Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1[CH2:22][CH2:21][O:20][CH2:19]C1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[CH2:22][CH:21]1[O:20][CH2:19]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1CC1CO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a solution of L-proline benzyl ester (156 mg, 0.49 mmol) in DMF (2 mL), cooled to 0° C., NMM (56 μL, 0.53 mmol) and HOBt (198 mg, 1.47 mmol) were added. The solution was stirred at 0° C. for 15 minutes and a solution of glycidic acid21 (100 mg, 1.13 mmol) in CH2Cl2 (2 mL) was added. Finally a solution of DCC (253 mg, 1.23 mmol) in CH2Cl2 (2 mL) was added. The mixture was stirred 16 h at room temperature and filtered to remove the precipitate. The residue was diluted with CH2Cl2 (10 mL) and washed with 10% KHSO4 (10 mL), 5% NaHCO3 (10 mL) and NaCl (10 mL, sat), dried (Na2SO4), filtered and concentrated. The crude oil was purified by column chromatography (silica gel, EtOAc/Hexanes 1/1) to yield 120 (95 mg, 70%) as white foam. Rf 0.26 (AcOEt/Hexanes 1/1). 1H-NMR (500 MHz, CDCl3): mixture of rotamers 1.87-1.92 (m, 2H), 1.91-1.98 (m, 2H), 1.99-2.03 (m, 1H), 2.19-2.20 (m, 2H), 2.20-2.22 (m, 1H), 2.66-2.68 (m, 1H), 2.80-2.82 (m, 1H), 2.94-2.95 (m, 2H), 3.30-3.31 (m, 1H), 3.56-3.57 (m, 2H), 357-370 (m, 2H), 3.72-3.85 (m, 1H), 4.57-4.59 (m, 1H), 4.70-4.72 (m, 1H), 5.16 (s, 2H), 5.22-5.29 (m, 2H), 7.25-7.38 (m, 10H). 13C-NMR (125 MHz, CDCl3): 22.2, 24.9, 28.7, 30.9, 31.5, 45.9, 46.3, 46.4, 47.2, 48.0, 48.5, 58.7, 59.3, 66.9, 67.4, 128.1, 128.2, 128.4, 128.5, 128.7, 170.0, 182.3. HRMS m/z cald for C15H17NO4a (M+Na): 298.1055 found 298.1047.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:35][C:34]3[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(Cn2ccc3c(-c4ccc(Cl)cc4)c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c32)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 from methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 4-methoxybenzyl chloride. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.57-7.64 (m, 1H) 7.43-7.49 (m, 2H) 7.37-7.43 (m, 1H) 7.24-7.29 (m, 2H) 6.99-7.06 (m, 1H) 6.83-6.90 (m, 2H) 5.93-6.00 (m, 1H) 5.70-5.83 (m, 2H) 5.30-5.36 (m, 1H) 3.79 (s, 3H) 3.68 (s, 3H) 1.01 (s, 9H); LCMS (m/z) ES+=509 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:22])[C:17]([O:19][CH2:20][CH3:21])=[CH:18][C:13]=2[NH:12][C:11](=S)[CH2:10][N:9]=1.CO[C:26](OC)([N:28](C)C)[CH3:27].[NH2:33]N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:22])[C:17]([O:19][CH2:20][CH3:21])=[CH:18][C:13]=2[N:12]=[C:11]2[NH:33][NH:28][C:26]([CH3:27])=[C:10]2[N:9]=1
Reactant: COC(C)(OC)N(C)C
Reactant: NN
Reactant: CCOc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=S)N2
Product: CCOc1cc2c(cc1F)C(c1ccccc1Cl)=NC1=C(C)NNC1=N2

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-ethoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVg) was prepared by reacting 0.0016 moles of 5-(2-chlorophenyl)-1,3-dihydro-8-ethoxy-7-fluoro-2H-1,4-benzodiazepin-2-thione (IIg) with 1,1-dimethoxy-N,N-dimethyl-ethanamine and then hydrazine in a manner analogous to Example 55. MH+/Z=371.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]([OH:29])=O)[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1.C(N(CC)CC)C>ClC(Cl)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]([NH:33][C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)=[O:29])[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:31][CH:32]=1
Reactant: O=C(O)CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21
Reactant: Nc1cccnc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: O=C(CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21)Nc1cccnc1
Reaction time: 8 h

