Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][N:8]3[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[O:17])[N:10]=[C:9]3[C:3]([NH2:27])([CH2:4][O:5]2)[CH2:2]1.[CH3:28][N:29]([CH3:35])[C:30](=[O:34])[C:31](O)=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:28][N:29]([C:30]([C:31]([NH:27][C:3]12[CH2:4][O:5][CH:6]([CH2:7][N:8]3[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]([NH:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[O:17])[N:10]=[C:9]31)[CH2:1][CH2:2]2)=[O:32])=[O:34])[CH3:35]
Reactant: NC12CCC(Cn3c1nc(C(=O)NCc1ccc(F)cc1)c(O)c3=O)OC2
Reactant: CN(C)C(=O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C(=O)NC12CCC(Cn3c1nc(C(=O)NCc1ccc(F)cc1)c(O)c3=O)OC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
To a stirred solution of 10-amino-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-(epoxymethano)pyrimido[1,2-a]azepine-2-carboxamide (70 mg, 0.187 mmol) and 2-(dimethylamino)-2-oxoacetic acid (32.8 mg, 0.280 mmol) in DMF (3 mL) was added diisopropyl-ethylamine (0.175 mL, 1.002 mmol), 4-(dimethylamino)pyridine (DMAP) (4.57 mg, 0.037 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (107 mg, 0.280 mmol) and the resulting mixture stirred at room temperature for 3 h. After work-up the crude was purified by preparative HPLC to afford the title compound as an off-white solid (35 mg, 40% yield). 1H NMR (500 MHz, CDCl3) δ: 12.11 (s, 1H), 8.73 (brs, 1H), 7.47 (s, 1H), 7.34 (dd, 2H, J=8.39 & 5.34 Hz), 6.98-7.03 (m, 2H), 4.62-4.70 (m, 2H), 4.53 (d, 2H, J=6.71 Hz), 4.49-4.52 (m, 1H), 4.29 (d, 1H, J=11.6 Hz), 4.08 (d, 1H, J=16.79 Hz), 3.21 (s, 3H), 2.89 (s, 3H), 2.46-2.53 (m, 1H), 2.33-2.38 (m, 1H), 1.86-1.92 (m, 1H), 1.53-1.58 (m, 1H). LCMS (M+H)=474.24. HPLC purity>95%.
Reaction SMILES: [CH:1]1([C:7]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH:25]=[N:26][N:27]([CH3:28])[C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([C:7]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH:25]=[N:26][N:27]([CH3:28])[C:13]4=[CH:12][N:11]23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N(C)N=CN12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN1N=CN2C1=Cn1c(cc3c(C4CCCCC4)cccc31)-c1cc(C(=O)O)ccc12
Temperature: 70 °C
Yield: 78.8 %

