Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.[CH2:16]([N:23]1[CH:28]2[CH:29]([C:31]#[N:32])[CH2:30][C:24]1([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:25](O)[CH2:26][CH2:27]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[CH2:16]([N:23]1[C@@H:28]2[C@@H:29]([C:31]#[N:32])[CH2:30][C@@:24]1([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:25]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH2:26][CH2:27]2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#CC1CC2(c3ccccc3)C(O)CCC1N2Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H]2[C@@H](C#N)C[C@]1(c1ccccc1)N2Cc1ccccc1
Reaction time: 0.25 h

Procedure:
t-Butyldimethylsilyl trifluoromethanesulphonate (23 ml, 76 mmol) was added dropwise to a stirred solution of (1R*,2R*5S*,6S*)-8-benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 41; 31 g), triethylamine (18 ml, 243 mmol) in dichloromethane (100 ml) at room temperature over 30 minutes. The reaction mixture was stirred for 15 minutes, quenched with saturated aqueous NaHCO3 and extracted into diethyl ether (3×100 ml). The combined organic extracts were washed with water, brine, dried (Na2SO4) and concentrated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=2)[CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=2)[CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=3)[CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN(c3ccc(OC(F)(F)F)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[[4-(trifluoromethoxy)phenyl]amino]piperidine (721 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [OH-].[Na+].[OH-].[K+].C([O:7][C:8]([C:10]1([CH3:40])[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)=[C:30]([Cl:39])[CH:29]=4)[O:25][N:24]=3)=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=[O:9])C.C(O)(=O)C>O.O1CCCC1.C(O)C>[Cl:39][C:30]1[CH:29]=[C:28]([C:26]2[O:25][N:24]=[C:23]([C:20]3[CH:19]=[CH:18][C:17]([CH2:16][N:13]4[CH2:12][CH2:11][C:10]([CH3:40])([C:8]([OH:9])=[O:7])[CH2:15][CH2:14]4)=[CH:22][CH:21]=3)[N:27]=2)[CH:33]=[CH:32][C:31]=1[CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCOC(=O)C1(C)CCN(Cc2ccc(-c3noc(-c4ccc(C5CCCC5)c(Cl)c4)n3)cc2)CC1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C(=O)O)CCN(Cc2ccc(-c3noc(-c4ccc(C5CCCC5)c(Cl)c4)n3)cc2)CC1
Temperature: 80 °C

Procedure:
A solution of sodium hydroxide (0.13 g, 0.0033 mol) and potassium hydroxide (85% assay, 0.22 g, 0.0033 mol) in demineralized water (5 mL) is added to a solution of 1-{4-[5-(3-chloro-4-cyclopentylphenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-methylpiperidine-4-carboxylic acid ethyl ester (0.43 g, 0.0008 mol) in a mixture of tetrahydrofuran and ethanol (1:1), 10 ML. The reaction mixture is heated at 80° C. temperature for 3 hrs. It is then concentrated under reduced pressure to give a crude residue which is treated with demineralized water (20 mL) and acidified to pH˜4-5 with 20% aqueous acetic acid solution (10 mL). The resultant solid is filtered, dried and washed with demineralized water (1×20 mL) and acetone (2×5 mL) respectively. Finally it is dried under reduced pressure to get 1-{4-[5-(3-chloro-4-cyclopentylphenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-methylpiperidine-4-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH:9]=[CH:8][CH:7]1OC(=O)C)=[O:5])[CH3:2].[ClH:22]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH:9]=[CH:8][CH:7]1[Cl:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccccc2)CCC=CC1OC(C)=O
Reactant: Cl
Solvent: CCO
Product: CCOC(=O)C1(c2ccccc2)CCC=CC1Cl

