Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)=[CH2:4].[CH3:11][C:12]([Si:15]([CH3:29])([CH3:28])[O:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18](Cl)=[O:19])([CH3:14])[CH3:13]>O1CCCC1.C(Cl)Cl>[CH3:14][C:12]([Si:15]([CH3:28])([CH3:29])[O:16][C@@H:17]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:18]([N:9]1[C@H:5]([CH:3]=[CH2:4])[CH2:6][CH2:7][C:8]1=[O:10])=[O:19])([CH3:11])[CH3:13]
Reactant: C=CC1CCC(=O)N1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](Cc1ccccc1)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C[C@@H]1CCC(=O)N1C(=O)[C@H](Cc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To 60% sodium hydride (336 mg, 10 mmol, in mineral oil) in tetrahydrofuran (20 mL) at 0° C. was added dropwise a solution of 5-vinylpyrrolidin-2-one (1.0 g, 9.0 mmol) in tetrahydrofuran (10 mL) over a 5 min period. The cooling bath was removed and the solution was allowed to warm to 25° C. to ensure complete anion generation. To the anion at 25° C. was added dropwise a solution of (2S)-2-((1,1-dimethylethyl)dimethylsilyloxy)-3-phenylpropanoyl chloride (4, 2.98 g, 10 mmol) in tetrahydrofuran (10 mL) over a 5 min period. TLC indicated that the reaction was complete upon addition of the acid chloride (silica gel plates; hexane and ethyl acetate, 9:1). The solvent was removed by rotary evaporation affording a thick slug. The slug was dissolved in methylene chloride (75 mL) and washed with water (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and dried (MgSO 4). Concentration and purification by flash chromatography on silica gel (EM 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 4.5 cm diameter×15 cm length) using hexane and ethyl acetate (19:1) afforded 1.54 g (46%) of (5S)-N-((2S)-2-((1,1-dimethylethyl)-dimethylsilyloxy)-3-phenylpropanoyl)-5-ethenylpyrrolidin-2-one (5a) as a white crystalline material: mp 92°-93.5° C.; 1H NMR (CDCl3) δ-0.316 (s,3 H), -0.217 (s,3 H), 0.703 (s, 9 H), 1.94 (t, J=9.6 Hz, 1 H), 2.29 (p, J=11.7 Hz, 1 H), 2.50-2.75 (m, 3 H), 3.11 (d, J=12.8 Hz, 1 H), 4.97-5.13 (m, 1 H), 5.12-5.18 (m, 2 H), 5.45 (d, J=9.8 Hz, 1 H), 5.75-5.86 (m, 1 H); 13C NMR (CDCl3) δ175.1, 174.1, 137.9, 135.4, 130.0, 128.0, 126.4, 115.8, 74.2, 58.1, 41.2, 31.7, 25.5, 24.3, 18.1, -5.50, -5.76.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=C)=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=[O:18])=[CH:5][CH:4]=1
Reactant: C=CCn1c(=O)ccc2ccc(OC)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2ccc(=O)n(CC=O)c2c1
Reaction time: 8 h
Yield: 71 %

Procedure:
To a stirred solution of 7-(methyloxy)-1-(2-propen-1-yl)-2(1H)-quinolinone (4.14 g, 0.019 mol) in 1,4-dioxane (80 ml) and water (40 ml) under N2 was added sodium periodate (9.5 g; 0.044 mol) and osmium tetroxide (10 ml, 4% aqueous solution) and stirred overnight. The reaction was concentrated and partitioned in 20% MeOH/DCM (300 ml) and water (200 ml). The organic layer was dried over magnesium sulphate, filtered, and concentrated. The product was obtained after column chromatography (neat ethyl acetate) to yield g (71%) of the title compound as a green solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:9][C:10]1[C:11]2[C:16]([C:17]([CH:24]=O)=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH2:28].[BH4-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6](=[O:26])[N:7]([CH3:8])[CH2:9][C:10]1[C:11]2[C:16]([C:17]([CH2:24][NH:28][CH3:27])=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN
Reactant: CN(Cc1c2ccccc2c(C=O)c2ccccc12)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1c2ccccc2c(CN(C)C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
Compound 4 (2.29 g, 6.56 mmol) was dissolved in the mixture of THF (50 mL) and MeOH (50 mL). To this solution was added the aqueous solution of methylamine (40%, wt, 20 mL), the reaction mixture was stirred at room temperature under nitrogen for 12 h. Sodium borohydride (1.00 g, 26.3 mmol) was added, and stirred for 30 min. After removal of the solvent in vacuo, the resulting residue was dissolved in ethyl acetate (100 mL), washed with water (3×50 mL), and dried over MgSO4. Solvent evaporation gave a crude product, which was purified on a silica gel column, eluting with MeOH/CH2Cl2 (1/2), giving compound 5 as a yellow solid (2.00 g, 83%). 1H NMR (CDCl3) δ 8.44-8.39 (m, 4H), 7.56-7.53 (m, 4H), 5.51 (s, 2H), 4.71 (s, 2H), 2.69 (s, 3H), 2.46 (s, 3H), 1.55 (s, 9H). 13C NMR (CDCl3) δ 155.6, 132.5, 131.0, 130.0, 125.8, 125.7, 125.4, 125.3, 124.9, 79.7, 47.8, 42.6, 36.9, 31.6, 28.6. IR (cm−1): 1686. HRMS (FAB) calcd for C23H28N2O2 (M+) 364.2151, found 364.2159. Anal. calcd for C23H28N2O2: C, 75.79; H, 7.74; N, 7.69. Found: C, 75.64; H, 7.71; N, 7.53.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:13])[CH:10]=[C:9]([CH3:11])[CH2:8][CH2:7][CH:6]([OH:12])[CH2:5]1.I[CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:15]([O:12][C:6]1[CH2:7][CH2:8][CH:9]([CH3:11])[CH2:10][C:4]([CH3:13])([CH3:3])[CH:5]=1)[CH3:16]
Reactant: CCI
Reactant: CC1=CC(C)(C)CC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC1=CC(C)(C)CC(C)CC1
Temperature: 72 °C

