Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:28])[CH2:10][CH2:9]1
Reactant: COc1ccc2c(c1)N(CC[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)C(=O)CO2
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: COc1ccc2c(c1)N(CC[C@H]1CC[C@H](N)CC1)C(=O)CO2

Procedure:
tert-Butyl{trans-4-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]cyclohexyl}carbamate (Intermediate 75) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([NH:13][CH:14]([CH:20]([CH3:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>ClCCCl>[CH3:21][CH:20]([CH3:22])[CH:14]([NH:13][C:11]1[O:12][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][N:10]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(NC(=O)NNC(=O)c1ccccc1)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)C(Nc1nnc(-c2ccccc2)o1)C(C)C
Temperature: 77.5 °C

Procedure:
To a solution of crude ethyl 2-(2-benzoylhydrazinecarboxamido)-3-methylbutanoate (assumed 5 mmol) in DCE (10 ml) was added POCl3 (1.5 g, 10 mmol). Upon completion of addition, the reaction was heated at 75-80° C. overnight. After this time, the excess solvent and POCl3 were removed in vacuo. The resulting remains were dissolved in EtOAc (75 ml) and washed sequentially with sat. aqueous NaHCO3 (2×25 mL) solution and sat. aqueous NaCl (25 mL) solution and dried over MgSO4. The solvent was removed in vacuo to give ethyl 3-methyl-2-(5-phenyl-1,3,4-oxadiazol-2-ylamino)butanoate in greater than 90% purity by LCMS; m/z (290, M+1).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH:7]=[C:8](Cl)[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:5]2=[N:4][CH:3]=1.Cl>O>[Cl:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:5]2=[N:4][CH:3]=1
Reactant: Clc1cn2c(Cl)cnc2c(N2CCNCC2)n1
Agent: Cl
Solvent: O
Product: Clc1cnc2c(N3CCNCC3)nccn12

Procedure:
Employing the procedure substantially as described in Example 2, Step B, but substituting for the starting material used therein an equimolecular amount of each of 3,6-dichloroimidazo[1,2-a]pyrazine and 8-bromo-3,6-dichloroimidazo[1,2-a]pyrazine, there is produced respectively: 3-chloro-6-(1-piperazinyl)imidazo[1,2-a]pyrazine. HCl.1/2 H2O (m.p. >300° C.); and 3,6-dichloro-8-(1-piperazinyl)imidazo[1,2-a]pyrazine.HCl (m.p. >350° C.).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)=[CH:8][CH:9]=2)[CH:4]=1.Cl.[NH+]1C=CC=CC=1>>[OH:19][C:15]1[CH:14]=[C:13]([C:7]2[CH:6]=[C:5]3[C:10]([CH:11]=[CH:12][C:3]([OH:2])=[CH:4]3)=[CH:9][CH:8]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(-c2ccc3ccc(OC)cc3c2)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Oc1cccc(-c2ccc3ccc(O)cc3c2)c1

Procedure:
The title compound was prepared by reacting 2-methoxy-7-(3-methoxyphenyl)naphthalene (0.52 g, 1.97 mmol) with pyridinium HCl (8 g) at 190° C. according to Method B to yield 0.13 g (28%) of a white solid: mp 163–165° C.; 1H NMR (DMSO-d6): δ 6.78–6.80 (1H, m), 7.08 (1H, dd, J=2.56 Hz, J=8.54 Hz), 7.13–7.14 (1H, m), 7.17–7.20 (2H, m), 7.27–7.30 (1H, m), 7.51 (1H, dd, J=2.14 Hz, J=8.54 Hz), 7.70 (1H, d, J=8.97 Hz), 7.83 (1H, d, J=8.54 Hz), 7.90 (1H, d, J=1.28 Hz), 9.55 (1H, s), 9.78 (1 H, s); MS (ESI) m/z 235 (M−H)−.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:13]=[C:14]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[CH:15]=1)(C(C)(C)C)(C)C.[C:31](Cl)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:40]1[CH:47]=[CH:46][C:43]([O:44][CH3:45])=[CH:42][CH:41]=1)[C:32]1[CH:39]=[CH:38][C:35]([O:36][CH3:37])=[CH:34][CH:33]=1.C(Cl)(Cl)Cl>CO>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:13]=[C:14]([CH2:16][O:17][C:31]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:40]2[CH:47]=[CH:46][C:43]([O:44][CH3:45])=[CH:42][CH:41]=2)[C:32]2[CH:39]=[CH:38][C:35]([O:36][CH3:37])=[CH:34][CH:33]=2)[CH:15]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(-c2ccccc2)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(OCc2cc(CO)cc(-c3ccccc3)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 96 h
Yield: 79 %

