 ml of methanol and 20 ml of dichloromethane was stirred at room temperature for 3 hours, and 200 ml of ether was added thereto. The resulting white solid was filtered, and then washed with ether. The obtained white solid was dissolved in water, and then 12 ml of hydrochloric acid (2 M) was added thereto. The resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][N:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][N:7]=[N:8]2)=[C:4]([NH:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: Clc1nc(Cl)c2[nH]nnc2n1
Solvent: CCCCO
Product: Clc1nc(NCc2ccccc2)c2[nH]nnc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-Dichloro-8-azapurine (0.84 mmol), prepared as described in Example 17, was dissolved in n-butanol (4 ml) and benzylamine (1.4 mmol) was added. The reaction mixture was stirred at room temperature overnight. After concentration in vacuo the product was purified by chromatography (SiO2, IV—from 1% MeOH and 0.25% acetic acid to 2% MeOH with 0.35% acetic acid).
Reaction SMILES: [CH:1]1([C:4]([C@H:6]2[C@H:11]([CH3:12])[CH2:10][C@H:9]3[C@H:13]4[C:22]([C@@H:23]([C:25]5[CH:30]=[CH:29][C:28]([C:31]6[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=6)=[CH:27][CH:26]=5)[CH2:24][C@:7]23[CH3:8])=[C:21]2[C:16](=[CH:17][C:18](=[O:37])[CH2:19][CH2:20]2)[CH2:15][CH2:14]4)=[O:5])[CH2:3][CH2:2]1.[ClH:38].O>C(#N)C>[ClH:38].[CH:1]1([C:4]([CH:6]2[CH:11]([CH3:12])[CH2:10][C@H:9]3[C@H:13]4[C:22]([CH:23]([C:25]5[CH:26]=[CH:27][C:28]([C:31]6[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=6)=[CH:29][CH:30]=5)[CH2:24][C@:7]23[CH3:8])=[C:21]2[C:16](=[CH:17][C:18](=[O:37])[CH2:19][CH2:20]2)[CH2:15][CH2:14]4)=[O:5])[CH2:3][CH2:2]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(-c4cccnc4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CC1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3C(c3ccc(-c4cccnc4)cc3)C[C@]2(C)C1C(=O)C1CC1

Procedure:
To a solution of (11β,16α,17β)-17-cyclopropylcarbonyl-16-methyl-11-[4-(3-pyridinyl)phenyl]estra-4,9-dien-3-one (40 mg, 0.081 mmol) in acetonitrile (1 mL) were added 2 N hydrochloric acid (40 μL) and water (5 mL). Lyophilisation of this mixture gave 11β,16α,17β)-17-cyclopropylcarbonyl-16-methyl-11-[4-(3-pyridinyl)phenyl]estra-4,9-dien-3-one hydrochloride in quantitative yield (40 mg, 0.08 mmol). 1H NMR (400 MHz, CDCl3): δ 0.34 (s, 3H), 0.80-2.85 (m, 24H), 4.47 (d, J=7 Hz, 1H), 5.81 (s, 1H), 7.31-7.35 (m, 2H), 7.51-7.55 (m, 2H), 7.64 (dd, J=8 and 5 Hz, 1H), 8.18 (dt, J=8 and 1 Hz, 1H), 8.62 (d, J=5 Hz, 1H), 8.90 (d, J=1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([I:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:28]O>S(=O)(=O)(O)O>[CH3:28][O:19][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:24]([F:26])([F:25])[F:27])[O:13][N:12]=2)=[CH:15][C:16]=1[I:23]
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1I
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1I

