Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:28]=2)[N:23](COCC[Si](C)(C)C)[N:22]=1>O1CCCC1.C(#N)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:12][N:11]=[N:10][N:9]=4)=[CH:4][CH:3]=3)[CH:28]=2)[NH:23][N:22]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Brc1ccc(-c2nnn[nH]2)cc1
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(-c4nnn[nH]4)cc3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.1 %

Procedure:
In a microwave vial 5-(4-bromo-phenyl)-1H-tetrazole (89.2 mg, 0.4 mmol), 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxy-methyl)-1H-pyrazolo[3,4-b]pyridine (200 mg, 0.40 mmol) in tetrahydrofuran/acetonitrile/1 N aqueous sodium bicarbonate (4 ml) was degassed with nitrogen and 1,1′-bis(diphenyl-phosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (32.4 mg, 0.04 mmol) was added and the vial sealed. This reaction mixture was irradiated to 150° C. for 30 minutes in a microwave reactor. The mixture was extracted with ethyl acetate (3×) and the combined organic layers were dried over magnesium sulfate and filtered through a silica gel plug MS: m/z 500.6 (M+H+). To this crude was added trifluoroacetic acid (1 ml) and the reaction mixture stirred for 16 hours at ambient temperature. The solvent was removed under reduced pressure and the resulting solid was purified by preparative mass-triggered reverse-phase HPLC to yield 3-(2-methoxy-phenyl)-5-[4-(1H-tetrazol-5-yl)-phenyl]-1H-pyrazolo[3,4-b]pyridine as a white solid (7.5 mg, 5%). 1H NMR (500 MHz, DMSO-d6) δ 3.87 (s, 3H); 6.56 (s, 3H); 7.11 (t, J=8 Hz 1H) 7.23 (d, J=8 Hz 1H); 7.48 (t, J=8 Hz, 1H); 7.66 (d, J=8 Hz 1H); 8.01 (t, J=9 Hz, 1H); 8.14 (d, J=9 Hz 1H); 8.44 (s, 1H); 8.94 (s, 1H); 13.84 (s, br, 1H); MS: m/z 369.3 (M+H+).
Reaction SMILES: N[C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[ClH:18].N([O-])=O.[Na+].C(OCC)(=O)C>C(O)(=O)C>[Cl:18][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)/C=C/c1ccc(C(C)C)c(N)c1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(C(C)C)c(Cl)c1
Reaction time: 0.5 h

Procedure:
4.67 g of ethyl (E)-3-(3-amino-4-isopropylphenyl)acrylate was dissolved in 46.7 ml of acetic acid. To the solution was added 46.7 ml of 2N hydrochloric acid with ice-cooling. To the mixture was dropwise added 10 ml of an aqueous solution containing 1.52 g of sodium nitrite. The mixture was stirred for 30 minutes at the same temperature. The reaction mixture was added to 30 ml of 6N hydrochloric acid solution containing 2.18 g of cuprous chloride, with ice-cooling. The mixture was stirred for 1 hour at the same temperature and then for 2 hours at room temperature. To the reaction mixture was added 100 ml of ethyl acetate. The organic layer was separated and washed with water. Thereto was added 50 ml of water. The mixture was adjusted to about pH 7 with sodium hydrogencarbonate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/ethyl acetate=20/1) to obtain 3.57 g of colorless oily ethyl (E)-3-(3-chloro-4-isopropylphenyl)acrylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[Br:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:13][CH2:14][CH2:15][O:12][C:4]1[CH:5]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(O)cc(F)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Temperature: 120 °C
Yield: 72.7 %

