Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C([O:4][C:5]([C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:6])C.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.O.[OH-].[Na+]>CN(C=O)C.CCO>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:10]2[N:9]=[N:8][C:7]([C:5]([OH:4])=[O:6])=[N:11]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1nnn[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2nnc(C(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1H-tetrazole-5-carboxylic acid ethyl ester sodium salt (500 mg, 3.05 mmol) in DMF (5 ml) at room temperature is added 4-methoxybenzyl chloride (747 μl, 5.48 mmol) and TEA (1500 μl, 10.76 mmol). The reaction mixture is stirred at room temperature overnight. The reaction is added water and extracted with EtOAc. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (10% to 30% EtOAc/Heptane). To a solution of the purified residue in EtOH (2 ml) at room temperature is added NaOH (2 ml, 2.000 mmol) and the mixture is stirred at room temperature. After stirring for 1 hour, the mixture is concentrated under reduced pressure to remove EtOH and extracted with EtOAC after being acidified to pH<5. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(4-methoxy-benzyl)-2H-tetrazole-5-carboxylic acid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C.[C:19]([O:27][CH2:28][C@H:29]1[O:37][C@@:32]([O:35][CH3:36])([CH2:33][OH:34])[C@@H:31]([OH:38])[CH2:30]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OC[C@H]1O[C@](OC)(CO)[C@@H](O)C1)(=O)C1C=CC=CC=1>CO>[C:19]([O:27][CH2:28][C@H:29]1[O:37][C:32]([O:35][CH3:36])([CH2:33][OH:34])[C@@H:31]([OH:38])[CH2:30]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CO[C@@]1(CO)O[C@H](COC(=O)c2ccccc2)C[C@@H]1O
Agent: CO[C@]1(CO)O[C@H](COC(=O)c2ccccc2)C[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC1(CO)O[C@H](COC(=O)c2ccccc2)C[C@@H]1O

Procedure:
A solution of the product of Step 5 (5.6 g) in anhydrous methanol (140 mL) containing p-toluenesulfonic acid (374 mg) was refluxed for 30 min. The reaction mixture was cooled and neutralized with triethylamine. The solution was evaporated to dryness and applied on a column of silica gel equilibrated and eluted with etylacetate-ethanolhexane (10:1:10). Two fractions were obtained, methyl 6-O-benzoyl-4-deoxy-α-D-fructofuranoside and methyl 6-O-benzoyl-4-deoxy-β-D-fructofuranoside; methyl 6 -O-benzoyl-4-deoxy-β-D-fructofuranoside was the more polar of the two. The yield of methyl 6-O-benzoyl-4-deoxy-α-D-fructofuranoside was 2.45 g (syrup). The yield of methyl 6-O-benzoyl-4-deoxy-β-D-fructofuranoside was 1.47 g. The structures of methyl 6-O-benzoyl-4-deoxy-α-D-fructofuranoside and methyl 6-O-benzoyl-4-deoxy-β-D-fructofuranoside were established by 1H and 13C nmr.