Procedure:
20 mg (0.042 mmol) of [4-(4-chlorobenzoyl)-2-oxo-2,3,4,5-tetrahydrobenzo[e][1,4]diazepin-1-yl]acetic acid trifluoroacetate was dissolved in 2 ml of dichloroethane. 5 mg (0.055 mmol) of 3-aminopyridine, 11 mg (0.055 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.018 ml (0.126 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[C:10](N(OC)C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][Mg]Br.CCOCC>C1COCC1>[CH2:27]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)[C:10](=[O:11])[CH3:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CON(C)C(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a 250 mL round bottom flask containing (S)-2-(dibenzylamino)-N-methoxy-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide (10.49 g, 23.0 mmol) was added THF (200 mL), and the flask was cooled to 0° C. Methylmagnesium bromide (3.16 M in ether, 12.7 mL, 40.2 mmol) was added dropwise over 10 minutes. After 2 hours, additional methylmagnesium bromide, 3.16 in ether (12.7 mL, 40.2 mmol) was added dropwise over 10 minutes. After 1 hour, the mixture was poured into ammonium chloride-ice (200 mL), washed with brine (100 mL), dried over sodium sulfate, and stored at −20° C. for 15 hours. Plate-like crystals formed the next morning. The mixture was decanted from sodium sulfate and evaporated to provide a yellow oil that crystallized in the freezer over the weekend. The solid was triturated with hexane and chilled at −20° C. before filtration. The product was obtained as a white crystalline solid. The yellow filtrate was adsorbed onto silica gel and purified by chromatography through a Redi-Sep® pre-packed silica gel column (330 g), eluting with a gradient of 0% to 70% EtOAc in hexane to provide additional product as an oil that crystallized under hi vacuum. The two lots were combined to provide (S)-3-(dibenzylamino)-4-(4-(trifluoromethyl)phenyl)butan-2-one (8.09 g, 85.6% yield) as a white solid. LCMS (ES+) m/z=412.3 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 2.13 (s, 3H) 2.93 (dd, J=13.30, 3.52 Hz, 2H) 3.21 (dd, J=13.30, 9.39 Hz, 1H) 3.50-3.60 (m, 3H) 3.82 (d, J=13.69 Hz, 2H) 7.19-7.30 (m, 4H) 7.30-7.35 (m, 8H) 7.46 (d, J=8.02 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][N:13]3[C:16](=[O:33])[C@@H:17]([NH:25]C(=O)OC(C)(C)C)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:9][CH:8]=2)[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O.[ClH:41]>ClCCl.CCOCC>[ClH:41].[NH2:25][C@@H:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:15]=2)[CH2:11][CH2:12]1)=[O:33]
Reactant: Cn1cc(-c2ccc3c(c2)N(C(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)CC3)cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2ccc3c(c2)N(C(=O)[C@@H](N)Cc2ccccc2)CC3)cn1
Reaction time: 3 h

