Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH2:22][O:23][C:24]1[N:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[N:25][C:24]([O:23][CH2:22][F:21])=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: O=C(O)c1cnc(OCF)cn1
Product: C[C@@]1(c2cc(NC(=O)c3cnc(OCF)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(fluoromethoxy)pyrazine-2-carboxylic acid [J. M. Ellard et al. WO2011009898 (2011)] following General Procedure G yielded the title compound as a colorless amorphous solid. MS: m/z=446.5 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([Cl:19])[CH:17]=3)[CH2:12][CH2:11][C:10]=12)=[O:5])[CH3:2].O(C(C)(C)C)[Li].[C:26]([O:30][C:31]([N:33]1[CH2:36][C:35]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([CH2:37]OS(C)(=O)=O)[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:37][C:35]2([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:34][N:33]([C:31]([O:30][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:32])[CH2:36]2)[N:8]=[C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([Cl:19])[CH:17]=3)[CH2:12][CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]nc2c1CCc1cnc(Cl)cc1-2
Reactant: CC(C)(C)OC(=O)NC1(COS(C)(=O)=O)CN(C(=O)OC(C)(C)C)C1
Agent: [Li]OC(C)(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2c(nn1CC1(NC(=O)OC(C)(C)C)CN(C(=O)OC(C)(C)C)C1)-c1cc(Cl)ncc1CC2
Temperature: 90 °C

Procedure:
8-Chloro-4,5-dihydro-2H-1,2,7-triaza-cyclopenta[a]naphthalene-3-carboxylic acid ethyl ester (320 mg; 1.15 mmol) in DMF (4 ml) is treated at 5° C. with LiOtBu (1N in THF; 1.16 ml; 1.16 m mol) for 5 minutes. 3-tert-butoxycarbonylamino-3-methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester (0.32 mg; 1.15 mmol) is added and the mixture heated to 90° C. for 30 minutes. The reaction mixture is poured on brine and extracted with TBME three times. The combined organic phases are dried over Na2SO4, evaporated to dryness and yield the title compound as colorless crystals. 1H-NMR (400 MHz; DMSO-d6: 8.38 (s, 1H); 7.65 (s, 1H); 7.42 (bs, 1H); 5.00 (bs, 2H); 4.34 (q, 2H); 4.03 (bd, 2H); 3.79 (m, 2H); 3.00 (m, 2H); 2.95 (m, 2H); 1.40 (s, 18H); 1.36 (t, 3H). MS (m/z) ES+: 562 (MH+).
Reaction SMILES: [C:1]([N:4]1[C@:8]([CH2:15][CH2:16][CH:17]([NH:20]CC2C=CC=CC=2)[CH2:18][F:19])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])=[N:5]1)(=[O:3])[CH3:2]>CO>[C:1]([N:4]1[C@:8]([CH2:15][CH2:16][CH:17]([NH2:20])[CH2:18][F:19])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][C:6]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2cc(F)ccc2F)C[C@@]1(CCC(CF)NCc1ccccc1)c1ccccc1
Solvent: CO
Product: CC(=O)N1N=C(c2cc(F)ccc2F)C[C@@]1(CCC(N)CF)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 167 mg (0.35 mmol) 2-5 in 25 mL MeOH was evacuated under reduced pressure and purged with nitrogen three times before 20 mg of 10% palladium on carbon was added. The resulting mixture was evacuated and purged twice more with nitrogen and then three times with hydrogen. The reaction was stirred for 17 h at ambient temperature under an atmosphere of hydrogen, filtered, and concentrated to give 2-6 as a gum. LC-MS: peak at rt=1.7 min, m/z=390 (M+1).
Reaction SMILES: [N+](C1C=CC=CC=1C=O)([O-])=O.C([N:14](CC)[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19](C)=[N:18][CH:17]=1)C.C(OC(=O)C)(=O)C.C(N(CC)C(=O)C1C=CC(C=CC2C=CC=CC=2[N+]([O-])=O)=NC=1)C>>[C:15]([NH2:14])(=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1
Reactant: CCN(CC)C(=O)c1ccc(C)nc1
Agent: CCN(CC)C(=O)c1ccc(C=Cc2ccccc2[N+](=O)[O-])nc1
Agent: O=Cc1ccccc1[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: NC(=O)c1cccnc1