Reaction SMILES: [Na].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)C)=[CH:7][C:6]=1[OH:15])(=[O:4])[CH3:3].[C:16](OCC)(=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>C(O)C.C(Cl)(Cl)Cl.O>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]2[C:2](=[O:4])[CH:3]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:15][C:6]=2[CH:7]=1
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(=O)c2ccc(N)cc2o1
Reaction time: 0.25 h

Procedure:
A solution of sodium metal, (18.4 g, 0.8 gatom), in dry ethanol (1200 ml), was treated with N-(4-acetyl-3-hydroxyphenyl)acetamide (30.88 g, 0.16 mole). This mixture was stirred for 15 mins then diethyl oxalate (58.4 g, 54.3 ml, 0.4 mole), was added dropwise over 30 mins. The resulting mixture was heated and stirred at 60° C. for 2 hrs, allowed to cool and poured into a mixture of chloroform (600 ml), conc HCl (85 ml), and water (2000 ml). The organic layer was isolated and combined with a chloroform wash of the aqueous layer. The combined chloroform extracts were washed well with water then evaporated to dryness. The residue was taken into ethanol (400 ml), and conc.HCl (10 ml), was also added. The solution was heated at reflux for 30 minutes then evaporated to dryness. The residue was treated with ether and ethanol was added dropwise until the residue began to solidify. Insoluble material was filtered off, washed again with ether and the required sub-title product was recovered as a brown solid (20.5 g), (55%), mp 192°-194°. NMR and mass spectra confirmed the structure.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+].[NH:27]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C@H:28]([C:33](ON1C(=O)CCC1=O)=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31].Cl>O1CCOCC1.O>[NH:27]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C@H:28]([C:33]([NH:1][C@H:2]([C:11]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
The H-Asp(OtBu)-Leu-OH (3.02 g), sodium bicarbonate (1.68 g), and 30 mL of water were mixed to give a mixture of pH 8. Z-Leu-OSu (3.63 g) in dioxane (30 mL) was added to the mixture and was stirred at room temp for 2 h. The reaction mixture was acidified by addition of conc. HCl to pH 1.0, then was extracted with ethyl acetate (30 mL×3). The combined extracts were dried over Na2SO4, filtered, and concentrated. The crude product was dissolved in methanol and chromatographed on a column of Sephadex™ LH20 to yield Z-Leu-Asp(OtBu)-Leu-OH as a foamy solid (4.43 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:10])[C:8]=1[I:9])[NH2:5].O.[N:12]([O-])=O.[Na+]>Cl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:12])[CH:6]=[C:7]([I:10])[C:8]=1[I:9]
Reactant: Nc1cc(I)c(I)c(I)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(I)c(I)c(I)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
3,4,5-Triiodoaniline was obtained by the procedure of L. Kalb (L. Kalb et al., Über substituierte Indol-2-carbonsäure-8-propionsäuren and einige jodierte Bensolderivate, Chem. Ber. 59 (1926) 1860-1870). 4 g (8.5 mmol) of 3,4,5-triiodoaniline were stirred with the solution of 2.3 mL of concentrated hydrochloric acid and 2.3 mL of water. The mixture was cooled to about −10° C. and the equivalent quantity of 2.5 M solution of NaNO2 was added dropwise with intensive stirring. The reaction mixture was continued stirring for 30 min at −10° C. Next, the cooled solution of 5.75 g (25.5 mmol) of SnCl2-2H2O in 6 mL of concentrated HCl was added dropwise at −10° C. to the suspension of diazocompound. The reaction mixture was kept at −10° C. for one hour and at 5° C. overnight. The obtained precipitate was filtered off and washed with water to yield 4.7 g of 3,4,5-triiodophenylhydrazine, as a double salt with tin chloride, which was used for following step without additional treatment or purification. 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 10.14 (2H, broad s, NH2), 8.46 (1H, s, NH), 7.5 (2H., s, arom.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:17])(=[O:16])[NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[NH3:27]>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:17])(=[O:16])[NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4]([NH2:27])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Yield: 91 %

Procedure:
The title compound was prepared by following procedure as described for step-2 of Intermediate-26 by using 2-chloro-5-(N-cyclopropylsulfamoyl)benzoic acid (3.0 g, 10.0 mmol), DCM (30 mL), oxalyl chloride, ammonia gas (1.2 mL, 13.0 mmol), DMF (2-3 drop) and THF (40 mL) to afford 2.500 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.41 (m, 2H), 0.47-0.51 (m, 2H), 2.12 (m, 2H), 7.74-7.82 (m, 4H), 8.11 (br s, 2H); MS (m/z): 273.00 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)[CH3:18].C([O-])([O-])=O.[K+].[K+].O1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O.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>[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]3[C:3]=2[C:2]2[CH:3]=[CH:4][C:37]([O:38][CH2:39][CH3:40])=[CH:36][CH:7]=2)=[CH:22][CH:21]=1)[CH3:18]
Reactant: C1COCCO1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
Reactant: CCOc1ccc(B(O)O)cc1
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
Product: CCOc1ccc(-c2ccn3c(=O)n(CC(C)C)nc3c2-c2ccc(OCC)cc2)cc1
Temperature: 200 °C

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.13 mmol), 4-ethoxyphenylboronic acid (40 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) in dioxane (1.0 mL) at 20° C. was added K2CO3 (40 mg, 0.25 mmol) in water (0.3 mL). The resulting reaction mixture was heated in a microwave reactor at 200° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (38 mg, 0.088 mmol) as a pale yellow solid. MS: [M+H]+=432.
