Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH2:37][O:38][CH3:39])=[N:22][C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[N:24][C:25]=1[CH3:26]>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH2:37][O:38][CH3:39])=[N:22][C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[N:24][C:25]=2[CH3:26])=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: COCc1nc(-c2cccc(C(F)(F)F)c2)nc(C)c1CCl
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(C)nc(-c3cccc(C(F)(F)F)c3)nc2COC)cc1C

Procedure:
In analogy to the procedure described in example 113A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-methoxymethyl-6-methyl-2-(3-trifluoromethyl-phenyl)-pyrimidine (example 148D]) to give the title compound as light yellow viscous oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[O:22]([CH2:29][CH2:30][NH2:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[NH:31][CH2:30][CH2:29][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O-:14])=[O:13]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: NCCOc1ccccc1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCCOc3ccccc3)cc2c1=O
Yield: 52 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (20 mg, 0.0628 mmol) is reacted with 2-phenoxy-ethylamine according to the GPA affording 14 mg (52%) of a red powder. Rt=5.25 min.
Reaction SMILES: [H-].[Na+].C1COCC1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[C:22]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33]Cl)=[CH:27][CH:26]=3)=[O:24])=[C:21]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[S:20][C:19]=2[CH:41]=1>O>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[C:22]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)=[CH:27][CH:26]=3)=[O:24])=[C:21]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[S:20][C:19]=2[CH:41]=1
Reactant: C1CCNC1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCCl)cc3)c(C3CCCCC3)sc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCC4)cc3)c(C3CCCCC3)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
48 mg of sodium hydride was added to a THF solution of 0.2 ml of pyrrolidine, followed by stirring at room temperature for 1 hour. 54 mg of (6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-(2-chloroethoxy)phenyl]methanone was added, followed by reflux with heating for 10 hours. Water was added, the mixture was extracted with ethyl acetate, and the extract was purified by TLC (developing solvent, chloroform:methanol=9:1) to obtain 12 mg of (6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone.
Reaction SMILES: [F:1][CH:2]([F:44])[O:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:5]=1>C(O)(C(F)(F)F)=O.CS(C)=O>[F:44][CH:2]([F:1])[O:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[NH:6][N:5]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(OC(F)F)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(OC(F)F)c2cn1)c1ccccc1

Procedure:
A solution of (R)-1-(3-(difluoromethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (58.5 mg, 0.099 mmol) in TFA (2 mL) was stirred at room temperature for 2.5 h. The reaction mixture was diluted with DMSO (2 mL) and purified by mass-triggered reverse-phase HPLC. The fractions containing pure product were freebased with a PL-HCO3 cartridge and concentrated in vacuo to give (R)-1-(3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C16H15F2N5O2 [M+1]+ 348. found 348. 1H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.66 (s, 1H), 7.64 (m, 2H), 7.52 (t, J=7.3 Hz, 1H), 7.32 (m, 4H), 7.23 (m, 1H), 4.85 (m, 1H), 1.39 (d, J=7.0 Hz, 3H). Example 53 was prepared according to Scheme 3 method A following similar procedures described for Example 52, which can be achieved by those of ordinary skill in the art of organic synthesis.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]2[C:7](=[C:8](Br)[CH:9]=[C:10]([F:17])[CH:11]=2)[N:6]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:65][N:66]1[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]2[C:7](=[C:8]([N:69]3[CH2:70][CH2:71][N:66]([CH3:65])[CH2:67][CH2:68]3)[CH:9]=[C:10]([F:17])[CH:11]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OC)c2cc(F)cc(Br)c2n1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OC)c2cc(F)cc(N3CCN(C)CC3)c2n1
Temperature: 80 °C
Yield: 90 %