Procedure:
10.7 ml of pyrizine was added to dissolve 0.4596 g of Compound (2) in an Ar atmosphere, and 0.9547 g (2.80 mmol, 1.3 eq) of DMTrCl was added. This was agitated for 96 hours in an Ar atmosphere. After extraction with chloroform the organic layer was washed with H2O, sat. NaHCO3 aq and sat. NaCl aq, and dried by addition of anhydrous NaSO4. The solvent was distilled off under reduced pressure, and 0.4231 g (0.82 mmol, 38%) of Compound (3) was isolated by silica gel chromatography (chloroform:methanol=100:1).
Reaction SMILES: [OH:1][C:2]1([C:10]#[N:11])[CH2:7][CH2:6][N:5]([O:8][CH3:9])[CH2:4][CH2:3]1.CN(C)C1C=CN=CC=1.CN(C1C=CN=CC=1)C.[CH3:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:32]=1[CH2:39][C:40](Cl)=[O:41].O>ClCCl>[C:10]([C:2]1([O:1][C:40](=[O:41])[CH2:39][C:32]2[C:31]([CH3:30])=[CH:36][C:35]([CH3:37])=[CH:34][C:33]=2[CH3:38])[CH2:3][CH2:4][N:5]([O:8][CH3:9])[CH2:6][CH2:7]1)#[N:11]
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Reactant: CON1CCC(O)(C#N)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CON1CCC(C#N)(OC(=O)Cc2c(C)cc(C)cc2C)CC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−20° C.) solution of 4-hydroxy-1-methoxy-piperidine-4-carbonitrile (0.32 g, 2.05 mmol) in 2 ml dichloromethane was added 4-dimethylaminopyridine DMAP (13 mg, 0.05 mmol) under argon. Then (2,4,6-trimethyl-phenyl)-acetyl chloride (0.52 g, 2.64 mmol) dissolved in dichloromethane (3 ml) was added dropwise. The reaction mixture was stirred at −20° C. for 30 minutes, then 30 minutes at 0° C. and finally left stirring overnight at room temperature. The reaction mixture was poured into water and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel to give pure (2,4,6-trimethyl-phenyl)-acetic acid 4-cyano-1-methoxy-piperidin-4-yl ester (compound P3.5) as white solid, mp 75-78° C. Yield: 480 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:16][CH2:15]2)=O)=[CH:5][C:4]=1[CH3:24].O>C(Cl)(Cl)Cl>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1([C:12]2[C:7]3[C:6](=[CH:5][C:4]([CH3:24])=[C:3]([O:2][CH3:1])[CH:8]=3)[CH2:9][CH2:10][N:11]=2)[CH2:16][CH2:15]1
Reactant: COc1ccc(CCNC(=O)C2(c3ccccc3Cl)CC2)cc1C
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1C)CCN=C2C1(c2ccccc2Cl)CC1

Procedure:
A mixture of the amide and 82% w/w solution of polyphosphate ester in chloroform (170 g) was heated gently for 16 hours, then poured into water (1200 ml) and the mixture washed with ether. The aqueous phase was basified by addition of aqueous ammonia solution and the product was extracted with ethyl acetate. The extracts were dried and concentrated to give 1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-6-methyl-3,4-dihydroisoquinoline as a solid. Yield 14.7 g.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:9]=3[NH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>CO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:9]=3[NH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc2[nH]cc(C3=CCCCC3)c2s1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1cc2[nH]cc(C3CCCCC3)c2s1
Yield: 98 %

Procedure:
A solution (0.1 M) of 6-cyclohex-1-en-1-yl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid in MeOH/AcOEt (2:1) was treated with 20% Pd(OH)2/C (10% wt.). The resulting suspension was stirred for 18 h under 45 psi of hydrogen then purged with nitrogen and filtered. The filtrate was concentrated to afford the title compound (98%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([NH:10]C(OC(C)(C)C)=O)=[N:7][C:6]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:29])[NH:25][CH:26]2[CH2:28][CH2:27]2)=[CH:20][CH:19]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([NH2:10])=[N:7][C:6]=1[C:18]1[CH:19]=[CH:20][C:21]([C:24](=[O:29])[NH:25][CH:26]2[CH2:28][CH2:27]2)=[CH:22][CH:23]=1)=[O:4]
Reactant: COC(=O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccc(C(=O)NC2CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1sc(N)nc1-c1ccc(C(=O)NC2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-tert-Butoxycarbonylamino-4-(4-cyclopropylcarbamoyl-phenyl)-thiazole-5-carboxylic acid methyl ester (0.28 g, 6.71 mmol) and TFA (5 mL) in dichloromethane (5 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to give 2-Amino-4-(4-cyclopropylcarbamoyl-phenyl)-thiazole-5-carboxylic acid methyl ester; MS: 417.1 (M+H+).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH3:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:9]=1
Reactant: C1CCNCC1
Reactant: Cc1ccc(C#N)c(F)c1
Product: Cc1ccc(C#N)c(N2CCCCC2)c1
Temperature: 80 °C
Yield: 65 %

