Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]>O>[C@H:2]([OH:3])([C:1]([OH:10])=[O:9])[C@H:4]([OH:5])[C:6]([OH:8])=[O:7].[C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O
Product: O=C(O)C(O)C(O)C(=O)O
Product: O=C(O)[C@@H](O)[C@@H](O)C(=O)O

Procedure:
To 40.126 kg of the reaction product of Example 4a, 15.241 kg of demineralized water and 3.00 kg of L-tartaric acid were added to get a clear solution with a meso-tartaric acid content of 66% of the total amount of tartaric acid. To 99.98 g of this mixture, 49.55 g of a 40 wt % FeCl3-solution in water were added. Using 16.6 g of a 50 wt % of sodium hydroxide solution in water, the pH was set to 4.35. Finally, 1163.6 g of demineralized water were added to obtain the desired final iron concentration.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][CH2:21][CH2:22][C:23]1[O:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:28]([C:26]3[N:27]=[C:23]([CH2:22][CH2:21][O:20][CH3:19])[O:24][C:25]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:29])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COCCc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: COCCc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-(2-methoxy-ethyl)-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=O)[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][O:32][CH2:33][C:34]1[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=1>CO>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:31][O:32][CH2:33][C:34]2[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=2)[C:27]([OH:29])=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cn1cncc1CON
Reactant: O=C(O)C(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CO
Product: Cn1cncc1CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
17.4 g of (2-tritylaminothiazol-4-yl)glyoxylic acid was dissolved in 500 ml of methanol under heating and the mixture was cooled to room temperature. A mixture of 100 ml of methanol and 5.5 g of 5-aminooxymethyl-1-methylimidazole was added to the mixture and then the resulting mixture was stirred overnight at room temperature. The precipitate formed was collected by filtration and washed with methanol to give 14.9 g of 2-(2-tritylaminothiazol-4-yl)-2-((1-methylimidazol-5-yl)methoxyimino)acetic acid with mp 231°-232° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]([CH2:12][CH3:13])[CH:4]=[C:5](OCC)[O:6]CC.C([O-])(=O)C.[NH4+:20].C(O)C.C(O)(=O)C>C(OC(=O)C)C>[OH:6][C:5]1[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:12]=[CH:13][N:20]=1
Reactant: CCOC(=CC(CC)C(F)(F)F)OCC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1cc(C(F)(F)F)ccn1

Procedure:
103.5 g (0.35 mol) 3-trifluoromethyl-diethoxypentene acid ethyl ester (mixture of isomers, amount based on GC area-%) and 51.3 g (0.665 mol) ammonium acetate were heated to 150-155° C. over 8 h. A mixture of ethanol, acetic acid and acetic acid ethyl ester (ca. 60 g) was distilled off through a small column (20 cm, filled with 3 mm rings) during this heating period. The sump (79.8 g) can directly be transferred to the next step (yield has been determined only after final methoxylation step).