Procedure:
200 g of 1-phenyl-2-acetoxy-cyclohex-3-ene-1-carboxylic acid-ethyl-ester are dissolved in 1 liter of 96% ethanol. The solution is charged with 190 g of HCl gas and heated under reflux for 2 hrs. The solvent is removed and the residue directly fractionated in the vacuum. b.p.°,1 130° C. Yield: 169 g.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10])([OH:3])=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O1CCOCC1>[N:14]1([C:1]([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=[O:10])=[O:3])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(OCC(=O)O)c1
Solvent: C1COCCO1
Product: O=Cc1cccc(OCC(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(Carboxymethoxy)benzaldehyde (1.63 g, 9.05 mmol) was dissolved in p-dioxane (20 ml) and cooled in an ice bath and then N,N'-carbonyldiimidazole (1.9 g) was added in one portion. The reaction mixture was stirred for 30 minutes, then morpholine (0.8 ml) was added and the mixture was warmed to room temperature and stirred until the reaction was complete. The solvent was removed in vacuo, the residue was partitioned between CHCl3 (100 ml) and 2N HCl (75 ml), the layers were separated, and the aqueous layer was extracted with CHCl3 (2×75 ml). The organic layers were combined, dried over MgSO4 and stripped to afford an oil which was combined with the product from a similar experimental run and purified by column chromatography on silica gel eluting with chloroform to afford 2.1 g of 3-[4-morpholinylcarbonylmethoxy]benzaldehyde.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[NH:20]/3)=[C:4]2[N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14](/[CH:15]=[C:16]4\[NH:20][C:19](=[O:21])[NH:18][C:17]\4=[O:22])=[C:4]3[N:3]=[C:2]([NH:23][C:24]3[CH:25]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:28][CH:29]=3)[CH:7]=2)[CH2:11][CH2:10]1
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(Cl)nc23)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(Nc2cc(NC3CC3)n3ncc(/C=C4\NC(=O)NC4=O)c3n2)c1
Yield: 12.1 %

Procedure:
(Z)-5-((5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (75 mg, 0.23 mmol) was suspended in 1,4-dioxane (1.6 mL). N-(3-aminophenyl)acetamide (52 mg, 0.35 mmol), Cs2CO3 (105 mg, 0.32 mmol), (±)-BINAP (9 mg, 0.06 mmol) and palladium(II) acetate (7 mg, 0.04 mmol) were then added. The mixture was sealed and irradiated at 120° C. for 30 min in the microwave. H2O (8 mL) was added and the precipitate was filtered off and dried. The crude residue was purified via flash column chromatography (2.5-3.5% MeOH/dichloromethane) to yield (Z)—N-(3-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-ylamino)phenyl)acetamide (12 mg, 12%) as a bright yellow solid. LCMS (ES): >90% pure, m/z 433 [M+1]+.
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36](Br)=[N:35][CH:34]=1.[CH:43]([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[CH:54][CH:53]=2)[CH2:48][CH2:47]1)([CH3:45])[CH3:44].C(N(CC)C(C)C)(C)C>CC(O)C.C(OCC)C>[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:58][C:55]2[CH:54]=[CH:53][C:52]([N:49]3[CH2:48][CH2:47][N:46]([CH:43]([CH3:45])[CH3:44])[CH2:51][CH2:50]3)=[CH:57][CH:56]=2)=[N:35][CH:34]=1
Reactant: CC(C)N1CCN(c2ccc(N)cc2)CC1
Reactant: Brc1ncc(Br)n2ncnc12
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Solvent: CCOCC
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)CC1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
This compound may be prepared using methods as described for Compound 6, step 1, using 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (2 g, 7.20 mmol), 4-(4-isopropyl-piperazin-1-yl)-phenylamine (1.89 g, 8.62 mmol) and N,N-diisopropylethylamine (1.88 mL, 10.8 mmol) in 2-propanol (30 mL) are stirred at 95° C. overnight. The title compound is isolated after trituration with diethyl ether and petroleum ether as a grey solid (2.59 g, 87%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[C:7](Cl)[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:18])(=[O:17])[CH2:4][CH2:3]1.C(O)C>[Zn].O>[CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([OH:15])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:18])(=[O:17])[CH2:4][CH2:3]1
Reactant: Cc1c(C(=O)O)cc(Cl)c2c1C(C)(C)CCS2(=O)=O
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)ccc2c1C(C)(C)CCS2(=O)=O
Yield: 77.1 %

