Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1/[CH:15]=[CH:16]/[C:17]([OH:19])=O.CN(C)C=O.Cl.[CH3:26][NH:27][O:28][CH3:29].CCN(C(C)C)C(C)C>ClCCl.CN(C)C1C=CN=CC=1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1/[CH:15]=[CH:16]/[C:17]([N:27]([O:28][CH3:29])[CH3:26])=[O:19]
Reactant: O=C(O)/C=C/c1cc(F)ccc1Br
Reactant: CNOC
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)/C=C/c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (2.0 M in dichloromethane, 2.08 mL, 4.16 mmol) was added to a suspension of (E)-3-(2-bromo-5-fluorophenyl)acrylic acid (678 mg, 2.77 mmol) in dichloromethane (8 mL). N,N-dimethylformamide (11 L, 0.14 mmol) was added, and the resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo, and 4-dimethylaminopyridine (3 mg, 0.025 mmol), N,O-dimethylhydroxylamine hydrochloride (270 mg, 2.77 mmol), Hunig's base (1.44 mL, 8.28 mmol), and dichloromethane (8 ml) were added. The mixture was stirred at 25° C. for 10 h, then transferred to a separatory funnel with dichloromethane (100 mL), and the organic layer was extracted sequentially with water (7 mL), 0.5 M sodium carbonate (7 mL), 1 M hydrochloric acid (7 mL), and half-saturated brine (7 mL), and then dried over sodium sulfate and concentrated. Purification of the concentrate by flash column chromatography (33% to 40% EtOAc/hexane) afforded the title compound as a white solid. MS m/z: 288 & 290 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH:16]([CH3:17])[CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][C:13]2=[O:24])=[O:11])=[CH:4][CH:3]=1.[CH2:25]1COCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:25][CH:9]2[C:10]([N:12]2[C@@H:16]([CH3:17])[C@H:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:14][C:13]2=[O:24])=[O:11])=[CH:6][CH:7]=1
Reactant: CC1C(c2ccccc2)OC(=O)N1C(=O)/C=C/c1ccc(Br)cc1
Reactant: C1CCOC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: C[C@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)C1CC1c1ccc(Br)cc1

Procedure:
To a solution of E-3-[3-(4-Bromo-phenyl)-acryloyl]4-methyl-5-phenyl-oxazolidin-2-one from Step 5 and Pd(OAc)2 (0.05 eq.) in THF (0.2M) was added portionwise CH2N2 until the reaction was completed. NMR of aliquots monitored the reaction. The resulting mixture was concentrated and flash chromatography (Hex:EtOAc; 3:2) to afford the two separate diastereoisomers. Each diastereoisomers were submitted to the procedures described in Step 2 and Step 3 to afford the (+) and (−) enantiomers of EXAMPLE 42
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]3[C:19]([N:20]=2)=[C:18]2[N:21]([C:25]4[C:26]([CH3:31])=[N:27][N:28]([CH3:30])[CH:29]=4)[C:22](=[O:24])[NH:23][C:17]2=[CH:16][N:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].I[CH2:35][CH3:36]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]3[C:19]([N:20]=2)=[C:18]2[N:21]([C:25]4[C:26]([CH3:31])=[N:27][N:28]([CH3:30])[CH:29]=4)[C:22](=[O:24])[N:23]([CH2:35][CH3:36])[C:17]2=[CH:16][N:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2ccc3ncc4[nH]c(=O)n(-c5cn(C)nc5C)c4c3n2)cc1OC
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2cn(C)nc2C)c2c3nc(-c4ccc(OC)c(OC)c4)ccc3ncc21
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A mixture of 8-(3,4-dimethoxy-phenyl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one (Example 249, 50 mg, 0.120 mmol) and NaH 55% (8 mg, 0.183 mmol) in DMF was stirred at rt for 25 min. Then iodoethane (0.015 ml, 0.186 mmol) was added and the RM was stirred at rt for 5.5 h. After that, the RM was quenched with saturated aqueous NaHCO3, the suspension was then filtered, the cake was washed with water and dried in the vacuum oven to give the title compound as a white solid. (HPLC: tR 2.74 min (Method A); M+H=445 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.03 (s, 1H), 8.40-8.32 (m, 1H), 8.25-8.19 (m, 1H), 7.95 (s, 1H), 7.60-7.52 (m, 1H), 7.41-7.36 (m, 1H), 7.04-6.97 (m, 1H), 4.11 (q, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 1.94 (s, 3H), 1.37 (t, 3H))
