Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([OH:14])[CH:8]=1)[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH2:20]=O>O>[OH:14][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[OH:13])[CH2:20][NH:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:6]2
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)[C@@H]1Cc2cc(O)c(O)cc2CN1
Reaction time: 8 h

Procedure:
(S)-2-Amino-3-(3,4-dihydroxy-phenyl)-propionic acid (90 g) was suspended in 0.8 L water, then 18.2 mL concentrated sulfuric acid in 0.5 L additional water was added with stirring. Formaldehyde solution (136 mL, 37 wt %) was then added while stirring and the mixture was stirred 18 hours at rt. It was quenched by addition of 24.4 g NaOH in 0.5 L water, dropwise over 1 h while cooling. The resulting mixture was stored overnight at 4° C., and the solid that formed was collected by filtration, washed with hot water (70° C.), cooled again and collected by filtration. The solid was treated with 0.5 L MeOH and evaporated, then stored under vacuum overnight to give 65 g desired product. 1H NMR (400 MHz, MeOH-d4): 6.64 (s, 1H), 6.59 (s, 1H), 4.29-4.21 (m, 3H), 3.29-3.21 (m, 1H), 3.11-3.01 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=O)[CH:5]=[CH:6][CH:7]=1.C[O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1>>[CH2:19]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:37][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][C:29]([OH:39])=[O:28])=[CH:36][CH:35]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cccc2c(-c3cccc(N)c3)c(C(=O)c3ccccc3)cnc12
Reactant: COC(=O)Cc1ccc(C=O)cc1
Product: Cc1cccc2c(-c3cccc(NCc4ccc(CC(=O)O)cc4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-methyl-quinolin-3-yl]-phenyl-methanone and (4-formyl-phenyl)-acetic acid methyl ester according to the procedure of Example 66. MS (ES) m/z 473.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[N:3]=1
Reactant: Cc1cccc(Cl)n1
Reactant: C1CCNCC1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(CN2CCCCC2)n1
Yield: 41 %

Procedure:
To 2-chloro-6-methylpyridine (50.0 g, 0.392 mole) in 393 mL of carbon tetrachloride was added N-bromosuccinimide (87.2 g, 0.49 mole) and 1.0 g of benzoyl peroxide. The mixture was stirred at reflux for 22 hours, cooled to 10° and filtered. The chilled filtrate then was treated slowly with piperidine (83.5 g, 0.98 mole) and allowed to stir at ambient temperature for 18 hours. After removal of the piperidine hydrobromide by filtration, the filtrate was concentrated to about half volume and extracted with 6N HCl (65 mL) and 3N HCl (40 mL). The acid extracts were made basic with 40% sodium hydroxide and the product was extracted into methylene chloride. The solvent was evaporated and the residue distilled to yield 41% of the title compound as a colorless oil, b.p. 101°-103°/0.45 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[C:27]1[N:36]=[C:35]2[C:30]([C:31](=[O:43])[C:32]([C:40]([OH:42])=[O:41])=[CH:33][N:34]2[CH:37]2[CH2:39][CH2:38]2)=[CH:29][C:28]=1[F:44].C[Si](C)(C)Cl.C(N(CC)CC)C>CS(C)=O>[C:22]([NH:21][CH2:20][C@@H:18]1[O:17][C:16](=[O:25])[N:15]([C:4]2[CH:5]=[CH:6][C:7]([NH:8][CH:9]3[CH2:14][CH2:13][N:12]([C:27]4[N:36]=[C:35]5[C:30]([C:31](=[O:43])[C:32]([C:40]([OH:42])=[O:41])=[CH:33][N:34]5[CH:37]5[CH2:39][CH2:38]5)=[CH:29][C:28]=4[F:44])[CH2:11][CH2:10]3)=[C:2]([F:1])[CH:3]=2)[CH2:19]1)(=[O:24])[CH3:23]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(NC3CCNCC3)c(F)c2)C(=O)O1
Agent: C[Si](C)(C)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(NC3CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1
Temperature: 150 °C
Reaction time: 0.12 h

