Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+]>O>[C:8]([OH:10])(=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]
Reactant: O=C(O)CCCCCCC(=O)O
Reactant: Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCCCCC(=O)Nc1ccccc1
Temperature: 175 °C
Reaction time: 0.33 h

Procedure:
In a 22 L flask was placed 3,500 g (20.09 moles) of suberic acid, and the acid melted with heat. The temperature was raised to 175° C., and then 2,040 g (21.92 moles) of aniline was added. The temperature was raised to 190° C. and held at that temperature for 20 minutes. The melt was poured into a Nalgene tank that contained 4,017 g of potassium hydroxide dissolved in 50 L of water. The mixture was stirred for 20 minutes following the addition of the melt. The reaction was repeated at the same scale, and the second melt was poured into the same solution of potassium hydroxide. After the mixture was thoroughly stirred, the stirrer was turned off, and the mixture was allowed to settle. The mixture was then filtered through a pad of Celite (4,200 g) (the product was filtered to remove the neutral by-product (from attack by aniline on both ends of suberic acid). The filtrate contained the salt of the product, and also the salt of unreacted suberic acid. The mixture was allowed to settle because the filtration was very slow, taking several days). The filtrate was acidified using 5 L of concentrated hydrochloric acid; the mixture was stirred for one hour, and then allowed to settle overnight. The product was collected by filtration, and washed on the funnel with deionized water (4×5 L). The wet filter cake was placed in a 72 L flask with 44 L of deionized water, the mixture heated to 50° C., and the solid isolated by a hot filtration (the desired product was contaminated with suberic acid which is has a much greater solubility in hot water. Several hot triturations were done to remove suberic acid. The product was checked by NMR [D6DMSO] to monitor the removal of suberic acid). The hot trituration was repeated with 44 L of water at 50° C. The product was again isolated by filtration, and rinsed with 4 L of hot water. It was dried over the weekend in a vacuum oven at 65° C. using a Nash pump as the vacuum source (the Nash pump is a liquid ring pump (water) and pulls a vacuum of about 29 inch of mercury. An intermittent argon purge was used to help carry off water); 4,182.8 g of suberanilic acid was obtained.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:44][N:45]=[C:46]=[O:47].O>C1COCC1>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:46]([NH:45][CH3:44])=[O:47])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: CN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound (31.8 mg) obtained in Example 25 and Et3N (8.4 μl) in THF (3 ml), methyl isocyanate (6.8 mg) was added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, and dried, and the solvent was evaporated under reduced pressure, and then the residue was purified by preparative HPLC to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:16])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH3:15])[CH:9]=1)[CH3:6])[CH3:2].[CH2:18]([C:22]1[C:27]([CH2:28][C:29](O)=[O:30])=[CH:26][N:25]=[C:24]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[N:23]=1)[CH2:19][CH2:20][CH3:21].C(OC(=O)CC(=O)CCCC)C>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([C:29](=[O:30])[CH2:28][C:27]2[C:22]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:23][C:24]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:37]=3)=[N:25][CH:26]=2)[CH3:15])[CH:9]=1)([CH3:16])[CH3:6])[CH3:2]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CC(=O)O
Reactant: CCOC(=O)C(C)(C)Oc1cccc(NC)c1
Agent: CCCCC(=O)CC(=O)OCC
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CC(=O)N(C)c1cccc(OC(C)(C)C(=O)OCC)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-(3-methylamino-phenoxy)-propionic acid ethyl ester (example 26 A]) was reacted with [4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared starting from 3-oxo-heptanoic acid ethyl ester in analogy to the sequences described in examples 27C] to 27F] and examples 26D] and 26E]) to give 2-[3-({2-[4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetyl}-methyl-amino)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow amorphous solid.
Reaction SMILES: CS(O[CH:6]([CH2:16][N:17]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]2[C:19]([N:20]([CH3:35])[C:21](=[O:34])[N:22]([CH3:33])[C:23]2=[O:32])=[CH:18]1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])(=O)=O.[C:36]([O-:39])(=[S:38])[CH3:37].[K+]>CN(C=O)C>[C:36](=[O:39])([S:38][CH:6]([CH2:16][N:17]1[C:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:24]2[C:19]([N:20]([CH3:35])[C:21](=[O:34])[N:22]([CH3:33])[C:23]2=[O:32])=[CH:18]1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:13])[CH3:14])([CH3:11])[CH3:10])[CH3:37]
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CC(CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O)cc2n(C)c1=O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC(CO[Si](C)(C)C(C)(C)C)Cn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 70 °C
Reaction time: 72 h