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:10]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:5]1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[C:11]3[C:6](=[N:5][N:4]([CH2:3][CH2:2][NH:1][C:46]([CH:43]4[CH2:44][CH2:45][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:41][CH2:42]4)=[O:47])[CH:12]=3)[N:7]=[C:8]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCn2cc3c(-c4ccc(F)cc4)c(-c4ccncc4)c(-c4ccc(F)cc4)nc3n2)CC1

Procedure:
Following a similar procedure to that described in example 48, but starting from 2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (obtained in example 90) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid, the desired compound was obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].O>CN(C)C=O>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCNCC
Reactant: CC(=O)O[C@H]1CC[C@H](c2ccc(CCl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)Cc1ccc([C@H]2CC[C@H](OC(C)=O)CC2)cc1
Temperature: 50 °C

Procedure:
A solution of 1 g (3.75 mmol) of trans-O-acetyl-4-(4-chloromethylphenyl)-cyclohexanol in 10 ml of dimethylformamide is mixed with 0.52 g (3.75 mmol) of potassium carbonate and 0.27 g (3.75 mmol) of diethylamine. This mixture is heated to 50° C. for 6 hours with stirring, then water is added and the mixture is extracted with methylene chloride. The organic phase is dried, evaporated down in vacuo and the residue remaining is purified by column chromatography (aluminium oxide basic, activity stage III, ICN; petroleum ether/ethyl acetate=15:1). Colourless oil. Yield: 0.79 g (69% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CCO.CO.[Pd]>[NH:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:4]1[CH:5]=[CH:6][C:7]([NH2:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(-c2ncc[nH]2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Cc1cc(-c2ncc[nH]2)ccc1N
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a mixture of 2-(3-methyl-4-nitrophenyl)-1H-imidazole (1.17 g, 5.76 mmol) and 10% Pd/C (0.8 g) in EtOH (5 mL) was added dropwise HCO2NH4 [3.63 g, 57.64 mmol., dissolving in MeOH (50 mL)]. After 1 h, TLC showed the reaction was complete. Filtration and the filtrate was evaporated under reduced pressure. The residue was dissolved in DCM (30 mL) and filtrated. The filtrate was concentrated to afford 4-(1H-imidazol-2-yl)-2-methylaniline as a yellow solid (1.0 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C@H:11]2[CH2:15][C:14](=[O:16])[N:13](CC=C)[CH2:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C[N+]1([O-])CC[O:32]CC1.C1COCC1.[CH3:41][C:42]([OH:45])(C)[CH3:43].O>[Os](=O)(=O)(=O)=O.CC(O)(C)C>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]([C@H:11]2[CH2:15][C:14](=[O:16])[N:13]([CH2:41][CH:42]([OH:45])[CH2:43][OH:32])[CH2:12]2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C=CCN1C[C@@H](N(Cc2ccccc2C)c2ccc(C#N)c(Cl)c2)CC1=O
Reactant: CC(C)(C)O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1CN(c1ccc(C#N)c(Cl)c1)[C@H]1CC(=O)N(CC(O)CO)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
2-Chloro-4-{[(2-methylphenyl)methyl][(3S)-5-oxo-1-(2-propen-1-yl)-3-pyrrolidinyl]amino}benzonitrile (30.0 mg, 0.08 mmol) and 4-methyl morpholine oxide (37.5 mg, 0.16 mmol) were dissolved in a mixture of THF/t-BuOH/H2O (0.5 mL/0.2 mL/0.1 mL). To this solution was added an osmium tetroxide/2-methyl-2-propanol solution (2.5 wt %, 81.3 mg, 0.008 mmol), and the mixture stirred at room temperature for 18 h. The reaction mixture was quenched with 5% NaHSO3 (2 mL), and the organic layer was separated and concentrated to afford the desired product as a white solid (12.0 mg, 37% yield). LC-MS (ES) m/e 413.7 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][N:12]3[C:16]([C@@:18]23[CH2:25][CH2:24][CH2:23][C@@H:22]2[CH2:21][C@H:20]([N:26]2[CH2:31][CH2:30][CH:29]([C:32]4[CH:33]=[C:34]([CH:40]=[CH:41][CH:42]=4)[C:35]([O:37]CC)=[O:36])[CH2:28][CH2:27]2)[CH2:19]3)=[O:17])[CH:4]=1.C[O-].[Na+].Cl>CO>[CH2:5]([NH:6][CH2:7][CH3:8])[CH3:4].[F:44][C:2]([F:1])([F:43])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][N:12]3[C:16]([C@@:18]23[CH2:25][CH2:24][CH2:23][C@@H:22]2[CH2:21][C@H:20]([N:26]2[CH2:27][CH2:28][CH:29]([C:32]4[CH:33]=[C:34]([CH:40]=[CH:41][CH:42]=4)[C:35]([OH:37])=[O:36])[CH2:30][CH2:31]2)[CH2:19]3)=[O:17])[CH:4]=1