Procedure:
To a solution of methyl 10-cyclohexyl-1-methyl-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine-7-carboxylate (173 mg, 0.406 mmol) in THF (7 mL) and MeOH (3.5 mL), was added aq NaOH (1.0N, 1.8 mL, 1.8 mmol). The reaction mixture was heated at 70° C. for 2 h and the solvents were removed. The resulting white solid residue was washed with water, isolated by centrifuge and dried under N2 to yield 10-cyclohexyl-1-methyl-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine-7-carboxylic acid (132 mg, 0.320 mmol, 79%) as a white solid, which was used without further purification. 1H NMR (500 MHz, d6-DMSO) δ 1.13-1.24 (m, 1H), 1.35-1.51 (m, 3H), 1.66-1.75 (m, 2H), 1.85-2.08 (m, 4H), 2.48 (s, 3H), 2.79-2.89 (m, 1H), 4.90 (d, J=15.6 Hz, 1H), 5.80 (d, J=15.6 Hz, 1H), 7.65-7.72 (m, 5H), 7.78-7.83 (m, 1H), 8.15 (s, 1H). LCMS: m/e 413 (M+H)+, ret time 2.01 min.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[CH2:29]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([N:26]2[CH2:27][CH2:28][N:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][CH3:15])[CH2:24][CH2:25]2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccccc1N1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium triacetoxyborohydride (21.2 g) was added portionwise to a stirred solution of 1-(2-methoxyphenyl)piperazine (commercially available, 19.23 g) and 1-benzyl-4-piperidone (commercially available, 18.93 g) in CH2Cl2 (300 mL) at room temperature, followed by glacial acetic acid (6 mL). The resulting mixture was stirred at room temperature for 24 hours. The reaction was made basic by careful addition of saturated aqueous NaHCO3. The organic layer was separated, washed with brine, dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator to give the desired product (20.65 g) as an off-white solid which was used without further purification. The compound was characterized as the dihydrochloride salt, which was formed by dissolving the free base in ethanol and treating it with an excess of 1 N HCl/Et2O to give a white solid, which was collected by vacuum filtration, washed with Et2O and dried in vacuo; MP. 238-242° C.; MS (ES) m/z (relative intensity) 366 (M+H)+ (100).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:30][CH2:29][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])=[O:19])[C:9]3=[O:28])[C:6]=2[CH:7]=1.BrC1C=CC2C3(COC=2C=1)C1C(=CC=CC=1)[N:40]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])C3=O>>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:18](=[O:19])[CH2:17][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2([C:6]3[CH:7]=[C:2]([C:50]4[CH:51]=[N:40][CH:47]=[CH:48][CH:49]=4)[CH:3]=[CH:4][C:5]=3[O:30][CH2:29]2)[C:9]1=[O:28]
Reactant: CCCCCN1C(=O)C2(COc3cc(Br)ccc32)c2ccccc21
Reactant: O=C(CN1C(=O)C2(COc3ccc(Br)cc32)c2ccccc21)Nc1ccccc1F
Product: O=C(CN1C(=O)C2(COc3ccc(-c4cccnc4)cc32)c2ccccc21)Nc1ccccc1F
Yield: 55 %

Procedure:
Following the procedure as described in EXAMPLE 37, and making non-critical variations using 2-(5-bromo-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide to replace 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, the title compound was obtained (55% yield) was obtained as a white solid: mp 98-100° C.; 1H NMR (300 MHz, CDCl3) δ 8.60-8.53 (m, 2H), 8.14 (dd, 1H), 7.65 (dd, 1H), 7.41 (dd, 1H), 7.32-6.90 (m, 11H), 5.02 (d, 1H), 4.76 (d, 1H), 4.72 (d, 1H), 4.56 (d, 1H); 13C NMR (75 MHz, CDCl3) δ 177.9, 164.8, 160.9, 154.2, 151.0, 147.1,141.7, 134.2, 131.7, 131.5, 129.9, 129.4, 129.1, 125.1, 124.6, 124.5, 124.2, 124.0, 122.5, 122.2, 115.1, 114.8, 111.0, 109.1, 80.0, 58.1, 44.6; MS (ES+) m/z 466.4 (M+1).
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:44]1[CH:53]=[C:52]2[C:47]([C:48]([C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][C:56]=3[O:65][CH3:66])=[N:49][C:50]([CH3:54])=[N:51]2)=[CH:46][CH:45]=1.CCN(C(C)C)C(C)C.[CH2:76]([SH:83])[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1>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]>[CH2:76]([S:83][C:44]1[CH:53]=[C:52]2[C:47]([C:48]([C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][C:56]=3[O:65][CH3:66])=[N:49][C:50]([CH3:54])=[N:51]2)=[CH:46][CH:45]=1)[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1
Reactant: SCc1ccccc1
Reactant: COc1cc(C(F)(F)F)ccc1-c1nc(C)nc2cc(Br)ccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1nc(C)nc2cc(SCc3ccccc3)ccc12
Reaction time: 1 h