Procedure:
A suspension of 100 mg N-{(5S)-3-[3-fluoro-4-(piperidin 4-ylamino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}acetamide (0.28 mmol), 80.66 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.28 mmol), 0.108 ml trimethylchlorosilane (0.84 mmol) and 0.16 ml triethylamine (1.12 mmol) in 2 ml DMSO was heated under stirring in a micro wave oven at 150° C. for 7 min. The DMSO was evaporated, the residue was purified by chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[C:12](Cl)([Cl:14])=[O:13]>C(Cl)(Cl)Cl>[Cl:14][C:12]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])=[O:13]
Reactant: O=C(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1CO
Solvent: ClC(Cl)Cl
Product: O=C(Cl)OCc1ccccc1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
15.3 g. (0.1 mole) of o-nitrobenzyl alcohol is dissolved in 200 ml. of chloroform in a glass bomb tube. The tube is cooled in an ice bath and phosgene is introduced until 20 g. has been condensed. The tube is sealed and heated at 65° C. for 4 hours. The solvent and excess reagent are then removed by distillation and the product, o-nitrobenzyl chloroformate, is obtained as a yellow oil.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([CH:42]=[CH:43][C:44]=1[CH3:45])[CH2:7][O:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]1)=[O:3].[CH3:46][O:47][CH2:48][CH2:49][NH2:50]>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][O:25][CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:14]2[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][CH:9]2[O:8][CH2:7][C:6]2[CH:42]=[CH:43][C:44]([CH3:45])=[C:4]([C:2](=[O:3])[NH:50][CH2:49][CH2:48][O:47][CH3:46])[CH:5]=2)=[CH:16][CH:17]=1
Reactant: COCCN
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)c(C(=O)Cl)c2)cc1
Product: COCCNC(=O)c1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C

Procedure:
Analogously to Example 127a, 0.222 g of tert-butyl 3-(3-chlorocarbonyl-4-methylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 127b) and 0.053 g of 2-methoxyethylamine are reacted. The title compound is obtained as a colourless oil. Rf=0.14 (1:2 EtOAc-heptane); Rt=5.54.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2]N.Cl.[C:8](=[NH:23])([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[O:16]([C:8]([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[N:23][NH:2][C:1]([O:5][CH3:6])=[O:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)NN
Reactant: N=C(Oc1ccccc1)Oc1ccccc1
Agent: Cl
Solvent: O
Product: COC(=O)NN=C(Oc1ccccc1)Oc1ccccc1
Reaction time: 4 h

