Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>O1CCCC1.O>[C:25]([O:24][C:22]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH:4]([O:29][CH2:30][C:31]([F:32])([F:33])[F:34])[C:3]([OH:35])=[O:2])=[CH:7][CH:8]=2)=[CH:20][CH:19]=1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(CC(OCC(F)(F)F)C(=O)O)cc2)cc1
Yield: 87.5 %

Procedure:
3-[4-(2-{4-tert-Butoxycarbonylaminophenyl}ethoxy)phenyl]-2-(2,2,2-tnifluoroethoxy)propanoic acid methyl ester (described in Example 60)(0.27 g; 0.52 mmole) was dissolved in tetrahydrofuran and water (2:1), lithium hydroxide (0.015 g; 0.62 mmole) was added and the reaction mixture was stirred over night. Water was added and tetrahydrofuran was evaporated. The remaining water residue was extracted once with diethyl ether, acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate. Evaporation gave 0.22 g (85% yield) of 3-[4-(2-{4-tert-butoxycarbonylaminophenyl}ethoxy)phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[N+:37]([O-:39])=[O:38])=[CH:22][C:18]=1[C:19](Cl)=[O:20])([O-:16])=[O:15]>C1(C)C=CC=CC=1>[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][C:28]=2[N+:37]([O-:39])=[O:38])=[CH:22][C:18]=1[C:19]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:20])([O-:16])=[O:15]
Reactant: OC1CCOC1
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCOC1)c1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])ccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and adtition funnel. A solution of 2-nitro-5-(2-nitro-4-trifluoromethylphenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-nitro-5-(2-nitro-4-trifluoromethylphenoxy)benzoate.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH3:12][C:13]([CH3:33])([CH3:32])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:22][C:23]1[CH:24]=[C:25]([C:29](=O)[CH3:30])[CH:26]=[CH:27][CH:28]=1)[CH2:20][CH3:21]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:13]([CH3:33])([CH3:32])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([CH3:1])=[CH2:30])[CH:24]=1)[CH2:20][CH3:21]
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(C(C)=O)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: C=C(C)c1cccc(CN(CC)C/C=C/C#CC(C)(C)C)c1
Yield: 73.6 %