Procedure:
A solution of Pd2(dba)3 (0.046 g, 0.050 mmol), Xantphos (0.058 g, 0.100 mmol), 7-bromo-4-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methylquinazoline (0.797 g, 2.007 mmol), and n,n-diisopropylethylamine (1.051 ml, 6.02 mmol) in 10 mL dioxane was heated to 60° C. and was treated with benzyl mercaptan (0.237 ml, 2.007 mmol). After stirring for one hour, LC/MS showed mostly product, so the reaction mixture was concentrated. This material was carried on to step 3 without purification. (M+H)+=441.0.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[C:19]([CH3:20])=[C:18]([CH3:21])[S:17][C:15]=2[N:16]=1>>[Cl:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[C:19]([CH3:20])=[C:18]([CH3:21])[S:17][C:15]=2[N:16]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Reactant: NCc1ccc(F)cc1
Product: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
Following the procedure of Example 1, the reaction of 4-fluorobenzylamine with 2,4-dichloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].Cl.N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>C(OCC)(=O)C.O>[N:4]([C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: [N-]=[N+]=Nc1c(Cl)cccc1Cl
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
To a 0° C. solution of 2,6-dichloroaniline (2.00 g) in ethyl acetate (40 mL) is added concentrated hydrochloric acid (12 mL). The reaction is stirred for 10 min. To this solution is added a solution of sodium nitrite (2.55 g) in water (7.5 mL) over 3 min. Upon completion of the addition, the reaction is stirred for an additional 30 min. A solution of sodium azide (2.41 g) in water (8 mL) is added over 5 min. After 30 min, pH 7 buffer (50 mL) is added and the reaction is transferred to a separatory funnel. The layers are separated and the aqueous layer is extracted with ethyl acetate. The organic layers are combined and washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (2.11 g). 1H NMR (400 MHz, CDCl3) δ 7.3-7.27 (d, 2H), 7.07-7.02 (t, 1H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[Br:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[Br:26][C:27]1[CH:32]=[C:31]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:5]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)nc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1cccc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)c1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 4-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl ester (example A.55) (1.6 g, 4.15 mmol) and commercially available 3-bromobenzeneboronic acid (0.751 g, 3.74 mmol) according to the general procedure Iba. Obtained as a light yellow oil (1.39 g, 85%). MS (ISP) 392.0 [(M+H)+] and 394.1 [(M+2+H)+].
Reaction SMILES: C[OH:2].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:31][CH2:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37])[C:9]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:10][S:11]2)=[CH:6][CH:5]=1>O>[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:31]([CH2:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:37])([F:38])[F:39])=[O:2])[C:9]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:10][S:11]2)=[CH:6][CH:5]=1
Reactant: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Reactant: CO
Solvent: O
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 45 %

Procedure:
Methanol (16 ml) and water (4 ml) were added to the mixture of (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylthio)nonyl]thiochroman (85 mg, 0.14 mmol) obtained in Example 33 and NaIO4 (34 mg, 0.16 mmol), and the reaction mixture was stirred for 3.5 hours at room temperature. Water was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then purified with preparative TLC (n-hexane:ethyl acetate=1:1) to obtain 39 mg (yield: 45%) of the title compound as a white solid. In this reaction, 13 mg (15%) of the unreacted starting 3RS,4RS-compound was recovered.
Reaction SMILES: FC(F)(F)COP([CH2:13][C:14]([O:16][CH3:17])=[O:15])(=O)OCC(F)(F)F.C1OCCOCCOCCOCCOCCOC1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[Br:48][C:49]1[C:50]([OH:58])=[C:51]([CH:54]=[C:55]([Cl:57])[CH:56]=1)[CH:52]=O>C1COCC1>[Br:48][C:49]1[C:50]([OH:58])=[C:51](/[CH:52]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])[CH:54]=[C:55]([Cl:57])[CH:56]=1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: O=Cc1cc(Cl)cc(Br)c1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cc(Cl)cc(Br)c1O
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
To a solution of bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate (3.18 g, 10.0 mmol) in THF (100 mL) at −78° C. was added 18-crown-6 (13.2 g, 50.0 mmol). The solution was stirred for 10 min then a solution of potassium hexamethyldisilazide in THF (0.91 M, 11.0 mL, 10.0 mmol) was added slowly. The reaction was stirred for 20 min then 3-bromo-5-chloro-2-hydroxy benzaldehyde (2.35 g, 10 mmol) was added. The reaction was allowed to stir at −78° C. for 2 hr, then was quenched with saturated NH4Cl (20 mL) The mixture was extracted with Et2O (3×100 mL) and the organic layer was dried (Na2SO4) and concentrated. Flash chromatography on silica gel (15% EtOAc/hexanes) gave, the title compound (2.48 g, 85%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=16.0 Hz, 1H), 7.50 (s, 1H), 7.44 (s, 1H), 6.57 (d, J=16.0 Hz, 1H), 3.84 (s, 3H); MS (ES) m/e 291, 293 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[C:10]([C:14]1[O:18][N:17]=[C:16]([N:19]=[C:20]=[O:21])[CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[C:10]([C:14]1[O:18][N:17]=[C:16]([NH:19][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=2)=[O:21])[CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Nc1ccc(F)c(O)c1
Reactant: CC(C)(C)c1cc(N=C=O)no1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(F)c(O)c2)no1
Temperature: 70 °C