Reaction SMILES: [C:1]([O:9]C(=O)C1C=CC=CC=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:18].[OH:19][C@H:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:21][C:22]([OH:24])=O.[OH-].[Na+]>C1COCC1>[C:1]([O:19][C@H:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:21][C:22]([Cl:18])=[O:24])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)O
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@H](CC(=O)Cl)OC(=O)c1ccccc1
Yield: 95 %

Procedure:
To a 20 L 3-neck round bottom flask equipped with a mechanical stirrer, nitrogen inlet, reflux condenser, heating mantle, vacuum system, and scrubber system for efficient removal of HCl and SO2 gases liberated during the reaction, is charged under nitrogen 15 moles of benzoic acid anhydride, 10 moles of concentrated anhydrous HCl in 4 L of THF, and 7.48 moles of the (3R)-3-hydroxy-tetradecanoic acid obtained from Example 1, above. The stirred mixture is placed under a N2 flow, which is vented to the scrubber system. The stirred mixture is heated to reflux for 3 hours during which the reaction becomes complete. The resulting solution is neutralized with 1N NaOH and the organic layer is separated from the aqueous layer. The aqueous layer is washed with THF and the resulting organic portions are combined, placed under vacuum and THF is removed. The resulting solid is dissolved in warm hexane, cooled and worked up to provide the product (3R)-3-benzoyloxy-tetradecanoyl chloride in about 95% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[S:15][CH:16]=[C:17]([C:19]#[N:20])[N:18]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[S:15][C:16]([Br:22])=[C:17]([C:19]#[N:20])[N:18]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2nc(C#N)cs2)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2nc(C#N)c(Br)s2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [(R)-1-(4-cyano-thiazol-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester (13.0 g, 42.2 mmol) in N,N-dimethylformamide (250 mL) was added N-bromosuccinimide (8.25 g, 46. mmol) and the mixture was stirred under argon at ambient temperature for 30 minutes. Analysis by thin layer chromatography (silica stationary phase eluted with 25% v/v ethyl acetate in hexanes) indicated clean conversion of [(R)-1-(4-cyano-thiazol-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester in to a slightly less polar compound. The reaction mixture was poured into water (1 L) and extracted with ethyl acetate (3×250 mL), the combined organic extracts were washed with brine (2×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give an off-white solid. The crude product was triturated with 1:1 v/v diethyl ether/petroleum ether (300 mL total volume). [(R)-1-(5-Bromo-4-cyano-thiazol-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester was obtained as a colorless solid by filtration, washing with 1:2 v/v diethyl ether/petroleum ether and drying by passage of air (14.33 g, 88%). An additional amount of [(R)-1-(5-bromo-4-cyano-thiazol-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester was obtained by purification of the residue obtained from concentration of the mother liquors by chromatography using a silica gel column gradient eluted from 5% up to 40% v/v ethyl acetate in hexanes. The product containing fractions were combined and concentrated in vacuo to obtain additional [(R)-1-(5-bromo-4-cyano-thiazol-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester as a colorless solid (1.18 g, 7%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19](O)=[O:20])=[C:9]1[CH:22]([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:33][NH2:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19]([NH:34][CH2:33][C:32]2[CH:35]=[CH:36][C:37]([F:38])=[C:30]([F:29])[CH:31]=2)=[O:20])=[C:9]1[CH:22]([CH3:23])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccc3)c2c1
Reactant: NCc1ccc(F)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-benzyl-2-isopropyl-6-methoxy-1H-indole-3-carboxylic acid (Compound 6, 226 mg, 0.70 mmol) in CH2Cl2 (7.0 ml) was added EDC (202 mg, 1.05 mmol) and DMAP (128 mg, 1.05 mmol) followed by 3,4-difluorobenzylamine (0.25 ml, 2.1 mmol). The reaction was stirred at room temperature for 18 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.CN(C)C=O.C(#N)C.[C:15]([N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].N1[CH:38]=[CH:37][CH:36]=CC=1>C(O)(C)(C)C>[C:37]([O:28][C:27](=[O:29])[C@@H:26]1[CH2:30][CH2:31][CH2:32][N:25]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])([CH3:36])([CH3:38])[CH3:1]
