Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:21][CH3:22])[C:10](=[O:20])[N:11]([CH3:19])[C:12]=2[C:16](O)=[O:17])[C:7]1=[O:23].C(Cl)(=O)C(Cl)=O.[CH3:34][NH:35][CH3:36].C1COCC1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:21][CH3:22])[C:10](=[O:20])[N:11]([CH3:19])[C:12]=2[C:16]([N:35]([CH3:36])[CH3:34])=[O:17])[C:7]1=[O:23]
Reactant: COc1c2c(c(C(=O)O)n(C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1c2c(c(C(=O)N(C)C)n(C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylic acid (8.50 g, 22 mmol) in methylene chloride (300 mL) at 0° C. was added oxalyl chloride (2.25 mL, 26 mmol) and 1 drop of anhydrous DMF. The reaction was stirred at 0° C. for 15 minutes during which time no bubbling was observed. The reaction was then allowed to warm to room temperature and stirred for 40 minutes. At this time bubbling had ceased, and all material was in solution. An aliquot of the solution was quenched with dimethylamine and checked by LCMS to confirm completion. To the solution of the acid chloride starting material at 0° C. was added dimethylamine in THF (43.56 mL, 87 mmol, 2.0 M). The green/yellow reaction was allowed to stir at room temperature overnight although the reaction appeared to proceed immediately by LCMS. The solvent was removed in vacuo, and the resulting residue was dissolved in chloroform. The solution was washed with water and 5% aqueous HCl solution and back extracted to recover the product. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting iridescent green/yellow residue was examined in several TLC solvent systems (95:5 CH2Cl2:MeOH, 2:1 acetone:hexanes, 1:1 EtOAc:hexanes) with the most efficient separation of some early running impurities achieved in the CH2Cl2:MeOH system. The material was purified by silica gel flash column chromatography, loaded as a solution in methylene chloride onto a 330 g RediSep column. Gradient elution consisted of 1.5 L each of neat CH2Cl2, 1% MeOH:CH2Cl2, 2% MeOH:CH2Cl2, 3% MeOH:CH2Cl2, 4% MeOH:CH2Cl2, and 5% MeOH:CH2Cl2, in sequential order. The desired material began to elute with 3% and was pushed off the column with 4% and 5%, yielding two sets of fraction. The earlier set afforded of the desired product plus a fluorescent green contaminant. The later set afforded clean material.
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][C:16]=2[S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH2:10][C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32]([N:34]([CH2:37][C@H:38]1[CH2:43][O:42][CH2:41][CH2:40][N:39]1C(OC(C)(C)C)=O)[CH2:35][CH3:36])[CH3:33].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>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:32]([N:34]([CH2:37][C@@H:38]1[N:39]([C:11](=[O:12])[CH2:10][C@@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:22])(=[O:23])=[O:24])=[CH:17][C:16]=2[S:25]([C:28]([F:29])([F:31])[F:30])(=[O:27])=[O:26])[CH2:8][S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:40][CH2:41][O:42][CH2:43]1)[CH2:35][CH3:36])[CH3:33]
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CCN(CC)C[C@H]1COCCN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCN(CC)C[C@H]1COCCN1C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution of (R)-4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino) butanoic acid (INTERMEDIATE 8, 500 mg, 1.00 mmol), (S)—N-ethyl-N-(morpholin-3-ylmethyl)ethanamine hydrochloride salt (INTERMEDIATE 86, 50 mg, 1.2 mmol), DIPEA (0.526 ml, 3.01 mmol), in DMA (5 ml) was added HATU (458 mg, 1.20 mmol). The mixture was stirred for 1 hour at room temperature and diluted with ethyl acetate (200 ml). The mixture was washed successively with 1 M aq. sodium bisulfate, saturated sodium bicarbonate, and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified column chromatography (ISCO, eluting with 0→100% DCM/10% 2 M ammonia in MeOH in DCM over 24 minutes) to give the title product (380 mg, yield: 58%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24]C(OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[Cl:35][CH2:36][C:37]1C=C[CH:40]=[C:39]([O:43][CH3:44])[CH:38]=1.Cl>>[ClH:35].[CH3:44][O:43][C:39]1[CH:40]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:23][S:22][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Reactant: COc1cccc(CCl)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: COc1cccc(CSc2cnc(Nc3nc(C)cs3)c(OCc3ccccc3)c2)c1
Yield: 74.7 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and 1-(chloromethyl)-3-methoxybenzene (0.024 mL, 0.17 mmol) were reacted according to the method of Example 43 to afford 5-(3-methoxybenzylthio)-3-(benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (61.7 mg, 75.4% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 7.84 (d, 1H), 7.57 (m, 3H), 7.44-7.33 (m, 3H), 7.17 (t, 3H), 6.80 (m, 4H), 5.29 (s, 2H), 4.17 (s, 2H), 3.68 (s, 3H), 2.30 (s, 3H); Mass spectrum (apci) m/z=450.0 (100), 359.0 (80), 238.0 (75).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([N:12]=NC2C=CC(Cl)=CC=2)=[C:4]([Cl:21])[N:3]=1.C(O)C.O>[Zn].C(O)(=O)C>[Cl:21][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]=1[NH2:12]
Reactant: Nc1nc(Cl)c(N=Nc2ccc(Cl)cc2)c(NCCO)n1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1nc(Cl)c(N)c(NCCO)n1
Temperature: 70 °C
Yield: 18.1 %