Procedure:
Into a 250 mL, 3 neck round bottom flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet is added 2.1 g (6.68 mmol, 1.0 equiv.) of 8-Bromo-6-fluoro-4-methoxy-quinoline-2-carboxylic acid methyl ester (Reference Example 29a) (122 mg, 0.134 mmol, 0.02 equiv.) of tris dibenzylidineacetone dipalladium, 499 mg (0.802 mmol, 0.12 equiv.) of racemic 2,2′-bis(diphenylphosphino)-1,1′-binapthyl and 1 g of 4 A molecular sieves and 80 mL of dry toluene. To the stirred suspension is then added 736 mg, 815 μL, (7.35 mmol, 1.1 equiv.) of 1-methylpiperazine, followed by 3.05 g (9.35 mmol, 1.4 equiv.) of cesium carbonate. The mixture is then heated to 80° C. for 36 hr. At the end of this time completion was monitored by LC/MS analysis of an aliquot. When the reaction was determined to be complete it was cooled to room temperature then filtered through a plug of celite, with toluene washing to remove solid by products. Purification by flash chromatography using a gradient of 5 to 20% methanol in methylene chloride as eluent yielded 2.0 g, (90%) of the desired product. Mass Spec.: calc. for [C17H20FN3O3+H]+ Theor. m/z=334; Obs.=334
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Cl.[F:12][C:13]([F:17])([F:16])[CH2:14][NH2:15].O>CN1CCCC1=O>[F:12][C:13]([F:17])([F:16])[CH2:14][NH:15][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: NCC(F)(F)F
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)c1ccc(NCC(F)(F)F)nc1
Temperature: 230 °C
Reaction time: 0.75 h
Yield: 34.9 %

Procedure:
A mixture of 1-(6-chloropyridin-3-yl)ethanone (1.0 g, 6.43 mmol) and 2,2,2-trifluoroethanamine hydrochloride (1.57 g, 11.8 mmol) in 1-methylpyrrolidin-2-one (10 mL) is stirred at 230° C. for 45 minutes under microwave irradiation. The reaction mixture is poured into water, extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (4:1 to 1:1) to give 490 mg (35% yield) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:13][S:14]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:16])=[O:15]
Reactant: CCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 500 cm3 round-bottomed flask, equipped with a magnetic stirrer and pressure equalising dropping funnel, was added butanol (55,6 g, 0.75 mol), triethylamine (55.7 g, 0.55 mol) and dichloromethane (300 cm3). Methanesulfonyl chloride (57.3 g, 0.05 mol) was then added dropwise over a two-hour period from the dropping funnel, with cooling from an ice bath. The mixture was stirred for a further 24 hours at room temperature. The reaction mixture was filtered, concentrated on a rotary evaporator, and distilled (bp −80−90° C. at 5 mm Hg). This gave 68.1 g (98%) of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14](Cl)[C:13]([F:17])=[CH:12][C:3]=1[C:4]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].[F-:18].[K+]>>[Cl:1][C:2]1[CH:15]=[C:14]([F:18])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5]
Reactant: O=C(OCC(F)(F)F)c1cc(F)c(Cl)cc1Cl
Reactant: [F-]
Agent: [K+]
Product: O=C(OCC(F)(F)F)c1cc(F)c(F)cc1Cl
Yield: 87.2 %

Procedure:
Into a 1 l glass reactor equipped with a condenser, 291 g (1 mol) of 2,2,2-trifluoroethyl 2,4-dichloro-5-fluorobenzoate, 87 g (1.5 mol) of spray dried potassium fluoride and 500 g of sulforane were charged and reacted at 180° C. for 9 hours under vigorous stirring. After cooling, the inorganic salt was removed by filtration, and the filtrate was distilled under reduced pressure to obtain 239.4 g (yield: 87.2%) of 2,2,2-trifluoroethyl 2-chloro-4,5-difluorobenzoate.
Reaction SMILES: CS([Cl:5])(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH:18]=[CH:19][CH2:20]O)[S:16][CH:17]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:5][CH2:20][CH:19]=[CH:18][C:15]1[S:16][CH:17]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)[N:14]=1
Reactant: OCC=Cc1nc(-c2ccc(F)cc2)cs1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2csc(C=CCCl)n2)cc1
Reaction time: 3 h
Yield: 98.5 %