Reactant: c1ccncc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CC#N
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
126.9 (1 mol) of oxalyl chloride is added dropwise over 15 minutes to a stirred mixture of 200 ml absolute dimethylformamide and 500 ml absolute acetonitrile cooled to -20°. The solution is stirred for a further 15 minutes at -20° and then 249 g (1 mol) N-carbobenzoxy-L-proline is added. After 15 minutes of stirring, the mixture is treated dropwise with a mixture of 250 ml of absolute tert.-butanol and 200 ml absolute pyridine at such a rate that the temperature of the mixture does not rise above -15°. Cooling of the mixture is then stopped, and the mixture is maintained at room temperature for 3 hours. The mixture is worked up by partitioning between 2N sodium carbonate solution and methylene chloride and obtaining the heading compound from the methylene chloride phase as an oil nD23 = 1.5015 which slowly crystallizes out.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:10][C:11]([CH:17]=O)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([O:34][C:35]([NH:37][CH:38](P(OC)(OC)=O)[C:39]([O:41][CH3:42])=[O:40])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C)C(=N)N(C)C>C1COCC1.C(OCC)(=O)C>[CH2:27]([O:34][C:35]([NH:37]/[C:38](=[CH:17]\[C:11]1[N:10]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1)/[C:39]([O:41][CH3:42])=[O:40])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: O=Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To a solution of 5-phenyl-4-(pyridin-2-ylmethylamino)quinazoline-2-carbaldehyde (0.9 g, 3 mmol) in THF (10 mL) was added methyl 2-benzyloxycarbonylamino-2(dimethoxyphosphinyl)acetate (0.96 g, 2.9 mmol) followed by tetramethyguanidine (0.66 mL. 5.3 mmol). The resulting solution was stirred at RT for 3 h. After this time, the reaction mixture was diluted with ethyl acetate, washed successively with water and brine, dried over Na2SO4, filtered then and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (30% ethyl acetate in hexane) to yield (Z)-methyl 2-(benzyloxycarbonylamino)-3-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)acrylate (0.7 g (48% yield). LCMS Method V: retention time 1.94 min; [M+1]=546.0.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)=[O:39]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)=[O:39])=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: NCC(=O)Nc1ccccn1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCC(=O)Nc2ccccn2)cc1
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
4-geranyloxybenzoic acid(1.81 g) was dissolved in chloroform(40 ml) and triethylamine(1.84 ml), and then diphenylphosphinic chloride(1.26 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 2-(aminoacetylamino)pyridine(1.00 g) added thereto, was stirred for 2 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 1.84 g of the aimed compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:27][CH3:28])[C:25]=1[OH:26])[C:20](O)=[O:21].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:20](=[O:21])[C:19]3[CH:23]=[C:24]([O:27][CH3:28])[C:25]([OH:26])=[C:17]([OH:16])[CH:18]=3)[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: COc1cc(C(=O)O)cc(O)c1O
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)Nc2cnn(Cc3c(C)noc3C)c2)cc(O)c1O
Reaction time: 0.08 h

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (example 4-1a) (228 mg, 1 mmol), 3,4-dihydroxy-5-methoxybenzoic acid (184 mg, 1 mmol), HOBt (135 mg, 1 mmol), and EDC (191 mg, 1 mmol) were dissolved in 2 mL DMF in a microwave vial followed by the addition of triethylamine (101 mg, 1 mmol). The reaction was placed in a microwave reactor at 165° C. for 5 minutes. The crude product was purified directly using Varian HPLC (10%-95% ACN in H2O: 25 minute gradient). The pure fractions were combined and concentrated to afford N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-3,4-dihydroxy-5-methoxybenzamide. (280 mg, 70%). LC/MS; [M+H] calculated for C17H18N4O5; expected 359.1; found 359.1.
