Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[Cl-].[Mg+2].[Cl-].[CH3:15][C:16]1([CH3:26])[O:20][C:19](=[O:21])[CH:18]([CH2:22]C(O)=O)[O:17]1.C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1.CN(C)C=O.C(N(CC)CC)C>[CH3:15][C:16]1([CH3:26])[O:20][C:19](=[O:21])[CH:18]([CH2:22][C:3](=[O:5])[CH2:2][C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[O:17]1
Reactant: CC1(C)OC(=O)C(CC(=O)O)O1
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CC1OC(C)(C)OC1=O
Yield: 77.2 %

Procedure:
132 g of mono-tert-butyl malonate was dissolved in 1.5 l of tetrahydrofuran, and 49.2 g of magnesium chloride and 134 ml of triethylamine were added thereto with stirring under cooling with ice. The mixture was stirred at room temperature for 3 hours. Added to this solution was a liquid separately prepared by stirring 60.0 g of 2,2-dimethyl-1,3-dioxolan-4-on-5-ylacetic acid (Tetrahedron Letter, vol. 28, p. 1685 (1987)) in a liquid mixture of 500 ml of tetrahydrofuran and 100 ml of dimethylformamide together with 64.2 g of 1,1'-carbonyldiimidazole at room temperature for 2 hours. The mixture was stirred at room temperature overnight. Insoluble matters were separated by filtration. Then, the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in a liquid mixture of ethyl ether and water and then adjusted to pH 3 to 4 by an addition of 1N hydrochloric acid. The organic layer was collected by separation, then washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and then passed through a column of 300 g of activated aluminum oxide. The solution passed through the column was evaporated to dryness under reduced pressure to obtain 72.4 g (yield: 77%) of tert-butyl 4-(2,2-dimethyl-1,3-dioxolan-4-on-5 -yl)-3-oxobutyrate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[CH:26]=[C:27]([C:29]4[N:30]([CH3:40])[C:31]([CH2:34][NH:35][CH2:36][CH2:37][O:38][CH3:39])=[CH:32][N:33]=4)[S:28][C:21]=23)=[C:15]([F:41])[CH:14]=1)=[O:11].[C:42]([O:46][C:47]([NH:49][C@@H:50]([CH:54]([CH3:56])[CH3:55])[C:51](O)=[O:52])=[O:48])([CH3:45])([CH3:44])[CH3:43].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:11])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[CH:26]=[C:27]([C:29]4[N:30]([CH3:40])[C:31]([CH2:34][N:35]([CH2:36][CH2:37][O:38][CH3:39])[C:51](=[O:52])[C@@H:50]([NH:49][C:47](=[O:48])[O:46][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:54]([CH3:56])[CH3:55])=[CH:32][N:33]=4)[S:28][C:21]=23)=[C:15]([F:41])[CH:14]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COCCNCc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5ccc(F)cc5F)cc4F)c3s2)n1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5ccc(F)cc5F)cc4F)c3s2)n1C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To a solution of the compound 351 (280 mg, 0.481 mmol) in DMF (10 ml) was added (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (209 mg, 2 eq, 0.961 mmol), iPr2NEt (0.252 ml, 3 eq, 0.1.442 mmol) and HATU (365 mg, 2 eq, 0.961 mmol) and the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc and washed with water, saturated NAHCO3 solution then brine. The organic phase was collected, dried over Na2SO4, filtered then concentrated. Purification of the residue by column chromatography (eluent 20% MeOH in EtOAc) afforded the desired compound 352 as an off-white solid (200 mg, 53% yield). MS (m/z)=782.7 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:17]C(=O)C)([O-:3])=[O:2]>Cl.O>[N+:1]([C:4]1[CH:9]=[C:8]([S:10]([C:13]([F:16])([F:14])[F:15])(=[O:11])=[O:12])[CH:7]=[CH:6][C:5]=1[NH2:17])([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Reflux N-(2-nitro-4-trifluoromethylsulfonyl-phenyl)-acetamide (600 mg) for 40 minutes in concentrated HCl (15 mL) and water (5 mL). Cool the mixture to room temperature and collect the precipitate obtain 2-nitro-4-trifluoromethylsulfonyl-phenylamine. D. 4-Trifluoromethylsulfonyl-benzene-1,2-diamine