Procedure:
4.31 g (46.9 mmol) of methyl carbazate were initially charged in water (40 ml) and admixed with 4.75 g (46.9 mmol) of conc. hydrochloric acid (36% strength). 10.0 g (46.9 mmol) of diphenyl imidocarbonate (preparation of diphenyl imidocarbonate similar to the method of Heydayatullah, M. Bull Soc. Chim Fr. 1967, 416) were added a little at a time to this solution, at 7° C. After 4 hours of stirring with ice-bath cooling, the mixture was extracted with ethyl acetate (4×100 ml). The combined organic phases were dried over magnesium sulphate and, after filtration, concentrated under reduced pressure. The residue was dried under reduced pressure at 25° C. This gave 7.62 g of crude product containing phenol and methyl N′-diphenoxymethylenehydrazinecarboxylate in a ratio of 10:1. The yield of methyl N′-diphenoxymethylene-hydrazinecarboxylate was 693 mg (5%).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]([CH:4]1[CH2:9][CH2:8][N:7]([CH2:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3[C:16](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:18])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)C1CCN(CCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
A solution of 4-isopropylpiperidine (3.3 g, 20.2 mmol), N-(2-bromoethyl)phthalimide (5.4 g, 21.3 mmol), potassium carbonate (5.9 g, 45.4 mmol) and acetonitrile (100 ml) and was heated under reflux for 2.5 hours and then stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated and the aqueous layer was extracted with further ethyl acetate (100 ml). The combined organic extracts were dried over anhydrous sodium sulphate and the solvent was removed by evaporation under reduced pressure. The resulting oil was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane changing to dichloromethane:diethyl ether (50:50, by volume) changing to diethyl ether to afford the title compound (3.3 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[CH:12]=[CH:13][C:14](OCC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][CH2:13][CH2:14][OH:15])[CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=Cc1cccc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1cccc(OCc2ccccc2)c1
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of ethyl 3-benzyloxycinnamate in tetrahydrofuran (300 ml) was added dropwise to a suspension of lithium aluminum hydride in tetrahydrofuran (300 ml) at 0° C. and then stirred for 2 hours. To the reaction mixture was added carefully water and the insoluble material was filtered off. The filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1N-hydrochloric acid and water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:4, v/v), 3-(3-benzyloxyphenyl)propanol (52.7 g, 62%) was obtained. Oily substance.
Reaction SMILES: [NH:1]([C:5]1[C:14]2[C:9](=[C:10]([Cl:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)C(C)=O.[OH-].[Na+]>CCO>[NH2:1][C:5]1[C:14]2[C:9](=[C:10]([Cl:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1cccc2c(Cl)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc2c(Cl)cccc12
Yield: 96.2 %

Procedure:
A solution of the above synthesized 1-acetamino-5-chloronaphthalene (52 mg, 0.24 mmol) in 3 mL EtOH was heated to reflux and treated with 0.5 mL 40% aqueous NaOH solution. The mixture was refluxed until no more starting material could be detected, cooled and concentrated under reduced pressure. The residue was taken up in CH2Cl2 (50 mL) and was washed with H2O (25 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to leave 41 mg (98%) of compound 213A as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.O[NH:26]/[C:27](=[N:46]/[H])/[C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][CH:34]=[C:33]2[CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:46]=[C:27]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:36]=3[NH:35][CH:34]=[C:33]4[CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[N:26]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: [H]/N=C(/NO)c1cccc2c(CCCCC(=O)OCC)c[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCOC(=O)CCCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.4 %

Procedure:
To a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (279 mg) in tetrahydrofuran (40 mL) stirred at room temp was added EDC (479 mg) and HOBT (363 mg). The reaction mixture was stirred at room temperature for 2 h. Then ethyl 5-{7-[(E)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}pentanoate (D55) (390 mg) was added. The reaction mixture was stirred at 60° C. for 1 h, and then TBAF (1.0 mol/L in THF, 5 mL) was added. The reaction solution was concentrated and transferred to a microwave vessel. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 145° C. for 3 h. After cooling the reaction, the solvent was removed and the residue was purified by Mass Directed AutoPrep to afford ethyl 5-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]pentanoate (D56) (120 mg) as a yellow solid. δH (CDCl3, 400 MHz): 1.25 (3H, t), 1.45 (6H, d), 1.75-1.78 (4H, m), 2.37 (2H, t), 2.84 (2H, t), 4.14 (2H, q), 4.68-4.74 (1H, m), 7.05 (1H, d), 7.14-7.15 (1H, m), 7.25 (1H, t), 8.08 (1H, dd), 8.09 (1H, dd), 8.27 (1H, d), 9.58 (1H, s). MS (ES): C26H28ClN3O4 requires 481; found 482.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[N:12][C:13]([OH:16])=[N:14][CH:15]=1)([O-:3])=[O:2].[I-].C[N+]1C=CN([C:24](=[O:33])[N:25]([CH3:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)C=1.C(N(CC)CC)C>C(#N)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[N:14][C:13]([O:16][C:24](=[O:33])[N:25]([CH3:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:12][CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1-c1cnc(O)nc1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ncc(-c2ccccc2[N+](=O)[O-])cn1)c1ccccc1
Yield: 31.9 %

