Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[CH:5]=1.C(=O)(O)[O-].[Na+].[C:18](Cl)(=[O:21])[CH:19]=[CH2:20]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][C:18](=[O:21])[CH:19]=[CH2:20])[CH:5]=1
Reactant: CNc1cccc(C(=O)OC)c1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(=O)CNc1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred mixture of 3-methylaminobenzoic acid methyl ester (3.11 g, 18.8 mmol) and sodium bicarbonate (3.16 g, 37.6 mmol) in DCM (20.0 mL) at 0° C. was added 2-propenoyl chloride (2.29 mL, 28.2 mmol). The reaction mixture was stirred overnight at room temperature. Saturated aqueous sodium bicarbonate solution was added and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (4.12 g, 100% yield), which was used in the next reaction without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.B(O)(O)[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cc(C#N)cc3c(C)c4n(c23)CCNC4=O)cc1

Procedure:
The title compound, light yellow solid (67 mg, 85%), MS (ISP) m/z=316.6 [(M+H)+], mp 277° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available p-tolylboronic acid (44.2 mg, 0.325 mmol).
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.[CH3:15][CH2:16][O:17][C:18]([CH:20]([C:24]([CH3:26])=O)[C:21]([CH3:23])=O)=[O:19]>>[CH2:16]([O:17][C:18]([C:20]1[C:21]([CH3:23])=[N:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]([F:13])([F:14])[F:2])=[CH:10][CH:9]=2)[C:24]=1[CH3:26])=[O:19])[CH3:15]
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Product: CCOC(=O)c1c(C)nn(-c2ccc(OC(F)(F)F)cc2)c1C
Yield: 72 %

Procedure:
In analogy to the procedure described in Example 38A], (4-trifluoromethoxy-phenyl)-hydrazine hydrochloride and ethyl diacetoacetate gave, after extraction (3× Et2O), drying (Na2SO4) and evaporation, the title compound in 72% yield as orange oil. MS: 328.9 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:29]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=5)[C:6]=4[CH:17]=3)=[CH:28][N:27]=[CH:26]2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: Clc1ccc(-n2ccnc2)cc1
Product: Fc1ccc(-n2cnc3ccc(-c4cncn4-c4ccc(Cl)cc4)cc32)cc1

Procedure:
The title compound, off-white solid (20 mg, 15%), MS (ISP) m/z=389.5 [(M+H)+], mp 254° C., was prepared in accordance with the general method of example 28 from 6-bromo-1-(4-fluoro-phenyl)-1H-benzo[d]imidazole (intermediate G) (204 mg, 0.7 mmol) and commercially available 1-(4-chloro-phenyl)-1H-imidazole (62.5 mg, 0.35 mmol).
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.[F:27][C:28]([F:38])([F:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36].N#N>ClCCl>[F:27][C:28]([F:37])([F:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[O:36]
Reactant: OCCCCCCCC(F)(F)F
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: N#N
Solvent: ClCCl
Product: O=CCCCCCCC(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2,2,6,6-Tetramethylpiperidine 1-oxyl (202 mg, 1.29 mmol) and (diacetoxyiodo)benzene (3.33 g, 10.4 mmol) were added to a solution of 8,8,8-trifluoro-octanol (˜8.63 mmol) in dichloromethane (34.5 mL) at 0° C. in an N2 atmosphere, and the mixture was stirred at 0° C. for five minutes and at room temperature for 1.5 hours. The reaction solution was diluted with dichloromethane (200 mL), and the organic layer was sequentially washed with a saturated aqueous sodium sulfite solution (100 mL), a saturated aqueous sodium bicarbonate solution (100 mL) and saturated brine (100 mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 8,8,8-trifluoro-octanal as a colorless oily substance (310 mg, two steps, 20%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:9]([CH2:11][CH3:12])[CH3:10])[C:6]=1[C:7]#[N:8].[CH3:13][N:14]=[C:15]=[O:16]>C(COC)OC>[C:7]([C:6]1[C:5]([CH:9]([CH2:11][CH3:12])[CH3:10])=[CH:4][S:3][C:2]=1[NH:1][C:15]([NH:14][CH3:13])=[O:16])#[N:8]
Reactant: CCC(C)c1csc(N)c1C#N
Reactant: CN=C=O
Solvent: COCCOC
Product: CCC(C)c1csc(NC(=O)NC)c1C#N