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14]2)[CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[NH:8]1[CH2:9][CH:10]([NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:25])[CH2:14]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(N[C@H]2CCN(C(=O)c3ccccc3)C2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1ccccc1)N1CC[C@H](NC2CNC2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound 5d (0.96 g, 2.78 mmol) in MeOH (5 mL) was added HCl solution in dioxane (4M, 10 mL) at room temperature. The mixture was stirred at room temperature for 4 h. The solvent was removed by evaporation. Ether (50 mL) was added to the residue. The off-white solid was collected by filtration, washed with hexanes, and dried under vacuum. The crude compound 5e was used in the next reaction without further purification. MS m/z (M+H+) 246.0.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:13]([N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc2c1cnn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
4-Nitro-1H-indazole (1.00 g; 6.13 mmol), benzyl bromide (1.15 g; 6.74 mmol) and potassium carbonate (1.69 g; 12.3 mmol) were mixed with DMF (15 mL) and stirred at ambient temperature under nitrogen for 16 hours. The reaction mixture was added to water (50 mL) and extracted into ethyl acetate. The combined extracted were dried (sodium sulfate), filtered and evaporated under reduced pressure to give a brown solid. The material was purified by silica gel chromatography eluting with hexane/ethyl acetate (20:1 to 10:1 to 5:1). The first component to elute was the desired regioisomer, which was obtained as a yellow solid (730 mg). The other regioisomer was the second component to elute (650 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[CH:8]=[C:9]([NH:24][C:25]([C:27]2[C:32]([CH3:33])=[N:31][CH:30]=[CH:29][N:28]=2)=[O:26])[CH:10]=[CH:11][C:12]=1[C:13]([O:22][CH3:23])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])[CH:4]([CH3:6])[CH3:5].[C:34](Cl)(=[O:40])[O:35][CH2:36][CH:37]([CH3:39])[CH3:38].Cl>C1COCC1>[CH2:36]([O:35][C:34]([N:24]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:22][CH3:23])([C:18]([F:20])([F:21])[F:19])[C:14]([F:17])([F:16])[F:15])=[C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=1)[C:25]([C:27]1[C:32]([CH3:33])=[N:31][CH:30]=[CH:29][N:28]=1)=[O:26])=[O:40])[CH:37]([CH3:39])[CH3:38]
Reactant: COC(c1ccc(NC(=O)c2nccnc2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1ccc(N(C(=O)OCC(C)C)C(=O)c2nccnc2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Sodium hydride (32 mg, 60% by weight, 0.8 mmol) was suspended in THF (10 ml) and a THF solution (5 ml) of N-{3-isobutyl-4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]Phenyl}-3-methylpyrazine-2-carboxamide (300 mg, 0.67 mmol) was dropwise added thereto. The reaction solution was stirred at room temperature for 30 minutes, and was dropwise added with a THF (2 ml) solution of isobutyl chlorocarbonate (110 mg, 0.8 mmol) and stirred for 2 hours. The reaction solution was poured into a diluted HCl solution, followed by extracting with ethyl acetate, and washing with water. The solution was dried over magnesium sulfate, and concentrated under reduced pressure, and then the residue was purified by using silica gel chromatography (hexane:ethyl acetate=3:1) to obtain 0.33 g of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(CN2CCOCC2)cc1