Reactant: CCOC(=O)c1cccc(C2CCN([C@H]3C[C@H]4CCC[C@@]4(C(=O)N4C[C@@H]5C[C@H]4CN5c4cc(C(F)(F)F)ccn4)C3)CC2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCNCC
Product: O=C(O)c1cccc(C2CCN([C@H]3C[C@H]4CCC[C@@]4(C(=O)N4C[C@@H]5C[C@H]4CN5c4cc(C(F)(F)F)ccn4)C3)CC2)c1
Yield: 0.05 %

Procedure:
The mixture from Example 9F (280 mg, 0.45 mmol), sodium methoxide (49.5 mg, 0.91 mmol) in methanol (10 mL) was refluxed for 12 hours. The mixture was acidified with 0.1 N aqueous hydrochloric acid to a pH around 5. The reaction mixture was partitioned with the addition of dichloromethane. The dichloromethane was collected and the aqueous solution was washed with dichloromethane (three times). The dichloromethane fractions were combined, dried and concentrated. The crude product was purified by preparative HPLC (Column: Phenomenex 150*30 mm; mobile phase: from 30% acetonitrile in H2O (0.01% TFA) to 70% acetonitrile in H2O (0.01% TFA) followed by chiral SFC purification (SFC condition: Column: AD-5 μm; Mobile phase:A, supercritical CO2; B, ethanol with 0.05% diethylamine, A:B=70:30 with a flow rate of 50 mL/min)) to give the title compound (peak 1 retention time: 5.58 minutes) and Example 10. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.24 (d, J=5.2 Hz, 1H), 7.80 (m, 2H), 7.28 (m, 2H), 6.78 (m, 2H), 5.10 (m, 2H) 3.30-3.79 (m, 6H), 3.20 (m, 1H), 2.70-2.96 (m, 3H), 2.25-2.65 (m, 1H), 1.50-2.15 (m, 15H), 1.38 (m, 1H); MS (ESI+) m/z 583 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:11]3[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:10]=3[CH2:9][CH2:8]2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C>C(#N)C>[C:25]([N:2]1[CH2:3][CH2:4][C:5]2([C:11]3[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:7]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc2c3c([nH]c2c1)C1(CCNCC1)CC3
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)N1CCC2(CCc3c2[nH]c2ccccc32)CC1
Temperature: 25 °C
Yield: 34 %

Procedure:
To a solution of 1,4-dihydrospiro[cyclopent[b]indole-3(2H),4'-piperidine] hydrochloride (1.0 g) and potassium carbonate (0.8 g) in acetonitrile (10 ml) was added benzoyl chloride (0.5g), under nitrogen, with stirring. The reaction mixture was heated under reflux for 5 hrs and allowed to cool to ambient temperature. Ethyl acetate (200 ml) was added, and the mixture was washed with water and saturated sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was flash chromatographed (silica gel), eluting with 0.5% methanol/dichloromethane. The appropriate fractions were collected and concentrated to give 0.40 g (33%) of product, mp 231°-232° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[S:21][C:20]=3[CH3:30])/[CH3:18])/[C:9]2=[O:31])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:43])[C:40]([CH3:42])=[CH2:41]>ClCCl>[C:39]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:15])[CH3:16])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[S:21][C:20]=3[CH3:30])/[CH3:18])/[C:9]2=[O:31])=[CH:4][CH:3]=1)(=[O:43])[C:40]([CH3:42])=[CH2:41]
Reactant: CC(C)=C1C(=O)N(c2ccc(O)cc2)C(=O)/C1=C(\C)c1cc(-c2ccccc2)sc1C
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccc(N2C(=O)C(=C(C)C)/C(=C(/C)c3cc(-c4ccccc4)sc3C)C2=O)cc1