Procedure:
258 μl (3.3 mmol) of methanesulfonyl chloride were slowly added to 265 mg (1.12 mmol) of 3-(4-(4-fluorophenyl)thiazol-2-yl)prop-2-en-1-ol and 456 mg (4.5 mmol) of triethylamine in 10 ml of dichloromethane at room temperature and the mixture was stirred for 3 h. After standing at room temperature over the weekend, the mixture was extracted with a sodium hydrogencarbonate solution. Evaporation of the organic phase yielded 280 mg of the title compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:11]([O:13][C:14]([C:16]1[C:17]([CH3:40])=[C:18]2[C:23](=[CH:24][C:25]=1[CH3:26])[N:22]=[C:21]([CH2:27][OH:28])[N:20]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36])[C:19]2=[O:39])=[O:15])[CH3:12]>N1C=CC=CC=1>[CH2:11]([O:13][C:14]([C:16]1[C:17]([CH3:40])=[C:18]2[C:23](=[CH:24][C:25]=1[CH3:26])[N:22]=[C:21]([CH2:27][O:28][C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])[N:20]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36])[C:19]2=[O:39])=[O:15])[CH3:12]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)c1c(C)cc2nc(CO)n(-c3ccccc3C(F)(F)F)c(=O)c2c1C
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)cc2nc(COC(=O)Oc3ccccc3)n(-c3ccccc3C(F)(F)F)c(=O)c2c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
Phenyl chloroformate (470 mg) was added to a solution of 420 mg of 6-ethoxycarbonyl-2-hydroxymethyl-5,7-dimethyl-3-[2-(trifluoromethyl)phenyl]-4(3H)-quinazolinone in 5 ml of pyridine. The reaction mixture was stirred at 80° C. for 3 hours, and the solvent was then evaporated off in vacuo. The residue was taken up with ethyl acetate, and the solution was washed successively with 1N aqueous hydrochloric acid and water, and dried over anhydrous sodium sulfate. The ethyl acetate was evaporated off to give 400 mg of crude 6-ethoxycarbonyl-5,7-dimethyl-2-(phenoxycarbonyloxymethyl)-3-[2-(trifluoromethyl)phenyl]-4(3H)-quinazolinone.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:21](=[O:24])[CH2:22][CH3:23])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCC(=O)Cl
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(=O)Nc1nc(-c2cc(C)cc(C)c2)c(-c2ccncc2)s1
Temperature: 80 °C
Reaction time: 14 h
Yield: 67.5 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.51 g, 1.8 mmol) and 4-dimethylaminopyridine (0.06 g, 0.52 mmol) in N,N-dimethylacetamide (20 mL) was added propionyl chloride (0.18 g, 1.96 mmol) and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.41 g, yield 67%).
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:11][CH2:12][CH3:13])C=CC=CC=1.[CH3:30][O:31][C:32]([CH3:40])([CH3:39])[CH2:33][CH2:34][CH2:35][C:36](=O)[CH3:37].O>CN(C)C=O>[CH2:16]1[CH2:15][O:14][C:10]([CH2:11][CH2:12][CH:13]=[C:36]([CH3:37])[CH2:35][CH2:34][CH2:33][C:32]([O:31][CH3:30])([CH3:40])[CH3:39])([CH3:9])[O:17]1
Reactant: COC(C)(C)CCCC(C)=O
Reactant: CCCC1(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)OCCO1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)(C)CCCC(C)=CCCC1(C)OCCO1
Temperature: 0 °C
Reaction time: 4 h
Yield: 42 %

Procedure:
8.15 g of potassium tert.-butylate were added to a solution of 38 g of triphenyl 2,2-ethylenedioxy-pentyl phosphonium bromide in 400 ml of dimethylformamide cooled to 0° C. and then 12.75 g of 6-methoxy-6-methyl-2-heptanone were added. The mixture was stirred for 4 hours at 0° C. and was then poured into water. The mixture was extracted with petroleum ether (b.p.= 40°-75° C.) and the extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The yellow oil was chromatographed over silica and was eluted with a 8-2 benzene-ethyl acetate mixture to obtain 9.15 g of 2,2-ethylenedioxy-10-methoxy-6,10-dimethyl-5-undecene in the form of a colorless oil which was a mixture of the E and Z isomers with respect to the double bond in the 5-position. A supplementary chromatography under pressure and elution with a 9-1 benzene-ethyl acetate mixture gave a separation of the E and Z isomers.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:6](C(OC)=O)[C:5](=[O:11])[C:4](=[O:12])[N:3]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(O)=O.O>[CH3:1][C:2]1([CH3:20])[N:3]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:4](=[O:12])[C:5](=[O:11])[CH2:6]1
Reactant: COC(=O)C1C(=O)C(=O)N(Cc2ccccc2)C1(C)C
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CC(=O)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.8 %