Reaction SMILES: CCN(CC)CC.Cl.[NH:9]1[CH2:12][CH2:11][CH2:10]1.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C(Cl)Cl>[N:9]1([C:18]([C:17]2[CH:21]=[CH:22][C:14]([Br:13])=[CH:15][CH:16]=2)=[O:19])[CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Br)cc1)N1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Et3N (2.00 mL, 14.3 mmol) and azetidine hydrochloride (462 mg, 4.94 mmol) were added to a solution of 4-bromobenzoyl chloride (1.07 g, 4.88 mmol) in CH2Cl2 (20 mL). The mixture was stirred at room temperature for 2 hr, diluted with CH2Cl2 (100 mL), and washed with 1N aqueous HCl (100 mL), H2O (100 mL), and brine (100 mL). The organic layer was dried over MgSO4 and concentrated to give a colorless oil (1.10 g, 94% yield). 1H NMR (400 MHz, CDCl3) δ 7.53 (ddd, J=17.43, 6.57, 2.27 Hz, 4 H) 4.21-4.32 (m, 4 H) 2.32-2.40 (m, 2 H); ); LCMS for C10H10BrNO m/z 241.00 (M+H)+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:30][CH3:31])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH:27]([F:29])[F:28])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.C(N(CC)CC)C.[CH3:39][C@H:40]1[CH2:42][O:41]1>C(O)C>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:30][CH3:31])=[C:7]([CH:5]4[CH2:6][N:3]([CH2:39][C@@H:40]([OH:41])[CH3:42])[CH2:4]4)[C:12]([F:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH:27]([F:29])[F:28])[C:20]=12
Reactant: C[C@H]1CO1
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C[C@H](C)O)C1
Temperature: 90 °C
Yield: 5.6 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (51 mg, 0.10 mmol, racemic intermediate from Example 73, Step 6) and triethylamine (57 pt, 0.41 mmol) in ethanol (1.7 mL) was added (S)-(−)-methyloxirane (18 μL, 0.26 mmol). The resulting mixture was heated at 90° C. for 3 h, and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2.7 mg, 5.3%). The product was isolated as a racemic mixture. LCMS calculated for C21H25ClF3N6O2 (M+H)+: m/z=485.2; Found: 485.1.
Reaction SMILES: NCCC[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:8]#[N:9].N1C=CC(C2C=CC(C(O)=O)=CC=2)=CC=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:19][O:18][CH2:17][CH2:16][O:15][CH2:14][O:13][C:12]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[CH:10][CH:11]=1
Reactant: COCCOCOc1ccc(C#N)cc1CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)c1ccc(-c2ccncc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOCOc1ccc(C#N)cc1
Temperature: 35 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
3-(3-Aminopropyl)-4-(2-methoxyethoxymethoxy)benzonitrile (88 mg, 0.33 mmol) in DMF (0.5 mL) is added to a mixture of 4-pyridin-4-yl benzoic acid (60 mg, 0.3 mmol), TBTU (106 mg, 0.33 mmol), and Et3N (0.043 mL, 0.033 mmol) in DMF (1 mL). The mixture is stirred at 35° C. for 4 hours. The solution is diluted with EtOAc (20 mL), washed with saturated NaHCO3 (3×17 mL) and brine (3×17 mL), dried over MgSO4, filtered and concentrated. The residue is chromatographed (4% MeOH/CH2Cl2) to give 3-[4-(pyridin-4-yl)-benzamido]propyl)-4-(2-methoxyethoxymethoxy)-benzonitrile (0.09 g, 0.20 mmol), contaminated with an unknown byproduct. The crude material (0.08 g, 0.18 mmol) is dissolved in CH2Cl2 (5 mL), treated with MCPBA (57-86%, 92 mg) at 0° C., a room temperature for 2 hours. The residue from aqueous workup and concentration is treated with anhydrous HCl/EtOH followed by ammonolysis as described in Example 307, part D. HPLC purification (10% MeCN/0.1% TFA in H2O to 100% MeCN) gave the title compound (0.007 g, 0.01 mmol). 1H NMR (CD3OD, 300 MHz) δ8.94 (bs, 1H), 8.65 (bs, 1H), 8.40 (m, 3H), 7.90 (m, 6H), 7.64 (d, 1H), 7.57 (dd, 1H), 6.93 (d, 1H), 3.43 (t, 2H), 2.77 (t, 2H), 1.97 (m, 2H). Ion spray MS [M+1]=391, [M+2]2+=196.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[CH2:9]([N:13]1[CH:17]=[CH:16][N:15]=[N:14]1)[CH2:10][C:11]#[CH:12].C(N(CC)CC)C.C(Cl)(Cl)Cl>CN(C=O)C.[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)=[N:6][CH:7]=1