Procedure:
To 2-amino-6-chloro-5-[(p-chlorophenyl)azo]-4-[(2-hydroxyethyl)amino]pyrimidine (3.0 g, 9.2 mmol) were added ethanol (76.0 ml), water (76.0 ml) and acetic acid (8.0 ml), and the mixture was heated to 70° C. A zinc powder (7.52 g) was added portionwise with stirring in a nitrogen stream and the mixture was stirred at the same temperature for 1.5 hours to give a solution. The reaction mixture was filtered and the solvent of the filtrate was distilled away under reduced pressure. Water was added to the residue and the mixture was extracted with chloroform, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give pale-brown crystals (0.34 g, 18.3%), m.p. 164-167° C.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].COCCOCCOC.[H-].[Na+]>C(O)(=O)C>[CH2:10]([O:28][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Temperature: 25 °C

Procedure:
A mixture of 30.0 g (0.157 mole) of 5-bromofuroic acid, 64.0 g (0.236 mole) of octadecanol and 500 ml of bis(2-methoxyethyl)ether is stirred at room temperature under nitrogen after which 9.45 g (0.393 mole) of sodium hydride is added. The mixture is refluxed about 22 hours, allowed to cool and poured into an ice-water mixture, acidified with acetic acid and extracted with ether. The ether layer is washed with water and salt water, dried over sodium sulfate, and filtered. The solvent is evaporated off replacing the ether with hexane. Upon cooling to room temperature a solid forms which is recrystallized from methanol to give 5-octadecyloxy-2-furoic acid, M.P. 117°-118° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[F:17][C:18]([C:21]([OH:23])=[O:22])([F:20])[F:19].[NH:24](C(OC(C)(C)C)=O)[CH2:25][C:26]([NH:28][C@H:29]([C:37](ON1C(=O)CCC1=O)=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27].C(OCC)(=O)C>C([O-])(O)=O.[Na+].CC(C)=O>[NH2:24][CH2:25][C:26]([NH:28][C@H:29]([C:37]([NH:1][C@H:2]([C:7]([O:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27].[F:17][C:18]([C:21]([OH:23])=[O:22])([F:20])[F:19]
Reactant: CCN(CC)CCOC(=O)[C@@H](N)CCSC
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCN(CC)CCOC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)CN
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.1 %