Procedure:
In a solution of 0.60 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-iodo benzoic acid synthesized similarly to Steps 1 to 4 of Synthetic Example 4 in 10 ml of methanol, 2 drops of concentrated sulfuric acid was added, and stirred under reflux with heat for 20 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was neutralized with 10 ml of saturated sodium hydrogen carbonate aqueous solution, then extracted with ethyl acetate (10 ml×2). The organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:4), and 0.56 g of the aimed product was obtained as colorless oily substance.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])=[C:7]([Cl:15])[N:6]=[CH:5][N:4]=1.[F:16][C:17]1[C:18]([C:23]2[NH:24][CH:25]=[CH:26][N:27]=2)=[N:19][CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[Cl:15][C:7]1[C:8]([CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])=[C:3]([CH2:2][N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[C:18]2[C:17]([F:16])=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[CH:5][N:6]=1
Reactant: Fc1cccnc1-c1ncc[nH]1
Reactant: CC(=O)OCCc1c(Cl)ncnc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCc1c(Cl)ncnc1Cn1ccnc1-c1ncccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 162 (8.4 mmol), 3-fluoro-2-(1H-imidazol-2-yl)-pyridine (described above) (1.38 g, 8.4 mmol) and K2CO3 (1.17 g, 8.4 mmol) in DMF (6 ml) is stirred at room temperature overnight. To the mixture are added EtOAc (20 ml) and water (10 ml). The organic layer is separated and the aqueous layer is extracted with EtOAc (3×10 ml). The combined extracts are washed with brine (10 ml), dried (Na2SO4) and solvent evaporated. PTLC separation of the residue (5% MeOH in CH2Cl2) gives the product (163) as a white solid.
Reaction SMILES: [Cl:1][C:2]([Cl:32])([Cl:31])[CH2:3][O:4][C:5](=[O:30])[CH:6]([S:18]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:20])=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[F:62][C:63]([F:73])([F:72])[C:64]1[CH:71]=[CH:70][C:67]([CH2:68]O)=[CH:66][CH:65]=1>CN(C=O)C.CCOC(C)=O>[Cl:32][C:2]([Cl:31])([Cl:1])[CH2:3][O:4][C:5](=[O:30])[CH:6]([S:18]([CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)(=[O:20])=[O:19])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([O:17][CH2:68][C:67]2[CH:66]=[CH:65][C:64]([C:63]([F:62])([F:72])[F:73])=[CH:71][CH:70]=2)=[O:16])=[CH:12][CH:13]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)Cc1ccc(CC(C(=O)OCC(Cl)(Cl)Cl)S(=O)(=O)CCc2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: O=C(Cc1ccc(CC(C(=O)OCC(Cl)(Cl)Cl)S(=O)(=O)CCc2ccc(F)cc2)cc1)OCc1ccc(C(F)(F)F)cc1
Reaction time: 18 h
Yield: 102.4 %

Procedure:
3-(4-Carboxymethyl-phenyl)-2-[2-(4-fluoro-phenyl)-ethanesulfonyl]-propionic acid 2,2,2-trichloro-ethyl ester (121 mg, 0.23 mmol) was dissolved in anhydrous DMF (2.0 mL) and TBTU (147 mg, 0.46 mmol), N-methyl morpholine (46.5 mg, 0.46 mmol) and 4-(trifluoromethyl)benzyl alcohol (81.06 mg, 0.46 mmol) were added under nitrogen atmosphere. The reaction was stired at ambient temperature for 18 h. EtOAc was added and the mixture was extracted with water and brine. After drying the organic layer over Na2SO4 the solvent was evaporated under reduced pressure to afford the crude product as an oil (161 mg, 102.3%). No further purification was done. 1H NMR (400 MHz, CDCl3): δ 7.44-7.62 (m, 6H), 7.12-7.23 (m, 4H), 6.97-7.02 (t, 2H)5.14 (s, 2H), 4.74 (s, 2H), 4.69 (d, 1H), 3.62 (s, 2H), 3.34-58 (m, 4H), 3.15-3.19 (t, 2H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].C(=O)([O-])[O-:11].[Ca+2:14]>O>[C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[C:1]([O:9][OH:11])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[Ca+2:14].[Ca+2:14].[OH:11][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[OH:11][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[OH:11][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3]
Reactant: O=C([O-])[O-]
Agent: O=C(O)CC(O)C(=O)O
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])CC(O)C(=O)OO

