Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[C:15](Br)Br)=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:32][O:33][P:34](Cl)([CH2:36][C@@H:37]([O:43][Si:44]([C:57]([CH3:60])([CH3:59])[CH3:58])([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:35]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[C:15][P:34]([O:33][CH3:32])([CH2:36][C@@H:37]([O:43][Si:44]([C:57]([CH3:58])([CH3:60])[CH3:59])([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:35])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@@H](CP(=O)(Cl)OC)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC(C)c1nc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=C(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C[C@@H](CP(=O)(C#Cc1c(-c2ccc(F)cc2)nc(-c2ccccc2)nc1C(C)C)OC)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
In a separate flask, a solution of 4-(4-fluorophenyl)-6-(1-methylethyl)-2-phenyl-5-(2,2-dibromovinyl)-pyrimidine obtained in step (v) above (1.000 gm, 2.10 mmol) in tetrahydrofuran (THF) (10 ml) was added dropwise to a -78° C. THF solution (15 ml) of n-butyl lithium (nBuLi) (2.5M in hexane, 1.68 ml, 4.20 mmol). The solution was allowed to stir 1 hour at -78° C., then cannulated into a THF solution (20 ml) of (S)-4-(methoxychlorophosphinyl)-3-[[(t-butyl)diphenylsilyl]-oxy]butanoic acid, methyl ester obtained in step (f) above which had also been cooled to -78° C. The resultant solution was stirred for 30 minutes, then quenched with saturated NH4Cl (15 ml) and warmed to 0° C. Then, saturated NaHCO3 was added to the solution which was subsequently warmed to room temperature. The mixture was diluted with ether and the organic layer was washed with brine, then dried over Na2SO 4, filtered and concentrated to give an orange oil. The oil was purified by flash chromatography on Merck silica gel in 30-50% EtOAc in hexane. The desired fractions were combined and evaporated to afford the title compound as yellow foam (0.732 gm, 49%). TLC: Rf =0.50 (50% EtOAc in hexane).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[CH:14]=[N:15][C:16]([I:17])=[C:10]2[CH:9]1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:30]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([Cl:30])=[N:15][C:16]([I:17])=[C:10]2[CH:9]1[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCn2cnc(I)c2C1CCc1ccc(C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2c(Cl)nc(I)c2C1CCc1ccc(C(F)(F)F)cc1
Temperature: 70 °C

Procedure:
To a solution of 1-iodo-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.000 g; 1.918 mmol) in chloroform (30 ml) was added N-chlorosuccinimide (307 mg; 2.298 mmol; 1.2 eq.), and the resulting mixture was heated to reflux (70° C.) for 2 h30. Additional N-chlorosuccinimide (120 mg; 0.898 mmol; 0.46 eq.) was then added and the resulting mixture was additionally refluxed for 2 h30. The reaction mixture was allowed to cool to rt, diluted with DCM (50 ml), and washed with brine (80 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/EA=1/1) afforded the expected product 3-chloro-1-iodo-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (475 mg; 45%). LC-MS: tR=1.13 min.; [M+H]+=556.24 g/mol.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[N:18]=3)=[CH:8][CH:7]=2)[CH2:3]1.[BH-](OC(C)=O)(OC(C)=O)O[C:24](C)=O.[Na+].C=O.C(O)(=O)C>CO>[Br:19][C:17]1[N:18]=[C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([CH:4]3[CH2:5][N:2]([CH3:24])[CH2:3]3)=[CH:11][CH:10]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: Cn1cc(Br)nc(Nc2ccc(C3CNC3)cc2)c1=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CC(c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 119.3 %

Procedure:
A mixture of 298c (100 mg, 0.24 mmol), NaBH(OAc)3 (100 mg, 0.48 mmol), HCHO (10 mL) and acetic acid (1 mL) in methanol (15 mL) was stirred at room temperature for 4 h. The solvent was evaporated in vacuo and the residue was neutralized with NaHCO3 solution until pH 8 was reached. The mixture was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to give 298d (100 mg), which was used for the next step without further purification. MS: [M+H]+ 349.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]#[CH:19])=[CH:13][CH:14]=2)[C:9]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[N:8][C:7]1=[O:29].[H-].[Na+].Br[CH2:36][CH2:37][O:38][CH3:39]>CN(C=O)C>[CH:26]([C:23]1[CH:24]=[CH:25][C:20]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]#[CH:19])[CH:11]=3)[N:6]([CH2:5][C:4]3[CH:30]=[CH:31][CH:32]=[C:2]([O:1][CH2:36][CH2:37][O:38][CH3:39])[CH:3]=3)[C:7](=[O:29])[N:8]=2)=[CH:21][CH:22]=1)([CH3:27])[CH3:28]
Reactant: COCCBr
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(OCCOC)c1
Temperature: 60 °C

Procedure:
To a solution of 100 mg (0.236 mmol) of 1-(3-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one in anhydrous DMF (5 ml) is added NaH (11 mg, 0.471 mmol) and the solution is allowed to stir until evolution of gas ceases. 1-Bromo-2-methoxy-ethane (34 μl, 0.236 mmol) is added and the mixture is heated for 2 days at 60° C. After cooling to room temperature, the reaction mixture is quenched with water and the mixture is acidified to pH 3 with 10% citric acid. The mixture is extracted with ether (2×20 ml). The combined organic layers are washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to provide a yellow solid which is purified by flash chromatography on silica gel using petroleum ether/ethyl acetate (9:1 to 1:1) to provide the title compound as a yellow oil. Yield:56 mg (49%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:18][OH:19])[C:4]([N:6]([CH3:17])[C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5].CN1CCOCC1.[CH3:27][C:28]1[N:32]([CH2:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]2)=[O:35])[N:31]=[C:30]([C:45]([F:48])([F:47])[F:46])[CH:29]=1.ON1C2C=CC=CC=2N=N1.CC(N=C=NC(C)C)C>O1CCCC1>[OH:19][CH2:18][C@H:3]([NH:2][C:42]([CH:39]1[CH2:40][CH2:41][N:36]([C:34](=[O:35])[CH2:33][N:32]2[C:28]([CH3:27])=[CH:29][C:30]([C:45]([F:46])([F:48])[F:47])=[N:31]2)[CH2:37][CH2:38]1)=[O:43])[C:4]([N:6]([CH3:17])[C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C(=O)[C@@H](N)CO)[C@@H]1CCCc2ccccc21
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)N[C@@H](CO)C(=O)N(C)[C@@H]2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
A solution of (2S)-2-amino-3-hydroxy-N-methyl-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]propanamide monohydrochloride (546.33 mg, 2.2 mmol) (i.e. the product of Example 17, Step B) and N-methylmorpholine (222.53 mg, 2.2 mmol) in 8 mL of tetrahydrofuran was cooled to 0° C. and 1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinylcarboxylic acid (638.56 mg, 2 mmol) (i.e. the product of Example 17, Step D) was added followed by N-hydroxybenzotriazole (27 mg, 0.2 mmol) and N,N-diisopropylcarbodiimide (265 mg, 2.1 mmol). The reaction mixture was stirred for 16 h at room temperature and filtered. The precipitate was washed with tetrahydrofuran and the resulting filtrate and washings were concentrated in vacuo. The residue was dissolved in dichloromethane and the resulting solution was washed with water, 1 M aqueous hydrochloric acid, water, saturated aqueous solution of sodium bicarbonate and brine, dried over MgSO4 and concentrated in vacuo. The resulting product was purified by medium-pressure liquid chromatography on silica gel using 0-20% methanol in ethyl acetate as eluant to give 600 mg of the title compound as a white solid.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].Cl(O)(=O)(=O)=O.[OH-].[Na+].C(O[C:21]([CH3:24])([CH3:23])[CH3:22])(=O)C>O>[O:6]=[C:5]1[NH:1][C@H:2]([C:7]([O:9][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:8])[CH2:3][CH2:4]1
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
