Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:24](Cl)(=[O:26])=[O:25])[CH:19]=[C:20]([F:23])[C:21]=1[F:22].[CH3:28][O:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C@H:32]([NH2:34])[CH3:33]>>[F:15][C:16]1[CH:17]=[C:18]([S:24]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:34][C@@H:32]([C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[O:29][CH3:28])[CH3:33])=[N:9]3)(=[O:26])=[O:25])[CH:19]=[C:20]([F:23])[C:21]=1[F:22]
Reactant: COc1ccccc1[C@@H](C)N
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=S(=O)(Cl)c1cc(F)c(F)c(F)c1
Product: COc1ccccc1[C@@H](C)Nc1ccc2c(NS(=O)(=O)c3cc(F)c(F)c(F)c3)cccc2n1

Procedure:
The title compound, MS: m/e=488.3 (M+H+), was prepared in accordance with the general method of example 61 from 5-nitro-2-chloroquinoline, 3,4,5-trifluorobenzenesulfonylchloride and (R)-2-methoxy-alpha-methylbenzylamine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:27])=[C:11]([CH:15](OC)[C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([CH3:27])=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][C:16]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(c1cccc(OCc2ccccc2)c1C)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cc2c[nH]c3ncccc23)cccc1OCc1ccccc1
Yield: 77.3 %

Procedure:
A mixture of 3-[(3-benzyloxy-2-methyl-phenyl)-methoxy-methyl]-1H-pyrrolo[2,3-b]pyridine (625, 24 mg, 0.067 mmol), trifluoroacetic acid (1 mL, 13 mmol), and triethylsilane (2 mL, 12.5 mmol) in acetonitrile (10 mL) was refluxed for 4 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was washed with saturated sodium bicarbonate, brine, and dried over sodium sulfate. After removal of solvent, the residue was washed with a mixture of ethyl ether and hexanes (1:1) to provide the compound as a yellow solid (P-1857, 17 mg, 75%). MS(ESI) [M+H+]+=329.24.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>[Cu](I)I.C(NC(C)C)(C)C>[CH3:23][Si:24]([C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1)([CH3:26])[CH3:25]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc(N(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1ccc(N(c2ccc(C#C[Si](C)(C)C)cc2)c2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Thereafter, to 200 ml of diisopropylamine were added 15.54 g (0.032 mol of tri(4-bromophenyl)amine, 1.35 g (1.92 mmol) of bis[triphenylphosphin]palladium dichloride and 9.43 g (0.96 mmol) of copper iodide. After the reaction mixture was stirred for 2 h at room temperature, 9.43 g, (96 mmol) of trimethylsilyl acetylene was slowly added to the reaction mixture. The reaction mixture was refluxed for 8 h and cooled. Solvent was removed under the reduced pressure. The residue was extracted with benzene and the benzene layer was washed with distilled water. The washed benzene layer was concentrated to give 13.84 g (81%) of tri(4-trimethylsilylethynylphenyl)amine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].[OH-].[Na+]>O.C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:17]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCC(=O)O
Yield: 70 %

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under Example 10, (20 g) and beta-alanine (9 g) are dissolved in 3:2 v/v water/ethanol (500 ml) containing NaOH (10 g) to provide a solution with a pH of at least 13. The solution is refluxed for 15 minutes whereupon it turns from a light orange to an intense red colour. The solution is acidified to pH 7.0 and the ethanol is removed by rotary evaporation. The resulting aqueous solution is washed twice with ethylacetate (100 ml). This solution is then subjected to rotary evaporation until the volume is reduced to 100 ml and this reduced volume of solution is acidified to pH 3.0 to give a white precipitate, which is filtered off to give 3-benzyloxy-1-(2'-carboxyethyl)-2-methylpyrid-4-one in 70% yield, m.p. 156°-157° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]2[N:7]([C:18]([O:21][CH3:22])=[N:19][N:20]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)([CH3:3])[CH3:2].Cl.[CH3:24][NH:25][O:26][CH3:27].ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:27][O:26][N:25]([CH3:24])[C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]1[C:18]([O:21][CH3:22])=[N:19][N:20]=[C:6]1[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[N:14]2)=[O:17]