Procedure:
A solution of 5 g 2-amino-3-cyano-4-sec-butylthiophene and 10 ml methyl isocyanate in 20 ml dimethoxyethane was stirred at about 25°C. for 2 days and then at reflux for 6 hours. The reaction mixture was evaporated under reduced pressure and the residue was chromatographed on a silica-gel column. The product, a white solid melting at 149°-152°C., was eluted with 70% ether-30% hexane. The infrared spectrum of the product showed cyano absorption at 4.5 microns. Sulfur analysis for the product is tabulated in Table I.
Reaction SMILES: COC1C=CC(N)=CC=1.Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([C:23]([OH:25])=[O:24])=[CH:16]2.Cl.[CH3:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1.N1C=CC=CC=1>S(Cl)(Cl)=O.C(OCC)C.C(N(CC)CC)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([C:23]([OH:25])=[O:24])=[CH:16]2.[CH3:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH:34][C:23]([C:17]2[CH:18]=[N:19][C:20]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:12][CH3:11])=[CH:22][CH:21]=3)=[O:25])[CH2:30][CH2:29]1
Reactant: C[C@H]1CC[C@H](N)CC1
Agent: COc1ccc2ncc(C(=O)O)cc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: COc1ccc(N)cc1
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(C(=O)N[C@H]3CC[C@H](C)CC3)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Methoxyquinoline-3-carboxylic acid was prepared from p-anisidine using the methods of Erickson (J. Med. Chem., 1979, 22, 7, 816–823). A solution of 6-methoxyquinoline-3-carboxylic acid hydrochloride (500 mg, 2.09 mmol) in thionyl chloride (25 mL) was heated at reflux for 1 hour. After this time the excess thionyl chloride was removed by distillation and the remaining solid dried under vacuum. The solid was suspended in dichloromethane (25 mL) and treated with trans-4-methylcyclohexylamine hydrochloride (368 mg, 2.46 mmol), pyridine (5 mL), and triethylamine (0.345 mL). The reaction was stirred at ambient temperature overnight. After this time the reaction mixture was diluted with diethyl ether (200 mL) and the resulting organic solution washed with 1 N NaOH (3×50 mL) and then brine (1×). The organic solution was then dried over anhydrous MgSO4, filtered, and concentrated to a solid. Chromatography of the crude product through a Biotage silica cartridge (8×4 cm i.d.) using a gradient of hexane to 50% ethyl acetate (in hexane) afforded 100 mg (16%) of 419:
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([O:30]C)[CH:24]=5)[C:20]([CH3:32])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[Si](I)(C)(C)C.CO.C(OCC)(=O)C>CC#N.O>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH3:32])=[C:21]([C:23]5[CH:28]=[C:27]([CH3:29])[NH:26][C:25](=[O:30])[CH:24]=5)[N:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc(C)n1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc(=O)[nH]1
Temperature: 55 °C
Reaction time: 1 h
Yield: 81584.3 %