129 g of L-pyroglutamic acid were suspended in 2 l of tert-butyl acetate. 30 ml of a 70% strength solution of perchloric acid in water were added thereto. The mixture was then stirred at room temperature for 12 h. It was cooled to 0° C. and the pH of the solution was adjusted to 7 by cautious addition of a 2N NaOH solution. The phases were separated and the organic phase was washed twice with 300 ml of a saturated sodium chloride solution each time. The organic phase was then dried with sodium sulfate. The solvents were removed in vacuo, and the residue was stirred with heptane. The solid obtained in this way was filtered off with suction. The mother liquor was concentrated in vacuo, and the solid obtained in this way was also filtered off with suction.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH:37]=[CH:36][C:23]([C:24]([O:26][CH2:27][C@@H:28]([F:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:25])=[CH:22][CH:21]=3)=[N:18][CH:19]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>[Pd]>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][C@@H:28]([F:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:25])=[CH:36][CH:37]=3)=[N:18][CH:19]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCCC[C@H](F)COC(=O)c1ccc(-c2ncc(C#Cc3ccc(CCCCC)cc3)cn2)cc1
Agent: [Pd]
Product: CCCCCC[C@H](F)COC(=O)c1ccc(-c2ncc(CCc3ccc(CCCCC)cc3)cn2)cc1

Procedure:
Hydrogenation of the compound obtained in Example 4 using hydrogen under atmospheric pressure at room temperature and using palladium/charcoal as catalyst gives (S)-2-fluorooctyl 4-{5-[2-(4-pentylphenyl)ethyl]-pyrimidin-2-yl}benzoate.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:22][CH:21]([C:23]#[N:24])[CH2:20]1>O1CCCC1>[C:7]([CH:9]=[C:19]1[CH2:22][CH:21]([C:23]#[N:24])[CH2:20]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: N#CC1CC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=C1CC(C#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (78.4 mL) at 0° C. was added drop wise a solution of diethyl cyanomethylphosphonate (13.3 mL, 0.0822 mol) in tetrahydrofuran (100 mL, 2 mol). The reaction was warmed to room temperature and then cooled at 0° C. again. To the reaction mixture was a solution of 3-oxocyclobutanecarbonitrile (7.10 g, 0.0746 mol) in tetrahydrofuran (70 mL). The reaction was allowed to warm up to room temperature and stirred overnight. After being quenched with water, the mixture was extracted with ether. The combined organic layers were washed with water, brine, dried over MgSO4, and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexanes, to give the desired product (2.05 g, 23.2%).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[NH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC.O>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:9]1[NH:8][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To trichloroacetyl chloride (48 mL; 0.43 mol) taken in anhydrous ether (150 mL) under nitrogen was added pyrrole (25 g, 0.37 mol) dissolved in anhydrous ether (500 mL) through a dropping funnel over a 2-hour period. The violet ether solution began to reflux during addition. Refluxing was continued for 1 h before the reaction was quenched with a solution of sodium carbonate (33 g, 0.31 mol) in water (200 mL). The layers were separated and the red organic layer was washed four times with water (4×50 mL) and once with brine (1×50 mL) and finally dried over anhydrous sodium sulphate. The red ether solution was then filtered through CELITE® and washed with ether. The solvent was removed under vacuum to afford 2-trichloroacetylpyrrole (Example 1A, 72 g, 91% yield).) as an ash colored solid (72 g, 91% yield). LC-MS, [M−H]+=212. 1H NMR (DMSO-d6, 300 MHz): δ 9.63 (brs, 1H), 7.39 (m, 1H), 7.19 (m, 1H), 6.40 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29]([NH2:31])[CH:28]=[N:27]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][C:29]4[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1cc(N)cn1
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)Nc2cnn(C)c2)cn1
Yield: 73 %

Procedure:
As described for example 254, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) was converted, using 1-methyl-1H-pyrazol-4-ylamine instead of 2-amino-2-methyl-1-propanol, to the title compound (90 mg, 73%) which was obtained as a white solid. MS: m/e=424.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].P(Cl)(Cl)Cl.[C:17]([OH:26])(=O)[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20]>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:11]=[C:10]([NH:12][C:17](=[O:26])[C:18]2[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=2)[OH:20])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:26])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20]