Procedure:
An aqueous solution of malic acid is prepared by mixing 134.09 g of malic acid with 50 mL of water. An aqueous solution of calcium carbonate is also prepared in a separate container by thoroughly mixing 200.18 g of calcium carbonate in 50 mL of water. The aqueous calcium carbonate solution is then slowly added to the aqueous malic acid solution. The resulting liquid is spray dried to produce a powdered dicalciumhydroxy malate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([CH2:29][C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: ClCc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(Cc4cccnc4)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A2 (0.12 mmol, 50 mg), 3-chloromethyl-pyridine (0.12 mmol, 20 mg) and triethylamine (0.63 mmol, 88 μL) were dissolved in DMF and microwaved at 80° C. for 10 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvent in vacuo provided Compound A6 pure as a yellow solid (39 mg, 66%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.09 (s, 1H), 8.45 (m, 2H), 8.33 (s, 1H), 7.90 (d, 2H), 7.78 (d, 2H), 7.65 (m, 1H), 7.21 (m, 1H), 5.41 (heptet, 1H), 3.52 (m, 2H), 3.01 (s, 3H), 2.65 (m, 2H), 2.47 (m, 2H), 1.98 (m, 2H), 1.94 (m, 2H). LCMS (ESI), m/z 484.3 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:39](O)[CH3:40].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]([O:21][CH2:39][CH3:40])=[O:20])=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:37][CH:38]=1
Reactant: O=C(O)c1ccc2c(c1)N(Cc1ccc(C(=O)N3CCCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Reactant: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)N(Cc1ccc(C(=O)N3CCCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Reaction time: 8 h

Procedure:
5 mg (0.009 mmol) of 4-(4-chlorobenzoyl)-2-oxo-1-[4-(1-pyrrolidinecarbonyl)benzyl]-2,3,4,5-tetrahydro-1H-benzo[e][1,4]-diazepine-8-carboxylic acid was dissolved in 5 ml of dichloromethane. 0.001 ml (0.018 mmol) of ethanol, 2 mg (0.011 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.003 ml (0.018 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.S(=O)(=O)(O)O>CCOCC.C1C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([C:3]2[CH2:4][C:5]3[C:10]([C:2]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:20])=[CH:17][CH:16]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccc(C(=O)C2Cc3ccccc3C2=O)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: c1ccccc1
Product: COc1ccc(C(=O)C2=C(c3ccccc3)c3ccccc3C2)cc1
Yield: 57 %

Procedure:
A slurry of 13.25 g (50 mmol) of 1-oxo-2-(4-methoxybenzoyl)indane in a mixture of 300 mL of ether and 300 mL of benzene was prepared. To the slurry was added 35.66 g (197 mmol) of phenylmagnesium bromide. The resulting mixture was heated to reflux for sixteen hours and poured into a mixture of ice and sulfuric acid. The mixture was allowed to separate and the organic layer was removed. The organic extract was washed with a bicarbonate solution, dried over sodium sulfate, filtered, and concentrated to a red oil. A small amount of ether was added to the oil and a crystalline precipitate formed. The crystals were removed by filtration. The filtrate was concentrated to dryness and the product crystallized from methanol to yield 9.3 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9](Cl)=[CH:8][C:7]([C:11]2[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][CH3:20])=[N:6][CH:5]=1.B(CC)(CC)[CH2:23][CH3:24].C([O-])([O-])=O.[Na+].[Na+].CCCCCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9]([CH2:23][CH3:24])=[CH:8][C:7]([C:11]2[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][CH3:20])=[N:6][CH:5]=1
Reactant: CCB(CC)CC
Reactant: CCc1cccc(CC)c1-c1cc(Cl)c(C(=O)OC)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCc1cc(-c2c(CC)cccc2CC)ncc1C(=O)OC
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-nicotinic acid methyl ester (2.5 g, 8.2 mmol), Et3B (1M in Hexane, 49 mL, 49 mmol), Na2CO3 (2M in H2O, 12.3 mL) and Pd(PPh3)4 (500 mg) in toluene (36 mL) is heated at 80° C. under argon for 2 days. On cooling, hexane (50 mL) is added and the organic layer separated. The organic layer is washed with saturated Na2CO3 and water, dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (hexane/EtOAc 4:1) to give 6-(2,6-diethyl-phenyl)-4-ethyl-nicotinic acid methyl ester. 1H NMR (CDCl3) 9.15 (s, 1H), 7.30 (m, 1H), 7.21 (s, 1H), 7.15 (d, 2H), 3.97 (s, 3H), 3.06 (q, 2H), 2.31 (m, 4H), 1.26 (t, 3H), 1.03 (t, 6H).