Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[CH:18]1[C:23]([CH:24]=O)=[CH:22][C:21]2[O:26][CH2:27][O:28][C:20]=2[CH:19]=1.C(=O)(O)[O-].[Na+]>CN(C)C(=O)C.O>[CH3:2][O:3][C:4]([C@@H:5]1[NH:6][C@H:24]([C:23]2[CH:18]=[CH:19][C:20]3[O:28][CH2:27][O:26][C:21]=3[CH:22]=2)[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:17]
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@@H](c2ccc3c(c2)OCO3)N1
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of D-Tryptophan methyl ester hydrochloride (100 g) in N,N-Dimethyl acetamide (500 ml), added Piperonal (65 g) and heated the reaction mass to 65–70° C. for 30–35 hours for completion of reaction. Reaction mass is then diluted with water, basified with sodium bicarbonate solution and extracted twice with dichloromethane (2×750 ml). The organic layer is then treated with aqueous hydrochloric acid (1000 ml). Dichloromethane is evaporated and the reaction mass is stirred for 6–10 hours at 55–60° C. Cooled the reaction mass to an ambient temperature and filtered the crude title compound in hydrochloride salt form. Then wet crude mass is charged in sodium bicarbonate solution and extracted twice with dichloromethane (2×750 ml). Dichloromethane layer is distilled out and the residual material is dissolved in Toluene and crystallized by addition of anti solvent like cyclohexane to get title compound (88.0 g).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:21])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:5]>>[CH2:4]([O:6][C:7]([C:8]1[NH:2][N:3]=[C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=1)=[O:21])[CH3:5]
Reactant: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Reactant: NN
Solvent: O
Product: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
Hydrazine hydrate (0.27 mL, 2.76 mmol) was added to a stirred solution of 2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester (0.69 g, 2.76 mmol in EtOH (3 mL)). The mixture was stirred at 80° C. overnight. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; DCM in AcOEt 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.66 g, 98% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]2[C:10]([CH3:29])=[N:11][C:12]3[C:17]([N:18]=2)=[C:16]([C:19]2[NH:23][C:22]4[C@@H:24]([CH3:28])[NH:25][C:26](=[O:27])[C:21]=4[CH:20]=2)[CH:15]=[CH:14][CH:13]=3)[CH2:3]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>C(Cl)Cl>[CH3:29][C:10]1[C:9]([NH:8][C@H:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:3]2)=[N:18][C:17]2[C:12]([N:11]=1)=[CH:13][CH:14]=[CH:15][C:16]=2[C:19]1[NH:23][C:22]2[C@@H:24]([CH3:28])[NH:25][C:26](=[O:27])[C:21]=2[CH:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1N[C@H]1CCC[C@@H](N)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1N[C@H]1CCC[C@@H](NS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 9.8 %

Procedure:
A mixture of (R)-2-(3-(((1S,3R)-3-aminocyclohexyl)amino)-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (483, 52 mg, 0.133 mmol), methanesulfonyl chloride (41.4 μL, 0.533 mmol), and triethylamine (74.2 μL, 0.533 mmol) in DCM (1.33 mL) was stirred at 0° C. for 5 min; the reaction mixture was warmed to RT and stir for 1 h when product was observed via LCMS. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (2×75 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-5% 2 M ammonia in MeOH/DCM to give N-((1R,3S)-3-((3-methyl-8-((R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinoxalin-2-yl)amino)cyclohexyl)methanesulfonamide (489, 6 mg, 0.013 mmol, 10% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.24-1.36 (m, 2H) 1.37-1.51 (m, 2H) 1.59 (d, J=6.65 Hz, 3H) 1.99-2.06 (m, 1H) 2.16-2.23 (m, 1H) 2.39 (d, J=11.15 Hz, 1H) 2.52-2.57 (m, 1H) 2.59 (s, 3H) 3.00 (s, 3H) 3.48-3.59 (m, 1H) 3.99-4.10 (m, 1H) 4.54 (d, J=7.04 Hz, 1H) 4.68 (q, J=6.98 Hz, 1H) 4.97 (d, J=6.65 Hz, 1H) 5.68 (s, 1H) 6.92 (d, J=1.37 Hz, 1H) 7.42 (t, J=7.82 Hz, 1H) 7.69-7.74 (m, 1H) 7.91-7.97 (m, 1H) 12.29 (br. s., 1H). MS (ESI, pos. ion) m/z: 469.1 (M+1).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO>>[Cl:18][C:15]1[N:14]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[C:7]([OH:27])=[C:8]2[C:16]=1[Cl:17]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2-c1ccc(OC)cc1
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-n2c(Cl)c(Cl)c3c(O)c(C(=O)NCC(=O)O)nc(C#N)c32)cc1