Procedure:
1-((tert-Butyldimethylsilyl)oxy)-3-(1,3-dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)propan-2-yl methanesulfonate (step 3)(1.3 g, 2.63 mmol) in dry DMF (20 ml) was treated with potassium thioacetate (1.5 g, 13.1 mmol). The resulting solution stirred for 7 h at 70° C. and at RT for 3 days. The mixture was heated at 70° C. overnight and after cooling to RT, the mixture was partitioned between EtOAc (100 ml) and water (150 ml). The layers were separated and the aqueous was extracted with EtOAc (×3). The organics were combined, washed with water, brine (×3), passed through a hydrophobic frit and concentrated in vacuo to yield the title compound as a brown oil;
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[N:6][C:7]=1[F:8].C([Mg]Cl)(C)C.C([Li])(C)(C)C.CN(C)[CH:30]=[O:31]>O1CCCC1.O>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][NH:9][C:5]1[N:6]=[C:7]([F:8])[C:2]([CH:30]=[O:31])=[CH:3][CH:4]=1
Reactant: Fc1nc(NCc2ccccc2Cl)ccc1Br
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(NCc2ccccc2Cl)nc1F
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 93.5 %

Procedure:
To (5-bromo-6-fluoro-pyridin-2-yl)-(2-chloro-benzyl)-amine (17, 1.85 g, 5.86 mmol) in 25.0 mL of tetrahydrofuran under an atmosphere of nitrogen at −78° C., isopropylmagnesium chloride (3.00 ML, 2.00 M in tetrahydrofuran, 6.00 mmol) was added over 10 minutes. After 50 minutes, tert-butyllithium (7.80 mL, 1.70 M in hexane, 13.3 mmol) was added over 5 minutes. After 20 minutes, N,N-dimethylformamide (1.09 mL, 14.0 mmol) was added and the reaction mixture stirred at −78° C. for 20 minutes, then brought to room temperature over 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 35% ethyl acetate in hexane. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (18, 1.45 g). MS (ESI) [M+H+]+=265.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](Cl)[CH:10]=1.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:21]2[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=2)[CH:10]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)c(Cl)c1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cn1cc(-c2cc(Oc3ccc(N)cc3Cl)ccn2)cn1
Temperature: 90 °C
Yield: 104.8 %