Procedure:
A solution of methyl 2,2-dimethyl-4,5-dioxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate (5.6429 g, 20.50 mmol) in 10:1 HOAc-water (100 mL) was heated at 100° C. and stirred for 2 days. The solution was cooled to room temperature and concentrated in vacuo. The residue was partitioned between DCM (200 mL) and sat. aq. NaHCO3 (100 mL). The aqueous phase was extracted with a fresh portion of DCM (50 mL), and the combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give crude 5,5-dimethyl-1-(phenylmethyl)-2,3-pyrrolidinedione (3.9096 g, 88% crude yield) as a light orange solid. LCMS: (M+H)+: 218.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:26])=[C:4]([C:18]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[O:19])[C:5]([I:17])=[C:6]([C:15]=1[I:16])[C:7]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[O:8].[Cl:27][CH2:28][C:29](Cl)=[O:30]>CN(C)C(=O)C.C(#N)C>[Cl:27][CH2:28][C:29]([O:25][CH:22]([CH2:23][O:24][C:29](=[O:30])[CH2:28][Cl:27])[CH2:21][NH:20][C:18](=[O:19])[C:4]1[C:3]([I:26])=[C:2]([NH:1][C:29](=[O:30])[CH2:28][Cl:27])[C:15]([I:16])=[C:6]([C:7]([NH:9][CH2:10][CH:11]([O:14][C:29](=[O:30])[CH2:28][Cl:27])[CH2:12][O:13][C:29](=[O:30])[CH2:28][Cl:27])=[O:8])[C:5]=1[I:17])=[O:30]
Reactant: O=C(Cl)CCl
Reactant: Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: O=C(CCl)Nc1c(I)c(C(=O)NCC(COC(=O)CCl)OC(=O)CCl)c(I)c(C(=O)NCC(COC(=O)CCl)OC(=O)CCl)c1I

Procedure:
reacting 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisopthalamide with chloroacetyl chloride in N,N-dimethylacetamide and acetonitrile, to produce N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide;
Reaction SMILES: OC([C:5]1[C:6]([CH3:15])=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][NH:9][C:8]2=[O:14])(C)C.C1C[O:19]CC1.OO.CS(O)(=O)=O>O>[OH:19][C:5]1[C:6]([CH3:15])=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][NH:9][C:8]2=[O:14]
Reactant: C1CCOC1
Reactant: Cc1c(C(C)(C)O)cn2nc[nH]c(=O)c12
Agent: CS(=O)(=O)O
Agent: OO
Solvent: O
Product: Cc1c(O)cn2nc[nH]c(=O)c12
Temperature: -2 °C
Reaction time: 1.58 h
Yield: 75.9 %