Procedure:
25 g of H-Met-OCH2CH2N(CH2CH3)2.TFA was dissolved in 300 ml of 5% NaHCO3. 22 g of Boc-Gly-Phe-OSu in 150 ml of acetone was added into the reaction mixture. The mixture was stirred for 5 h at RT. 500 ml of ethyl acetate was added into the mixture. The ethyl acetate solution was washed with water (3×100 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. The residue was dissolved in 250 ml of dichloromethylene. 200 ml of trifluoroacetic acid was added into the mixture and the mixture was stirred for 30 min. The mixture was evaporated to dryness to yield 25 g of H-Gly-Phe-Met-OCH2CH2N(CH2CH3)2.TFA.
Reaction SMILES: [I-].[K+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH:4]([CH3:6])[CH3:5].[Br:17]Br>O>[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[Br:17])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)COc1ccc([N+](=O)[O-])cc1
Reactant: BrBr
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CC(C)COc1ccc([N+](=O)[O-])cc1Br
Temperature: 60 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Subsequently, a catalytic amount of potassium iodide was added to 4-isobutoxynitrobenzene (203 g) and the mixture was heated to 60° C. Bromine (183 g) was added dropwise over 3 h. The mixture was stirred further for 1 h. The reaction mixture was poured into water and extracted with toluene. The organic layer was washed with aqueous sodium sulfite solution and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The obtained oily substance was distilled under reduced pressure to give 2-isobutoxy-5-nitrobromobenzene (248 g), boiling point: 135–140° C./0.25 mmHg.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[CH2:12][CH2:11][N:10]([C:15](=[O:36])[CH:16]([N:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:9][C:8]=3[CH:7]=[N:6][C:5]=2[NH:4][N:3]=1.[ClH:37]>ClCCl.O1CCOCC1>[Cl-:37].[Br:1][C:2]1[C:14]2[C:13]3[CH2:12][CH2:11][N:10]([C:15](=[O:36])[CH:16]([N:23]4[CH2:24][CH2:25][NH2+:26][CH2:27][CH2:28]4)[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:9][C:8]=3[CH:7]=[N:6][C:5]=2[NH:4][N:3]=1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(C(=O)N2CCc3c(cnc4[nH]nc(Br)c34)C2)c2ccccc2)CC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(C(c1ccccc1)N1CC[NH2+]CC1)N1CCc2c(cnc3[nH]nc(Br)c23)C1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a solution of tert-butyl 4-(2-(1-bromo-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-oxo-1-phenylethyl)piperazine-1-carboxylate (0.075 g, 0.17 mmol) in dichloromethane (12 mL) and 1,4-dioxane (6 mL) was added a 4 M solution of HCl gas in 1,4-dioxane (0.82 mL, 3.4 mmol). The reaction was shaken at room temperature for 16 hours. During the reaction a pale tan solid precipitate was formed. The solvent was removed under reduced pressure to give the pure desired product, 4-(2-(1-bromo-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-oxo-1-phenylethyl)piperazin-1-ium chloride (0.064 g, 71%) as an tan solid. M.p.>245° C.; 1H NMR (400 MHz, DMSO-d6) δ13.98 (s, 1H), 9.92 (brs, 2H), 8.44/8.21 (s, 1H, rotamers), 7.44-7.68 (m, 5H), 6.28 (m, 1H), 4.75-4.92 (m, 2H), 4.11 (m, 8H), 3.90 (m, 1H), 3.66 (m, 1H), 3.29 (m, 1H), 2.62 (m, 1H); LCMS [M+H]: 455.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Na+]>CO>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:4]([OH:21])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title A compound, 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (3.6 g, 12.3 mmol) is dissolved in 25 mL of methanol and aqueous NaOH (0.70 g, 17.5 mmol in 4 mL of water) is added and the mixture is stirred at RT overnight. The methanol is removed under reduced pressure and the residue is diluted with 100 mL of water and extracted with ether. The aqueous layer is then acidified with 1N HCl and then extracted with ethyl acetate. The combined ethyl acetate layers are dried over anhydrous magnesium sulfate, filtered and reduced under vacuum to a crude orange oil. The crude oil is triturated with 100 mL of hexane/10-15 mL of ether to produce 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid as a solid: 1H NMR (400 MHz, CDCl3) δ1.0-1.1 (m, 2H), 1.4-1.8 (m, 5H), 1.8-1.9 (m, 2H), 2.1-2.25 (m, 2H), 3.74 (t, 1H, J=7.8), 7.51 (d, 2H, J=8.8), 8.19 (d, 2H, J=8.8); LC/MS 218 (—CO2, M−1), 279 (M+NH4+).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:10][CH2:11][CH2:12][NH2:13])([CH2:6][CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][P:4]([CH2:10][CH2:11][CH2:12][NH:13][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=1)([CH2:6][CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCCCP(=O)(CCCN)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCP(=O)(CCCNCc1ccc(Cl)cc1)OCC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4.14 g of 3-aminopropyl(n-butyl)phosphinic acid ethyl ester are mixed with 2.51 g of p-chlorobenzaldehyde, and first 1.2 g of glacial acetic acid and then a solution of 0.42 g of sodium cyanoborohydride in 5 ml of methanol are added, whereupon an exothermic reaction takes place. The mixture is then stirred at room temperature for 2.5 hours and adjusted to pH 8, and the volatile constituents are removed under reduced pressure. The residue is dissolved in dichloromethane, washed with water, dried over sodium sulfate and concentrated by evaporation. The residue is purified by chromatography on silic gel, yielding 3-(p-chlorobenzylamino)propyl(n-butyl)phosphinic acid ethyl ester; 1H--NMR spectrum (in CDCl3): δ=7.30-7.32 (4H,m); 4.02 (2H,q); 3.74 (2H,s); 2.67 (2H,t); 2.5-2.2 (1H,S); 1.79-1.64 (6H,m); 1.53 (2H,m); 1.42 (2H,m); 1.31 (3H,t); 0.81 (3H,t); 31P--NMR spectrum (in CDCl3); δ=58.16.
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([S:19](O)(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2].S(Cl)(Cl)=O.[NH3:30]>CN(C)C=O>[CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:30])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2]
Reactant: N
Reactant: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(CC)c1=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCn1c(=O)c2[nH]c(-c3ccc(S(N)(=O)=O)cc3)nc2n(CC)c1=O
Temperature: 25 °C