Reactant: O=C(O)c1ccccc1O
Reactant: COC(=O)c1ccc(N)cc1N
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: COC(=O)c1ccc(NC(=O)c2ccccc2O)cc1NC(=O)c1ccccc1O
Temperature: 90 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
In 200 ml of pyridine was dissolved 8.3 g of methyl 2,4-diaminobenzoate, and to the solution was added a solution of 4.4 ml of phosphorus trichloride in 30 ml of pyridine under cooling with ice, followed by stirring at 50° to 70°C for one hour. To the mixture was added 21 g of salicylic acid was added, followed by heating at 90°C for three hours. After the cooling of the mixture by allowing it to stand, undissolved substances were filtered off and the filtrate was subjected to concentrate under reduced pressure. The concentrate was added to cold diluted hydrochloric acid to precipitate crystals. The crystals were recovered by filtration, washed with water and recrystallized from an acetone-dioxane-water mixture to obtain 11.1 g of methyl 2,4-bis(salicylamido)-benzoate having a melting point between 259° - 260°C. It was confirmed that the product was identical to that obtained in Example 7.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[N:17]=[N:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[N:14]2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[OH-].[K+]>C(O)C>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[N:17]=[N:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[N:14]2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCn2nnc(CCCC(=O)OCC)n2)ccc(C(C)=O)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1c(OCCCCn2nnc(CCCC(=O)O)n2)ccc(C(C)=O)c1O
Temperature: 50 °C

Procedure:
Ethyl 2-[4-(4-acetyl-3-hydroxy-2-(n-propyl) phenoxy)butyl]-2H-tetrazole-5-butanoate (2.4 g) was combined with 5N potassium hydroxide solution (20 ml) in absolute ethanol (20 ml). The mixture was heated to 50° C. for 0.5 hours then cooled to room temperature. The cooled mixture was partitioned between ethyl acetate and water. The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo. The concentrate was chromatographed by preparatory-scale HPLC (silica column) eluted with a gradient of 25% to 50% ethyl acetate in hexane plus 1% acetic acid to yield the title product: n.m.r. (300 MHz, CDCl3) δ: 12.80 (s, 1H); 7.54 (d, 1H); 6.35 (d, 1H); 4.60 (t, 2H); 4.01 (t, 2H); 2.82 (m, 2H); 2.57 (t, 2H); 2.51 (s, 3H); 2.20 (m, 4H); 1.95 (m, 2H); 1.80 (m, 2H); 1.46 (m, 2H); 0.88 (t, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].N1([O:16][C:17]2[C:18]3[O:25][CH:24]=[C:23]([CH:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)[C:19]=3[N:20]=[CH:21][N:22]=2)C2C=CC=CC=2N=N1.[N:39]1([C:44]2[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=2)[CH:43]=[N:42][N:41]=[N:40]1.O>CN(C=O)C>[N:39]1([C:44]2[CH:49]=[CH:48][C:47]([O:16][C:17]3[C:18]4[O:25][CH:24]=[C:23]([CH:26]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:28][CH2:27]5)[C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:46][CH:45]=2)[CH:43]=[N:42][N:41]=[N:40]1
Reactant: Oc1ccc(-n2cnnn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2coc3c(On4nnc5ccccc54)ncnc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2coc3c(Oc4ccc(-n5cnnn5)cc4)ncnc23)CC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
Potassium carbonate (5.0 mg, 0.035 mmol) was added to a solution of the tert-butyl 4-{4-[(1H-benzo[d][1,2,3]triazol-1-yl)oxy]furo[3,2-d]pyrimidin-7-yl}piperidine-1-carboxylate obtained in Step 7 of Example 1 (10.0 mg, 0.023 mmol) and 4-(1H-tetrazol-1-yl)phenol (4.0 mg, 0.025 mmol) in DMF (0.2 mL), followed by stirring at 70° C. for 5 hours. Water was added to the reaction liquid, and the reaction liquid was extracted with chloroform:methanol=5:1 and concentrated under a reduced pressure. The obtained residue was purified by using silica gel chromatography (chloroform:methanol=50:1) to give the titled compound (7.4 mg, 70%) as a white solid.