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dichloro-7-cyano-4-hydroxy-1-(4-methoxy-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 435 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([O:19]CC)=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([F:12])[CH:11]=1.[OH-].[Li+].Cl>C1COCC1.CO>[F:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([OH:19])=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(F)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(F)cn2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
550 mg of ethyl 8-[(2,6-difluorobenzyl)oxy]-6-fluoro-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 10A; 1.5 mmol, 1 equivalent) were dissolved in 64 ml of THF and 12 ml of methanol, 7.5 ml of 1 N aqueous lithium hydroxide solution were added and the mixture was stirred at RT overnight. 8 ml of 1 N aqueous hydrochloric acid were then added, and the mixture was concentrated under reduced pressure. The solid formed was filtered off and washed with water. This gave 429 mg of the title compound (80% of theory).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N+:4]([CH3:13])([CH3:12])[CH2:5][CH2:6][CH2:7][S:8]([O-:11])(=[O:10])=[O:9].[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([F:50])[C:23]=1[CH2:24][S:25][C:26]1[N:27]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[C:28]([C:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([O:41][CH3:42])[CH:35]=2)([CH3:33])[CH3:32])=[CH:29][N:30]=1)[C:18](O)=[O:19].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>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([F:50])[C:23]=1[CH2:24][S:25][C:26]1[N:27]([C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)[C:28]([C:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([O:41][CH3:42])[CH:35]=2)([CH3:33])[CH3:32])=[CH:29][N:30]=1)[C:18]([NH:1][CH2:2][CH2:3][N+:4]([CH3:12])([CH3:13])[CH2:5][CH2:6][CH2:7][S:8]([O-:11])(=[O:9])=[O:10])=[O:19]
Reactant: C[N+](C)(CCN)CCCS(=O)(=O)[O-]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)NCC[N+](C)(C)CCCS(=O)(=O)[O-])cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 0.33 h
Yield: 63.3 %

Procedure:
A solution of tert-butyl 2-(dimethylamino)ethylcarbamate (1.8 g, 7.98 mmol) and 1,3-sultone (1.07 g, 8.77 mmol) in toluene was heated 4 h at 60° C. to form a white solid. After cooling to room temperature, the solids were collected by filtration and rinsed with hexanes (2×30 mL). The solids were dissolved in DCM (5 mL) and charged dropwise with TFA (5 mL). After 30 min, the reaction mixture was concentrated under reduced pressure to yield 3-((2-aminoethyl)-dimethylammonio)propane-1-sulfonate as a white solid (2.15 g). This quartarnary amine (82 mg, 0.266 mmol) was added to a solution of 3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)-propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzoic acid (100 mg, 0.1776 mmol) in DMF (1 mL) followed by DIPEA (137 mg, 1.06 mmol) and HATU (74.2 mg, 0.195 mmol). After 20 min, the reaction was determined to be complete by LC-MS. The product mixture was concentrated and purified by HPLC (MeCN/H2O, 10-99%) to yield the title compound as a white solid (85 mg). 1H NMR (400 MHz, MeOD) δ 8.96 (t, J=5.3 Hz, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.60 (dd, J=10.0, 1.6 Hz, 1H), 7.28-7.18 (m, 1H), 6.98 (d, J=8.6 Hz, 1H), 6.95 (d, J=8.6 Hz, 1H) 6.57-6.52 (m, 2H), 6.51-6.45 (m, 2H), 4.18 (s, 2H), 3.89 (t, J=5.5 Hz, 2H), 3.75 (s, 3H), 3.68-3.56 (m, 4H), 3.23 (s, 6H), 2.87 (t, J=6.7 Hz, 2H), 2.25 (dt, J=14.2, 7.1 Hz, 2H), 1.60 (s, 6H). LC-MS: 655.3 [M]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15](O)[C:6]2=[N:5][N:4]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:30]>C(#N)C>[Cl:30][C:15]1[C:6]2[N:7]([C:3]([C:2]([F:18])([F:17])[F:1])=[N:4][N:5]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc2ccccc2n2c(C(F)(F)F)nnc12
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: FC(F)(F)c1nnc2c(Cl)nc3ccccc3n12

Procedure:
To a suspension of 1-(trifluoromethyl)[1,2,4]triazolo[4,3-a]quinoxalin-4-ol (2.5 g; 0.01 mole) in 60 ml of acetonitrile, Et4N+Cl- (2.4 g) followed by N,N-dimethylaniline (1.7 ml) and POCl3 (3.75 ml) were added. Reaction mixture was refluxed for 20 hours. Volatiles were removed under reduced pressure, residue was dissolved in CHCl3 (100 ml) and added to the ice-water. Layers were separated, the aqueous layer was extracted with chloroform (2×200 ml). The combined extract was washed with 5% NaHCO3 (2×120 ml) followed by brine (2×50 ml). It was dried over MgSO4, filtered, and volatiles were removed. The residue was crystallized from chloroform-hexane affording 1.78 g of 4-chloro-1-(trifluoromethyl)[1,2,4]triazolo[4,3-a]quinoxaline; mass spectrum m/e, 272 (m+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[Cl:13][C:14]([CH2:16]Cl)=[CH2:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][CH2:16][C:14]([Cl:13])=[CH2:15])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: C=C(Cl)CCl
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(Cl)COc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Yield: 52.8 %

Procedure:
A mixture of 2-chloro-4-fluoro-5-nitrophenol (20.3 g) and 2,3-dichloropropene (11.7 g) was dissolved in N,N-dimethylformamide (200 ml), and potassium carbonate (14.6 g) was added thereto at room temperature, and the resultant mixture was stirred at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was purified by silica gelchromatography (eluent: hexane/ethyl acetate=4/1) to give 4-chloro-5-(2-chloro-2-propenyloxy)2-fluoronitrobenzene (14.8 g; yield, 53%).
Reaction SMILES: [C:1]1([CH2:7][C:8](NC2C(=O)N3C2CCOC3(C)C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[N:28]1[CH:31]([CH2:32][CH2:33][O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH:30]([NH2:41])[C:29]1=[O:42]>>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[N:28]1[CH:31]([CH2:32][CH2:33][O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH:30]([NH:41][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:29]1=[O:42]
Reactant: NC1C(=O)N(C2CCCCO2)C1CCOC1CCCCO1
Reactant: CC1(C)OCCC2C(NC(=O)Cc3ccccc3)C(=O)N21
Product: O=C(Cc1ccccc1)NC1C(=O)N(C2CCCCO2)C1CCOC1CCCCO1

Procedure:
Following the procedure described for the preparation of 7-phenylacetamido-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo-[4.2.0]octane from 7-amino-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane (Example 6) and using 1-(2-tetrahydropyranyl)-3-amino-4-[2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone there is obtained 1-(2-tetrahydropyranyl)-3-phenylacetamido-4-[2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:24][C:25]1[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31]([C:26]3[C:25]([F:24])=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:32])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)c1ncccc1F
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Product: C[C@@]1(c2cc(NC(=O)c3ncccc3F)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F (R3=Me) and 3-fluoro-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].[Br:4][CH2:5][C:6](=O)[C:7]([CH3:10])([CH3:9])[CH3:8].C(O)C>O>[Br:4][CH2:5][C:6](=[N:2][OH:3])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C(=O)CBr
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)C(CBr)=NO
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
A solution of 69.5 g (1.0 m) of hydroxylamine hydrochloride in 100 ml of water is chilled in an ice bath as 90 g (0.5 m) of 1-bromo-3,3-dimethyl-2-butanone is added. After addition of 100 ml of 95% ethanol, the mixture is stirred for 16 hours and allowed to warm to room temperature. The resulting white slurry is filtered, and the solid is washed with water and dried to give 55 g of the desired compound, m. 111°-112° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Yield: 93.6 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (50.1 g) in N,N-dimethylacetamide (550 ml) was added sodium hydride (10.5 g) with stirring under ice-cooling, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, to the reaction mixture was added dropwise a solution of 4-fluoronitrobenzene (42.2 g) in N,N-dimethylacetamide (100 ml) with stirring at the same temperature, and the resulting mixture was furthermore stirred at room temperature overnight. After stirring, to the reaction mixture was added water and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (13:7) as the eluent to afford the title compound (75.1 g, yield: 93%) as a pale yellow solid.