Procedure:
A mixture of 3-fluoro-5-methylsulfonyl-phenol (4.2 g, 22.08 mmol), 1,2-dibromoethane (24 ml, 27.7 mmol) and potassium carbonate (6.1 g, 44.2 mmol) in acetonitrile (36 ml) was divided into 6 aliquots which were each heated under microwave radiation at 120° C. for 30 min. The reaction mixtures were cooled to room temperature, filtrated and pooled. The volatiles were evaporated, aqueous sodium carbonate (100 ml, 10%) was added and the mixture was extracted with ethyl acetate (2×100 ml). The combined organic phase was washed with brine (75 ml), dried (Na2SO4) and evaporated. Purification by flash column chromatography (ethyl acetate/isooctane, 0:1 to 1:0) gave the title compound (4.77 g, 73%). MS m/z (relative intensity, 70 eV 298 (M+, 18), 296 (M+, 18), 109 (bp), 107 (99), 82 (15).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH2:5][C:6]([O:14][CH3:15])([CH:11]=[CH:12][CH:13]=1)[C:7](OC)=[O:8].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.CO>CCCCCC>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH2:5][C:6]([O:14][CH3:15])([CH:11]=[CH:12][CH:13]=1)[CH:7]=[O:8]
Reactant: COC(=O)C1=CC=CC(OC)(C(=O)OC)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)C1=CC=CC(C=O)(OC)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a -78° to -100° solution of 1.0 mol of 3-methoxyisophthalic acid dimethyl ester in 1-10.1 of toluene is slowly added 1.0 mol of diisobutylaluminum hydride as a 1 M solution in n-hexane. The reaction is stirred for 3 hours after the addition and then quenched by the addition of 10 mol of anhydrous methanol. The reaction is allowed to warm to room temperature and stirred until a filterable precipitate forms. The reaction is filtered and the filtrate evaporated to a residue. The residue is purified by crystallization, distillation or chromatography to yield 3-methoxyisophthalaldehydic acid methyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[N:8]=[N:7][C:6]([CH2:9][O:10][CH2:11][C:12]2[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:5]1.C(N(CC)CC)C.[Cl:43][C:44]1[CH:49]=[C:48](Cl)[N:47]=[CH:46][N:45]=1>C(O)C>[Cl:43][C:44]1[N:45]=[CH:46][N:47]=[C:48]([NH:1][CH2:2][CH2:3][N:4]2[N:8]=[N:7][C:6]([CH2:9][O:10][CH2:11][C:12]3[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=4[Cl:30])[C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:5]2)[CH:49]=1
Reactant: CCOC(=O)C1=C(COCc2nnn(CCN)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: Clc1cc(Cl)ncn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(COCc2nnn(CCNc3cc(Cl)ncn3)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 80.8 %

Procedure:
A solution of 2-(2-aminoethyl)-5-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}tetrazole (0.52 g), triethylamine (0.5 ml) and 4,6-dichloropyrimidine (0.16 g) in ethanol (20 ml) was heated under reflux for 23 hours and then evaporated. The residue was purified by chromatography on silica (8 g) using dichloromethane plus from 0 to 100% by volume of ethyl acetate as eluant. Appropriate fractions were combined and evaporated to give 2-{[(6-chloro-4-pyrimidinyl)amino]ethyl}-5-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}tetrazole (0.51 g) as a colourless foam. A solution of this crude product in morpholine (3 ml) was heated on a steam-bath for 90 minutes and then partitioned between 2M hydrochloric acid and dichloromethane. The acidic layer was extracted into dichloromethane and the combined organic layers were washed with water and 10% aqueous sodium carbonate solution, dried over anhydrous sodium sulphate and evaporated. The residue was purified by chromatography on silica (10 g) using dichloromethane plus from 0 to 50% by volume of ethyl acetate followed by dichloromethane plus from 1 to 5% by volume of methanol as eluant. Appropriate fractions were combined and evaporated. The residual oil was triturated with diethyl ether and the resulting solid collected, washed with diethyl ether and dried to give the title compound (0.51 g), m.p. 160°-162° C. Found: C,52.24; H,5.20; N,18.24. C30H35Cl2N9O6 requires: C,52.33; H,5.09; N,18.31%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1.[OH-:30].[Na+]>ClCCl>[CH3:1][S:2]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)(=[O:27])=[O:30]
Reactant: [OH-]
Reactant: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
1-(4-Methylsulfanylphenoxy)-4-nitrobenzene (86 g, 330 mmol) prepared in Step A was dissolved in dichloromethane (500 mL). mCPBA (3-chloroperbenzoic acid) (83 g, 330 mmol) was added thereto, and the mixture was stirred for 2 h at 0° C. to room temperature. After completion of the reaction, excess 6N aqueous sodium hydroxide solution was added. The reaction mixture was extracted with ethyl acetate and dichloromethane, washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate to give the title compound (28 g, Yield 100%).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[OH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:7]([O:6][C:5]([NH:4][CH2:3][CH2:2][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:11])([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCCNC(=O)OC(C)(C)C)c1
Reaction time: 12 h
Yield: 45.5 %