Procedure:
The procedure described in Example 9 was repeated, except that methyl triphenylphosphonium bromide (2.35 g; 6.6 mmol), n-butyl lithium in n-hexane (1.56 M: 4.2 ml; 6.6 mmol), and Compound 43 (1.3 g; 4.4 mmol) were used, to thereby yield 950 mg of the target compound (yield: 73.6%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([CH2:33]Br)=[O:32])=[CH:27][CH:26]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:1][C:2]1([CH3:21])[N:6]([CH2:33][C:31](=[O:32])[C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)[C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20]
Reactant: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)CN2C(=O)N(C(=O)c3cccc4ccccc34)C(=O)C2(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (35 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 2-bromo-4-methylacetophenone (27 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 12 mg of white crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C:25]5=[O:30])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]([F:35])([F:34])[F:33])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C[C:37]([N:39](C)C)=O>[C-]#N.[C-]#N.[Zn+2].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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[Zn]>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C:25]5=[O:30])=[CH:22][CH:23]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]([F:35])([F:34])[F:33])=[N:10]2)=[CH:3][C:2]=1[C:37]#[N:39]
Reactant: O=C1CCCCN1c1ccc(N2CCc3c(C(F)(F)F)nn(-c4ccc(F)c(Cl)c4)c3C2=O)cc1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1cc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(N4CCCCC4=O)cc2)CC3)ccc1F
Temperature: 140 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
1-(3-chloro-4-fluorophenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one (0.35 g, 0.69 mmol), Zn(CN)2 (81 mg, 0.69 mmol), Pd2(dba)3 (63 mg, 0.07 mmol), dppf (77 mg, 0.14 mmol), and Zn (9 mg, 0.14 mmol) were added to 15 mL of DMAC. The mixture was degassed under argon and stirred at 140° C. under N2 for 12 h. The reaction was cooled to rt, ethylacetate (75 mL) was added and the mixture was filtered through Celite®. The filtrate was washed with saturated NaHCO3 solution (30 mL), water (30 mL×3), and brine (20 mL). It was then dried over Na2SO4, filtered, and concentrated. The residue was purified via flash chromatography on silica gel with 10% methanol in dichloromethane to give 2-fluoro-5-[7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl]benzonitrile (0.17 g, 50% yield). LRMS (AP+): 498.2 (M+H)+. 1H NMR (CDCl3) δ 7.91-7.85 (m, 2H), 7.31 (s, 4H), 7.28-7.25 (m, 1H), 4.16 (t, 2H), 3.63-3.61 (m, 2H), 3.18 (t, 2H), 2.56 (t, 2H), 1.96-1.93 (m, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][N:13]=[C:12]([C:15]([OH:17])=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:42]1([C@@H:48]([NH2:50])[CH3:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][N:13]=[C:12]([C:15]([NH:50][C@H:48]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH3:49])=[O:17])[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C(O)c1cc(-c2ccc3[nH]ncc3c2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cc(-c2ccc3[nH]ncc3c2)on1)c1ccccc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
5-(1H-Indazol-5-yl)isoxazole-3-carboxylic acid (36 mg, 0.16 mmol, Example 71A), was dissolved in N,N-dimethylformamide (1.0 mL) followed by the addition of HATU (60 mg, 0.16 mmol) dissolved in N,N-dimethylformamide (0.5 mL). Then a solution of (S)-1-phenylethanamine (22 mg, 0.18 mmol), dissolved in N,N-dimethylformamide (0.6 mL) was added, followed by diisopropylethylamine (56 μL, 0.32 mmol) dissolved in N,N-dimethylformamide (0.2 mL). The resulting mixture was shaken for 3 hours at 40° C. The reaction was filtered, checked by LC/MS and concentrated to dryness. The residues were dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase HPLC (Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm), 50 mL/min, 10-100% acetonitrile/0.1% trifluoroacetic acid in water) to provide the title product. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 1.50 (d, 3H), 5.06-5.22 (m, 1H), 7.23-7.29 (m, 2H), 7.34-7.38 (m, 2H), 7.40-7.45 (m, 2H), 7.70-7.75 (m, 1H), 7.87-7.92 (m, 1H), 8.25-8.27 (m, 1H), 8.39-8.41 (m, 1H), 9.28 (d, 1H). MS (ESI+) m/z 333 (M+H)+; (ESI−) m/z 331 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([C:21]3[C:26]([F:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:29]([OH:31])=O)[CH2:12]1)(=[O:10])=[O:9].[CH:32]1([NH:35][C:36](=[O:45])[C:37](=[O:44])[C@@H:38]([NH2:43])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:34][CH2:33]1>>[Cl:28][C:24]1[CH:25]=[C:26]([F:27])[C:21]([C:18]2([C:16]([N:14]3[CH2:15][C@H:11]([S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:9])=[O:10])[CH2:12][C@H:13]3[C:29]([NH:43][C@@H:38]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:37](=[O:44])[C:36]([NH:35][CH:32]3[CH2:34][CH2:33]3)=[O:45])=[O:31])=[O:17])[CH2:19][CH2:20]2)=[N:22][CH:23]=1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1
Reactant: CC(C)C[C@H](N)C(=O)C(=O)NC1CC1
Product: CC(C)C[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-Amino-5-methyl-2-oxo-hexanoic acid cyclopropylamide in step 1. MS (m/e)=667.15 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][N:19]=[C:20]=[O:21].O1CCCC1>CN(C)C=O>[CH3:18][NH:19][C:20]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:21]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Reaction time: 3.5 h
Yield: 23 %

Procedure:
A solution of 0.15 gm (0.65 mMol) 5-amino-3-(1-methyl-piperidin-4yl)pyrrolo[3,2-b]pyridine and 0.046 mL (0.78 mMol) methyl isocyanate in 6 mL 5:1 tetrahydrofuran: dimethylformamide was stirred at room temperature for 5 hours. At this point an additional 0.020 mL methyl isocyanate were added and stirring continued for another 3.5 hours. The reaction mixture was then concentrated under reduced pressure. The residue was partitioned between 3:1 chloroform:isopropanol and 1N sodium hydroxide. The phases were separated and the aqueous phase extracted well with 3:1 chloroform:isopropanol. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to radial chromatography (2mm silica gel plate), eluting with dichloromethane containing from 20-40% methanol and 1% ammonium hydroxide. Fractions shown to contain produce were combined and concentrated under reduced pressure. The residue was crystallized from aqueous ethanol to provide 0.043 gm (34%) of the title compound. m.p.=228.8-230.4° C. MS(m/e): 288(M+1) Calculated for C15H21N5O: Theory: C, 62.70; H, 7.37; N, 24.37. Found: C, 62.49; H, 7.29; N, 24.40.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:13]3[CH2:15][CH2:16][CH2:17][NH:18][C:12]=3[CH:11]=[CH:10][C:9]=2[NH:8][C:7](=[O:19])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].CN(C)C=O.ClCCl.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(N(CC)CC)C>[C:29]([N:18]1[C:12]2[CH:11]=[CH:10][C:9]3[NH:8][C:7](=[O:19])[C:6](=[O:20])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:14]=3[C:13]=2[CH2:15][CH2:16][CH2:17]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCn1c(=O)c(=O)[nH]c2ccc3c(c21)CCCN3
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCn1c(=O)c(=O)[nH]c2ccc3c(c21)CCCN3C(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
The product from Example 89 (0.14 g, 0.5 mmol) was solubilized in a minimal amount of dimethylformamide and then treated with 2 mL dichloromethane, acetic anhydride (0.15 g) and triethylamine (0.15 g). After the mixture stirred at room temperature for 18 h, it was poured onto dichloromethane/water. The aqueous layer was washed with dichloromethane and the combined organic layers over sodium sulfate, filtered and evaporated to give a dark syrup. The syrup was purified by silica gel chromatography (ethyl acetate as eluant) to give the title compound (30 mg, 19% yield).
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[O:5]=[C:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>ClCCl>[O:5]=[C:6]1[CH2:10][CH2:9][CH2:8][C@@:7]1([CH2:4][CH2:3][CH:1]=[O:2])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: C=CC=O
Reactant: CC(C)(C)OC(=O)C1CCCC1=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@]1(CCC=O)CCCC1=O