Procedure:
A mixture of 5-amino-2-fluorophenol (1.3 g, 10.2 mmol) and 5-tert-butyl-3-isocyanatoisoxazole (1.7 g, 10.2 mmol) in toluene (60 mL) was heated at 70° C. overnight. The solid was filtered and dried under vacuum to afford 1-(5-tert-butylisoxazol-3-yl)-3-(4-fluoro-3-hydroxyphenyl)urea as solid.
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].O[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Reactant: O=Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)N1CCC(CCC(=O)Oc2ccc(C=O)cc2)CC1
Yield: 36.4 %

Procedure:
A mixture of 4.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 2.1 g of p-hydroxybenzaldehyde was suspended in 20 ml of dry pyridine. 3.5 g of dicyclohexylcarbodiimide was added with stirring to the suspension, and the resulting mixture was stirred overnight at room temperature. After removal of any insoluble materials, the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was stirred to give crystals. The crystals were recrystallized from methanol-ether to obtain 2.1 g (yield: 36.4%) of p-formylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 144° to 147° C.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:50])=[N:17][C:18]([CH3:49])=[C:19]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)=[CH:35][CH:34]=2)[C:20]=1[N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)[C:9]([O:11]C(C)C)=[O:10])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:50])=[N:17][C:18]([CH3:49])=[C:19]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)=[CH:37][CH:38]=2)[C:20]=1[N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)[C:9]([OH:11])=[O:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(c3ccccc3)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(c3ccccc3)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
The potassium hydroxide (72.2 mg, 1.28 mmol) was added to a solution (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)acetate (84 mg, 0.13 mmol) in ethanol (3 mL) and stirred for 3 h at 90° C. The reaction mixture was neutralized with 1N HCl solution, extracted with EtOAc, and the organic layer was washed with brine, and dried (MgSO4). The crude material was purified by prep HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)acetic acid 51.2 mg (65%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.41-7.39 (m, 2H), 7.28-7.22 (m, 3H), 7.17-7.13 (m, 5H), 7.05-7.01 (m, 3H), 5.88 (br. s, 1H), 4.24 (t, J=6.2 Hz, 2H), 3.59-3.58 (m, 1H), 3.09-3.06 (m, 2H), 2.75-2.71 (m, 1H), 2.58-2.56 (m, 1H), 2.47 (s, 3H), 2.26-2.22 (br. s, 1H), 2.05 (s, 3H), 1.94-1.81 (m, 2H), 1.65-1.50 (m, 3H), 1.18 (s, 9H). UPLC (M+H)=611.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[N:14][N:13](C3CCCCO3)[C:12](=[O:22])[CH:11]=2)=[N:6][CH:7]=1.Cl>CO.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[N:14][NH:13][C:12](=[O:22])[CH:11]=2)=[N:6][CH:7]=1
Reactant: O=c1cc(OCc2ccc(F)cn2)cnn1C1CCCCO1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=c1cc(OCc2ccc(F)cn2)cn[nH]1
Reaction time: 16 h
Yield: 77.9 %