Procedure:
To a solution of tert-butyl 2-bromoethylcarbamate (5 g) and methyl 3-hydroxybenzoate (3.4 g) in dimethylformamide (60 ml) was added caesium carbonate (14.5 g) and the reaction stirred for 12 hours before partitioning between water and ethyl acetate. The organic layer was separated, dried with MgSO4 and the solvent removed by evaporation. Purification by flash chromatography (ethyl acetate:isohexane 92.5:7.5) gave the sub-title product as a colourless oil (3 g).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][N:2]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:11]=[C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:1]=[N:2][N:3]1[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCCBr
Reactant: O=c1[nH]nnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1nnc2ccccc2c1=O
Temperature: 25 °C
Yield: 76.6 %

Procedure:
In a dry round bottom flask, 1,2,3-benzotriazin-4(3H)-one (50 g), ethyl 4-bromobutanoate (86.2 g) and potassium carbonate (141 g) were taken and dissolved in dimethylformamide (350 mL) and heated to 60° C. to 70° C. for 3 to 4 hours. After cooling to room temperature, water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layer was washed with water and brine and dried over anhydrous sodium sulfate. Solvents were evaporated under reduced pressure and the crude product was purified by silica gel flash column chromatography over silica gel using 20% ethylacetate in hexane as eluant to afford the title compound (68 g).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[C:29](Cl)[CH:28]=[CH:27][C:26]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:38]([O:55][CH2:56][C@H:57]1[N:62]([CH2:63][CH2:64][C@@H:65]([NH:74][C:75]2[CH:80]=[CH:79][C:78]([S:81]([NH2:84])(=[O:83])=[O:82])=[CH:77][C:76]=2[S:85]([C:88]([F:91])([F:90])[F:89])(=[O:87])=[O:86])[CH2:66][S:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:61][CH2:60][O:59][CH2:58]1)([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(Cl)C[Cl:94]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:94])=[CH:34][CH:33]=1)[CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:84][S:81]([C:78]3[CH:79]=[CH:80][C:75]([NH:74][C@H:65]([CH2:64][CH2:63][N:62]4[CH2:61][CH2:60][O:59][CH2:58][C@H:57]4[CH2:56][O:55][Si:38]([C:51]([CH3:52])([CH3:53])[CH3:54])([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:66][S:67][C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[C:76]([S:85]([C:88]([F:89])([F:90])[F:91])(=[O:86])=[O:87])[CH:77]=3)(=[O:83])=[O:82])=[O:22])=[CH:18][CH:17]=2)[CH2:14][CH2:15]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1cc(Cl)ccc1-c1ccccc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)[Si](OC[C@@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F)(c1ccccc1)c1ccccc1
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOC[C@H]4CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 253 %