Reaction SMILES: [CH3:1][O-].[Na+].[C:4]([O:8]CC)(=O)[CH2:5][CH3:6].C(OC)=O.Cl.[NH2:16][C:17]([NH2:19])=[NH:18].Cl>CN(C=O)C.CO>[CH3:1][C:5]1[C:4](=[O:8])[NH:16][C:17]([NH2:19])=[N:18][CH:6]=1
Reactant: C[O-]
Reactant: N=C(N)N
Reactant: CCOC(=O)CC
Agent: Cl
Agent: [Na+]
Solvent: COC=O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cnc(N)[nH]c1=O
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
Freshly prepared sodium methoxide (10.8 g, 200 mmol) was suspended in a solution of ethyl propionate (15.3 g, 150 mmol) in DMF (20 mL) at room temperature. Methyl formate (6.0 g, 100 mmol) was added over a period of 1 hour. After stirring for 30 minutes, a solution of guanidine hydrochloride (9.6 g g, 100 mmol) in MeOH (35 mL) was added rapidly and the reaction mixture was refluxed for 12 hours. After cooling to 30° C. and adjusting the pH to 6.0 with concentrated hydrochloric acid, the slurry was kept at 5° C. for 30 minutes. The solid was collected, washed with methanol, crystallized from water and dried in vacuo to give 5-methylisocytosine (7.3 g, 58.4% yield). 1H NMR (300 MHz, DMSO): δ 10.83 (br s, 2H), 7.38 (s, 1H), 6.26 (br s, 2H), 1.72 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]([NH2:18])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20](=O)[C:21](=O)[CH3:22].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28](S(O)(=O)=O)=[CH:27][CH:26]=1>CN(C=O)C>[C:12]1([C:9]2[N:8]([N:18]=[C:20]([C:21](=[N:18][N:8]3[C:35]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:10][CH:11]=[C:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:22])[CH3:19])[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][CH:10]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)C(C)=O
Reactant: Nn1c(-c2ccccc2)ccc1-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CC(=Nn1c(-c2ccccc2)ccc1-c1ccccc1)C(C)=Nn1c(-c2ccccc2)ccc1-c1ccccc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A suspension of 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one (2.45 g, 8.1 mmol) in toluene (28 mL) was treated with DMF (14 mL), 2,5-diphenyl-pyrrol-1-ylamine (1.99 g, 8.5 mmol) and p-toluene sulfonic acid (73 mg). The resulting suspension was fitted with a Dean Stark trap and heated to reflux in an oil bath for 21 h, then cooled to rt and allowed to stand under Ar for 4 days. The desired compound did not crystallize, therefore the solution was concentrated in vacuo. Approximately half of the residue was purified by flash chromatography (SiO2, 5-100% EtOAc/heptane) to afford some pure desired 2,3-bis(2,5-Diphenyl-pyrrol-1-ylimino)-butane (780 mg) and some desired contaminated with starting 2,5-diphenyl-pyrrol-1-ylamine. The remaining crude residue was flash chromatographed (SiO2, 33-50% CH2Cl2/heptane) in an attempt to remove excess amino pyrrole. No separation was achieved, therefore all of the fractions were combined, together with the impure material from the first column and concentrated in vacuo. This mixture was suspended in toluene (15 mL) and treated with DMF (5 mL), 2,3-butanedione (0.81 mL, 9.24 mmol) and p-toluene sulfonic acid (7 mg). The resulting suspension was heated to 70° C. in an oil bath, and stirred under Ar for 3 h, then cooled to rt and concentrated in vacuo. The resulting solid was washed with water, heptane and toluene (to remove 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one and 2,3-butanedione) and dried in vacuo to afford 2,3-bis(2,5-Diphenyl-pyrrol-1-ylimino)-butane (1.42 g) as a yellow solid. Overall, 2.2 g (52% based on 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one) of 2,3-bis(2,5-Diphenyl-pyrrol-1-ylimino)-butane was isolated as a yellow solid: 1H NMR (CDCl3, chemical shifts in ppm relative to TMS): 1.71 (s, 6H), 6.44 (s, 4H), 7.22-7.36 (m, 20H).
Reaction SMILES: [Na+].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([S:22]([OH:25])(=[O:24])=[O:23])[CH:7]=[C:8]2[C:13]=1[C:12]([S:14]([O-:17])(=[O:16])=[O:15])=[CH:11][C:10]([S:18]([O-:21])(=[O:20])=[O:19])=[CH:9]2>O.[OH-].[Na+]>[NH2:3][C:4]1[CH:5]=[C:6]([S:22]([OH:25])(=[O:24])=[O:23])[CH:7]=[C:8]2[C:13]=1[C:12]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:11][C:10]([S:18]([OH:21])(=[O:19])=[O:20])=[CH:9]2
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A solution of 51.2 g of 8-amino-1,3,6-naphthalenetrisulfonic acid disodium salt in a mixture of 120 ml of water and 21.0 ml of 5 N sodium hydroxide was warmed and then filtered. The filtrate was slowly diluted with 400 ml of ethanol. The mixture was cooled to room temperature and the solid was collected by filtration, washed with ethanol, then ether and dried at 110° C. overnight giving 46.0 g of 8-amino-1,3,6-naphthalenetrisulfonic acid, trisodium salt.