Procedure:
Sodium hydride (60% in mineral oil) (5.4 gm) was added to 60 gm toluene in a reaction flask and stirred under nitrogen. 3,3,5-Trimethyl-4-cyclohepten-1-ol (15.4 gm) was added over 10 minutes at room temperature and stirred for 25 minutes. Iodoethane (23.4 gm) was next added over five minutes. The reaction was heated to 72° C. over 1.5 hours and then four hours at 112° C. The crude oil was washed once with 50 mL saturated sodium bicarbonate solution and distilled through a short Vigreux column. A heart cut fraction, 3,3,5-trimethyl-cyclohepten-1-yl ethyl ether, was obtained that weighed 14.9 gm and had a boiling point of 89° C. at 10 mm pressure. Its GC purity was 94%. The fraction was evaluated for its odor quality and characterized as having fresh diffusive citrus lime notes as well as fruity-peach/prune-rose floral.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[OH:3].[CH3:21]I>>[CH3:21][O:3][CH:2]([C:4]1[N:5]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH3:1]
Reactant: CC(C)Cn1c(C(C)O)nc2cnc3ccccc3c21
Reactant: CI
Product: COC(C)c1nc2cnc3ccccc3c2n1CC(C)C

Procedure:
Using the general method of Example 49, α-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol (3 g; 11 mmol, Example 63) was reacted with methyl iodide to provide 2.4 g of the desired product. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of 3-fluoro-4-nitrophenol (5.0 g, 32 mmol) and 4-fluorobenzyl bromide (6.3 g, 33 mmol) in acetone (50 mL) containing potassium carbonate (5.3 g, 38 mmol) was heated under reflux for 2 h. After cooling to room temperature the mixture was filtered and evaporated to leave the title compound (7.3 g, 86%) as a light yellow solid. MS: m/e=265.1 (M++H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]4[C:26]5[CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32][C:27]=5[N:28]([CH3:31])[C:29]=4[CH:30]=3)[C:18](=[O:43])[CH:17]=2)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]4[C:26]5[CH2:35][NH:34][CH2:33][CH2:32][C:27]=5[N:28]([CH3:31])[C:29]=4[CH:30]=3)[C:18](=[O:43])[CH:17]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C(=O)OC(C)(C)C)C5)c(=O)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCNC5)c(=O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl 7-(4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (74 mg, 0.15 mmol) in CH2Cl2 (1 mL) under N2 and stirred for 2 h at ambient temperature. The mixture was concentrated, and the residue was partitioned between CH2Cl2 and saturated NaHCO3 solution. The organic phase was removed, and the aqueous phase was extracted with CH2Cl2 (4×25 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4 and concentrated under reduced pressure. Flash column chromatography (12 g ISCO CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes to 0:100 over 20 column volumes and hold for 5 column volumes) yielded the title compound (46 mg, 78%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J=9.0 Hz, 2H), 7.50-7.46 (m, 2H), 7.36 (d, J=2.0 Hz, 1H), 7.05 (dd, J=8.5, 2.0 Hz, 1H), 7.00 (d, J=8.5 Hz, 2H), 6.86 (d, J=1.5 Hz, 1H), 6.49 (dd, J=7.0, 2.0 Hz, 1H), 4.08 (s, 2H), 3.87 (s, 3H), 3.63 (s, 3H), 3.27 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.5 Hz, 2H).
Reaction SMILES: OO.[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([OH:36])[C:30]([CH3:38])([CH3:37])[CH2:29]3)[N:20]=[C:19]([NH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]3[CH2:49][C:48]([CH3:51])([CH3:50])[N:47]([OH:52])[C:46]([CH3:54])([CH3:53])[CH2:45]3)[N:18]=2)[CH2:6][C:5]1([CH3:56])[CH3:55].S([O-])([O-])=O.[Na+].[Na+].[C:63]([OH:67])([CH3:66])([CH3:65])[CH3:64]>O.C(OCC)(=O)C>[OH:67][C:63]([CH3:66])([CH3:65])[CH2:64][O:52][N:47]1[C:46]([CH3:54])([CH3:53])[CH2:45][CH:44]([CH2:43][CH2:42][CH2:41][CH2:40][NH:39][C:19]2[N:18]=[C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:7]3[CH2:6][C:5]([CH3:56])([CH3:55])[N:4]([O:3][CH2:64][C:63]([CH3:66])([OH:67])[CH3:65])[C:9]([CH3:11])([CH3:10])[CH2:8]3)[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][C:32]([CH3:34])([CH3:35])[N:31]([O:36][CH2:64][C:63]([CH3:66])([OH:67])[CH3:65])[C:30]([CH3:38])([CH3:37])[CH2:29]3)[N:20]=2)[CH2:49][C:48]1([CH3:51])[CH3:50]
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(O)C(C)(C)C3)nc(NCCCCC3CC(C)(C)N(O)C(C)(C)C3)n2)CC(C)(C)N1O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(O)CON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OCC(C)(C)O)C(C)(C)C3)nc(NCCCCC3CC(C)(C)N(OCC(C)(C)O)C(C)(C)C3)n2)CC1(C)C
Temperature: 60 °C
Yield: 37.2 %