Procedure:
Reaction of o-nitrobenzaldehyde (41.7 g., 0.276 mole) with N,N-diethyl-6-methylnicotinamide (53.1 g., 0.276 mole) in the presence of acetic anhydride (56.3 g., 0.552 mole) according to the method of L. Horwitz, J. Org. Chem., 21, 1039 (1956) provides 67.4 g. (75%) of N,N-diethyl-6-(o-nitrostyryl)nicotinamide. Crystallization from acetonitrile affords the analytically pure nicotinamide having a melting point of 145°-147°C. (corr.).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S([N:25]=[N+]=[N-])(=O)=O)=CC=1.[BH4-].[Na+].O>C1COCC1.CCCCCC.[Cl-].[Na+].O>[C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][C:13]=1[NH2:25])(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Cl)s1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1sc(Cl)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solutuion of 5-chloro-thiophene-2-sulfonic acid tert-butylamide (310 mg, 1.22 mmol) in THF (10 mL) at −78° C. was added n-Buli (1.6 M in hexane, 1.7 mL, 2.7 mmol) dropwise. The resultant solution was warmed up to −30° C. and maintained at −20° C.–−30° C. for 10 min. It was rmixed with a solution of 4-methylbenzenesulfonyl azide (361 mg, 1.83 mmol) in THF (2 mL). The mixture was stirred at ambient temperature for 1 h before diluted with brine solution (30 mL) and washed with toluene (20 mL). The organic phase was separated and mixed with NaBH4 (500 mg, 13.2 mmol) and H2O (5 mL). The mixture was stirred for 2 h. at room temperature, then diluted with brine solution (50 mL) and washed with ethyl acetate (50 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated. Flash chromatography (hexanes/ethyl acetate, 4:1) then provided 3a (250 mg) as a yellow oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([Cl:10])[C:7]([S:11][CH3:12])=[C:6]([Cl:13])[N:5]=1)[CH3:2].C([NH:16]C1C(SC)=C(Cl)N=C(Cl)N=1)C>CO>[CH2:1]([NH:3][C:4]1[N:5]=[C:6]([Cl:13])[C:7]([S:11][CH3:12])=[C:8]([Cl:10])[N:9]=1)[CH3:2].[NH3:16]
Reactant: CCNc1nc(Cl)nc(Cl)c1SC
Agent: CCNc1nc(Cl)c(SC)c(Cl)n1
Solvent: CO
Product: N

Procedure:
2.5 Grams of 2-ethylamino-4,6-dichloro-5-methylthio-pyrimidine, 9 g of the mixture of 2-ethylamino-4,6-dichloro-5-methylthio-pyrimidine and 4-ethylamino-2,6-dichloro-5-methylthio-pyrimidine obtained in the first stage of Example 1, 165 g of methanol and 16 g of ammonia are introduced into a 500 ml autoclave. The mixture is heated for 2 hours at 120° C., then cooled. The solution obtained is concentrated under reduced pressure and the residue is washed with water. 8.2 Grams of a mixture melting at 76° C. are thus obtained. The analysis of the mixture by gas chromatography and mass spectrometry shows that it contains 56.6% of 2-amino-6-chloro-4-ethylamino-5-methylthio-pyrimidine, 37.8% of 4-amino-2-ethylamino-6-chloro-5-methylthio-pyrimidine and 5.6% of 6-amino-4-ethylamino-2-chloro-5-methylthio-pyrimidine.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15])=[O:7].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1COCC1>[Cl:18][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=2)=[CH:17][C:13]=1[CH2:14][OH:15]
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)c(CO)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a solution of intermediate 1 (Example 2) (1.4 g, 4.1 mmol) in anhydrous THF (20 mL) at room temperature under argon, 1.5 M diisobutylaluminum hydride in toluene (DIBAL-H, 9 mL, 13.5 mmol) was added. After the reaction mixture was stirred at room temperature for 1 h, the solution was refluxed under argon for overnight. The solution was quenched by minimum amount of methanol and water. The organic solvent was removed by reduced pressure. The crude was suspended in water (50 mL) and extracted by ethyl acetate (2×50 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and filtered. The organic solvent was removed and the crude product was purified by silica gel column with CHCl3 as an eluent to give the final product as a white solid (700 mg, 52%).
Reaction SMILES: Cl.[F:2][C:3]([F:20])([F:19])[C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=1.N1C=CC=CC=1.Cl[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29]>C(OCC)(=O)C>[F:2][C:3]([F:19])([F:20])[C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][NH:15][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])=[CH:12][CH:13]=1
Reactant: CC(C)OC(=O)Cl
Reactant: NNc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)NNc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 4-[3-(trifluoromethyl)phenoxy]phenylhydrazine hydrochloride (11 g) and pyridine (6.0 mL) in ethyl acetate (100 mL) at 0° C. was added dropwise isopropyl chloroformate (38 mL, 1M in toluene) over a period of 30 min. The mixture was then stirred at room temperature for 5 hour, quenched with 1M aqueous HCl (100 mL). The organic layer was separated, washed twice with water (100 mL), dried over anhydrous sodium sulfate, and finally evaporated under reduced pressure to yield a light brown solid (11 g).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[NH:13][CH:14]=1)C1C=CC=CC=1>CO.O.[Pd]>[OH:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[NH:13][CH:14]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Cc1cc(=O)c(O)c[nH]1
Reaction time: 3 h
Yield: 70.5 %