Procedure:
0.88 Gram (2.90 mmol) of 4,4,5-trimethyl-8-chlorothiochroman-6-carboxylic acid-1,1-dioxide was dissolved in-ethanol having a water content of 60%, 0.55 g (8.70 mmol) of a zinc powder was added, and the mixture was refluxed under heat for 5 hours. After the completion of the reaction, 5 ml of water was added, the zinc powder was removed by filtration, and the remainder was extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure to give 0.60 g (yield 78%) of 4,4,5-trimethylthiochroman-6-carboxylic acid-1,1-dioxide.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]4[CH:29]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[S:27][C:18]=4[N:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:39][O:40][CH2:41][CH2:42][NH2:43]>CO>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:16]3[C:17]4[CH:29]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[S:27][C:18]=4[N:19]=[C:20]([C:22]([NH:43][CH2:42][CH2:41][O:40][CH3:39])=[O:23])[N:21]=3)[CH2:14][CH2:15]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2cc(-c3ccc(F)cc3)sc2n1
Reactant: COCCN
Solvent: CO
Product: COCCNC(=O)c1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2cc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a suspension of ethyl 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine-2-carboxylate (30 mg, 0.05 mmol) in MeOH (7 ml) was added 2-methoxyethylamine (0.7 ml). The mixture was stirred at room temperature for 3 hours. The solvents were removed under reduced pressure and the crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (29 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][N:10]1[C:21]([O:23][CH3:24])=[O:22]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:14][C@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][N:10]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)N1CCC(c2cc(=O)[nH]o2)CC1c1ccc(Cl)cc1Cl
Solvent: CC#N
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1c1ccc(Cl)cc1Cl
Yield: 39.1 %

Procedure:
Methyl 2-(2,4-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.870 g, 2.34 mmol) was subjected to chiral preparative HPLC: Separation 1: The enantiomers were separated using chiral preparative HPLC (Column: ReproSil (250×50 mm), 8 μm particle size, mobile phase: Heptane/EtOH/FA 60/40/0.1, flow rate 120 mL/min) to yield a mixture of one cis- and one trans-enantiomer. Separation 2: The enantiomers were separated using chiral preparative HPLC (Column: CelluCoat (250×20 mm), 5 μm particle size, mobile phase: Heptane/IPA/FA 80/20/0.1, flow rate 18 mL/min) (2R,4S)-Methyl 2-(2,4-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (334 mg, 38%) was isolated. Chiral purity 99.7% de, Optical rotation [α]D20=+64.0 (acetonitrile, c=1.0), 1H NMR (400 MHz, cdcl3) δ 1.79-1.92 (m, 2H), 2.25-2.48 (m, 2H), 3.02-3.13 (m, 1H), 3.53-3.64 (m, 4H), 4.12-4.21 (m, 1H), 5.16 (dd, 1H), 5.64 (s, 1H), 7.12-7.22 (m, 2H), 7.36 (d, 1H). (2S,4R)-methyl 2-(2,4-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (340 mg, 39%) was isolated. Chiral purity 99.9% de, Optical rotation [α]D20=−65.1 (acetonitrile, c=1.0), 1H NMR (400 MHz, cdcl3) δ 1.79-1.92 (m, 2H), 2.26-2.38 (m, 1H), 2.39-2.48 (m, 1H), 3.03-3.13 (m, 1H), 3.53-3.64 (m, 4H), 4.12-4.22 (m, 1H), 5.16 (dd, 1H), 5.64 (s, 1H), 7.13-7.22 (m, 2H), 7.36 (d, 1H). (2S,4S)-Methyl 2-(2,4-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (67 mg, 8%) was isolated. Chiral purity 98.7% de, Optical rotation [α]D20=+11.5 (acetonitrile, c=1.0), 1H NMR (400 MHz, cdcl3) δ 1.72 (dq, 1H), 2.01-2.19 (m, 2H), 2.40-2.49 (m, 1H), 2.74 (tt, 1H), 3.43 (dt, 1H), 3.66 (s, 3H), 4.40 (d, br., 1H), 5.61-5.71 (m, 2H), 7.14-7.24 (m, 2H), 7.40 (d, 1H). (2R,4R)-Methyl 2-(2,4-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (75 mg, 9%) was isolated. Chiral purity 98.5% de, Optical rotation [α]D20=−10.9 (acetonitrile, c=1.0), 1H NMR (400 MHz, cdcl3) δ 1.72 (dq, 1H), 2.01-2.19 (m, 2H), 2.40-2.49 (m, 1H), 2.74 (tt, 1H), 3.43 (dt, 1H), 3.68 (s, 3H), 4.40 (d, br., 1H), 5.61-5.71 (m, 2H), 7.14-7.24 (m, 2H), 7.41 (d, 1H).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:19][C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][N:22]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[C:27]([O:26][C:24]([NH:23][C:20]1[S:19][C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:31])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:22][CH:21]=1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(NC(=O)OC(C)(C)C)s3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2ncc(NC(=O)OC(C)(C)C)s2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.7 %