Procedure:
A solution of 40 g (0.35 mol) of 30% aqueous hydrogen peroxide is added over 1.25 hours to a mixture of 11.7 g (0.011 mol) of 2,4,6-tris[N-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl]butylamino}-s-triazine and 3.0 g (0.015 mol) of ferrous chloride tetrahydrate in 100 g of tert-butyl alcohol and 9 g of water. The reaction temperature is maintained at 60-65° C. during the peroxide addition. Two equal portions (2 g, 0.29 mol) of 50% aqueous hydrogen peroxide are added to the reaction mixture while the temperature is maintained at 60° C. for 9.5 hours. After the reaction mixture is diluted with ethyl acetate and cooled to room temperature, a solution of 100 g of 20% aqueous sodium sulfite is added. The reaction mixture is heated at 60° C. for one hour to decompose the excess peroxide. The aqueous layer is extracted with ethyl acetate, and the combined organic layers are concentrated. The crude product is purified by flash chromatography on silica gel with 2:1 (v/v) cyclohexane/ethyl acetate to afford a material which is triturated with 1:1 (v/v) cyclohexane/acetone to give 4.0 g of the title compound as a white solid, melting at 172-176° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[F:19][C:16]([F:18])([F:17])[C:13]1[N:11]2[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:25][C:24]4[CH:27]=[CH:28][CH:29]=[C:22]([C:21]([F:20])([F:30])[F:31])[CH:23]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4c3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine with 3-(trifluoromethyl)benzaldehyde was carried out according to General Synthetic Method 9. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[4-[[3-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][C:9]([CH3:28])([CH3:27])[C:10]([NH:12][C:13]2[S:14][C:15]([C:24](O)=[O:25])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)=[O:11])=[O:7])=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:62]([N:69]1[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]1)([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63]>CN(C=O)C>[C:65]([O:64][C:62]([N:69]1[CH2:74][CH2:73][N:72]([C:24]([C:15]2[S:14][C:13]([NH:12][C:10](=[O:11])[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:29]=[CH:30][C:2]([F:1])=[CH:3][CH:4]=3)([CH3:27])[CH3:28])=[N:17][C:16]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:25])[CH2:71][CH2:70]1)=[O:63])([CH3:68])([CH3:66])[CH3:67]
Reactant: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccccc2)c(C(=O)O)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2sc(NC(=O)C(C)(C)NC(=O)c3ccc(F)cc3)nc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[2-(4-Fluoro-benzoylamino)-2-methyl-propionylamino]-4-phenyl-thiazole-5-carboxylic acid (46 mg, 0.11 mmol), HBTU (50 mg, 0.13 mmol), triethylamine (22 uL, 0.16 mmol) and N-Boc piperazine (27 mg, 0.15 mmol) in DMF (2 mL) was stirred at RT for 18 h and partitioned between ethyl acetate and aq. K2CO3. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 596.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:16][CH:15]([C:5]2=1)[CH2:14][CH2:13]3.[C:17]([C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1)#[CH:18]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](/[CH:18]=[CH:17]\[C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:6]1[CH2:11][C@H:12]3[NH:16][C@@H:15]([C:5]2=1)[CH2:14][CH2:13]3
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCC(C3)N1
Reactant: C#Cc1ccc(C)nc1
Product: Cc1ccc2c(c1)c1c(n2/C=C\c2ccc(C)nc2)C[C@@H]2CC[C@H]1N2