Reactant: C#CCCn1ccnn1
Reactant: Brc1cnc(I)nc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Brc1cnc(C#CCCn2ccnn2)nc1
Reaction time: 3 h

Procedure:
5-Bromo-2-iodo-pyrimidine (1.14 g, 4.0 mmol), 1-but-3-ynyl-1H-[1,2,3]triazole (0.533 g, 4.4 mmol) and triethyl amine (NEt3) (2 ml) are dissolved in DMF (1 ml) and copper iodide (CuI) (0.38 g, 0.2 mmol) is added under stirring. After passing a stream of argon through the mixture for 10 min bis(triphenylphosphine) palladium(II) dichloride (0.140 g, 0.2 mmol) is added and stirring is continued for 3 h at r.t. Chloroform (300 ml) is added; the mixture is washed with 1N HCl and water, dried over MgSO4 and concentrated in vacuo. The residue is purified by flash column chromatography (chloroform (100%)->ethyl acetate (100%)) yielding 5-bromo-2-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrimidine as a beige solid. Yield 0.96 g (86%).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O.CC(C)=O>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)[C@@H](N)C(=O)O
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a solution of D-valine (2000 g, 17.09 mol) in water (16.9 L) and acetone (9.5 L), cooled to 5° C., is added triethylamine (4769 mL, 34.22 mol), and the reaction is stirred for 30 minutes. Then a solution of 4-methoxybenzenesulfonyl chloride (3524 g, 18.48 mol) in acetone (7.4 L) is added over 30 minutes, and the reaction is stirred at room temperature overnight. Most of the acetone is evaporated off, and the pH is adjusted to pH=8.25 with 6N sodium hydroxide. The crude product is washed with toluene (2×10 L), and then the pH is re-adjusted to pH=2.2 with 6N hydrochloric acid. The mixture is then extracted with methylene chloride (3×12 L), the combined organic layers are washed with 2N hydrochloric acid, water, dried (Na2SO4), and the solvent is evaporated to provide N-[4-methoxybenzenesulfonyl]-(D)-valine.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])OCC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:26][C@H:27]([C:29]([N:31]([CH3:38])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:30])[CH3:28].C(N(CC)CC)C>O1CCCC1.C1C=CC=CC=1>[CH2:16]([O:15][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([NH:26][C@H:27]([C:29]([N:31]([CH3:38])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:30])[CH3:28])=[O:18])[CH3:17]
Reactant: CCOC(=O)CN(C)C(=O)[C@H](C)N
Reactant: CCOP(=O)(CCCCc1ccccc1)OCC
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C)C(=O)[C@H](C)NP(=O)(CCCCc1ccccc1)OCC
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of (4-phenylbutyl)phosphonic acid, diethyl ester (0.97 g., 3.6 mmole), dry benzene (10 ml.), and phosphorus pentachloride (0.75 g., 3.6 mmole) is refluxed under argon for 20 minutes. The phosphorus oxychloride and benzene are removed in vacuo, and the residue is taken up in dry tetrahydrofuran (10 ml.) and treated with N-(L-alanyl)-N-methylglycine, ethyl ester, hydrochloride (0.67 g., 3.0 mmole). The resulting suspension is cooled to 0° (ice-bath) and treated dropwise with triethylamine (1.2 ml., 3.0 eq.) in tetrahydrofuran (5 ml.) over a period of 2 minutes in an argon atmosphere. After stirring at 0° for 20 minutes the ice bath is removed and the reaction mixture is stirred for an additional 4 hours. The reaction mixture is then diluted with ethyl acetate and washed successively with 5% potassium bisulfate, saturated sodium bicarbonate, brine, dried (MgSO4), and evaporated. The residue (1.4 g.) is chromatographed on silica gel (60 g.) eluting with toluene/acetone (1:1) to give 1.0 g. of N-[N-[ethoxy(4-phenylbutyl)phosphinyl]-L-alanyl]-N-methylglycine, ethyl ester as an oil after evaporation. Tlc (toluene/acetone; 1:1) shows a single spot at Rf =0.19.