Procedure:
4-Bromobenzyl bromide (Aldrich Co., 2.0 g) and morpholine (0.73 ml) were dissolved in acetonitrile (15 ml), potassium carbonate (1.3 g) was added, and the mixture was heated under reflux for 4 hr. The insoluble material was filtered off, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (5:1)) to give 4-(4-bromobenzyl)morpholine (1.55 g). 4-(4-Bromobenzyl)morpholine (1.55 g), 1-(tert-butoxycarbonyl)piperazine (1.27 g), 2-(di-tert-butylphosphino)biphenyl (37 mg), tris(dibenzylideneacetone)dipalladium (57 mg) and sodium tert-butoxide (1.2 g) were added to toluene (13 ml), and the mixture was heated under reflux for 5 hr. The insoluble material was filtered through a Celite (trademark) filter, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography. The obtained 4-[4-(morpholine-4-ylmethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in dichloromethane, trifluoroacetic acid was added and the mixture was stirred overnight at room temperature. The mixture was neutralized with an aqueous sodium hydroxide solution, and extracted with dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-(4-piperazin-1-ylbenzyl)morpholine (1.06 g, yield 51%).
Reaction SMILES: [OH-].[K+].[C:3](=[S:5])=S.[Cl:6][C:7]1[CH:8]=[C:9]([NH2:15])[C:10]([NH2:14])=[CH:11][C:12]=1[I:13]>O.CCO>[Cl:6][C:7]1[C:12]([I:13])=[CH:11][C:10]2[NH:14][C:3](=[S:5])[NH:15][C:9]=2[CH:8]=1
Reactant: S=C=S
Reactant: Nc1cc(Cl)c(I)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: S=c1[nH]c2cc(Cl)c(I)cc2[nH]1

Procedure:
KOH (15.7 g, 238 mmol) in water (50 mL), followed by carbon disulfide (14.4 mL, 238 mmol), was added to a solution of 4-chloro-5-iodobenzene-1,2-diamine (50 g, 198 mmol) in EtOH (300 mL). The mixture was heated at reflux for 3 h, cooled and filtered. To the filtrate was added water (300 mL) and then AcOH (25 mL) in water (50 mL). The resulting precipitate was collected, washed with water and a small amount of EtOH, and then dried to afford the desired product as a brown powder, which was used in the next step without further purification.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[CH3:26][C:27]1[C:31]([CH3:32])=[C:30]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[O:29][N:28]=1.NC1ON=C(C)C=1C>>[CH3:26][C:27]1[C:31]([CH3:32])=[C:30]([NH:33][C:34]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:35])[O:29][N:28]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: Cc1noc(NC(=O)Oc2ccccc2)c1C
Agent: Cc1noc(N)c1C
Agent: Cl
Product: Cc1noc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)c1C

Procedure:
Following the procedure in Example 1, Step 6, 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (150 mg, 0.40 mmol, from Example 1, Step 5) and phenyl 3,4-dimethylisoxazol-5-ylcarbamate (94 mg, 0.40 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 5-amino-3,4-dimethylisoxazole) were used to provide the title compound (187 mg). MS (APCI 10V) AP+ 473.3, AP− 471.2; 1H NMR (400 MHz, CD3OD) δ ppm 1.83 (s, 3H) 2.18 (s, 3H) 2.41-2.49 (m, 2H) 2.53-2.62 (m, 2H) 3.49-3.57 (m, 2H) 3.58-3.66 (m, 2H) 6.46 (s, 1H) 6.97-7.05 (m, 2H) 7.10-7.20 (m, 2H) 7.40 (tt, J=7.64, 0.76 Hz, 1H) 8.08 (dd, J=8.65, 2.51 Hz, 1H) 8.33-8.51 (m, J=2.31, 1.33, 0.88, 0.74 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[C:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=3)[C:4]=12)#[CH:2].[F:20][C:21]([F:31])([F:30])[C:22]1[N:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>O.C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[C:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][CH2:28][C:25]4[CH:26]=[N:27][C:22]([C:21]([F:31])([F:20])[F:30])=[CH:23][CH:24]=4)=[N:17][CH:18]=3)[C:4]=12)#[CH:2]
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: C#Cc1ccnc2[nH]cc(Cc3ccc(N)nc3)c12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: C#Cc1ccnc2[nH]cc(Cc3ccc(NCc4ccc(C(F)(F)F)nc4)nc3)c12
Yield: 10.4 %