Procedure:
3-Chloro-4-(2-chloropyridin-4-yloxy)benzenamine (0.89 g, 3.49 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole (0.871 g, 4.19 mmol) and K2CO3 (1.302 g, 9.42 mmol) were combined in DME (6 ml)/H2O (7.5 ml) and the headspace was flushed with Ar for 10 min. Pd(Ph3P)4 (0.202 g, 0.174 mmol) was then added and the biphasic reaction was stirred with heating at 90° C. overnight. The reaction was cooled to RT and filtered to remove insoluble material. The filtrate was diluted with THF and washed with brine (3×). The combined aqueous phases were extracted with THF (2×). The combined organics were washed with brine (1×), dried (MgSO4), concentrated in vacuo and purified by silica gel chromatography (MeOH/CHCl3) to afford 3-chloro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine (1.10 g, 83% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.30-8.29 (m, 1H), 8.22 (s, 1H), 7.92 (s, 1H), 7.12 (m, 1H), 7.00-6.98 (m, 1H), 6.72 (br s, 1H), 6.58-6.54 (m, 1H), 6.47-6.44 (m, 1H), 5.44 (s, 2H), 3.84 (s, 3H); MS (ESI) m/z: 301.1 (M+H+): 303.0 (M+2+H+).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:23][C:24](=O)[CH2:25][CH2:26][CH2:27]Cl)[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[O-].[Na+]>CO>[CH2:16]([N:6]1[C:5]2=[N:4][N:3]3[CH:23]=[C:24]([CH:25]4[CH2:27][CH2:26]4)[NH:1][C:2]3=[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7]1=[O:15])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCCn1c(=O)c2c(N)n(CC(=O)CCCCl)nc2n(Cc2ccccc2)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCn1c(=O)c2c(nn3cc(C4CC4)[nH]c23)n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
3-Amino-7-benzyl-2-(5-chloro-2-oxopentyl)-5-propylpyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.8 g) was suspended in methanol (20 ml). To the suspension was added a solution of 28% NaOMe in methanol (4 ml). The mixture was stirred at room temperature for 30 minutes and then at 60° C. for 3 hours. The reaction solution was concentrated to dryness. The residue was dissolved in methylene chloride, washed with water and concentrated to dryness to obtain crude crystals. Recrystallization from isopropyl ether gave colorless crystals (0.52 g), m.p. 264°-265° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32]>>[OH:32][C@@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[NH:25][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N[C@@H]2CCCC[C@H]2O)cn1
Yield: 91 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using (1R,2R)-2-amino-cyclohexanol hydrochloride (1:1) instead of 2-aminoethyl isopropylether, to the title compound (240 mg, 91%) which was obtained as a white solid. MS: m/e=406.2 [M−H]−.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[CH:15]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:17][CH2:16]1>C(#N)C>[CH:15]1([N:18]2[CH2:23][CH2:22][N:21]([C:8]3[CH:7]=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([O:3][CH:2]([F:14])[F:1])[CH:9]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16]1
Reactant: C1CN(C2CC2)CCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1OC(F)F
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCN(C3CC3)CC2)cc1OC(F)F
Temperature: 100 °C
Yield: 74.5 %

Procedure:
To 2.07 g (10.0 mmol) of the product prepared in step 14.1 in 30 mL of acetonitrile are added 5.99 mL (35.0 mmol) of diispropylethylamine and then 2.09 g (10.5 mmol) of finely ground N-cyclopropylpiperazine (supplier). The reaction mixture is heated at 100°C. for 1 hour 30 minutes, cooled and concentrated under vacuum. The residue is taken up in 75 mL of ethyl acetate and washed with saturated aqueous NaHCO3 solution and with saturated aqueous NaCl solution. The organic phase is dried over Na2SO4, filtered and concentrated under vacuum. After triturating in cyclohexane, the solid is drained by suction and dried in an oven under vacuum. 2.33 g of the expected product are obtained in the form of a yellow solid, which is used as obtained in the following step. Yield=74.5%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Oc1ccc(I)cc1
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCOc1ccc(I)cc1
Yield: 90.2 %

Procedure:
A mixture of 4-iodophenol (6.6 g), 1-bromopentane (4.5 g), anhydrous potassium carbonate (13.8 g) and acetone (100 ml) was stirred at reflux for 24 hours, with the additions of a further quantity of 1-bromopentane after 4 hours (4.5 g) and 8 hours (4.5 g). The acetone was removed by evaporation. The residue was triturated with water (50 ml) and extracted with ether (3×30 ml). The organic extracts were combined, dried (MgSO4) and evaporated. The residue, a colourless oil, was distilled at 160° C. and 0.05 mm pressure (using a Kugelrohr oven) to give 4-n-pentyloxyiodobenzene as a colourless oil (7.8 g); microanalysis, found C, 45.7; H, 5.4%; C11H15IO requires: C, 45.5; H, 5.2%; NMR(DMSO-d6): 0.84-0.95(3H,t), 1.25-1.48(4H,m), 1.62-1.77(2H,m), 3.88-3.97(2H,t), 6.72-6.8(2H,d), 7.52-7.6(2H,d); m/z 290 (M).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][C:11]([O:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C.O>CC#N.CCOC(C)=O>[Br:1][C:2]1[C:3]([N:22]2[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:15](=[O:16])[O:14][C:11]([CH3:12])([CH3:10])[CH3:13])[CH2:20][CH2:21]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CCN(c2nc(Cl)ncc2Br)CC1
Temperature: 25 °C
Reaction time: 40 h
Yield: 75.2 %