Reactant: CNOC
Reactant: COc1nnc2c(NC(C)C)nc3cc(C(=O)O)ccc3n12
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nnc2c(NC(C)C)nc3cc(C(=O)N(C)OC)ccc3n12
Temperature: 23 °C
Reaction time: 12 h

Procedure:
A mixture of 4-isopropylamino-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid (127 mg), N,O-dimethylhydroxylamine hydrochloride (41 mg), 1-hydroxy-7-azabenzotriazole (57 mg), and EDC (81 mg) in DMF (2.0 mL) was stirred at 23° C. for 12 hrs. The solution was then diluted with EtOAc and washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride (2×) solutions. The organic layer was dried over sodium sulfate. The residue was purified by flash chromatography to afford 4-isopropylamino-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid-methoxy-methyl-amide. MS (M+H)+=345.7.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C@@H:4]1[C:13]1[CH:25]=[CH:24][C:16]([CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:15][CH:14]=1.[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1.C([BH3-])#N.[Na+].CCN(C(C)C)C(C)C>CO.C(O)(=O)C>[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:21]2[CH2:20][CH2:19][N:18]([CH2:17][C:16]3[CH:15]=[CH:14][C:13]([C@@H:4]4[O:3][C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=5[O:6][CH2:5]4)=[CH:25][CH:24]=3)[CH2:23][CH2:22]2)=[CH:31][CH:30]=1
Reactant: c1ccc2c(c1)OC[C@H](c1ccc(CN3CCNCC3)cc1)O2
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CN2CCN(Cc3ccc([C@H]4COc5ccccc5O4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-piperazine dihydrochloride (80 mg, 0.21 mmol), 4-formyl-benzoic acid methyl ester (41 mg, 0.25 mmol), sodium cyanoborohydride (26 mg, 0.42 mmol), and DIPEA (0.07 mL, 0.42 mmol) in MeOH (5 mL) is treated with 2 drops of acetic acid. The resulting mixture is stirred at room temperature for 16 h, concentrated, diluted with water, and extracted with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated. The residue is purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM to give 4-{4-[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-piperazin-1-ylmethyl}-benzoic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]([CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][C:4]=2[CH:3]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Cl[CH2:33][O:34][CH3:35]>CCOC(C)=O>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:33][O:34][CH3:35])[C:7]([CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[N:8][C:4]=2[CH:3]=1
Reactant: COCCl
Reactant: CN(Cc1nc2cc(Br)ccc2[nH]1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCn1c(CN(C)C(=O)OC(C)(C)C)nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl [(5-bromo-1H-benzimidazol-2-yl)methyl]methylcarbamate (1.54 g) and DMF (20 mL) were added K2CO3 (1.88 g) and chloromethylmethyl ether (516 μL) under ice-cooling, followed by stirring at room temperature overnight. The reaction mixture was diluted with EtOAc, and washed with water and brine in this order. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=80/20-55/45) to obtain a mixture (1.25 g) of tert-butyl {[5-bromo-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate and tert-butyl {[6-bromo-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate.