Procedure:
To a solution of (R)-4-(4-((tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 183 mg, 0.34 mmol) in DCM (3 ml) were added sequentially DMAP (125 mg, 1.02 mmol), 4-((R)-4-((S)-3-((tert-butyldiphenylsilyloxy)methyl)morpholino)-1-(phenylthio)butan-2-yl amino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 105, 280 mg, 0.34 mmol) and EDC (131 mg, 0.68 mmol). The resulting solution was stirred at room temperature overnight. Evaporation of the volatiles under reduced pressure gave a residue which was purified by column chromatography (ISCO, 27 g silica gel column, eluting with 0→20% EtOAc/hexanes) to give 4-(4-((R)-(tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)-N-(4-((R)-4-((S)-3-((tert-butyldiphenylsilyloxy)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide (EXAMPLE 24, STEP 1,153 mg) which was used in the preparation of EXAMPLE 24, STEP 2 without further purification.
Reaction SMILES: O[N:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([OH:9])[CH:3]1O.[C:11](OC([O-])=O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(OC(=O)C)C>O1CCCC1.O>[OH:9][C:4]1[CH2:3][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7]([OH:8])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: OC1=CC=C(O)N(O)C1O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(O)=CC=C1O
Reaction time: 5 h
Yield: 95.8 %

Procedure:
1 g (12 mmol) of 1,2,3,6-tetrahydroxypyridine and 2.76 g (12.6 mmol) of t-butyl dicarbonate was dissolved in 40 mL of tetrahydrofurane/water (1:1), and after stirring for 5 hour, 100 mL of ethylacetate was added thereto. After washing with water, an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 2.1 g (11.5 mmol) of the title compound in a yield of 91%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[Cl:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:41](=[O:42])[C:40]3[CH:44]=[CH:45][C:37]([Cl:36])=[CH:38][CH:39]=3)=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(N)cc2CN(CC)C(=O)OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(NC(=O)c3ccc(Cl)cc3)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
{4′-Amino-2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester (0.08 g, 0.2 mmol), 4-chlorobenzoyl chloride (0.04 mL, 0.3 mmol), and triethylamine were reacted in CH2Cl2 to give the title compound.
Reaction SMILES: OC1C=C(NC2N=C(NC3C=C[CH:19]=[C:18]([OH:22])C=3)C(F)=CN=2)C=CC=1.Cl[C:25]1[N:30]=[C:29](Cl)[C:28]([N+:32]([O-:34])=[O:33])=[C:27]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:26]=1.Cl.[CH2:41]([O:43][C:44](=[O:47])[CH2:45][NH2:46])[CH3:42]>C(N(CC)CC)C>[CH2:41]([O:43][C:44]([CH2:45][NH:46][C:25]1[N:30]=[C:29]([NH:26][CH2:27][C:35]([O:22][CH2:18][CH3:19])=[O:36])[C:28]([N+:32]([O-:34])=[O:33])=[C:27]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:26]=1)=[O:47])[CH3:42]
Reactant: CCOC(=O)CN
Reactant: CCOC(=O)c1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1nc(NCC(=O)OCC)c([N+](=O)[O-])c(C(=O)OCC)n1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, with the addition of triethylamine, 2,4-dichloro-6-ethoxycarbonyl-5-nitropyrimidine and glycine ethyl ester hydrochloride were reacted to yield N2,N4-bis(ethoxycarbonylmethyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine. 1H NMR (CDCl3): mixture of rotamers δ 8.99 and 8.80 (2bs, 1H), 6.22 and 6.00 (2bs, 1H), 4.45 (t, 2H, J=7.2 Hz), 4.31-4.21 (m, 6H), 4.14 (d, 2H, J=5.1 Hz), 1.39 (t, 3H, J=7.2 Hz), 1.34-1.28 (m, 6H); LCMS: ret. time: 26.06 min.; purity: 99%; MS (m/e): 400 (MH+).
Reaction SMILES: [Br-].[C:2]1([I+:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O-:23])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+]>>[C:15]([O:23][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:2]1([I:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc([I+]c2ccccc2)cc1
Reactant: O=C([O-])c1ccccc1
Agent: [Br-]
Agent: [Na+]
Product: Ic1ccccc1
Product: O=C(Oc1ccccc1)c1ccccc1

Procedure:
Diphenyliodonium bromide has been reacted with sodium benzoate to form phenyl benzoate and phenyl iodide, and the reaction has been found to be faster in strong bases. F. M. Beringer, et al., 75 J. Amer. Chem. Soc. 2708 (1963).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[CH3:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([O:22][CH3:23])[C:13]=1Br.C(COC)OC.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:13]2[C:14]([O:22][CH3:23])=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]=2[O:11][CH3:10])[CH:2]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2ccccc2c(OC)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COc1cc2ccccc2c(OC)c1-c1cccnc1
Yield: 77.8 %