Procedure:
A mixture of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6dioxo-1H-purin-8-yl)benzenesulfonic acid (5.0 g, 0.014 moles) and N,N-dimethylformamide (150 ml) is cooled to 0° and treated with thionyl chloride (3.3 g, 0.027 moles). When the addition is complete, the reaction mixture is permitted to warm to ambient temperature and stirred vigorously until a thick slurry results. To this slurry is added N,N-dimethylformamide saturated with ammonia (100 ml). The resulting mixture is then saturated with gaseous ammonia and concentrated on a rotary evaporator. The residue is taken up in water, filtered, triturated with ethanol and dried at 68° C. to yield 2.9 grams of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonamide, mp 350°-353° C.(d).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:17])=[C:4]([C:13](=[O:16])[NH:14][CH3:15])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:9])=[O:8].C(OCC(NC1C(I)=C(C(=O)NC)C(I)=C(C=1I)C(Cl)=O)=O)(=O)C.[C:42]([O:45][CH:46]([CH2:50][O:51][C:52](=[O:54])[CH3:53])[C:47](Cl)=[O:48])(=[O:44])[CH3:43]>CC(N(C)C)=O>[C:42]([O:45][CH:46]([CH2:50][O:51][C:52](=[O:54])[CH3:53])[C:47]([NH:1][C:2]1[C:3]([I:17])=[C:4]([C:13](=[O:16])[NH:14][CH3:15])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:9])=[O:8])=[O:48])(=[O:44])[CH3:43]
Reactant: CC(=O)OCC(OC(C)=O)C(=O)Cl
Reactant: CNC(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I
Agent: CNC(=O)c1c(I)c(NC(=O)COC(C)=O)c(I)c(C(=O)Cl)c1I
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1c(I)c(NC(=O)C(COC(C)=O)OC(C)=O)c(I)c(C(=O)Cl)c1I

Procedure:
Compound (11) is prepared from compound (2) in an analogous manner as compound (3) described in Example I, B. Thus, 5-amino-3-methylcarbamoyl-2,4,6-triiodobenzoyl chloride (2) reacted with 2,3-diacetoxypropionyl chloride in DMAc provides 5-(2,3-diacetoxypropionylamino)-3-methylcarbamoyl-2,4,6-triiodobenzoyl chloride (11) in approximately 90% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6](CC1C=CC(OC)=CC=1)[C:5]2([CH3:22])[CH3:21]>C(#N)C.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2([CH3:22])[CH3:21]
Reactant: COc1ccc(CN2C(=O)c3ccc(Br)cc3C2(C)C)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)NC(=O)c2ccc(Br)cc21
Yield: 86 %

Procedure:
A solution of 5-bromo-2-(4-methoxybenzyl)-3,3-dimethyl-2,3-dihydroisoindol-1-one (640 mg, 1.78 mmol) and ceric ammonium nitrate (2.91 g, 5.33 mmol) in acetonitrile (11 mL) and water (5 mL) is stirred at 0° C. for 45 min. The solution is diluted with ethyl acetate (100 mL) and washed with brine (40 mL). The organic solvents are dried over MgSO4 and evaporated under reduced pressure. The residue is purified by silica chromatography, eluting with 10% to 50% ethyl acetate in petroleum ether to afford the title compound (367 mg, 1.53 mmol).
Reaction SMILES: [K+].[Br:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[C:12](=[O:16])[C:13]([O-:15])=O.[C:17]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([N:25]1[CH2:30][CH2:29][N:28]([C:13](=[O:15])[C:12]([C:8]2[C:7]3[C:11](=[C:3]([Br:2])[N:4]=[CH:5][CH:6]=3)[NH:10][CH:9]=2)=[O:16])[CH2:27][CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: O=C([O-])C(=O)c1c[nH]c2c(Br)nccc12
Agent: [K+]
Product: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1)c1c[nH]c2c(Br)nccc12