Reaction SMILES: C([N-][CH:5]([CH3:7])[CH3:6])(C)C.[Li+].[C:9]1(=[O:15])[CH2:14]CCC=[CH:10]1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18].[Cl-].[NH4+]>C(OCC)C>[CH3:21][O:20][C:16]([CH:17]1[CH2:18][CH:14]2[CH2:7][CH2:5][CH:6]1[CH2:10][C:9]2=[O:15])=[O:19]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1C=CCCC1
Reactant: C=CC(=O)OC
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCOCC
Product: COC(=O)C1CC2CCC1CC2=O
Reaction time: 8 h

Procedure:
To a cooled (−3° C.) solution of lithiumdiisopropylamide (0.9 M in methylcyclohexane, 607 mL, 546 mmol, 1.05 eq) was added a solution of cyclohex-2-enone (52.6 g, 53 mL, 520 mmol, 1.0 eq) in diethyl ether (650 mL) over 90 min. During addition, the temperature was kept below −3° C. The mixture was stirred for an additional 25 minutes before a solution of methyl acrylate (46.8 mL, 520 mmol, 1.0 eq) in diethyl ether (450 mL) was added dropwise over 60 minutes. The temperature of the mixture was kept below 0° C. overnight. The mixture was poured out in saturated solution of ammonium chloride (1.0M) and stirred for 10 min. The sticky polymer was removed by filtration (P3). The organic layer was separated and the aqueous layer was extracted with tert-butyl methyl ether (2×300 mL). The combined organic layers were dried over sodium sulfate and concentrated. The title compound was isolated by distillation (0.001 mbar at 120-130° C.) and was isolated as a slightly yellow oil (39.8 g, 220 mmol, 42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]([N:18]1[CH2:27][CH2:26][C@H:25]2[C@H:20]([CH2:21][CH2:22][C:23](=[O:28])[CH2:24]2)[CH2:19]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C>C1COCC1>[C:10]([N:18]1[CH2:27][CH2:26][C@H:25]2[C@H:20]([CH2:21][CH2:22][C:23]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)([OH:28])[CH2:24]2)[CH2:19]1)(=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CC[C@@H]2CN(C(=O)c3ccccc3)CC[C@@H]2C1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)N1CC[C@@H]2CC(O)(c3ccc(F)cc3)CC[C@@H]2C1

Procedure:
Following the general procedure described in Example 25, a solution of p-fluorophenyl magnesium bromide in THF (1.0M, 2.61 mL, 2.61 mmol) was reacted with cis-2-benzoyl-6-oxodecahydroisoquinoline (670 mg, 2.61 mmol) in anhydrous THF at -78° C. Column chromatography (ethyl acetate) afforded the product, a solid (478 mg):mp 84°-85° C.; NMR (CDCl3, 200 MHz): 7.5-7.35 (m, 7H), 7.0 (t, 2H, J=8), 4.65-4.35 (m, 1H), 3.8-3.6 (m, 1H), 3.3-3.1 (m, 1H), 3.1-2.8 (m, 1H), 2.65-2.35 (m, 1H), 2.1-1.4 (m, 10 H); Anal. Calcd for C22H24FNO2 : C, 74.76, H, 6.84, N, 3.96, F, 5.38; Found: C, 74.59, H, 6.93, N, 3.79, F, 5.53.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[N:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]([C:21]2[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[S:23](=[O:32])(=[O:31])[N:22]=2)[C:11]1=[O:33].CO.[BH4-].[Li+].Cl>O1CCCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]([C:21]2[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[S:23](=[O:32])(=[O:31])[N:22]=2)[C:11]1=[O:33]
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=Cc1ccccc1Br
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NCc1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 265A (0.068 g, 0.129 mmol) in tetrahydrofuran (3.0 mL) and methanol (0.011 mL, 0.258 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.184 mL, 0.368 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (8.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with dichloromethane/diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.11 (brs, 2 H) 6.24 (t, J=6.80 Hz, 1 H) 7.06 (t, J=7.54 Hz, 1 H) 7.28 (m, 3 H) 7.56 (m, 3 H) 7.67 (m, 4 H) 8.08 (dd, J=7.91, 1.29 Hz, 1 H) 16.27 (s, 1 H). (ESI−) m/z 524 (M−H)−.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[Br:6]N1C(=O)CCC1=O.[C:14]([OH:17])(=[O:16])[CH3:15]>>[C:14]([O:17][CH2:1][CH:2]=[C:3]([CH3:4])[CH2:5][Br:6])(=[O:16])[CH3:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CC(=C)C