Procedure:
To a suspension of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,6′-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (12 mg, 26.5 μmol) in CH3CN (0.5 mL) was added TMSI (7.5 μL, 52.9 μmol) drop wise. The reaction was stirred at 55° C. for 1 hour. MeOH (1.0 mL) was added followed by ethyl acetate (3 mL) and water (1 mL). The organic layer was separated and washed with NaHSO3 (2×), and brine (1×). The organic layer was then dried over Na2SO4, filtered and evaporated under reduced pressure to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-methyl-2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide as a white solid (9.5 g, 81.7%); ESI-MS m/z calc. 439.4. found 440.5 (M+1)+. Retention time 1.60 minutes.
Reaction SMILES: Br[C:2]1C=CC2N(C(C3SC(SC)=CC=3)=CN=2)C=1.CC1(C)C(C)(C)OB(C2C(C3C=CC(C(OC)=O)=CC=3)=NN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=2)O1.[CH3:61][S:62][C:63]1[S:67][C:66]([C:68]2[N:72]3[CH:73]=[C:74]([C:77]4[C:78]([C:101]5[CH:110]=[CH:109][C:104]([C:105]([O:107][CH3:108])=[O:106])=[CH:103][CH:102]=5)=[N:79][N:80]([C:82]([C:95]5[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=5)([C:89]5[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=5)[C:83]5[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=5)[CH:81]=4)[CH:75]=[CH:76][C:71]3=[N:70][CH:69]=2)=[CH:65][CH:64]=1>>[CH3:61][S:62][C:63]1[S:67][C:66]([C:68]2[N:72]3[CH:73]=[C:74]([C:77]4[C:78]([C:101]5[CH:102]=[CH:103][C:104]([C:105]([O:107][CH2:108][CH3:2])=[O:106])=[CH:109][CH:110]=5)=[N:79][N:80]([C:82]([C:83]5[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=5)([C:95]5[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=5)[C:89]5[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=5)[CH:81]=4)[CH:75]=[CH:76][C:71]3=[N:70][CH:69]=2)=[CH:65][CH:64]=1
Reactant: COC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccc(SC)s4)n3c2)cc1
Reactant: CSc1ccc(-c2cnc3ccc(Br)cn23)s1
Agent: COC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccc(SC)s4)n3c2)cc1

Procedure:
260 mg 6-bromo-3-[5-(methylsulfanyl)-2-thienyl]imidazo[1,2-a]pyridine (compound in Production Example 58) and 1 g mixture of methyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-3-pyrazolyl]benzoate and methyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-3-pyrazolyl]benzoate were reacted in the same manner as in Example 10, whereby 515 mg mixture of methyl 4-{4-[3-(5-methylsulfanylthiophen-2-yl)imidazo[1,2-a]-pyridin-6-yl]-1-trityl-1H-pyrazol-3-yl}benzoate and ethyl 4-{4-[3-(5-methylsulfanylthiophen-2-yl)imidazo[1,2-a]-pyridin-6-yl]-1-trityl-1H-pyrazol-3-yl}benzoate was obtained as a pale yellow amorphous. A mixture of 300 mg of this ester derivative, 1.3 mL of 1 N aqueous sodium hydroxide and 7 mL ethanol was stirred at 50° C. for 5 hours. An aqueous saturated ammonium chloride solution, ethylacetate, tetrahydrofuran and water were added to the reaction solution, and the organic layer was separated. To dissolve insolubles, dichloromethane and methanol were added to this organic layer which was then dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The resulting residue was subjected to azeotropic distillation with toluene to give 416 mg crude product of 4-{4-[3-(5-methylsulfanylthiophen-2-yl)imidazo[1,2-a]pyridin-6-yl]-1-trityl-1H-pyrazol-3-yl}-benzoic acid as white crystals. From 414 mg of this carboxylic acid, 62 mg of the title compound was obtained as a pale yellow amorphous by the same reaction as in Example 361.
Reaction SMILES: CC([CH:5]([N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH:21]([CH3:32])[CH2:22][C:23]([NH:25][C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])=O)=[CH:16][CH:15]=2)[N:11]=[CH:10]1)[C:6]([O-:8])=[O:7])(C)C.[BH4-].[Na+].[Cl-].[Mg+2].[Cl-].C(O)(=O)[CH2:39][C:40]([CH2:45]C(O)=O)([C:42](O)=O)O.Cl>C(O)C.C(Cl)Cl>[CH3:32][C@H:21]1[CH2:22][C@@H:23]([NH:25][C:26]([O:28][CH:29]([CH3:30])[CH3:31])=[O:27])[C:16]2[C:17](=[CH:18][CH:19]=[C:14]([C:12]3[N:11]=[CH:10][N:9]([CH2:5][C:6]([O:8][C:40]([CH3:45])([CH3:42])[CH3:39])=[O:7])[CH:13]=3)[CH:15]=2)[NH:20]1
Reactant: CC(CC(=O)NC(=O)OC(C)C)Nc1ccc(-c2cn(C(C(=O)[O-])C(C)(C)C)cn2)cc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)OC(=O)N[C@@H]1C[C@H](C)Nc2ccc(-c3cn(CC(=O)OC(C)(C)C)cn3)cc21
Temperature: -15 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of 1,1-dimethylethyl[4-(4-{[1-methyl-3-({[(1-methylethyl)oxy]carbonyl}amino)-3-oxopropyl]amino}phenyl)-1H-imidazol-1-yl]acetate (for a preparation see intermediate 89) (980 mg, 2.21 mmol) in ethanol (20 mLl) was cooled to −15° C. The solution was treated with sodium borohydride (75 mg, 1.98 mmol) followed by magnesium chloride (1M in water, 2.43 mL, 2.43 mmol) maintaining the temperature below −10° C. The reaction mixture was stirred at a temperature lower than 0° C. for 1 h then at room temperature for 1 h. The suspension formed was poured onto a stirred mixture of citric acid (1.06 g, 5.51 mmol), HCl (1M in water, 25 mL) and DCM (15 mL). The resulting mixture was stirred at room temperature for 30 min and the layers were separated. The aqueous layer was basified by the addition of solid K2CO3 then was extracted with AcOEt (3×20 mL). The combined organic phases (DCM+EtOAc) were washed with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 2% MeOH in DCM) gave 1,1-dimethylethyl {(cis)-4-[2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazol-1-yl}acetate (645 mg, 1.505 mmol, 68%) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[NH:31][C:30]([CH3:35])=[CH:29]4)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[NH:31][C:30]([CH3:35])=[CH:29]4)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N3CCCc4cc(F)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2cc(-c3nc4ccc(C(=O)O)cc4nc3N3CCCc4cc(F)ccc43)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of methyl 3-(6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylate (118 mg, 0.25 mmol) in methanol (20 ml) and water (1.0 ml) was added sodium hydroxide (40 mg, 1.00 mmol). The reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (20 mL) and adjusted to pH 4 with hydrogen chloride (3 N). The solids were collected by filtration to afford 3-(6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylic acid as a light yellow solid (81 mg, 71%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([C@H:23]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:24]1)=[N+]=[N-].O>O1CCCC1>[NH2:20][C@H:23]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[C@H:25]([CH2:35][O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:24]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])C[C@H]1COCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](N)C[C@H]1COCc1ccccc1
Yield: 53.6 %