Reaction SMILES: C([NH:4][C:5]1[C:6](I)=[C:7]([C:11](I)=[C:12]([NH:15][C:16](=[O:22])[CH2:17][C:18]([OH:21])([OH:20])[OH:19])[C:13]=1I)[C:8]([OH:10])=[O:9])(=O)C.[N+](C1C(NC(=O)C(CO)(CO)CO)=C(C=CC=1)C(O)=O)([O-])=O>>[NH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:15][C:16](=[O:22])[CH2:17][C:18]([OH:21])([OH:20])[OH:19])[CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: CC(=O)Nc1c(I)c(NC(=O)CC(O)(O)O)c(I)c(C(=O)O)c1I
Agent: O=C(O)c1cccc([N+](=O)[O-])c1NC(=O)C(CO)(CO)CO
Product: Nc1cc(NC(=O)CC(O)(O)O)cc(C(=O)O)c1

Procedure:
In the preparation of the 3-acetamido-2,4,6-triiodo-5-trishydroxymethylacetamido-benzoic acid of the invention, 3-nitro-trishydroxymethylacetamido-benzoic acid is reduced to form 3-amino-5-trishydroxymethylacetamido-benzoic acid. The latter is then iodinated to form 3-amino-2,4,6-triiodo-5-trishydroxymethylacetamidobenzoic acid, after which the 3-amino compound is acylated to form the desired 3-acetamido-2,4,6-triiodo-5-trishydroxymethylacetamido-benzoic acid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:9][C:10]([NH:13][C:14]2[CH:15]=[C:16]([NH2:29])[C:17]([C:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH:27]=3)=[CH:18][C:19]=2[O:20][CH3:21])=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH:27]=3)=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1C1=CCN(C)CC1
Reaction time: 3 h
Yield: 72.7 %

Procedure:
A solution of acryloyl chloride (0.026 mL, 0.32 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of N′-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,3-diamine (Intermediate 55, 150 mg, 0.32 mmol) and DIPEA (0.062 mL, 0.36 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 3 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (120 mg, 72%) as a yellow foam; 1H NMR: 2.28 (3H, s), 2.38 (2H, s), 2.54 (2H, t), 2.98 (2H, d), 3.81 (3H, s), 5.62-5.73 (2H, m), 6.14 (1H, dd), 6.43 (1H, dd), 6.88 (1H, s), 7.12 (1H, dt), 7.39-7.47 (1H, m), 7.83 (1H, s), 8.41-8.50 (2H, m), 8.63 (1H, s), 8.85 (1H, d), 8.95 (1H, s), 9.36 (1H, s); m/z: ES+ MH+ 516.25.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[O:3][CH2:2]1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([NH:22][CH2:21][C:20]3[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=3)[CH2:11][CH2:10]2)[O:3][CH2:2]1
Reactant: O=C1CCN(CCC2CCOCO2)CC1
Reactant: NCc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Fc1ccc(CNC2CCN(CCC3CCOCO3)CC2)cc1
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a solution of 128NLS50 (1.73 g, 8.13 mmol) in methanol (100 mL) was added dropwise 4-fluorobenzylamine (0.93 mL, 8.13 mmol) and acetic acid. Sodium cyanoborohydride (2.15 g, 40 mmol) was added slowly to the mixture at 0° C. and stirring was continued at rt overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane and 1M NaOH, the aqueous layer extracted twice with dichloromethane and the combined organic layers dried over Na2SO4, filtered and evaporated to dryness. Purification of the residue by a short silica gel column chromatography eluting with 0–30% methanol in dichloromethane gave the title compound (1.51 g, 58%) as a colourless solid.