Procedure:
A solution of 5-benzyloxy-2-methyl-1H-pyridin-4-one (2 g, 9.29 mmol) in methanol (30 ml) and water (8 ml) was placed in a Parr bottle. 10% Pd/C was added and the mixture was hydrogenated at 50 psi for 3 hours. A bed of CELITE™ was placed on a sintered glass, and washed with 0.1N HCl and then water. The content in the Parr bottle was removed from the Parr hydrogenator and flushed with nitrogen. The solution was filtered under suction. The filtrate was evaporated to give a white solid (820 mg, 70% yield).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([CH2:14][NH2:15])[OH:13]>C(O)C>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[NH:15][CH2:14][CH2:12][OH:13]
Reactant: O=[N+]([O-])c1cccc(F)c1F
Reactant: NCCO
Solvent: CCO
Product: O=[N+]([O-])c1cccc(F)c1NCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
2,3-Difluoronitrobenzene (15 g, 94.3 mmol) is dissolved in 200 mL of ethanol. Ethanolamine (11.4 ml, 188.7 mmol, 2 equiv) is added and the mixture stirred at room temperature overnight (reaction complete by TLC). Ethanol is evaporated and the resulting residue is dissolved in ethyl acetate, washed with water (to eliminate excess ethanolamine), dried over magnesium sulphate, filtered and evaporated to dryness, giving the desired product as a deep orange oil (18.3 g, 97%). This crude material was used for the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:16][C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:16][C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:18]1
Reactant: CCOC(=O)c1cccc(OCCBr)c1
Reactant: F[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cccc(OCCN2CC[C@@H](F)C2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-[(2-bromoethyl)oxy]benzoate D46 (200 mg) and (3R)-3-fluoropyrrolidine (129 mg, 1.025 mmol) in Acetonitrile (10 ml) was added K2CO3 (213 mg, 1.538 mmol). The reaction mixture was stirred at 60° C. overnight. The reaction mixture was filtered and the filtrate was concentrated to give the expected product D48 in 220 mg. LCMS: rt=1.63 min, M+H=282.1 (5 min run)
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[S:16][C:17]([C:20]#[N:21])=[CH:18][N:19]=2)[C:9]=1[CH3:22])(C)(C)C.C1C=CN=CC=1.F.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[S:16][C:17]([C:20]#[N:21])=[CH:18][N:19]=2)[C:9]=1[CH3:22]
Reactant: Cc1c(C(C)(C)O[SiH2]C(C)(C)C)ccnc1Nc1ncc(C#N)s1
Agent: F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1c(CO)ccnc1Nc1ncc(C#N)s1
Temperature: 25 °C

Procedure:
2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-3-methyl-pyridin-2-ylamino]-thiazole-5-carbonitrile (10-3, 0.920 g, 2.55 mmol) was dissolved in 5 mL THF. HF-pyridine (Aldrich), 0.5 mL, was added and the reaction was stirred at room temperature. After 4 hours an additional 0.5 mL of HF-pyridine was added and the reaction was allowed to stir overnight. After a total of 18 hours the reaction was diluted with water and the pH was adjusted to 7 with K2CO3 (s). The resulting precipitate was filtered and washed with water. Air drying afforded the crude product as an orange solid, which was used in the next step without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.Br[C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH3:19])[CH:13]=1>>[CH3:19][C:14]1[CH:13]=[C:12]([C:2]2[CH:7]=[CH:6][N:5]3[CH:8]=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH:17]=[C:16]([CH3:18])[N:15]=1
Reactant: Cc1cc(Br)cc(C)n1
Reactant: Ic1ccn2ccnc2c1
Product: Cc1cc(-c2ccn3ccnc3c2)cc(C)n1