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23]([O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[CH2:24][CH2:25][CH2:26][CH3:27]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH2:23]([O:28][C:29]1[CH:30]=[CH:31][C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:33][CH:34]=1)[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCOc1ccc(B(O)O)cc1
Reactant: O=C(O)c1ccc(-c2ccc(I)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCOc1ccc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)cc1
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
20.1 g of 4′-iodobiphenyl-4-carboxylic acid, 13.1 g of sodium carbonate and 21.4 g of glycol ester of 4-n-pentoxyphenylboronic acid are introduced into 260 g of dimethyl sulfoxide (DMSO) and, after addition of 160 mg of PdCl2(PPh3)2, heated at 100-110° C. for 2 hours. The solid is filtered off at 40° C., washed with dimethyl sulfoxide and suspended in 100 ml of water. It is then heated to 80° C., and 47 g of 37% strength sulfuric acid are added dropwise over the course of 1 hour. The mixture is stirred at 80° C. for a further 30 minutes, cooled at 40° C. and filtered. Drying and crystallization from dimethylacetamide results in 18 g (81%) of 4″-n-pentoxy-[1,1′:4′,1″]-terphenyl-4-carboxylic acid with a purity of >99%.
Reaction SMILES: Cl.O.N[CH:4]([CH2:8]C1C=CC=CC=1)[C:5](O)=O.[CH2:15]([O:18][C:19]1[CH:30]=[CH:29][C:22]([CH2:23][C@@H:24]([C:26]([OH:28])=[O:27])[NH2:25])=[CH:21][CH:20]=1)[C:16]#[CH:17]>[OH-].[Na+].CO>[CH2:8]([O:27][C:26](=[O:28])[CH:24]([NH2:25])[CH2:23][C:22]1[CH:29]=[CH:30][C:19]([O:18][CH2:15][C:16]#[CH:17])=[CH:20][CH:21]=1)[C:4]#[CH:5]
Reactant: NC(Cc1ccccc1)C(=O)O
Reactant: C#CCOc1ccc(C[C@H](N)C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#CCOC(=O)C(N)Cc1ccc(OCC#C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The propargyl ester (1.6 g, 5.5 mmol) from the previous step was dissolved in a mixture of aqueous 2 N NaOH (14 mL) and MeOH (10 mL). After stirring for 1.5 h at room temperature, the pH was adjusted to 7 by adding conc. HCl. Water (20 mL) was added and the mixture was kept at 4° C. overnight. The precipitate was filtered, washed with ice-cold H2O, and dried under vacuum yielding, 1.23 g (90%) of 1 in FIG. 11 (2-Amino-3-phenylpropionic acid (1) (also known as p-propargyloxyphenylalanine) as a white solid. 1H NMR (400 MHz, D2O) (as the potassium salt in D2O) δ 7.20 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 4.75 (s, 2H), 3.50 (dd, J=5.6, 7.2 Hz, 1H), 2.95 (dd, J=5.6, 13.6 Hz, 1 H), 2.82 (dd, J=7.2, 13.6 Hz, 1H); 13C NMR (100 MHz, D2O) δ 181.3, 164.9, 155.6, 131.4, 130.7, 115.3, 57.3, 56.1, 39.3; HRMS (CI) m/z 220.0969 [C12H13NO3 (M+1) requires 220.0968].
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:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[C:23]1(C)C=C[CH:26]=[CH:25][CH:24]=1.ClC(Cl)([O:33][C:34](=O)[O:35]C(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)CCC.C(N(CC)CC)C>[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:22]=[CH:21][C:19]([NH:20][C:34](=[O:33])[O:35][CH2:26][CH2:25][CH2:24][CH3:23])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCCO
Product: CCCCOC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 46 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-butanol (19 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (34 mg, yield 46%).