Procedure:
Pyridine-3-boronic acid (3.94 g 32 mmol, Frontier Scientific, Inc.), 1,3-dimethoxy -2-bromonaphthalene 8 (6.6 g, 24.7 mmol), glyme (200 ml), and tetrakis(triphenylphosphine) palladium (Ph3P)4Pd (3 g, 2.7 mmol) were stirred for 15 minutes followed by the addition of potassium carbonate (11.4 g in 50 mL of water). After refluxing over-night, the reaction mixture was poured into 800 ml of 1:1 water:ethyl acetate. The organic layer was washed with water (300 ml×2) and brine (200 ml), solvent was removed, and the crude product was purified by silica-gel chromatography eluting with dichloromethane and acetone (0% to 5% acetone) yielding 5.1 g (84%) of 9.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:6]([NH:8][C@H:9]([C:34](=[O:41])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][C:20](=[O:22])[N:19](CC3C=CC(OC)=CC=3)[S:18]2(=[O:33])=[O:32])=[CH:13][CH:12]=1)=[O:7])(=[O:3])[CH3:2].C([SiH](C)C)(C)(C)C>C(O)(C(F)(F)F)=O.CC#N.O>[C:1]([NH:4][C@@H:5]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:6]([NH:8][C@H:9]([C:34](=[O:41])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:21][C:20](=[O:22])[NH:19][S:18]2(=[O:33])=[O:32])=[CH:15][CH:16]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCNC(=O)[C@H](Cc1ccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Agent: C[SiH](C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CCCCCNC(=O)[C@H](Cc1ccc(N2CC(=O)NS2(=O)=O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: 80 °C
Reaction time: 0.12 h

Procedure:
A solution of the title C compound, (S)-2-acetylamino-N-((S)-2-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-3-phenyl-propionamide (49 mg, 0.07 mmol) in TFA (1.4 mL) containing t-butyldimethylsilane (0.035 mL, 0.21 mmol) is heated at 80° C. for 1 h. The reaction is concentrated under nitrogen stream to give an oil which is taken up in 60% MeCN in water. Water (1 mL) is added, and the mixture filtered through a 0.1 micron Acrodisc filter. The resulting mixture is loaded onto a preparative reverse phase HPLC column (YMC CombiPrep Pro C18, 50×20 mm I.D., particle size S-5 micron, 12 nM) in three aliquots and eluted at 30 mL/min with a gradient of 90:10 (0.1% TFA in water:MeCN) to 10:90 over 5 min. Then held at 10:90 until 7 min. Fractions containing product are combined and concentrated on a Savant Speedvac to yield (S)-2-acetylamino-N-((S)-1-pentylcarbamoyl-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-ethyl)-3-phenyl-propionamide as a white solid: [M−1]−=556.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](O)=[O:20])[CH2:13][CH2:12]2)=[O:10])[N:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([NH:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)=[O:20])[CH2:15][CH2:16]2)=[O:10])[N:3]=1
Reactant: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3C(=O)O)CC2)n1
Reactant: Nc1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3C(=O)Nc3ccncc3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To 2-{4-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-benzoic acid (0.051 g, 0.150 mmol) in 2 mL of CH2Cl2 at 4° C. is added 2 M oxalyl chloride solution (0.100 mL, 0.200 mmol) and 2 drops of dry DMF. The mixture is allowed to warm to room temperature over 1 h. To this is added 4-aminopyridine in one portion and diisopropylethyl amine (0.100 mL, 0.310 mmol). The mixture is stirred for 16 h. The mixture is concentrated and then purified via preparative HPLC (20-80% CH3CN/H2O). The product is further purified using a SiO2 prep-plate, eluting with (10% MeOH/CH2Cl2) to give 0.032 g of the title compound in 63% yield. MS MH+=419.2