Procedure:
To commercially available 2-fluoro-4-methylbenzonitrile 15b (2.5 g, 18.5 mmol) was added piperidine (4 equiv., 7.3 ml) and the solution was heated at 80° C. overnight. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The organic phase was evaporated obtaining 2.3 g of a white solid. Yield=65% 1HNMR (DMSO, 200 MHz) δ 1.62 (6H, m), 2.32 (3H, s), 3.07 (4H, m), 6.87 (1H, dd, J=7.8 Hz, J′=0.8 Hz), 6.95 (1H, s), 7.53 (1H, d, J=7.8 Hz)
Reaction SMILES: [CH2:1](I)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:13][CH2:12][CH2:9][CH2:10][CH2:11][CH2:6][CH:7]=[CH2:8]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: C=CCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C

Procedure:
All the five compounds were prepared by the same method. The compounds I-8, I-9, I-10, I-11 and I-12 were synthesized by separately reacting allyl iodide, compounds I-4, I-5, I-6 and I-7 with 4-hydroxybiphenyl-4'-carboxylic acid. The synthesis of compound I-12 was described below as an example. 3.62 g (0.0157 mole) 4-hydroxylbiphenyl-4'-carboxylic acid, 500 ml ethanol, 50 ml water, 0.5 g KI and 2.02 g (0.036 mole) NaOH were heated to reflux for one hour. 7 g compound I-7 was then added dropwise. The mixture was refluxed for 12 hours and then 100 ml of 10% NaOH aqueous solution was added. The mixture was again heated to reflux for 2 hours, and cooled to room temperature. Water and diluted HCl were poured into the cooled mixture to precipitate, and the precipitated white solid was filtered and recrystallized from acetic acid to obtain 4.43 g of white crystals. mp: I-8: 231.8° C.; I-9: 223.7° C.; I-10: 213.9° C.; I-11: 202.8° C.; I-12: 161.4° C. Yield: I-8: 66.9%;I-9: 84.03%; I-10: 81.4%; I-11: 89.96%; I-12: 80.6%. 1H-NMR:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])C=O.[CH:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])OCC.[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]([O:15][CH2:16][CH3:17])[O:18][CH2:19][CH3:20])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CCO
Product: CCOC(OCC)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.9 %

Procedure:
A 250 mL flask was charged with 3-bromo-4-fluorobenzaldehyde (13.5 g, 66.5 mmol), triethyl orthoformate (13.3 mL, 79.8 mmol), and anhydrous EtOH (150 mL). Tetrabutylammonium tribromide was added and the reaction mixture was allowed to stir at room temperature for 48 hours. The crude reaction was poured into aqueous NaHCO3 and extracted with ethyl acetate (75 ml). The organic layers were combined, dried with Na2SO4 and reduced under vacuum to afford the intermediate (16.2 g, 88%) as a clear oil. 1HNMR (CDCl3) δ ppm: 7.71 (1H), 7.40 (1H), 7.12 (1H), 5.48 (1H), 3.65-3.51 (4H), 1.28-1.24 (6H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:5]=[CH:4][N:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:23][C:22]1[C:17]([C:13]2[N:12]([CH2:11][C:6]3[C:7]([CH2:8][CH2:9][CH3:10])=[C:2]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[N:3]=[CH:4][N:5]=3)[CH:16]=[CH:15][N:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: OB(O)c1cccnc1
Reactant: CCCc1c(Cl)ncnc1Cn1ccnc1-c1ncccc1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncnc1-c1cccnc1
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-6-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidine (268 mg, 0.81 mmol), 3-pyridyl boronic acid (1.84 mmol), Pd2(dba)3 (37 mg, 0.04 mmol), (t-Bu)3P (8 mg, 0.04 mmol) and Cs2CO3 (600 mg, 1.84 mmol) in dioxane (6 mL) is degassed. The mixture is then heated at 100° C. for 6 hours. The solvent is removed in vacuo and water (10 mL) and EtOAc (15 mL) is added. The layers are separated and the aqueous layer is extracted with EtOAc (15 mL). The combined extracts are washed with brine (20 mL), dried (Na2SO4), and evaporated. Preparative TLC purification of the residue provides the title product. 1H NMR (CDCl3) 8.95 (s, 1H), 8.69 (s, 2H), 8.24 (d, 1H), 7.79 (d, 1H), 7.51 (t, 1H), 7.40-7.43 (m, 1H), 7.32 (s, 1H), 7.21-7.25 (m, 1H), 7.19 (s, 1H), 5.91 (s, 2H), 2.65-2.69 (m, 2H), 1.41-1.47 (m, 2H), 0.81 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:34])[C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:25])[CH:18]=2)=[CH:15][CH:16]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Li+]>O1CCCC1>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:34])[C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:25])[CH:18]=2)=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CC(OCC)C(=O)OCC)cn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CC(OCC)C(=O)O)cn2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.7 %