Procedure:
Prepare from 7-iodo-imidazo[1,2,a]pyridine and 4-bromo-2,6-dimethylpyridine (Acta. Chemica. Scandinavica. B42, (1988) pages 373-377) using a procedure similar to Preparation 27A. MS(ES), m/z 224 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:24])=[O:23]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2c(C)cc(Cl)cc2Cl)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (34.6 mg) with purity >90%: LCMS (pos) m/z 409.0, 411.0; HRMS m/z 407.9753 (calc. of monoisotopic mass for C14H14Cl2N2O4S2 gives 407.9772).
Reaction SMILES: S(=O)(=O)(O)O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][C:16]([OH:18])=[O:17])=[CH:7]1.[OH-].[Na+].[CH3:21]O>O.C([O-])([O-])=O.[K+].[K+].CC(OC)(C)C>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][C:16]([O:18][CH3:21])=[O:17])=[CH:7]1
Reactant: CO
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
Concentrated sulfuric acid (0.2 equiv.) was carefully added to a solution of 1H-indol-3-ylacetic acid in MeOH (1 M) and the reaction was stirred at rt for 2.5 h. The solution was cooled with an ice bath, and aqueous 2 N NaOH (0.18 equiv.) was slowly added such that T<10° C. The solution was diluted with water, and solid K2CO3 was then added until pH was neutral. The solution was extracted with MTBE (2×), washed with water (2×), brine, dried over Na2SO4, filtered, and concentrated to give a brown syrup. The crude syrup was dissolved in MTBE (1.4 mL/g) and transferred to a three necked flask fitted with a temperature probe, mechanical stirrer, addition funnel and nitrogen inlet. Hex was then slowly added to the stirring solution over 1 h. More Hex was then added over 2 h then left overnight. The suspension was filtered, washed with Hex, and dried on the fit under nitrogen for 20 h to give the title compound (81%) as a light orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CN([CH:28]=[O:29])C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([F:12])([C:13]2[CH:18]=[CH:17][C:16]([CH:28]=[O:29])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(Br)cc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=O)cc2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 106.4 %

Procedure:
To a stirred solution of 3-(4-bromo-phenyl)-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester (5 g, 15.14 mmol, 1 eq) in dry THF (60 mL) was added n-BuLi (16.6 mL, 18.17 mmol, 1.2 eq) at −78° C. under nitrogen atmosphere. Reaction mixture was stirred for 10 minutes at −78° C. under nitrogen atmosphere. At −78° C., DMF (1.748 mL, 22.71 mmol, 1.5 eq) was added in drop wise manner over a period of 10 minutes. Resulting reaction mixture was allowed to warm to −20° C. and stirred for 3 hours at −20° C. After complete consumption of starting material, reaction was quenched with 10% NH4Cl solution (10 mL) followed by water (100 mL) and extracted with ethyl acetate (3×40 mL). Combined organic phase was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford title compound as pale yellow thick oil (4.5 g, Crude). Crude compound was used as such for next reaction. LC-MS (m/z): 279.3 (M+H).
Reaction SMILES: [ClH:1].C([O:6][C:7]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:8])(C)(C)C.FC(F)(F)C(O)=O>>[ClH:1].[C:7]([CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:24])[CH2:19][CH2:18]2)=[CH:15][CH:16]=1)([OH:8])=[O:6]
Reactant: CC(C)(C)OC(=O)COc1ccc(N2CCN(C(=O)OC3CCNCC3)CC2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(N2CCN(C(=O)OC3CCNCC3)CC2)cc1

Procedure:
Prepared from 1-(4-tert-butyloxycarbonylmethyloxyphenyl)-4-[(piperidin-4-yl)oxycarbonyl]piperazine hydrochloride and trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([CH2:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH3:20].[H-].[Na+].[CH3:23]I.CO>C1(C)C=CC=CC=1.CN(C)C=O.C(O)(=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:23])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(CC1CCCC1)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(CC1CCCC1)C2
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 73 %