Procedure:
To a solution of [6-(5-tert-butoxycarbonylamino-thiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (270 mg, 0.6 mmol) in THF (7 mL) was added LiOH (76 mg, 1.8 mmol) in water (3.5 mL). The mixture was stirred at room temperature for 3 h and acidified by 1N HCl to pH 3. The mixture was extracted by ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by HPLC affording the title compound (100 mg, 40%) as a white solid. 1H NMR (CD3OD) δ 7.29 (s, 1H), 7.19 (s, 1H), 6.75 (s, 1H), 5.69 (dd, 1H), 3.19 (m, 1H), 2.40 (s, 3H), 2.35 (m, 1H), 1.52 (s, 9H). MS found: (M+H)+=421.20.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[C:4]([CH:27]=[O:28])[CH:3]=1.[C:29](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:29])=[O:16])=[C:4]([CH:27]=[O:28])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CN(CCCCCCC(=O)O)c2ccc(Br)cc2C=O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)CCCCCCN(Cc1ccc(OC)cc1)c1ccc(Br)cc1C=O
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of 7-((4-bromo-2-formylphenyl)(4-methoxybenzyl)amino)heptanoic acid (41.0 g) and potassium carbonate (15.2 g) in DMF (400 ml) was added dropwise a DMF (100 ml) solution of iodomethane (18.2 g) under nitrogen atmosphere at 0° C. After returning to room temperature, the reaction mixture was stirred for 2 hours, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with water five times and with saturated brine once, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to give methyl 7-((4-bromo-2-formylphenyl)(4-methoxybenzyl)amino)heptanoate (40.8 g) as a brown oily material.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CCN(C(C)C)C(C)C.[C:13]([C:17]1[N:21]([CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:20]2[CH:29]=[CH:30][C:31]([S:33]([N:36]3[CH:40]=[C:39]([C:41](O)=[O:42])[CH:38]=[N:37]3)(=[O:35])=[O:34])=[CH:32][C:19]=2[N:18]=1)([CH3:16])([CH3:15])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:13]([C:17]1[N:21]([CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:20]2[CH:29]=[CH:30][C:31]([S:33]([N:36]3[CH:40]=[C:39]([C:41]([NH:3][CH2:1][CH3:2])=[O:42])[CH:38]=[N:37]3)(=[O:35])=[O:34])=[CH:32][C:19]=2[N:18]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Reactant: CCN
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: CCNC(=O)c1cnn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1
Yield: 49.2 %

Procedure:
Following the same procedure in Example 24, Step A, using ethylamine (73 uL, 2.0 M in THF, 0.15 mmol), DIPEA (28 uL, 21 mg, 0.16 mmol), 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.073 mmol) and HATU (44 mg, 0.12 mmol) in DMF (2.5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 17 mg (48%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.15 (t, J=7.23 Hz, 3 H), 1.40-1.57 (m, 4 H), 1.59 (s, 9H), 2.21-2.41 (m, 1 H), 2.79 (s, 1 H), 3.29-3.35 (m, 4 H), 3.84-3.95 (m, 2 H), 4.41 (d, J=7.42 Hz, 2 H), 7.91 (d, J=9.0 Hz, 1 H), 7.98 (dd, J=9.0, 1.7 Hz, 1 H), 8.03 (s, 1 H), 8.33 (d, J=1.56 Hz, 1 H), 8.74 (s, 1 H); MS (ESI) (M+H)+=474.0; Anal. Calcd for C23H31N5O4S+0.70 TFA+0.30 EtOAc+0.40H2O (590.66): C, 52.67; H, 5.96; N, 11.86. Found: C, 52.63; H, 5.99; N, 11.81.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>O1CCOCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10](=[CH:17][N:18]([CH3:20])[CH3:19])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1COCCO1
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O