Procedure:
In a round bottom flask, 5-(4-ethynyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (164, 0.055 g, 0.22 mmol) was combined with 6-trifluoromethyl-pyridine-3-carbaldehyde (160, 50.4 mg, 0.288 mmol), 0.682 mL of acetonitrile, trifluoroacetic acid (0.0853 mL, 1.11 mmol), and triethylsilane (0.212 mL, 1.33 mmol) and the reaction heated to reflux for 3 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with methanol and dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-1717, 9.3 mg). MS (ESI) [M+H+]+=408.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18](I)=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:27][CH3:28].[C:29]([Cu])#[N:30]>CN1C=CC=CC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18]([C:29]#[N:30])=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: N#C[Cu]
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(I)c4cccnc43)CC2)ccc1Cl
Agent: Cn1ccccc1=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(C#N)c4cccnc43)CC2)ccc1Cl
Temperature: 165 °C

Procedure:
1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanone (128 Mg) and CuCN (112 Mg) were combined in N-methylpyridone (NMP) (1 mL) and heated at 165° C. for 16 hr, then cooled to room temperature. The reaction mixture was purified on preparative HPLC to afford 1-{2-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile as a white powder: LCMS (ES) M+H411.5, Rf 2.33 min (Agilent Zorbax SB-C18, 2.1×50 Mm, 5μ, 35° C., 1 mL/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile).
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([OH:17])[CH:8]=1.Cl[C:19]([F:25])([F:24])C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:17][CH:19]([F:25])[F:24])[CH:8]=1
Reactant: COC(=O)C(F)(F)Cl
Reactant: COC(=O)c1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Br)cc1OC(F)F
Temperature: 60 °C
Reaction time: 60 h
Yield: 23 %

Procedure:
To a 70 ml dimethylformamide solution of 5.0 g (21.7 mmol) of methyl 4-bromo-2-hydroxybenzoate, 3.4 ml (32.6 mmol) of methyl chlorodifluoroacetate and 3.0 g (21.7 mmol) of potassium carbonate were added. The mixture was stirred at 60° C. for 6 hours and at room temperature for 60 hours. Then, water was added to the reaction mixture, and the mixture was extracted with ether. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. The washed system was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=8/1) to obtain 1.4 g (23%) of the captioned compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:13]=1[C:14](Cl)=[O:15].CCOCC.CCCCCC>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:14](=[O:15])[C:13]2[C:12]([Cl:11])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:21])[CH:3]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(Nc1cc(Cl)ncn1)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.5 %

Procedure:
To a cooled (0° C.) solution of 6-chloropyrimidin-4-amine (1.295 g, 10 mmol) in DMF (25 mL) was added sodium hydride (1.2 g, 30 mmol, 60% dispersion in mineral oil) in one portion. The mixture was stirred at 0° C. for 10 min and then 2,6-dichlorobenzoyl chloride (2.304 g, 11 mmol) was added dropwise. The mixture was warmed to room temperature and stirred under nitrogen overnight. The mixture was quenched with ice water and the resulting precipitate was collected by filtration. The solid was washed with water, then 1:1 ether/hexane (10 mL,) to give N-(6-chloropyrimidin-4-yl)-2,6-dichlorobenzamide (1.95 g, yield: 64%). 1H NMR (500 MHz, DMSO) δ 12.09 (s, 1H), 8.84 (s, 1H), 8.24 (s, 1H), 7.61-7.56 (m, 2H), 7.53 (dd, J=9.2, 6.8 Hz, 1H). LCMS (ESI) m/z: 302.1 [M+H+].
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[CH3:9][S:10][S:11](C)(=O)=O>O.C(O)C>[CH3:9][S:10][S:11][N:2]([CH3:1])[C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5]
Reactant: CSS(C)(=O)=O
Reactant: CN[C@@H](CS)C(=O)O
Solvent: O
Solvent: CCO
Product: CSSN(C)[C@@H](CS)C(=O)O
Reaction time: 2 h
Yield: 60 %