Procedure:
60 mg (0.13 mmol) of ethyl 2-ethoxy-3-{6-[3-(3-heptyl-1-methylureido)phenyl]pyrid-3-yl}propanoate are placed in 4 ml of tetrahydrofuran, 0.2 ml (0.2 mmol) of aqueous 1M lithium hydroxide solution is added and the mixture is stirred at room temperature for 24 hours. After acidic hydrolysis to pH 4.5-5, the reaction medium is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with a 50/50 heptane/ethyl acetate mixture and then a 90/10 dichloromethane/methanol mixture. 40 mg (70%) of 2-ethoxy-3-{6-[3-(3-heptyl-1-methylureido)phenyl]pyrid-3-yl}propanoic acid are obtained in the form of a white solid with a melting point of 142-143° C.
Reaction SMILES: [ClH:1].[F:2][CH:3]([F:26])[CH:4]([NH:18]C(OC(C)(C)C)=O)[CH2:5][CH2:6][CH:7]([NH:10]C(OC(C)(C)C)=O)[C:8]#[CH:9]>CCOCC>[ClH:1].[ClH:1].[F:2][CH:3]([F:26])[CH:4]([NH2:18])[CH2:5][CH2:6][CH:7]([NH2:10])[C:8]#[CH:9]
Reactant: C#CC(CCC(NC(=O)OC(C)(C)C)C(F)F)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: C#CC(N)CCC(N)C(F)F
Reaction time: 8 h

Procedure:
A saturated solution of dry hydrogen chloride in dry ether (10 ml) is added to 1,1-difluoro-2,5-di-(N-tert.butoxycarbonylamino)-6-heptyne obtained as in Step E above (1 mmole) and left overnight at room temperature. The dichlorohydrate which forms as crystals is filtered, washed with ether, and dried to give the title compound (0.23 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH:23]([OH:25])[CH2:22][CH2:21][NH:20]3)=[C:15]([O:26]CC3C=CC=CC=3)[CH:14]=2)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34](OC(=O)CC)(=O)[CH2:35][CH3:36].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:34]([N:20]1[CH2:21][CH2:22][C@H:23]([OH:25])[CH2:24][C@@H:19]1[C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:10]([CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:11])=[CH:14][C:15]=1[OH:26])[CH2:35][CH3:36]
Reactant: CC(CCCc1ccccc1)Oc1ccc(C2CC(O)CCN2)c(OCc2ccccc2)c1
Reactant: CCC(=O)OC(=O)CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCN1CC[C@H](O)C[C@@H]1c1ccc(OC(C)CCCc2ccccc2)cc1O

Procedure:
Acylation of 2-[4-(5-phenyl-2-pentyloxy)-2-benzyloxyphenyl]-4-piperidinol with propionic anhydride by the method of Example 8, followed by lithium aluminum hydride reduction of the resulting N,O-dipropionyl intermediate by the method of Example 9, Part A, and finally, debenzylation by the method of Example 9, Part B, provides the title compound in like manner.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.S([O-])([O-])(=O)=[O:11].[Na+].[Na+].ClC1C=C(C=CC=1)C(OO)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N+:3]=1[O-:11]
Reactant: COc1ccc(C)nc1
Reactant: O=S(=O)([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.2 %