Procedure:
A solution of acrolein (4.19 g; 74.83 mmoles—2.5 eq.) in 10 mL of anhydrous dichloromethane is poured, over 30 minutes, at −25° C., under argon and with slow stirring, into a solution of tert-butyl 2-oxo-cyclopentanecarboxylate (5.51 g; 29.93 mmoles) and catalyst Q (1.46 g; 2.99 mmoles—0.1 eq.) in 60 mL of anhydrous dichloromethane
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])[OH:3].[C:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:21]1[CH2:22][CH2:23][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19][CH2:20]1)[OH:3]
Reactant: CC(O)c1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(O)c1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl-2-aminophenyl carbinol from Step 1 above (0.86 g, 6.3 mmol), N-Boc-4-piperidone (2.5 g, 12.6 mmol), and acetic acid (1.08 mL, 1.13 g, 18.9 mmol) were combined in methanol (10 mL). Sodium cyanoborohydride (0.79 g, 12.5 mmol) was added in portions, and the mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated in vacuo. Ethyl acetate (100 mL) was added to the residue and the resulting mixture was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was chromatographed on silica gel eluted with 1:9 then 15:85 EtOAc:hexane. The combined product fractions were evaporated to dryness in vacuo to give methyl-(2-(1-Boc-4-piperidinylamino)phenyl) carbinol.
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH2:7][CH2:6][CH:5]([C:8]([CH3:10])=[CH2:9])[C:4]=1[CH2:11]Cl.[C:13](=[O:15])=[O:14].Cl.[Na]>O1CCCC1.CCOCC>[C:8]([CH:5]1[CH2:6][CH2:7][C:3]([CH3:2])([C:13]([OH:15])=[O:14])[C:4]1=[CH2:11])([CH3:10])=[CH2:9]
Reactant: O=C=O
Reactant: C=C(C)C1CCC(C)=C1CCl
Agent: Cl
Agent: [Mg]
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(C)C1CCC(C)(C(=O)O)C1=C
Temperature: -10 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
75 ml of dry tetrahydrofuran and 23 g of magnesium shavings are added to a round flask which is fitted with a stirrer, thermometer, dropping funnel and reflux condenser. Without stirring there is added thereto slowly (within 4 hours) a solution of 112.4 g of 1-methyl-2-chloromethyl-3-(prop-1-en-2-yl)-cyclopent-1-ene in 100 ml of tetrahydrofuran. The mixture is brought to 60°-65° for 1 hour and then cooled to -10°. A carbon dioxide stream is conducted through the solution, which is cooled to -10° C. The amount of carbon dioxide introduced is weighed; it amounts to 29.5 g. The mixture is left to stand at room temperature overnight. The mixture is then cooled to 10° C. and decomposed with 300 ml of a 10% hydrochloric acid solution. The acid solution is extracted with ether, the organic acid formed is taken up as the sodium salt (treatment with 10% sodium hydroxide) from the ether into the aqueous phase, which is washed with ether. After acidifying with 10% orthophosphoric acid, the mixture is extracted with ether and the etherial solution is dried over sodium sulphate. The solvent is evaporated and there are obtained 78.2 g (yield: 66%) of crude 3-isopropenyl-2-methylene-1-methyl-cyclopentanecarboxylic acid, which are recrystallized with hexane.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.FC1C=C2C(=CC=1)N=C(CCl)C=C2.[OH:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[O:33][CH2:32][C@@H:31]([O:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)[C@H:30]2[OH:44]>>[N:40]1[CH:41]=[CH:42][CH:43]=[C:38]([O:37][C@H:31]2[C@@H:30]([OH:44])[C:29]3[C:34](=[CH:35][CH:36]=[C:27]([O:26][CH2:2][C:3]4[CH:12]=[CH:11][C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[N:4]=4)[CH:28]=3)[O:33][CH2:32]2)[CH:39]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1ccc2c(c1)[C@H](O)[C@H](Oc1cccnc1)CO2
Agent: Fc1ccc2nc(CCl)ccc2c1
Product: O[C@H]1c2cc(OCc3ccc4ccccc4n3)ccc2OC[C@H]1Oc1cccnc1