Procedure:
A solution of N-methylcysteine (7a) (Undhein, K., & Eidem, A., 23 Acta Chem. Scandinavica 3129-3133 (1970)) (1.5 g, 11.1 mmol) in H2O (20 mL) was stirred at room temperature, under an atmosphere of argon, and treated with a solution of methyl methanethiol sulfonate (3.0 mL, 29.2 mmol) in ethanol (10 mL). The reaction mixture was stirred at this temperature for two hours and then diluted with H2O (100 mL) and washed with ether (4×40 mL). The aqueous layer was acidified to pH 2 and passed through an Amberlite IRA 93 (—OH form) column. The column was washed with water and the effluent was collected and evaporated to dryness under reduced pressure to give a white solid (1.2 g, 60%), mp 194-195° C. 1H NMR (D2O, TMS ext. standard): δ2.2(3H,s), 2.5(3H,s), 3.2(2H,d), 3.7(1H,q).
Reaction SMILES: Br.[CH2:2]([C:4]1[N:5]=[C:6]([C@@H:9]([NH2:20])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[S:7][CH:8]=1)[CH3:3].[C:21]([NH:24][C@H:25]([C:33](O)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:23])[CH3:22].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[C:21]([NH:24][C@@H:25]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]([NH:20][C@H:9]([C:6]1[S:7][CH:8]=[C:4]([CH2:2][CH3:3])[N:5]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:34])(=[O:23])[CH3:22]
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCc1csc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1csc([C@H](Cc2ccc([N+](=O)[O-])cc2)NC(=O)[C@H](Cc2ccccc2)NC(C)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide, 3, (0.343 g, 0.957 mmol), N-acetyl-L-phenylalanine (0.218 g), 1-hydroxybenzotriazole (HOBt) (0.161 g), diisopropyl-ethylamine (0.26 g), in DMF (10 mL) at 0°, is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.201 g). The mixture is stirred at 0° C. for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5% aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.313 g (70% yield) of the desired product which is used without further purification. LC/MS ESI+ 467 (M+1).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].N1C=CC=CC=1.[CH2:22]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43](Cl)=[O:44])=[CH:39][CH:38]=2)=[CH:33][CH:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C([O-])(O)=O.[Na+].CCOC(C)=O>CCOC(C)=O>[CH2:6]([O:5][P:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:43]([C:40]1[CH:39]=[CH:38][C:37]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:32][CH:33]=2)=[CH:42][CH:41]=1)=[O:44])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)c1ccccc1N
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Nc3ccccc3P(=O)(OCC)OCC)cc2)cc1
Reaction time: 0.42 h

Procedure:
At rt, to a solution of (2-Amino-phenyl)-phosphonic acid diethyl ester in EtOAc are added 10 equivaltents of pyridine followed by 1 equivalent of 4′-octyloxy-biphenyl-4-carbonylchloride (VAW132) and the mixture obtained is stirred for ca. 25 minutes. The mixture obtained is subjected to an aqueous work-up (NaHCO3/EtOAc), the organic phase obtained is dried, solvent is evaporated and the evaporation residue is subjected to column chromatography. {2-[(4′-Octyloxy-biphenyl-4-carbonyl)-amino]-phenyl}-phosphonic acid diethyl ester is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[N:7]=1)=[O:5])C.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=2[O:22]1>>[O:22]1[C:23]2[CH:24]=[CH:25][C:26]([C:17]3[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:8]4[N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:11]=[CH:10][CH:9]=4)=[CH:19][CH:18]=3)=[CH:27][C:28]=2[O:29][CH2:21]1
Reactant: CCOC(=O)c1cccc(COc2ccc(I)cc2)n1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: O=C(O)c1cccc(COc2ccc(-c3ccc4c(c3)OCO4)cc2)n1

Procedure:
6-(4-Benzo[1,3]dioxol-5-yl-phenoxymethyl)-pyridine-2-carboxylic acid was prepared using general procedure 3 from 6-(4-iodo-phenoxymethyl)-pyridine-2-carboxylic acid ethyl ester (of Intermediate 3) and 3,4-methylenedioxybenzeneboronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=350.