Reactant: CC(=O)O
Product: CC(=O)OCC=C(C)CBr
Temperature: 15 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
Into acetic acid (500 ml) were dissolved 85 g (1.25 mol) of isoprene. Under stirring at 15° C., 260 g (1.45 mol ) of N-bromosuccinimide were added therein dividedly four times little by little over two hours. Thereafter, the resulting mixture was stirred for additional two hours. The reaction liquid was added into ice water and extracted with ether. After the organic layer was washed with water, washed with a 5% aqueous solution of sodium hydrogencarbonate, washed with water and dried, the solvent was distilled off. The resulting residue was distilled under reduced pressure, whereby 115 g of the title compound were obtained. (Yield: 52.3%)
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].O>[N+](C)([O-])=O>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]#[N:37])=[CH:34][CH:35]=1)([O:27][CH3:28])=[O:26])[C:13]([OH:15])=[O:14]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccc(C#N)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: O
Solvent: C[N+](=O)[O-]
Product: COP(=O)(CCC(N)C(=O)O)Oc1ccc(C#N)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
Next, 0.95 g (1.82 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[(4-cyanophenyl)(methyl)phosphono]butanoate and 1.18 g (10.9 mmol) of anisole were dissolved in 10 mL of dry nitromethane and mixed with 0.73 g (5.46 mmol) of aluminum trichloride at room temperature. After stirring was carried out at room temperature for 1 hour, 20 mL of water was added and stirred for 10 minutes. The mixture was washed with 50 mL of an ether three times and a water layer was separated, and methanol was added to adjust the final concentration of methanol to be 30%. The solution was passed through a short column of neutral silica gel 60N to remove aluminum hydroxide. Without being concentrated, the effluent was purified by medium pressure reversed-phase column chromatography ODS-S-50B. The column was eluted with a linear gradient of 30 to 60% methanol at a flow rate of 6 mL/min and the fractions containing the compound eluted at 45% methanol were collected. The elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration). After vacuum concentration, freeze drying was carried out to obtain 2-amino-4-[(4-cyanophenyl)(methyl)phosphono]butanoic acid (0.38 g, yield 70%) as a colorless solid.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:34])([F:33])[S:20](OC1C=CC([N+]([O-])=O)=CC=1)(=[O:22])=[O:21].CCOC(C)=O>CN(C=O)C>[F:18][C:19]([F:34])([F:33])[S:20]([O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])(=[O:22])=[O:21]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of vanillin (20.0 g, 131 mmol) in DMF (200 mL) at room temperature was added potassium carbonate (36 g, 263 mmol) and 4-nitrophenyl trifluoromethanesulfonate (54.0 g, 197 mmol) and the reaction mixture was stirred for 8 h. EtOAc (600 mL) was added to the reaction mixture and the organic layer was washed three times with water, dried, filtered, and concentrated. The crude compound was then purified by flash chromatography (ethylacetate/hexanes 1:9→3:7) to provide 4-formyl-2-methoxyphenyl trifluoromethanesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:23][CH3:24])[CH:17]=1.[CH2:25]([N:27]1[CH:32]=[C:31]([C:33](O)=[O:34])[C:30](=[O:36])[N:29]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:28]1=[O:44])[CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:33]([C:31]2[C:30](=[O:36])[N:29]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:28](=[O:44])[N:27]([CH2:25][CH3:26])[CH:32]=2)=[O:34])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2OC)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxy-phenylamine and 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. LCMS m/z=587 (M+1); 1H NMR (CDCl3) δ: 11 (S, 1H), 8.63 (s, 1H), 8.54 (d, 1H, J=9 Hz), 8.49 (d, 1H, J=5 Hz), 7.55 (s, 1H), 7.42 (s, 1H), 7.26-7.23 (m, 3H), 6.82 (dd, 1H, J=3, 9 Hz), 6.74 (d, 1H, J=3 Hz), 6.52 (d, 1H, J=6 Hz), 4.05 (d, 6H), 4.01 (q, 2H, J=8 Hz), 3.85 (s, 3H), 1.45 (t, 3H, J=8 Hz).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>C(O)CC(C)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][N:26]([C:3]3[NH:12][C:11](=[O:13])[C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[N:4]=3)[CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)CCO