Procedure:
Tert-butyl (S)-1-(6-(1-methyl-1H-pyrazol-4-yl)indolin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamate (60.0 mg, 134 μmol) was dissolved in dichloromethane (1.5 mL) and TFA (1.50 mL, 19 mmol) was added and the solution was stirred for three hours. The reaction mixture was then concentrated to dryness and then taken up in ethyl acetate and extracted and basified with saturated sodium bicarbonate solution. The organic layer was then concentrated and the residue was dissolved in ethyl acetate and 3.0 equivalents of 1M HCl in ether solution was added forming an off-white precipitate that was filtered and washed with hexanes to give (2S)-2-amino-1-(6-(1-methyl-1H-pyrazol-4-yl)indolin-1-yl)-3-phenylpropan-1-one hydrochloride 82. MS ESI (pos.) m/e: 347.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([NH2:17])[CH:5]=1.[N-:19]=[N+:20]=[N-:21].[Na+].[CH:23](OCC)(OCC)OCC>CC(O)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[C:6]([N:17]2[CH:23]=[N:21][N:20]=[N:19]2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:9]=1
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cn2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-n2cnnn2)c1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
To a solution of 3-amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (362 mg, 1.51 mmol) and NaN3 (182 g, 2.8 mmol) in AcOH was added HC(OEt)3 (1074 mg, 7.25 mmol) at room temperature. The reaction mixture was heated to reflux for 4 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was purified by silica-gel chromatography to give 3-(5-methyl-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid methyl ester as a light yellow solid (440 mg, 100%). MS (M+H)=296.
Reaction SMILES: CC(C)([O-:4])C.[K+].[C:7]([O:11][C:12](=[O:36])[NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH:20]2[CH2:33][C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=4)[N:25]=[CH:24][C:23]=3[O:22][CH2:21]2)[CH2:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8]>CS(C)=O.C(O)(C)(C)C>[C:7]([O:11][C:12](=[O:36])[NH:13][C@H:14]1[CH2:15][CH2:16][C@H:17]([CH:20]2[CH:33]([OH:4])[C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=4)[N:25]=[CH:24][C:23]=3[O:22][CH2:21]2)[CH2:18][CH2:19]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: COc1ccc2ncc3c(c2c1)C(O)C([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (354 mg, 3.15 mmol, 2.5 eq) is added at room temperature to a stirred solution of [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester (2.6 g, 1.26 mmol, 1.0 eq) in dimethyl sulfoxide (45 mL) and tert-butanol (13 mL) under oxygen atmosphere. After 1 hour stirring under oxygen atmosphere, the reaction mixture is purged with nitrogen, and extracted with dichloromethane (3×200 mL) and water (200 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 250:1 to 100:1, v/v) to afford [trans-4-(4-hydroxy-6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester as a white solid that is further purified by preparative HPLC to obtain a white solid (70 mg, 42% yield).
Reaction SMILES: C([Li])CCC.C1[CH2:10][O:9]CC1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Si:19]([CH3:22])([CH3:21])[CH3:20])[N:14]=1.Cl[Si:24]([CH3:27])([CH3:26])[CH3:25]>[Cl-].[Na+].O.CCCCCC.O>[CH3:11][O:12][C:13]1[C:18]([CH:10]=[O:9])=[C:17]([Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[C:15]([Si:19]([CH3:21])([CH3:20])[CH3:22])[N:14]=1
Reactant: COc1cccc([Si](C)(C)C)n1
Reactant: C[Si](C)(C)Cl
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: COc1nc([Si](C)(C)C)cc([Si](C)(C)C)c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
n-Butyllithium (1.6 M in n-hexane, 2.8 mL, 2.76×1.6 mmol) was added dropwise to a dry THF (6.6 mL) solution of 2-methoxy-6-(trimethylsilyl)pyridine (MTP, 0.500 g, 2.76 mmol) under an argon atmosphere at between −15° C. and 0° C. (this temperature was kept during the reaction) and stirred for 1 hour, and a dry THF (2 mL) solution of FEO (0.434 g, 2.76×1.2 mmol) was then added dropwise and stirred for 1 hour. Subsequently, n-butyllithium (1.6 M in n-hexane, 2.4 mL, 2.76×1.4 mmol) was added dropwise and stirred for 1 hour, and a dry THF (3 mL) solution of chlorotrimethylsilane (697 μL, 2.76×2.0 mmol) was then added dropwise and stirred for 1 hour. The temperature was raised to room temperature, followed by adding water, brine, and n-hexane (50 mL). The organic layer was separated, dried over Na2SO4, filtered, and then concentrated to dryness. The residue was purified by medium pressure silica gel column chromatography (n-hexane), and desired fractions were combined and concentrated to dryness. TMS-MTPC (0.305 g, 1.08 mmol, 39%) was obtained as a colorless transparent liquid.
Reaction SMILES: [O:1]1CCCC1.[F:6][C:7]1[C:8]([C:17]([NH2:19])=O)=[N:9][CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14].[C:20]([N:27]1C=CN=C1)(N1C=CN=C1)=[O:21].N12CCCN=C1CCCCC2>O>[F:6][C:7]1[C:8]([C:17]2[NH:19][O:1][C:20](=[O:21])[N:27]=2)=[N:9][CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14]
Reactant: C1CCOC1
Reactant: NC(=O)c1nccc(C(F)(F)F)c1F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=c1nc(-c2nccc(C(F)(F)F)c2F)[nH]o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3 ml of tetrahydrofuran were added 0.3 g of 3-fluoro-4-trifluoromethylpyridine-2-carboxamide=oxime and 0.31 g of 1,1′-carbonyldiimidazole, and the mixture was stirred at room temperature for 2 hours. Thereafter, 0.29 g of 1,8-diazabicyclo[5,4,0]undec-7-ene was added, and the mixture was stirred for 4 hours. To the reaction solution were added water and a 10% aqueous HCl solution, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.19 g of 3-(3-fluoro-4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (50)).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.Cl.Cl.[CH3:40][O:41][CH2:42][CH:43]([NH:45][C:46](=[O:54])[CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:44]>>[Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:34])[CH3:35])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27]([N:51]3[CH2:52][CH2:53][N:48]([CH2:47][C:46]([NH:45][CH:43]([CH3:44])[CH2:42][O:41][CH3:40])=[O:54])[CH2:49][CH2:50]3)=[O:28])[C@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:12]=2)[CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COCC(C)NC(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)COC)CC1

Procedure:
2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-(2-methoxy-1-methyl-ethyl)-acetamide was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and N-(2-methoxy-1-methylethyl)-2-piperazin-1-yl-acetamide (example 15) in an analogous manner as described in example 25. LR-MS: 753.4 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1Br)=[O:9])([CH3:6])[CH3:5].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/B(O)O)=[CH:25][CH:24]=1.[F-].[Cs+]>CO.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>[CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1/[CH:30]=[CH:29]/[C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=1)=[O:9])([CH3:6])[CH3:5]
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1/C=C/c1ccc(Cl)cc1
Yield: 65.3 %