Procedure:
Triphenylphosphine (421 mg) was added to a solution of tert-butyl (2S,4R)-4-azido-2-[(benzyloxy)methyl]pyrrolidine-1-carboxylate (455 mg) [see Preparation 33] in dry tetrahydrofuran (10 ml). The reaction mixture was then stirred until the evolution of nitrogen gas had ceased, water (0.036 ml) was added, the mixture was then stirred for a further 72 hours. The solvent was then removed under reduced pressure and the residue was dissolved in diethyl ether and hexane added until the mixture became cloudy. The supernatant liquid was separated and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 90:10, by volume, dichloromethane : methanol to afford tert-butyl (2S,4R)-4-amino-2-[(benzyloxy)methyl]pyrrolidine-1-carboxylate (225 mg) as a colourless oil.
Reaction SMILES: [CH:1]([CH:4]1[C:8](=[O:9])[O:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[N:5]1[C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:6][N:5]([C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])[CH:4]([CH:1]([CH3:3])[CH3:2])[C:8]([OH:9])=[O:7])=[CH:11][CH:12]=1)#[N:23]
Reactant: CCCCC(=O)N1C(c2ccc(-c3ccccc3C#N)cc2)OC(=O)C1C(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)C(C(=O)O)C(C)C
Temperature: 75 °C