Procedure:
A one liter, 3-neck, round bottom flask as equipped with mechanical stirrer and a cooling bath of ice/acetone. To this was charged 20 g of 6-(1-hydroxy-1-methyl-ethyl)-5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one, 235 mL of THF and 47 mL 50% aqueous hydrogen peroxide. An exotherm from −7° C. to 7.3° C. was observed and the mixture became a solution. To this was added a pre-cooled solution of 28.5 mL water and 63 mL methanesulfonic acid over 40 min, keeping the temperature between −5° C. and −0.7° C. The solution was stirred at −2° C. for 95 min until HPLC indicated reaction was complete; reaction mixture was quenched, while keeping it at −2° C., by adding it portion wise to a cooled solution of 28.5 mL water, 89 g NaHSO3 and 128 mL 28% aqueous ammonium hydroxide over 40 min, at 15° C. to 25° C. The mixture was stirred at room temperature for 20 min; pH was 6.80 and a peroxide test was negative. The layers were separated and the aqueous layer was extracted with 100 mL THF. The two organic layers were combined and concentrated, removing 280 mL solvent. To the thick slurry was added 250 mL water and the concentration continued until 88 mL of solvent was removed. The slurry was filtered and the cake was washed with 25 mL water twice and then 25 mL acetonitrile. It was dried by suction on the filter to constant weight to yield 12.51 g of 6-hydroxy-5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one, 75.9% yield, 96.5% purity.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([NH:11][C:12](=[O:22])[NH:13][C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:6]([O:8]CC)=O)C.[OH-].[Li+:32]>O1CCCC1.CO>[CH2:23]([C:5]1([C:4]([O-:3])=[O:30])[C:6](=[O:8])[N:13]([C@@H:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])[C:12](=[O:22])[NH:11]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1.[Li+:32]
Reactant: CCOC(=O)C(Cc1ccccc1)(NC(=O)N[C@H](C)c1ccccc1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C(=O)NC(Cc2ccccc2)(C(=O)[O-])C1=O
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step C (7.8 g, 18.91 mmol) in tetrahydrofuran (60 mL) and methanol (20.00 mL) was added a 1 M lithium hydroxide solution (19.86 mL, 19.86 mmol) and the mixture stirred for 30 min. The solvent was removed in vacuo and the residue azeotroped with toluene (3×25 mL) to afford the title compound as a colorless amorphous solid. LC/MS 339.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:19]([O:18][C@H:15]1[CH2:16][CH2:17][C@@H:12]([C:10](=[O:11])[NH:9][CH2:8][C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:14]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NCc1nccnc1Cl)[C@H]1CC[C@@H](O)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@H](C(=O)NCc2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To (cis)-N-((3-chloropyrazin-2-yl)methyl)-4-hydroxycyclohexanecarboxamide (57.4 mmol, 15.47 g) and 4-dimethylaminopyridine (5.74 mmol, 0.701 g) in pyridine (125 ml) at 0° C. was added dropwise acetic anhydride (60.2 mmol, 5.69 ml) and the mixture was stirred at room temperature for one hour. Then the reaction was quenched with 4 N hydrochloric acid to a pH of four and extracted with ethyl acetate three times. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was taken up in toluene and concentrated in vacuo again. The residue was dissolved in dichloromethane (100 ml) and washed with 1 M hydrochloric acid (100 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give (cis)-4-((3-chloropyrazin-2-yl)methylcarbamoyl)cyclohexyl acetate (16.5 g)
Reaction SMILES: [F:1][CH:2]([N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[I-].[CH3:15][S+](C)(C)=O.O1CCCC1>CS(C)=O>[C:4]([C:3]1([CH:2]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)[F:1])[CH2:15][O:8]1)([CH3:7])([CH3:5])[CH3:6]
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)C(=O)C(F)n1cncn1
Agent: [I-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)C1(C(F)n2cncn2)CO1
Temperature: 60 °C
Reaction time: 6 h
Yield: 32.1 %

Procedure:
A mixture of 20 g of 1-fluoro-1-(1H-1,2,4-triazol-1-yl)-3,3-dimethyl-2-butanone, 13.5 g of potassium tertiary butylate, 24.0 g of trimethylsulfoxonium iodide, 80 ml of tetrahydrofuran and 20 ml of dimethyl sulfoxide is stirred at 60° C. for 6 hours. The reaction mixture is then taken up in ice water and extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Crystallisation from petroleum ether gives 6.9 g of 2-tert.-butyl-2-[(1H-1,2,4-triazol-1-yl)-fluoromethyl]-oxirane, melting point 72°-74° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18]>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: Oc1ccccc1F
Product: O=[N+]([O-])c1cc(Br)ccc1Oc1ccccc1F

Procedure:
2-Fluorophenol and 2,5-dibromo-1-nitrobenzene were reacted together under Ullmann conditions to give 1-bromo-4-(2-fluorophenoxy)-3-nitrobenzene which was reduced and deaminated to give the desired product b.p. 112°-116°C./0.8mm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)=[CH:23][CH:22]=1)[C:10]([O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:37]1C=CC(I)=C(C)C=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)=[CH:23][C:22]=1[CH3:37])[C:10]([O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Br)ccc1I
Reactant: CC(C)(C)OC(=O)N[C@@H](C/C=C/c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC1CCCC1
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1/C=C/C[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCC1

Procedure:
Synthesised by analogous methods to Intermediate 5a, using 4-bromo-2-methyl-iodobenzene at Stage 2 of Scheme 4. m/z 500 [M+H]+.