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][C:18]2=[N:31][S:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33]>C1COCC1>[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][C:18]2([CH2:2][C:1]([O:4][CH3:5])=[O:3])[NH:31][S:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33]
Reactant: CC(C)(C)S(=O)N=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Reactant: COC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC1(NS(=O)C(C)(C)C)CC(c2ccccc2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
To a solution of methyl acetate (383 mg, 0.41 mL, 5.17 mmol) in anhydrous THF (10 mL) at −78° C. under N2 atmosphere is added 2 M LDA solution in THF (3.4 mL, 6.8 mmol) dropwise, and the solution is stirred another 30 min at the same temperature after the addition. To this mixture is added TiCl(OiPr)3 (1.681 g, 6.45 mmol) dropwise. The mixture is then stirred another 30 min at −78° C. To this mixture is added a solution of N-(6-bromo-2-phenylchroman-4-ylidene)-2-methylpropane-2-sulfinamide (1.050 g, 2.58 mmol) in anhydrous THF (10 mL) dropwise within 30 min. The reaction mixture is stirred another 3 h at −78° C. then quenched with sat. aq. NH4Cl. The mixture is stirred 10 min after being warmed to rt and filtered through a pad of Celite, and washed with EA (80 mL). The filtrate is transferred to separating funnel and the separated organic phase is washed with brine, and dried over anhydrous Na2SO4, filtered and concentrated, and the residue is purified through chromatography on silica gel to afford methyl 2-(6-bromo-4-(1,1-dimethylethylsulfinamido)-2-phenylchroman-4-yl)acetate 427 mg as an oil. MS ESI+ve m/z 480 (M+H)+.
Reaction SMILES: [Br-:1].[Li+].C1COCC1.Cl[CH2:9][C:10]1[CH:27]=[CH:26][C:13]2[N:14]([CH2:24][CH3:25])[C:15](=[O:23])[C:16]([CH3:22])([CH3:21])[C:17](=[O:20])[N:18]([CH3:19])[C:12]=2[CH:11]=1>O>[Br:1][CH2:9][C:10]1[CH:27]=[CH:26][C:13]2[N:14]([CH2:24][CH3:25])[C:15](=[O:23])[C:16]([CH3:22])([CH3:21])[C:17](=[O:20])[N:18]([CH3:19])[C:12]=2[CH:11]=1
Reactant: [Br-]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCl)ccc21
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CBr)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
Lithium bromide (0.678 g) was added to an THF solution (2.3 ml) of 7-chloromethyl-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (0.23 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with magnesium sulfate, and was condensed under reduced pressure to give the title compound (0.24 g) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CC(C)=O.O>[N:12]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[N+:13]=[N-:14]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a stirred solution of p-bromomethylbenzoic acid (13.607 g, 63.3 mmol) in acetone (300 ml) and H2O (15 ml) was added dropwise at room temperature a solution of NaN3 (4.123 g, 63.4 mmol) in H2O (40 ml). The reaction mixture was stirred at room temperature overnight(ca 20 h). After evaporation of the acetone, the residual solid was suspended in water and filtered, yielding 10.13 g (57.2 mmol, 90.3%) of p-azidomethylbenzoic acid as a white powder: 1Hmr (DMSO-d6 4.57 (2H, s, --CH3N3), 7.43-7.55-7.93-8.07 (4H, A2 'B2 ', aromatic Hs) and 12.7 ppm (br, s, --CO2H): ir (nujol) νmax : (--N3) and 1670 cm-1 (--CO2H).