Procedure:
A solution of 5-(2-nitrophenyl)-pyrimidin-2-ol (0.35 g, 1.61 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (0.55 g, 1.61 mmol) and triethylamine (0.22 ml, 1.61 mmol) in acetonitrile (15 ml) was heated at 50° C. for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.18 g, 32% yield) as a yellow oil.
Reaction SMILES: [C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]1O)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[C:1]([C:5]1[CH2:13][C:12]2[C:7]([CH:6]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1Cc2ccccc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)C1=Cc2ccccc2C1
Yield: 99.8 %

Procedure:
A solution of 2-t-butyl-1-indanol (8.19 g, 43.1 mmol) and p-toluenesulfonic acid (0.200 g, 1.05 mmol) in benzene was heated under reflux for 0.5 h. Water (20 mL) was added. Aqueous layer was extracted with ether (4*50 mL). All organic layers were combined, washed with water (20 mL), brine (10 mL) and concentrated to produce 7.41 g (100 g) of 2-t-butyl-indene. 1H-NMR (CDCl3) δ 1.18 (s, 9 H), 3.30 (s, 2H), 6.45 (s, 1H), 7.02 (tdd, J=7.3, 1.4, 0.3 Hz, 1H), 7.14 (br t, J=7.5 Hz, 1H), 7.19 (br d, J=7.3 Hz, 1H), 7.31 (br d, J=7.3 Hz, 1 H). 13C-NMR (CDCl3) δ 30.44, 33.45, 37.84, 120.09, 123.42, 123.50, 123.63, 126.25, 143.11, 145.49, 150.16.
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]([O:18][CH3:19])=[O:17])#[N:2].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:27]2[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][CH:39]=3)=[N:30][N:29]=[N:28]2)C=CC=CC=1>>[C:1]([C:3]1[N:7]([CH2:44][C:41]2[CH:42]=[CH:43][C:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:39][CH:40]=2)[C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]([O:18][CH3:19])=[O:17])#[N:2]
Reactant: CCCc1nc(-n2cccc2C(=O)OC)c(C#N)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCc1nc(-n2cccc2C(=O)OC)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Using the procedure from Example 13, methyl 1-(5-cyano-2-propylimidazol-4-yl)-1H-pyrrole-2-carboxylate (Example 34) and N-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (Example 12) were reacted and deprotected to give the title compound. MS (CI, CH4 +NH3) 507(M+CH3).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:20][F:21])([CH3:19])[C:4](=[O:18])[CH:5](Br)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1>C(#N)C>[F:1][CH2:2][C:3]([CH2:20][F:21])([CH3:19])[C:4](=[O:18])[CH:5]([N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1
Reactant: c1nc[nH]n1
Reactant: CC(CF)(CF)C(=O)C(Br)Oc1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: CC(CF)(CF)C(=O)C(Oc1cccc(C(F)(F)F)c1)n1cncn1
Yield: 82.5 %

Procedure:
100 g (0.267 mole) of 3,3-bis fluoromethyl-1-bromo-1-(3-trifluoromethylphenoxy)-butan-2-one and 37.2 g (0.54 mole) of 1,2,4-triazole in 600 ml of acetonitrile were heated to 65° C. for 6 hours, while stirring. The solvent was then distilled off under a waterpump vacuum, the residue was taken up in 800 ml of methylene chloride and the mixture was washed twice with 1,000 ml of water each time. The organic phase was dried over sodium sulphate and concentrated. The oily residue was distilled under a high vacuum. 80 g (82.4% of theory) of 3,3-bisfluoromethyl-1-(1,2,4-triazol-1-yl)-1-(3-trifluoromethylphenoxy)-butan-2-one of boiling point 136°-41° C./0.1 mm Hg were obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](C3C=CC=CC=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:19][CH2:20][O:21]S(C1C=CC(C)=CC=1)(=O)=O.[CH2:32]([O:34][C:35](=[O:56])[C:36]([O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([CH3:48])[CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1)[CH3:33]>C(O)C>[CH2:32]([O:34][C:35](=[O:56])[C:36]([CH3:48])([O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]([O:21][CH2:20][CH2:19][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:40][CH:39]=1)[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1cccc2ccccc12)Oc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccccc12)Oc1ccccc1
Temperature: 55 °C
Yield: 2 %