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution obtained by dissolving 430 mg of N-(4-hydroxyphenyl)-2-[(E)-1-(2-methyl-5-phenyl-3-thienyl)ethylidene]-3-isopropylidenesuccinimide obtained in Example 8 in 10 ml of dichloromethane, 202 mg of triethylamine was added, followed by dropwise addition of 209 mg of methacryloyl chloride in 10 minutes. The reaction was carried out at room temperature for further 1 hour. After the reaction, the reaction solution was washed with water, dried over anhydrous magnesium sulfate, and subjected to removal of the solvent by distillation. The resulting residue was purified by column chromatography (filler: Wakogel C-300, eluent: a mixed solution of n-hexane and ethyl acetate) to give organce crystals of N-(4-methacryloyloxyphenyl)-2-[(E)-1-(2-methyl-5-phenyl-3-thienyl)ethylidene]-3-isopropylidenesuccinimide in yield of 44.0%.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH:13]=O.[CH:21]([N+:24]#[C-:25])([CH3:23])[CH3:22].Cl(O)(=O)(=O)=O>CO>[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[C:13]1[NH:1][C:2]2[N:6]([C:25]=1[NH:24][CH:21]([CH3:23])[CH3:22])[N:5]=[CH:4][C:3]=2[C:7]#[N:8]
Reactant: [C-]#[N+]C(C)C
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: N#Cc1cn[nH]c1N
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: COc1ccc(-c2[nH]c3c(C#N)cnn3c2NC(C)C)c(OC)c1
Reaction time: 15 h

Procedure:
To a mixture of 5-amino-1H-pyrazole-4-carbonitrile (771 mg, 7.13 mmol) and 2,4-dimethoxybenzaldehyde (1.19 g, 7.13 mmol) in a vial under nitrogen atmosphere were added methanol (20 mL) followed by iso-propyl isonitrile (500 mg, 581 μL, 7.13 mmol) and perchloric acid (143 mg, 128 μL, 1.43 mmol) at RT. Then, the resulting brown solution was stirred for 15 h by which time LC/MS analysis indicated the presence of the desired product. Then, the solvent was removed under vacuum and the residue was purified using an ISCO (80 g) column chromatography eluting with 0-50% ethyl acetate in hexanes. The desired fractions were combined and the solvent was removed under vacuum to obtain 647 mg (28% yield) of 2-(2,4-dimethoxyphenyl)-3-(iso-propylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile as a light yellow solid. LC/MS calcd. for C17H19N5O2 (m/e) 325.37, obsd. 326.0 (M+H, ES+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:32]=[C:33](O)[CH:34]=[CH:35][CH:36]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:30])[CH:36]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Reactant: Cc1cccc(O)c1
Product: Cc1cccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Br)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-methylphenol: ESMS m/e: 549.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C@@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:24][C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:16])[C@@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](N[C@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-3-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.4 g, 25.3 mmol) was dissolved in dichloromethane (75 mL). R-(+)-α-Methylbenzylamine (3.1 g, 3.2 mL, 25.3 mmol) was added followed by sodium triacetoxyborohydride (10.7 g, 50.6 mmol). The reaction was stirred overnight at room temperature. LC/MS analysis revealed four components, with only one component clearly separated. The reaction was diluted with dichloromethane (150 mL) and extracted twice with water, once with brine and dried over MgSO4. Filtration and concentration in vacuo afforded a white foam that was purified by flash column chromatography (84.5:15:0.5 CH2Cl2:acetonitrile:NH4OH) to afford a clear oil. The material was rechromatographed (89.5:10:0.5 CH2Cl2:acetonitrile:NH4OH) to afford the title compound as a clear oil. Wt.: 547 mg (7%). 1H NMR (300 MHz, CDCl3) δ 7.31 (m, 3H), 7.22 (m, 2H), 3.85 (m, 3H), 2.68 (m, 1H), 2.46 (m. 1H), 2.17 (m, 1H), 1.67 (m, 1H), 1.40 (s, 9H), 1.30 (d, 3H), 1.08 (m, 2H), 0.97 (d, 3H); LC/MS m/z 319 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][SH:10])=[CH:7][CH:6]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23](OS(C)(=O)=O)[CH2:22][C@:21]1([C:31](=[O:33])[NH2:32])C)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+].O1CCC[CH2:37]1>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([S:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH2:22][C@H:21]1[C:31](=[O:33])[NH:32][CH3:37])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc(CS)cc1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@@]1(C)C(N)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