Reaction SMILES: [N:1]1([C:6]2[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:15]/[N:16]=[C:17](\Cl)/[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[N:21]1[CH:22]=[CH:23][C:18]([C:17]2[CH:7]3[CH2:8][N:9]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:11][C:6]3([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[O:15][N:16]=2)=[CH:19][CH:20]=1
Reactant: O/N=C(\Cl)c1ccncc1
Reactant: CC(=O)N1CC=C(N2CCCC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC2(N3CCCC3)ON=C(c3ccncc3)C2C1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
1-(4-(Pyrrolidin-1-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (1.2 g, 6.176 mmol) (synthesis: see below) was dissolved in methylene chloride (10 ml) and the solution was cooled to 0° C. under an inert gas. (Z)-N-Hydroxyisonicotinimidoyl chloride (1.45 g, 9.264 mmol), dissolved in methylene chloride (5 ml), and triethyl-amine (2.1 ml, 14.82 mmol), dissolved in methylene chloride (5 ml), were added, stir for 15 h, during this allow to warm to room temperature. The mixture was diluted with methylene chloride (30 ml) and washed water (20 ml) and citric acid (10%, 20 ml). The aqueous phase was neutralized with sodium bicarbonate and extracted with methylene chloride and the combined organic phases were washed with saturated sodium chloride solution, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol/ammonia (25% eq.) 100/10/1. The yield was 0.64 g (33%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][C@@H:3]1[CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[OH:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@@H:3]1[CH2:15][NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@@H](CNC(=O)OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@H]1CNCC[C@H]1O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a flask containing 1,1-dimethylethyl (3S,4R)-4-hydroxy-3-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-piperidinecarboxylate (E2)(500 mg; 1.37 mmol) was added 20 mL of TFA/DCM (50%). The reaction mixture was stirred for 1 h and then concentrated. The crude product was taken up in chloroform, treated with 500 mg of MP-carbonate resin (2.9 mmol/g) and stirred overnight. After filtration and concentration the product was obtained as its free base (370 mg; 100%).
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C1COCC1.[Fe]>[CH2:3]([O:10][C:11]1[N:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(OCc2ccccc2)nc1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 106.5 %

Procedure:
Ammonium chloride (325 mg, 6.0 mmol) in water (10 mL) was added to a solution of 2-benzyloxy-5-nitro-pyridine (350 mg, 1.5 mmol) in THF (15 mL) and the resulting mixture stirred at 75° C. for 30 minutes. Iron powder (340 mg, 6 mmol) was then added portion wise and the mixture stirred for 5 hours at 75° C. The reaction mixture was filtered over celite. The filtrate was basified with sodium bicarbonate solution and the product extracted with ethyl acetate. The organics were washed with brine solution, dried over Na2SO4 and concentrated to afford 320 mg (100%) of 6-benzyloxy-pyridin-3-ylamine.
Reaction SMILES: N.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:10]=[C:11]([C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13].[NH2:24][C:25]([CH3:32])=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(O)(C)(C)C>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:10]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:24][C:25]([CH3:32])=[C:26]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: COC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)c1ccccc1
Reactant: CCOC(=O)C=C(C)N
Agent: N
Solvent: CC(C)(C)O
Product: CCOC(=O)C1=C(C)NC(c2ccccc2)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 9.3 %

Procedure:
Ammonia (0.5 ml, d=0.88) was added to a solution of methyl alpha-(2,3-dichlorophenylmethylene)-beta-oxobenzenepropanoate (2 g, 7.3 mmoles) and ethyl 3-amino-2-butenoate (0.77 g, 6.0 mmoles) in tert. butanol (8 ml) at 60°. The reaction was maintained at this temperature for 16 hours. The solvent was removed in vacuo and the residue was chromatographed on silica eluting with ethyl acetate/petroleum ether (60°-80°) mixtures. The title compound (0.25 g) was obtained after crystallisation from 2-propanol mp 185°-6°.