Product: COc1cccc(N2CCN(c3nc4c(c(=O)[nH]3)CCCC4)CC2)c1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol), 1-(3-methoxyphenyl)piperazine hydrochloride (116.5 mg; 0.51 mmol) and triethylamine (141.3 μl; 1.02 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 (reaction time 4 h) and worked up; yield: 79 mg (45%), crystals;
Reaction SMILES: [OH-:1].[K+].C([O:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]([CH3:30])([CH3:29])[CH2:13]1)(=O)C1C=CC=CC=1>C(O)C>[OH:1][CH:12]1[CH2:17][C:16]([CH3:18])([CH3:19])[N:15]([O:20][CH:21]([O:20][N:15]2[C:14]([CH3:29])([CH3:30])[CH2:13][CH:12]([OH:11])[CH2:17][C:16]2([CH3:18])[CH3:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]([CH3:30])([CH3:29])[CH2:13]1
Reactant: [OH-]
Reactant: CCCCCCCCON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Agent: [K+]
Solvent: CCO
Product: CCCCCCCC(ON1C(C)(C)CC(O)CC1(C)C)ON1C(C)(C)CC(O)CC1(C)C

Procedure:
The title compound is prepared by basic hydrolysis (potassium hydroxide in ethanol) of the compound prepared in Example 3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[OH:36][C:37]1[CH:38]=[CH:39][C:40]2[O:45][CH2:44][C@H:43]([CH2:46][NH2:47])[O:42][C:41]=2[CH:48]=1>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][NH:47][CH2:46][CH:43]2[CH2:44][O:45][C:40]3[CH:39]=[CH:38][C:37]([OH:36])=[CH:48][C:41]=3[O:42]2)=[CH:2]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: NC[C@H]1COc2ccc(O)cc2O1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc2c(c1)OC(CNCCCc1c[nH]c3ccccc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
3-Indolepropionic acid (1.4 g, 7.4 mmole), 1-hydroxybenzotriazole hydrate (1.2 g, 8.9 mmole) and 1,3-diisopropylcarbodiimide (2.8 ml, 17.8 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise (S)-7-hydroxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.6 g, 7.4 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.5 g (60%) of the desired product, (S)-(7-hydroxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-propanamide, as a white fluffy solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.B1([C:23]2[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=2)OCCCO1>>[CH3:15][N:14]([CH2:13][CH2:12][CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:10]=2)[CH:6]=[CH:7]1)[CH3:16]
Reactant: CN(C)CCCn1ccc2ccc(Br)cc21
Reactant: c1cncc(B2OCCCO2)c1
Product: CN(C)CCCn1ccc2ccc(-c3cccnc3)cc21

Procedure:
(9.8 mg, 13%); from 6-bromo-1-(3-(N,N-dimethylamino)propyl) indole (75.0 mg, 0.267 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (87.0 mg, 0.534 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:6])[CH3:2].O=[C:17]([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19]>ClCCCl>[CH3:21][O:20][C:18](=[O:19])[CH2:17][CH2:22][CH2:23][N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH3:6]
Reactant: CCC(=O)C(=O)OC
Reactant: CCOC(=O)C(C)NCc1ccccc1
Solvent: ClCCCl
Product: CCOC(=O)C(C)N(CCCC(=O)OC)Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Benzylamino-propionic acid ethyl ester (1.4 g, 6.7 mmol), methyl oxo-butanoate (1.7 g, 13.5 mmol), LEA (1.9 mL, 13.5 mmol) and NaBH(Oac)3 (2.9 g, 13.5 mmol) are taken up in 1,2-DCE (35 mL) and stirred at rt for 4 h. The reaction is partitioned between DCM and saturated aqueous NaHCO3. The organic layer is removed, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude residue is used without further purification. MS (ESI) m/z 308.3 (M+1).