Procedure:
6,7-Dichloro-2-cyclopentylmethyl-2,3-dihydro -5-methoxy-1H-inden-1-one (56.7 g., 0.181 mole) dissolved in dry toluene (200 ml.) is added dropwise with stirring under nitrogen over 1 hour at room temperature to a suspension of sodium hydride (56% in mineral oil, 8.74 g. 0.204 mole) in toluene (50 ml) and dry dimethylformamide (220 ml.) The mixture is stirred at room temperature for 1.75 hours after completion of the addition, cooled to 0° C., and then methyl iodide (25 ml., 0.4 mole) is added at 0°-5° C. After stirring at 5° for 25 minutes and for one hour at room temperature, methanol (15 ml.) is slowly added followed by acetic acid (10 ml.). The mixture is poured into ice water (1500 ml.) the layers are separated and the aqueous phase extracted three times with toluene (150 ml.) and then with methylene chloride (150 ml.). The combined organic extracts are washed with water, dried over magnesium sulfate and concentrated under vacuum. The residue is triturated with a mixture of hexane and petroleum ether (1:1) are filtered. The solid (50 g.) is recrystallized from a mixture of methylcyclohexane (110 ml.) and hexane (55 ml.) to obtain 38 g. of product, m.p. 75°-77° C. The filtrates from the recrystallization are concentrated and the residue recrystallized from methylcyclohexane to obtain a second drop of 5.5 g. for a total yield of 73%.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([CH3:51])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:16]([CH2:47][C:48](O)=[O:49])[CH2:15]2)=[CH:10][CH:9]=1)[CH3:2].[CH2:52]([NH:54][CH2:55][CH3:56])[CH3:53]>>[CH2:52]([N:54]([CH2:55][CH3:56])[C:48](=[O:49])[CH2:47][C@H:16]1[CH2:15][C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][O:6][CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[CH3:51])=[CH:13][CH:12]=2)[C@@H:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:18][N:17]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:38])=[O:39])[CH3:53]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CC(=O)O)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reactant: CCNCC
Product: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CC(=O)N(CC)CC)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1

Procedure:
According to general procedure D, 1.0 mmol of [(2R,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl) -phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid (example 1g) are reacted with diethylamine to afford the title compound, which is identified based on its Rf value.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[OH:18][C:19]1[C:23]([OH:24])=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:21]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:20]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CCO>[CH2:1]([O:18][C:19]1[C:23]([OH:24])=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:21]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:20]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)OCC)n1-c1ccc(OC)cc1
Reactant: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1c(O)c(OCc2ccccc2)c(C(=O)OCC)n1-c1ccc(OC)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
Benzyl bromide (2.13 ml, 17.9 mmol) was added dropwise to a suspension of DIPEA (3.12 mL, 17.9 mmol) and diethyl 3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (UL2-001) (5 g, 14.3 mmol) in EtOH (200 mL). The reaction mixture was stirred at 50° C. for 18 h. Additional benzyl bromide (0.85 mL, 7.20 mmol) and DIPEA (1.25 mL, 7.20 mmol) were added and the reaction stirred at 60° C. for 24 h, after which further portions of benzyl bromide (0.85 ml, 7.20 mmol) and DIPEA (1.25 mL, 7.20 mmol) were added and the reaction mixture stirred at 60° C. for 24 h. The reaction mixture was allowed to cool to RT, and partitioned between EtOAc (200 mL) and sat. NaHCO3 (aq.) (200 mL), the organic layer was separated and washed with sat. NaHCO3 (aq.) (2×200 mL) dried (MgSO4), filtered and solvents removed in vacuo to give an orange oil. The residue was purified by silica gel chromatography (80 g, 0-100% EtOAc in isohexane) to afford a yellow solid. The product was recrystallised from EtOH (100 mL) to afford diethyl 3-(benzyloxy)-4-hydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (23) (2.89 g, 37%) as a pale yellow solid: m/z 440 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 8.82 (s, 1H), 7.52-7.30 (m, 5H), 7.16-7.03 (m, 2H), 6.94-6.83 (m, 2H), 5.09 (s, 2H), 4.10-3.91 (m, 4H), 3.79 (s, 3H), 1.02-0.92 (m, 6H).