Procedure:
Precursor 5g, 1-benzoyl-4-[(7-bromo-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a, starting from (7-bromo-6-azaindol-3-yl)-oxoacetic acid potassium salt, Precursor 4g, and 1-benzoylpiperazine. MS m/z: (M+H)+ calcd for C20H18BrN4O3: 441.06; found 441.07. HPLC retention time: 1.43 minutes (column B).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1.[Br:22][C:23]1[N:28]=[C:27]([C:29](O)=[O:30])[C:26]([F:32])=[CH:25][CH:24]=1>>[Br:22][C:23]1[N:28]=[C:27]([C:29]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:9]2)=[O:30])[C:26]([F:32])=[CH:25][CH:24]=1
Reactant: O=C(O)c1nc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc(Br)ccc2F)C1

Procedure:
Following Method 11 (Example 305), (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate was coupled to 6-bromo-3-fluoropicolinic acid yielding (S)-tert-butyl 1-(3-(6-bromo-3-fluoropicolinamido)pyridin-4-yl)piperidin-3-ylcarbamate which was used directly as is. LCMS (m/z): 496.2 (MH+); LC Rt=2.71 min.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([C:8]([NH:10][NH:11][C:12]([C:14]2[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[O:13])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].I[CH3:29]>CC(C)=O>[CH3:29][S:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][NH:11][C:12]([C:14]2[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[O:13])=[O:9])=[CH:26][CH:27]=1)=[NH:2]
Reactant: CI
Reactant: COC(=O)COc1ccc(C(=O)NNC(=O)c2ccc(C(N)=S)cc2)cc1
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(=O)NNC(=O)c2ccc(C(=N)SC)cc2)cc1
Reaction time: 4 h

Procedure:
Methyl 4-[3-(4-thiocarbamoylbenzoyl)carbazoyl]phenoxyacetate (10.5 g) was suspended in acetone (1 L) and iodomethane (100 ml) was added. The reaction mixture was heated to 40°-45° C. with stirring for 4 hours and then cooled to ambient temperature before a further aliquot of iodomethane (20 ml) was added. The reaction mixture was stirred at ambient temperature overnight. A further aliquot of iodomethane (20 ml) was added and the reaction mixture was heated again to 40°-45° C. with stirring for 3 hours. Removal of the solvents in vacuo yielded methyl 4-[3-[4-(methylthio)carbonimidoylbenzoyl]carbazoyl]phenoxy-acetate as an orange-brown solid which was not purified further. A portion of the residue (10 g) was suspended in a mixture of methanol (300 ml) and dichloromethane (300 ml), and covered with a blanket of argon before a solution of dry ammonium acetate (27 g) in methanol (100 ml) was added. The reaction mixture was stirred under argon for 2-3 days. Removal of the solvents in vacuo yielded a solid residue which was crystallised, with filtration, from boiling methanol to give the title compound (8.57 g) as a pale yellow solid; m.p. 208°-210° C. (decomposes); NMR Spectrum (DMSO--d6) 1.76 (3H, s), 3.72 (3H, s), 4.91 (2H, s), 7.06 (2H, d), 8.05 (2H, d), 7.90 (4H, m); Mass Spectrum m/Z 371 (M+H)+ ; Elemental Analysis: calculated for C18H18N4O5. 1.0 CH3CO2H.1.0 CH3OH. 1.0 H2O: C, 52.5%; H, 5.87%; N, 11.7%; found: C, 52.1%; H, 6.0%; N, 11.7%.
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][CH2:17][CH2:18][C:19]2[CH:28]=[CH:27][C:22]([C:23](OC)=[O:24])=[CH:21][CH:20]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O.[NH2:30][NH2:31].ClCCl>CO>[OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][CH2:17][CH2:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([NH:30][NH2:31])=[O:24])=[CH:21][CH:20]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reactant: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: NNC(=O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1

Procedure:
A solution of methyl 4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoate (4.1 g., 0.01 mole) and hydrazine hydrate (2.5 g., 0.05 mole) in methanol (25 ml.) is stored at 25° C. for 48 hours. The solvent is then removed by distillation at reduced pressure. The residue is treated with water and enough 2 N hydrochloric acid to give a neutral mixture. The title compound is isolated by extraction into dichloromethane and subsequent drying and evaporation of the extract.