Procedure:
5-((5-Fluoropyridin-2-yl)methoxy)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (1.1 g, 3.6 mmol) was stirred in MeOH (5 mL) and 2 N HCl in Et2O (20 mL) was added. After 16 h, the mixture was diluted with Et2O (100 mL), and the solid was filtered off. The solid was stirred in NaHCO3 solution (15 mL) for 15 minutes and then refiltered to provide the title compound (620 mg, 78%) as a pink solid: 1H NMR (300 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.60 (d, J=2.8 Hz, 1H), 7.85-7.78 (td, J=8.7, 2.9 Hz, 1H), 7.76 (d, J=2.7 Hz, 1H), 7.67-7.63 (dd, J=8.6, 4.5 Hz, 1H), 6.31 (s, 1H), 5.25 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].CC(C[AlH]CC(C)C)C>>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:10][C:3]=1[CH:4]=[O:5]
Reactant: CON(C)C(=O)c1cc(-n2cccn2)ccc1Cl
Agent: CC(C)C[AlH]CC(C)C
Product: O=Cc1cc(-n2cccn2)ccc1Cl
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-N-methoxy-N-methyl-5-pyrazol-1-yl-benzamide (280 mg, 1.05 mmol) was added DIBAL-H (1.16 mL, 1.16 mmol) slowly at −78° C. The reaction was stirred 2 h, quenched with water, extracted with ether, concentrated, and purified by flash chromatography to give 2-chloro-5-pyrazol-1-yl-benzaldehyde.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([N:8]([CH3:24])[C@H:9]([C:13]([N:15]1[CH2:23][CH2:22][CH2:21][C@H:16]1[C:17]([O:19][CH3:20])=[O:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4]>CO.[Pd]>[NH2:1][C@H:2]([C:6]([N:8]([CH3:24])[C@H:9]([C:13]([N:15]1[CH2:23][CH2:22][CH2:21][C@H:16]1[C:17]([O:19][CH3:20])=[O:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](N)C(C)C
Yield: 104.4 %

Procedure:
29.3 g (61.6 mmol) of Z-Val-MeVal-Pro-OMe were dissolved in 230 ml of methanol. After addition of 1.15 g of 10% palladium/charcoal, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 21.96 g of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:17][OH:18].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:17][OH:18]
Reactant: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1CO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)COCCCCN1C(=O)CCC[C@@H]1CO
Reaction time: 2.25 h
Yield: 89.1 %

Procedure:
Palladium on carbon (10 wt. %, 25 mg) was added to a solution of [(Z)4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-enyloxy]-acetic acid methyl ester (318 mg, 1.17 mmol) in MeOH (5.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 2.25 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (30% EtOAc/CH2Cl2→50% EtOAc/CH2Cl2, gradient, then 2% MeOH(CH2Cl2→5% MeOH/CH2Cl2) afforded 285 mg (89%) of [4-((R)-2-hydroxymethyl-6-oxo -piperidin-1-yl)-butoxy]-acetic acid methyl ester.
Reaction SMILES: [CH2:1]([Si:9]([CH3:12])([CH3:11])Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:13][C:14]([CH3:25])([C:16](=[O:24])[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].C(N(CC)CC)C>C(OCC)C>[CH2:1]([Si:9]([CH3:12])([CH3:11])[O:24][C:16](=[CH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]([CH3:13])([CH3:15])[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[Si](C)(C)Cl
Reactant: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCC[Si](C)(C)OC(=CC(=O)C(C)(C)C)C(C)(C)C

Procedure:
A dehydrating compound was prepared by the dropwise addition of octyldimethylchlorosilane to an equal molar solution of 2,2,6,6-tetramethyl-3,5-heptanedione and triethylamine in ethyl ether. The mixture was heated until it refluxed for a period of 6 hours, and filtered to remove salts. The solvent was removed under reduced pressure to yield 3-(octyldimethylsiloxy)-2,2,6,6-tetramethylhept-3-ene-5-one.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CC(C)=O.O>[N:12]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a stirred solution of p-bromomethylbenzoic acid (13.607 g, 63.3 mmol) in acetone (300 ml) and H2O (15 ml) was added dropwise at room temperature a solution of NaN3 (4.123 g, 63.4 mmol) in H2O (40 ml). The reaction mixture was stirred at room temperature overnight(ca 20 h). After evaporation of the acetone, the residual solid was suspended in water and filtered, yielding 10.13 g (57.2 mmol, 90.3%) of p-azidomethylbenzoic acid as a white powder: 1Hmr (DMSO-d6 4.57 (2H, s, --CH3N3), 7.43-7.55-7.93-8.07 (4H, A2 'B2 ', aromatic Hs) and 12.7 ppm (br, s, --CO2H): ir (nujol) νmax : (--N3) and 1670 cm-1 (--CO2H).