Procedure:
A solution of N-Boc-4-piperidone (10.0 g, 50.19 mmol) and N,N-dimethylformamide dimethylacetal (20.16 mL, 150.57 mmol) in 1,4-dioxane (100 mL) was heated at reflux for 15 hours. The solvent was removed in vacuo and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 8% MeOH in EtOAc) to obtain the title compound as an orange oil which crystallized on standing (7.64 g, 60%).
Reaction SMILES: [O:1]=[C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]CC.[Mg+2].[O-]CC.Br[CH2:23][CH:24]([CH3:26])[CH3:25]>>[CH3:23][CH:24]([CH3:26])[CH2:25][CH:9]([C:2](=[O:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: CC(C)CBr
Agent: CC[O-]
Agent: [Mg+2]
Product: CCOC(=O)CC(=O)C(CC(C)C)C(=O)OCC
Yield: 61.9 %

Procedure:
Diethyl 3-oxopentanedioate (45.5 ml, 0.25 mol) was added to a suspension of magnesium ethoxide (prepared from magnesium turnings (9 g, 0.375 mol) and iodine (0.1 g) in dry ethanol (275 ml)), and the mixture was heated under reflux for 90 min. 1-Bromo-2-methylpropane (54 ml, 0.5 mol) was added, and the reaction was heated under reflux for 16 h. Further 1-bromo-2-methylpropane (27 ml, 0.25 mol) was added to the boiling mixture, and after 3 h the solvent was evaporated in vacuo. The residue was partitioned between 2 N hydrochloric acid and ether. After extracting the aqueous phase with ether, the combined organics were washed successively with water, 5% sodium bicarbonate, water and brine, then were dried (Na2SO4) and evaporated in vacuo. The residue was distilled to give the title compound as a colourless oil (40 g, 62%), bp 118°-120° C. (1 mmHg). δ (CDCl3): 0.9 (6H, d, J=6Hz), 1.25 (6H, t, J=7Hz), 1.4-1.9 (3H, m), 3.5 (2H, s), 3.7 (1H, d, J=9Hz) and 4.2 (4H, q, J=7Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.[Cl:34][CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.Cl>CC(C)=O>[ClH:34].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:24][CH:25]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(c2ccc(O)cc2)C2CCCc3ccccc32)cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(c2ccc(OCCN3CCCC3)cc2)C2CCCc3ccccc32)cc1

Procedure:
A mixture of (4-methoxyphenyl)-(4-hydroxyphenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane (400 mg, 0.001 mol), anhydrous K2CO3 (2.0 gm, 0.14 mol), 1-(2-chloroethyl)pyrrolidine hydrochloride (400 mg, 0.002) and dry acetone (25.0 ml) was refluxed for 10 hrs. K2CO3 was filtered off, acetone was distilled off and the residue was diluted with water. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil which was filtered through basic alumina column using benzene as the eluent, and concentrated to give an oil. The oil thus obtained was treated with ethanolic HCl. The solvent was evaporated and the compound was crystallized with absolute alcohol and dry ether, filtered under anhydrous conditions, and dried to give the title compound of formula I. Yield 350 mg. (68.35%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10]CC2C=CC=CC=2)[CH:7]=[CH:6][C:5]=1/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:3])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1C(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(O)cc1C(C)=O
Temperature: 15 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl (2E)-3-[2-acetyl-4-(benzyloxy)phenyl]prop-2-enoate (1.09 g, 3.36 mmol, 1.00 equiv), ethyl acetate (30 mL), Palladium on carbon (700 mg), hydrogen was introduced last. The resulting solution was stirred overnight at 15° C. in an oil bath. The reaction progress was monitored by LCMS. The solids were removed by filtration and washed with EA. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the resulting mixture was concentrated under reduced pressure to give 0.8 g (96%) of ethyl 3-(2-acetyl-4-hydroxyphenyl)propanoate as a light yellow solid. Mass spectrum (ESI, m/z): Calcd. for C13H16O4, 235.1 (M−H). found 235.1.