Procedure:
To a mixture of 5-bromo-2,4-dichloropyrimidine (0.256 mL, 2.00 mmol) and 4-N-Boc-aminomethylpiperidine (428 mg, 2.00 mmol) in CH3CN (5 mL), DIEA (0.700 mL, 4.02 mmol) was added. The mixture was stirred at room temperature for 40 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give tert-butyl (1-(5-bromo-2-chloropyrimidin-4-yl)piperidin-4-yl)methylcarbamate (610 mg).
Reaction SMILES: [C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:17]>>[C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:8])[O-:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:17]
Reactant: O=P(O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=P([O-])(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
In 2.18 g (10.0 mmol) of diphenylphosphinic acid (manufactured by Aldrich Inc., Product No. 10, 852-9), 20 mL (10.0 mmol) of 0.5 N sodium hydroxide was added, stirred at room temperature for 10 minutes, then water was distilled off under reduced pressure. The obtained solid was washed with a small amount of methanol and dried to obtain 2.35 g (yield 98%) of the aimed product as white crystal. Decomposition temperature: 469° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([CH:30]=O)[CH:20]=1)[CH2:17][CH3:18]>>[CH2:16]([C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([CH2:30][NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH:20]=1)[CH2:17][CH3:18]
Reactant: CCCc1cc(C=O)nn1-c1ccccc1
Reactant: NCCN1CCN(c2ccccc2)CC1
Product: CCCc1cc(CNCCN2CCN(c3ccccc3)CC2)nn1-c1ccccc1
Yield: 55.6 %

Procedure:
Compound 4 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 5-propyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16](O)=[O:17])[CH:14]=2)[CH:9]=[CH:8]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOCC.O>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:17])[CH:14]=2)[CH:9]=[CH:8]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Yield: 75.9 %

Procedure:
A solution of morpholine (1.320 mL, 15.14 mmol), 1H-indole-6-carboxylic acid (2.0332 g, 12.62 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (3.63 g, 18.92 mmol), 1-hydroxybenzotriazole (HOBt) (2.90 g, 18.92 mmol) and diisopropylethylamine (DIPEA) (6.61 mL, 37.8 mmol) in DMF (31.5 mL) was stirred overnight. The reaction was poured into a 1:1 water:brine solution and extracted with EtOAc (2×). The organic layers were combined and washed with 0.25 M aqueous KHSO4, water, brine and 10% aqueous LiCl; dried over Na2SO4, filtered and concentrated in vacuo. Trituration with Et2O provided the desired product (2.20 g, 9.58 mmol, 76% yield) as a light tan solid.
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].BrC1C=CC=CC=1.[C:19]1([CH3:38])[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[B:27]([C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=1[CH3:37])F>O1CCCC1.O>[C:19]1([CH3:38])[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[B:27]([C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=1[CH3:37])[C:8]1[CH:7]=[CH:6][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cc(C)c(B(F)c2c(C)cc(C)cc2C)c(C)c1
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: Brc1ccccc1
Product: Cc1cc(C)c(B(c2ccccc2)c2c(C)cc(C)cc2C)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.1 equivalents of 1.6 M butyllithium in hexane (37.5 ml, 0.066 mol) are added over the course of 15 minutes at -78° C. to a solution of 9.42 g (0.06 mol) of bromobenzene in 80 ml of tetrahydrofuran (THF). The reaction mixture is stirred at this temperature for 3 h. Then 16.1 g (0.06 mol) of solid dimesitylfluoroborane are added, and the mixture is allowed to warm to room temperature and stirred for a further hour. The mixture is poured into 500 ml of water and the resulting suspension is filtered. The product is purified by trituration with boiling methanol, to give 16.9 g (86% of theory) of the product as a white solid with a melting range of 185-187° C. The shifts δ in the 1H NMR, measured in CDCl3 are 7.50 ppm (d,2,J=7 Hz), 7.46 ppm (t,1,J=10 Hz), 7.50 ppm (br t, 2, J=7 Hz), 6.82 ppm (s, 4), 2.30 ppm (s,6) and 2.00 ppm (s,12).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[H][H]>CO.[Ni]>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[NH2:12])(=[O:5])=[O:4])[CH3:2]
Reactant: [H][H]
Reactant: CCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: CCS(=O)(=O)c1cccc(N)c1