1.80 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added, whilst ice-cooling, to a solution of 5.70 ml of 4-methoxybenzyl mercaptan dissolved in 100 ml of dry tetrahydrofuran, and the mixture was then stirred at 0° to 5° C. for 30 minutes. At the end of this time, a solution of 11.00 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-methanesulfonyloxy-2-methyl-carbamoylpyrrolidine [prepared as described in step (2) above] in 80 ml of dry dimethylformamide was added to the mixture, and the mixture was stirred at 34° C. for 4.5 hours. The reaction mixture was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with a 5:1 by volume mixture of ethyl acetate and hexane) to afford 4.35 g of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.C(N(CC)CC)C.[C:23](Cl)(=[O:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>ClCCl>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:23](=[O:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Reactant: CCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) (0.5 g, 2.46 mmole) in 20 mL of dichloromethane was treated successively with 0.51 mL of triethylamine (1.5 eq.) and 0.35 mL of hexanoyl chloride (1 eq.). The reaction mixture was stirred at room temperature for two hours, diluted with an additional 20 mL of dichloromethane and washed with two 50 mL portions of water and one 50 mL portion of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo, giving 740 mg (100%) of hexanoic acid (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amide (15) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:12](NC(=O)C(Cl)(Cl)Cl)([CH3:15])([CH3:14])[CH3:13].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C1CCCCC1.C(Cl)Cl>[C:12]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CC(C)(C)NC(=O)C(Cl)(Cl)Cl
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Cc1cccc(Br)c1
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of 3-bromo-phenyl-acetic acid (10 gm, 46.5 mmol) and methylene chloride (47 mL) was added a solution of t-butyl-2,2,2-trichloroacetamidate (20.3 g, 93.0 mmol) and cyclohexane (186 mL) followed by borontrifluoride etherate (0.93 mL, 7.3 mmol). After stirring overnight, solid sodium bicarbonate was added and the reaction then filtered through a pad of silica gel utilizing methylene chloride as solvent. Concentration gave 9.11 g (72%) of a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:8])[CH:7]=1)=O.C([O:17][C:18](=[O:22])[CH:19](Br)[CH3:20])C>C1C=CC=CC=1.O.[Zn].[Hg](Br)Br>[CH3:20][C:19](=[CH:1][C:3]1[S:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:8])[CH:7]=1)[C:18]([OH:22])=[O:17]
Reactant: Cc1cc(C=O)sc1-c1ccccc1
Reactant: CCOC(=O)C(C)Br
Agent: Br[Hg]Br
Agent: [Zn]
Solvent: O
Solvent: c1ccccc1
Product: CC(=Cc1cc(C)c(-c2ccccc2)s1)C(=O)O

Procedure:
A mixture of 2-formyl-4-methyl-5-phenylthiophene (20.2 g, 0.1 mol) and ethyl-2-bromopropionate (0.12 mol, 15.5 mL) was added to a suspension of Zn (7 g, 0.1 mol) in 150 mL of benzene with a catalytic amount of HgBr2. The resulting mixture was refluxed under stirring while all amount of Zn will not be dissolved, and subsequently dissolved in water. The organic layer was isolated, washed with a 10% aq. solution of HCl, dried over MgSO4 and evaporated off to dryness. The residue, corresponding to 2-methyl-3-(4-methyl-5-phenyl-2-thienyl)ethyl acrylate, was used without further purification in the synthesis of the related acid. In fact, it was added to a 30% aq. solution of sodium hydroxide in 100 mL of ethanol and refluxed for 2 h. The resulting reaction mixture was diluted in water, acidified and filtered. The precipitate was dried under P2O5. Yield 16.7 g (65%).