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.132 mmol) (see Ex. 1, Part I) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 2-phenoxy-3-(naphthalen-1-yl)-2-methylpropionic acid ethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue dissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by mass-directed HPLC to produce a white solid (2%). MS [EI+] 584 (M+H)+, [EI−] 582 (M−H)+
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH2:10][CH2:9][N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.Cl>>[CH2:17]([N:8]1[CH2:9][CH2:10][CH:11]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1c1ccsc1
Agent: Cl
Product: O=C(O)C1CN(Cc2ccccc2)CCC1c1ccsc1

Procedure:
The product from step c) (4.5 g, 13.7 mmol) was treated with 4 M HCl at 1000C for 16 hours. Next, the reaction was evaporated to dryness, azeotrope with toluene (2×50 ml) and placed on the high vacuum to give the subtitle compound that was used without further purification. MS calculated for C17H19NO2S−H 300, observed 300.
Reaction SMILES: [F:1][C:2]1([F:28])[CH2:5][N:4]([C:6]([C:8]2[C:12]3[CH:13]=[C:14]([CH:26]=O)[C:15]([N:18]4[CH2:23][C@@H:22]([CH3:24])[O:21][C@H:20]([CH3:25])[CH2:19]4)=[C:16]([F:17])[C:11]=3[O:10][N:9]=2)=[O:7])[CH2:3]1.[NH:29]1[C:36](=[O:37])[CH2:35][C:33](=[O:34])[NH:32][C:30]1=[O:31]>C(O)C>[F:28][C:2]1([F:1])[CH2:3][N:4]([C:6]([C:8]2[C:12]3[CH:13]=[C:14]4[C:15](=[C:16]([F:17])[C:11]=3[O:10][N:9]=2)[N:18]2[CH2:23][C@@H:22]([CH3:24])[O:21][C@@H:20]([CH3:25])[C@@H:19]2[C:35]2([C:33](=[O:34])[NH:32][C:30](=[O:31])[NH:29][C:36]2=[O:37])[CH2:26]4)=[O:7])[CH2:5]1
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(C(=O)N4CC(F)(F)C4)noc3c2F)C[C@@H](C)O1
Solvent: CCO
Product: C[C@@H]1CN2c3c(cc4c(C(=O)N5CC(F)(F)C5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Yield: 81.5 %

Procedure:
3-(3,3-difluoroazetidine-1-carbonyl)-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-5-carbaldehyde (Intermediate 245, 2.08 g, 5.23 mmol) was dissolved in ˜100 ml of ethanol and heated with barbituric acid (0.704 g, 5.50 mmol) at 105° C. (external temperature) for 6 days. The reaction was absorbed onto celite then purified on by silica gel chromatography using a gradient of DCM to ethyl acetate. Fractions were combined and concentrated. This material was then purified by Supercritical Fluid Chromatography (separation of diastereomers), using a Chiralpak AD, 21×250 mm, 5μ column (elution with 40% isopropanol, 60% CO2 at 60 ml/min, 40° C., and 100 bar with detection at 220 nm), to give the title compound (2.16 g, 4.26 mmol, 81%) as the first eluting compound.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[Cl:17][C:18]1[N:23]=[N:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[N:23]=[N:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:12][C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:15]([CH3:16])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)=[O:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)nn2)cc1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(Cl)nn4)cc3)cn12

Procedure:
Operations similar to Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-(6-chloro-3-pyridazinyl)benzenecarboxylic acid, to provide the title compound as white solid.