Procedure:
50 mg 2-[(1-bromo-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester, 49.5 mg tetrakis(triphenylphosphine)palladium (0), 28.7 mg trans-2-(4-chloro-phenyl) vinylboronic acid and 43 mg CsF were suspended in 1 ml of MeOH and 3 ml of dimethoxyethane, deoxygenated with Argon, and heated to 80° for 14h. The reaction was filtered, purified by RP-HPLC and freeze-dried to give 38 mg of 2-({1-[(E)-2-(4-Chloro-phenyl)-vinyl]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid methyl ester (65%).
Reaction SMILES: [CH:1]([C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:2].Br[C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:21]=1>>[OH:2][C@H:1]([C:17]1[S:18][C:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:21]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Reactant: Brc1ccc(-c2ccccc2)s1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(-c2ccccc2)s1

Procedure:
(4R,5R)-5-[(1S)-Hydroxy(5-phenyl(2-thienyl))methyl]-1-methyl-4-phenyl-pyrrolidin-2-one was prepared from Intermediate Z and 2-bromo-5-phenylthiophene by a method analogous to that described for Example 6, then separated using the HPLC Separation B apparatus.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]([F:28])([F:27])[F:26])=[C:23]([C:29](Cl)=[O:30])[CH:22]=[N:21]2)=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:12][C:29]([C:23]1[CH:22]=[N:21][N:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[C:24]=1[C:25]([F:28])([F:26])[F:27])=[O:30]
Reactant: O=C(Cl)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Reactant: Nc1cccc(C(F)(F)F)c1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(C(F)(F)F)c1F)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-Fluoro-3-trifluoromethyl-phenylamine (0.007 g; 0.039 mmol) was added to a suspension of 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.010 g; 0.032 mmol) and PS-DIEA (0.1 g) in acetonitrile (2 mL). The reaction mixture was shaken at room temperature for 12 h at which time PS-TSCl (0.2 g) high loading was added to remove the excess amine. After an additional 12 h of shaking, the reaction mixture was filtered and concentrated to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (2-fluoro-3-trifluoromethyl-phenyl)-amide. LCMS m/z=449.9 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([O:22][CH2:34][C:33]4[CH:36]=[CH:37][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=4)=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: C/C(=C\c1ccc(C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a manner analogous to that described in Example 11, from p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid and 4-nitro-benzaldehyde there can be obtained 4-nitrobenzyl p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoate of melting point 183°-184° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:12]2[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[N:16]=2)([OH:11])[CH3:10])=[CH:4][CH:3]=1.Br[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=1.C[Sn](C)C.C[Sn](C)C>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:21][C:18]([CH3:22])([CH2:19][CH3:20])[CH2:17][C:15]1[N:16]=[C:12]([C:9]([OH:11])([CH3:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=3)=[CH:3][CH:4]=2)[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(Br)cc2)n1
Reactant: Fc1ccc(Br)nc1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccc(F)cn3)cc2)n1

Procedure:
Palladium tetrakis(triphenylphosphine) (221 mg, 0.19 mmol) was added to a degassed, ambient temperature solution of 2-[2-(4-bromophenyl)-1-hydroxy-1-methylethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Intermediate 11) (900 mg, 1.9 mmol), 2-bromo-5-fluoropyridine (336 mg, 1.9 mmol) and hexamethylditin (626 mg, 1.9 mmol) in 1,4-dioxane (20 mL). After stirring at reflux overnight, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-60% ethyl acetate/hexane afforded 4-(2,2-dimethylbutyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH2:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:7][C:5]=2[N:6]=1.C1(O)C=CC=CC=1.Br.CCOCC>O>[CH3:1][C:2]1[S:3][C:4]2[CH2:9][NH:8][CH2:7][C:5]=2[N:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3nc(C)sc3C2)cc1
Agent: Br
Solvent: O
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: Cc1nc2c(s1)CNC2
Reaction time: 0.17 h

Procedure:
To the product from Step B (100 mg) was added phenol (32 mg) followed by hydrogen bromide solution in water (48%, 2 mL). The mixture was refluxed for 90 min and cooled to ambient temperature Water (2 mL) and ether (5 mL) were added and the mixture stirred for 10 min and the ether layer removed. This wash was repeated and the aqueous layer was then treated with acetonitrile and filtered to give a pale brown solid. The solid was purified by preparative thin layer chromatography using an Analtech® 1500 micron plate (10% methanol/ethyl acetate, 1% ammonium hydroxide) to give the title compound as a dark solid. LC/MS 141.1 (M+1).