Procedure:
6.0 g (15.4 mmoles) of 4′-(4-isopropyl-5-oxo-3-pentanoyl-oxazolidin-2-yl)-biphenyl-2-carbonitrile is reacted in 30 ml of ethanol with 3.8 g of ammonium formate (61.6 mmoles) and 2 g of 5% Pd/C catalyst. The temperature is raised to 75° C., keeping these conditions for 3 hours. The mixture is cooled and the catalyst is filtered off. The organic phase is concentrated under reduced pressure to a residue to obtain 2-[(2′-cyano-biphenyl-4-yl-methyl)-pentanoyl-amino]-3-methylbutyric acid.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([F:13])=[CH:6][C:5]=1F.Cl[CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([F:13])=[CH:6][C:5]=1[CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1cc(F)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
Crushed sodium hydroxide pellets (2.26 g, 56.5 mmol) were added portionwise over 20 minutes to solution of 1,2,4-trifluoro-5-nitrobenzene (5.0 g, 28.2 mmol) and diethyl chloropropanedioate (4.57 ml, 56.5 mmol) in dry DMF (50 ml) at 0° C. under argon. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to OC and acidified with 2N Hydrochloric acid (50 ml) then extracted with ethyl acetate (150 ml) and washed with water (150 ml). The organic layer was dried over magnesium sulphate, filtered and evaporated to an orange oil. Purified by chromatography on silica gel (Biotage SP4, 100 g silica column) eluting with 0-20% ethyl acetate/hexane to give the title compound as a yellow oil (4.84 g, 15.3 mmol). LC/MS: Rt=3.07, [MH]− 316.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]([OH:18])=[O:17])[C:6]([Cl:11])=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br.ClCCl>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]([OH:18])=[O:17])[C:6]([Cl:11])=[CH:7][C:8]=1[OH:9]
Reactant: COc1cc(Cl)c(C=CC=CC(=O)O)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)C=CC=Cc1cc(O)c(O)cc1Cl
Temperature: 20 °C
Reaction time: 24 h
Yield: 45.5 %

Procedure:
To a solution containing 0.54 g of the product obtained in Example 35 in 6 ml dichloromethane 6 ml of 1 molar boron tribromide-dichloromethane solution was added and stirred for 24 h at 20° C. The solvent was evaporated in vacuo and 2N hydrochloric acid was added to the residue. The product was filtered and washed with water. Recrystallization from isopropanol-water yielded 0.22 g (46%) of the product desired, m.p. 203°-206° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])[CH2:24][CH2:23]2)[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18](OC)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:37]>>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])=[O:29])[CH2:24][CH2:23]2)[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]#[N:37])[CH2:10]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: N
Reactant: COC(=O)[C@@H]1CS[C@H]2C[C@](NC(=O)OC(C)(C)C)(C3CCN(C(=O)OCC[Si](C)(C)C)CC3)C(=O)N21
Product: CC(C)(C)OC(=O)N[C@]1(C2CCN(C(=O)OCC[Si](C)(C)C)CC2)C[C@@H]2SC[C@@H](C#N)N2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
153 mg of methyl (3R,6S,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-[1-(2-trimethylsilanylethoxycarbonyl)piperidin-4-yl]hexahydropyrrolo[2,1-b]thiazole-3-carboxylate were dissolved at 0° C. in 30 ml of ammonia-saturated methanol. The mixture was allowed to reach room temperature over the course of 5 h, and then the solvents were removed in vacuo. The residue was taken up in 5 ml of THF, and 100 μl of triethylamine and 60 μl of trifluoroacetic anhydride were successively added. The mixture was stirred at room temperature for 2 h. It was then partitioned between 60 ml of 0.5 M HCl and 60 ml of ethyl acetate. The aqueous phase was extracted twice with 20 ml of ethyl acetate each time, and the combined organic phases were washed once with 30 ml of saturated sodium bicarbonate solution. After drying with MgSO4, the solvents were removed in vacuo. The residue was chromatographed on silica gel.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:27]O[Si](C(C)C)(C(C)C)C(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:18]([F:21])([F:19])[F:20])[C:22]([F:23])([F:24])[F:25])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](OCc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1)(C(C)C)C(C)C
Agent: [Pd]
Solvent: CO
Product: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Yield: 93.9 %

Procedure:
A solution of 31 mg (0.055 mmol) of 2-(1-benzyl-2-triisopropylsilanyloxymethyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 41.3) in 1 mL of methanol was hydrogenated at atmospheric pressure for 12 hours in the presence of 30 mg of Pd/C (10% Pd). Removal of the catalyst by filtration through decalite and evaporation of the solvent yielded 20 mg (93%) of 2-(1-benzyl-2-methyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, red solid, MS: 388 (MH+).