Procedure:
1-(Ethylsulfonyl)-3-nitro-benzene (1.9 g; 9 mmol) was dissolved in 80 mL of methanol then 1 g of Raney-Nickel is added and the mixture treated with hydrogen gas. The reaction mixture was subsequently filtered and concentrated to yield 1.5 g (8.1 mmol; yield=93%) of an yellow oil.
Reaction SMILES: N1C(C)=CC=CC=1C.S([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])(C(F)(F)F)(=O)=O.[F:24][CH2:25][CH2:26][CH2:27]O>C(Cl)Cl>[F:24][CH2:25][CH2:26][CH2:27][O:16][S:17]([C:20]([F:21])([F:22])[F:23])(=[O:18])=[O:19]
Reactant: OCCCF
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=S(=O)(OCCCF)C(F)(F)F
Temperature: 25 °C

Procedure:
To a cold (−25° C.), stirred solution of 2,6-Lutidine (4.60 mL, 39.5 mmoL) in DCM (30 mL) was added triflic anhydride (6.00 mL, 35.5 mmoL) over 3 min. Then 3-fluoropropane-1-ol (1.61 g, 20.6 mmoL) was added. The reaction mixture was warmed to room temperature for 2.5 h. The reaction mixture was then concentrated to half its volume and purified by flash chromatography (Teledyne ISCO CombiFlash, isocratic DCM, REDISEP® SiO2 120 g, detecting at 254 nM, and monitoring at 220 nM). Concentration of the appropriate fractions provided Intermediate S-4A (2.92 g, 67.4%). 1H NMR (400 MHz, chloroform-d) δ ppm 4.69 (2H, t, J=6.16 Hz), 4.65 (1H, t, J=5.50 Hz), 4.54 (1H, t, J=5.61 Hz), 2.25 (1H, dt, J=11.39, 5.86 Hz), 2.19 (1H, dt, J=11.44, 5.94 Hz)
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:23])[C:12]=1[C:13](OCC)=[O:14])[C:3](=[O:10])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH3:9].COC1C=C(C=C(OC)C=1O)C=CC(NC1C=CC(C([O-])=O)=CC=1)=O>>[CH2:25]([O:24][C:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:11]2[C:12]=1[C:13]([OH:14])=[C:4]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:3](=[O:10])[N:2]2[CH3:1])=[O:23])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCOC(=O)c1cccc(N(C)C(=O)COCCCC)c1C(=O)OCC
Agent: COc1cc(C=CC(=O)Nc2ccc(C(=O)[O-])cc2)cc(OC)c1O
Product: CCCCCCCCCCOC(=O)c1cccc2c1c(O)c(OCCCC)c(=O)n2C

Procedure:
In accordance with EXAMPLE 20, ethyl 2-[N-methyl-N-(butoxyacetyl)amino]-6-decyloxycarbonyl-benzoate was used instead of ethyl 2-[N-methyl-N-octyloxyacetyl)amino]-4-[(3,5-dimethoxy-4-hydroxycinnamoyl)amino]-benzoate, the title compound (68)was obtained.