Procedure:
By the methods of the preceding Example, substituting a molar equivalent of 2-chloromethylquinoline for the 6-fluoro-2-chloromethylquinoline, the title product of Example 74 (0.26 g) was converted to present chromatoqraphed title product, 0.35 g (88%), also recrystallized from isopropyl ether/CH2Cl2, m.p. 126-128° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([CH:13]([CH3:15])[CH3:14])[C:11](=[O:16])[O:10]C2=O)=[CH:4][CH:3]=1.FC1C=CC(CO)=CC=1OC1C=CC=CC=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@H:12]([C:11]([OH:16])=[O:10])[CH:13]([CH3:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: Cc1ccc(N2C(=O)OC(=O)C2C(C)C)cc1
Agent: OCc1ccc(F)c(Oc2ccccc2)c1
Product: Cc1ccc(N[C@H](C(=O)O)C(C)C)cc1

Procedure:
Following the above procedure, 3-(4-methylphenyl)-4-isopropyloxazolidine-2, 5-dione is reacted with 4-fluoro-3-phenoxybenzyl alcohol to give the 4-fluoro-3-phenoxybenzyl ester of N-(4-methylphenyl) valine.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N:21]2[C:25]([CH3:26])=[N:24][N:23]=[N:22]2)[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([N:21]3[C:25]([CH3:26])=[N:24][N:23]=[N:22]3)[CH:12]=2)[C:3]([OH:27])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(-n2nnnc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnnn1-c1cc(C(CC2CCCC2)C(=O)O)ccc1S(C)(=O)=O
Temperature: 47.5 °C
Yield: 89.4 %

Procedure:
A solution of 3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]propionic acid methyl ester (102 mg, 0.26 mmol) in ethanol (3 mL) was treated with a 1N aqueous sodium hydroxide solution (0.6 mL). The solution was heated at 45-50° C. for 5 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (20 mL) and extracted with diethyl ether (1×30 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×25 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid (88 mg, 89%) as an amorphous white solid: EI-HRMS m/e calcd for C17H22N4O4S (M+) 378.1362, found 378.1364.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH:16]=[CH:17][C:18]=1[C:19]([F:20])([F:21])[F:22]
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(C(F)(F)F)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1ccc(-c2ccc(C(F)(F)F)c(Cl)c2)cc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 4 h
Yield: 101.1 %

Procedure:
A mixture of 4-bromo-2-nitroaniline (2.17 g), 3-chloro-4-trifluoromethyl-phenylboronic acid (3.5 g), and Na2CO3 (3.5 g), tetrakis(triphenylphosphine)palladium(0) (0.5 g), in DME (60 mL) and water (60 mL) was degassed under vacuum and the vacuum was broken with N2 gas. The resultant reaction mixture was kept stirring at 90-100° C. for 4 h. The reaction mixture was cooled to room temperature, separated the organic layer and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was dried over sodium sulfate, filtered off sodium sulfate, the filtrate was concentrated and the residue was purified by column chromatography using a silica gel stationary phase and ethyl acetate in hexanes (2:8) as an eluent to afford 3′-chloro-3-nitro-4′-trifluoromethyl-biphenyl-4-ylamine (3.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([CH:23]=[O:24])[CH2:21][CH2:20][C:19]([C:25]([O:27]C)=[O:26])=[CH:18][C:17]=3[CH:29]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([CH:23]=[O:24])[CH2:21][CH2:20][C:19]([C:25]([OH:27])=[O:26])=[CH:18][C:17]=3[CH:29]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-(3,4-diethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.33 g). To the solution was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-(3,4-diethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.32 g) as colorless crystals.