Procedure:
To a solution of 2-methyl-5-methoxy-pyridine (2.93 g, 24 mmol) in DCM (100 mL) was added sodium sulphate (5 g, 35 mmol), followed by m-chloro-peroxy-benzoic acid (10 g, 58 mmol), and mixture was stirred at room temperature for ˜48 hours. The reaction mixture was filtered, and the white solid was washed with DCM. The filtrate was concentrated and purified by normal phase chromatography eluting with a gradient of 1:1 EtOAc/heptane to EtOAc to give 2-methyl-5-methoxy-pyridine-N-oxide (2.41 g, 72%).
Reaction SMILES: Cl.[CH3:2]/[C:3](=[CH:10]\[CH3:11])/[CH2:4][O:5][CH:6]1[CH2:9][NH:8][CH2:7]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:43]=[C:44]1[NH:53][C:52]2[N:51]=[CH:50][C:49](/[CH:54]=[CH:55]/[C:56](O)=[O:57])=[CH:48][C:47]=2[CH2:46][CH2:45]1>CN(C)C=O.O.C(OCC)(=O)C>[CH3:2]/[C:3](=[CH:10]\[CH3:11])/[CH2:4][O:5][CH:6]1[CH2:9][N:8]([C:56](=[O:57])/[CH:55]=[CH:54]/[C:49]2[CH:48]=[C:47]3[C:52](=[N:51][CH:50]=2)[NH:53][C:44](=[O:43])[CH2:45][CH2:46]3)[CH2:7]1
Reactant: C/C=C(\C)COC1CNC1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C/C=C(\C)COC1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Reaction time: 8 h

Procedure:
(E)-3-(2-Methylbut-2-enyloxy)azetidine hydrochloride (168 mg, 0.94 mmol), EDCI (182 mg, 0.94 mmol), HOBt (132 mg, 0.94 mmol) and diisopropylethylamine (276 μL, 1.58 mmol) were successively added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (161 mg, 0.63 mmol) in dimethylformamide (12 mL) at room temperature. The reaction mixture was stirred overnight then diluted by addition of ethyl acetate (40 mL) and water (40 mL). The aqueous layer was separated and extracted with ethyl acetate (2×40 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (98:2) as eluent. After trituration in diethyl ether, petroleum ether and methanol, the title product was obtained as a white solid (46 mg, 21%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10]([CH2:15][CH:16]=[CH2:17])[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[NH:20]1[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27]O)[N:22]=[CH:21]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10]([CH2:15][CH:16]=[CH2:17])[C:9]=2[C:8](=[O:18])[N:7]([CH2:27][CH2:26][CH2:25][C:23]2[N:22]=[CH:21][NH:20][CH:24]=2)[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Reactant: OCCCc1c[nH]cn1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCn1c(Cl)nc2c1c(=O)n(CCCc1c[nH]cn1)c(=O)n2CCCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.8 %

Procedure:
A solution of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.8 g, 9.9 mmol) in anhydrous THF (60 ml) was treated with 3-(1H-imidazol-4-yl)-1-propanol (1.5 g, 12 mmol) in anhydrous THF (10 ml) and PPh3 (3.4 g, 13 mmol). DBAD (2.9 g, 13 mmol) was added in one portion and the mixture was left to stir at rt, under nitrogen for 18 h. The mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted and washed with EtOAc. The organic layers were combined, washed with brine, dried (MgSO4) and concentrated. The crude product was purified by a silica SPE cartridge using a MeOH/EtOAc gradient (0.5%-7% MeOH). The product fractions were combined and concentrated by to give the title compound as a white solid (2.16 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[C:43]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:41]=[CH:40][C:3]=1[CH2:4][N:5]([CH2:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16](COCC)[C:17]2[NH:21][N:20]=[N:19][N:18]=2)[CH:11]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[C:43]([C:44]([F:47])([F:45])[F:46])=[CH:42][CH:41]=[CH:40][C:3]=1[CH2:4][N:5]([CH2:26][CH:27]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)[CH:11]=1
Reactant: CCOCC(c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1)c1nnn[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cccc(CN(CCCOc2cccc(Cc3nnn[nH]3)c2)CC(c2ccccc2)c2ccccc2)c1Cl
Reaction time: 8 h
Yield: 43.4 %

Procedure:
To a stirring solution of (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(ethoxymethyl-1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine (mixture of regioisomers, 125 mg, 0.19 mmol) in dichloromethane (11 ml) was added triethylsilane (116 mg, 1.08 mmol). The reaction mixture was treated with TFA (3 ml) and then stirred overnight. Solvent was removed and the residue was purified by preparative HPLC (YMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile:water, UV detection at 254 nm) to afford 50 mg (44%) the title compound as a yellow oil. MS (ESI) 607.0(M+H+).