Reaction SMILES: C([O:8][C:9](=[O:39])[CH2:10][C@@H:11]([N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)=[CH:23]1)[C:12]([NH:14][C@@H:15]([CH2:20][OH:21])[C:16]([OH:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CCO.CCOC(C)=O>[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:29]=[CH:28][C:27]([C:24]2[CH:25]=[CH:26][N:22]([C@@H:11]([C:12]([NH:14][C@@H:15]([CH2:20][OH:21])[C:16]([OH:19])([CH3:17])[CH3:18])=[O:13])[CH2:10][C:9]([OH:39])=[O:8])[CH:23]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(O)[C@H](CO)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(O)[C@H](CO)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 1.83 h
Yield: 74.9 %

Procedure:
According to the procedure described in Example 1(a), a mixture of 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1(S)-(hydroxymethyl)-2-methylpropyl]succinamic acid benzyl ester (137 mg, 0.26 mmol) in EtOH (2.5 mL) and EtOAc (2.5 mL) was hydrogenolyzed after 110 minutes to give a white solid, which was triturated with CH2Cl2/hex to provide 85 mg (75%) of 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1(S)-(hydroxymethyl)-2-methylpropyl]succinamic acid as a white solid, mp 150-2° C.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[C:16]([CH:23]=[CH2:24])[N:15]=3)=[CH:10][CH:9]=2)=[CH:5][C:4]=1[C:27]([F:30])([F:29])[F:28])#[N:2].[C:31](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([O:22][CH3:31])=[O:21])[CH:17]=[C:16]([CH:23]=[CH2:24])[N:15]=3)=[CH:10][CH:9]=2)=[CH:5][C:4]=1[C:27]([F:30])([F:29])[F:28])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: C=Cc1cc(C(=O)O)nc(-c2ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)cc2)n1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cc(C(=O)OC)nc(-c2ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 50-mL vial with a screw-top septum 2-(4-(4-cyano-3-(trifluoromethyl) phenoxy)phenyl)-6-vinylpyrimidine-4-carboxylic acid (340 mg, 0.83 mmol) was dissolved in DMF (5 mL) and treated with potassium carbonate (343.6 mg, 2.49 mmol) and iodomethane (0.5 mL). The mixture was stirred at room temperature for three hours, diluted with 100 mL water, and extracted with 2×50 mL diethyl ether. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to provide methyl 2-(4-(4-cyano-3-(trifluoromethyl) phenoxy)phenyl)-6-vinylpyrimidine-4-carboxylate. The residue was used in the next step without purification. LC/MS: m/z=426 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C(=O)(O)[O-].[Na+].[NH2:15][C:16]1[C:21]([C:22]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])=[O:23])=[CH:20][N:19]=[C:18](S(CC)(=O)=O)[N:17]=1.O>CN(C)C=O>[NH2:15][C:16]1[C:21]([C:22]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])=[O:23])=[CH:20][N:19]=[C:18]([NH:2][CH:3]2[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]2)[N:17]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2cc(F)ccc2OC)c(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCC(O)CC2)nc1N
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a stirred solution of trans-4-amino-cyclohexanol hydrochloride (108 mg, 0.71 mmol, Aldrich) in dimethylformamide, were added sodium bicarbonate(98 mg, 0.92 mmol) and (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (201 mg, 0.59 mmol, Example 48) and the mixture was stirred at 90° C. for 1 hour. The mixture was poured into water and extracted with ethyl acetate. The extracts were dried with sodium sulfate and concentrated. The residue was chromatographed (2.5% methanol in dichloromethane) to give a white solid. 172 mg, 81%. MS(ES) (M+H)+=361.