Procedure:
The coupling of 2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (212 mg, 1.00 mmol; Example 4A) and 5-ethynyl-2-methylpyridine (586 mg, 5.00 mmol; WO2005090333) was performed as described in Example 20 to afford the racemate of the title compound. The individual enantiomers were separated by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine) to afford the title compound as the second-eluting peak: 1H NMR (300 MHz, methanol-d4) δ ppm 1.37-1.52 (m, 1H), 1.97-2.15 (m, 3H), 2.32 (d, J=17 Hz, 1H), 2.38 (s, 3H), 2.40 (s, 3H), 3.00 (dd, J=16, 4 Hz, 1H), 3.86-3.91 (m, 1H), 4.53 (d, J=4 Hz, 1H), 6.58 (d, J=9 Hz, 1H), 6.80-6.88 (2H), 6.90 (d, J=8 Hz, 1H), 7.02-7.13 (m, 2H), 7.27 (s, 1H), 7.93 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 330 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([O:38][CH3:39])=[O:37]>CN(C)C=O.C(OCC)(=O)C>[CH3:39][O:38][C:36]([C:35]1[CH:34]=[C:33]([CH:42]=[CH:41][CH:40]=1)[CH2:32][N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)=[O:37]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Temperature: 60 °C
Reaction time: 60 h

Procedure:
To a solution of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.15 g, 0.45 mmol) and potassium carbonate (0.124 g, 0.9 mmol) in N,N-dimethylformamide (4 mL), was added methyl 3-(bromomethyl)benzoate (0.114 g, 0.5 mmol). After stirring at 60° C. for 60 hours, the reaction mixture was diluted with ethyl acetate (25 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4, filtered and concentrated to a yellowish brown solid (0.2 g, 93%); 1H NMR (DMSO-d6): δ 1.45 (s, 9H), 1.64 (d, 2H, J=13.6 Hz), 2.41-2.49 (m, 2H), 3.48 (br, 2H), 3.85 (s, 3H), 3.86-3.90 (m, 2H), 4.59-4.64 (m, 4H), 6.68 (d, 2H, J=8.4 Hz), 6.77 (t, 1H, J=7.4 Hz), 7.17 (t, 2H, J=8 Hz), 7.54-7.60 (m, 2H), 7.89-7.92 (m, 2H); MS for C27H33N3O5 m/z 480.08 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-])=O)[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CNC>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: Oc1ccc(F)cc1
Agent: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1cccc(Oc2ccc(F)cc2)c1
Yield: 91.2 %

Procedure:
Alternatively, 3-(4-fluoro-phenoxy)-phenylamine was prepared by a two-step procedure by heating a suspension of m-fluoronitrobenzene (4.06 g, 28.7 mmol), p-fluorophenol (3.21 g, 28.6 mmol) and K2CO3 (8.13 g, 58.8 mmol) in DMA (dimethylamine) (60 mL) at 150° C. for 3 hours. The brown reaction mixture was concentrated to one-quarter original volume, diluted with ethyl acetate (220 mL) and washed successively with water (220 mL), 1N NaOH (220 mL) and brine (220 mL). The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford the diphenylether (5.30 g, 80%) as a brown oil.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[N:7]=[N:8][S:9][C:10]=1[C:11]([OH:13])=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:11]([C:10]1[S:9][N:8]=[N:7][C:6]=1[CH3:5])(=[O:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccccc1
Reactant: Cc1nnsc1C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: Cc1nnsc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To 2.0 g (15 mmol) of thionyl chloride was added 0.50 g (3.5 mmol) of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid. After heating the mixture with stirring for 2 hours, the thionyl chloride was distilled off under reduced pressure, and the residue was added to a solution of 1.8 g (15 mmol) of aluminum chloride in 20 ml benzene and made to react with heating for 3 hours. After the reaction was completed, the reaction mixture was poured into ice water, the objective product was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous solution of sodium chloride and dried, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using 4:1 mixture of n-hexane and ethyl acetate. Thus, 0.69 g of the objective compound was obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:19])=[C:10]([C:16]([OH:18])=O)[N:11]=[C:12]2[Cl:15])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl.C[O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25]>>[CH:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:19])=[C:10]([C:16]([C:24]([NH2:25])([CH3:26])[C:23]([OH:27])=[O:22])=[O:18])[N:11]=[C:12]2[Cl:15])=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](C)N
Reactant: CC(C)Oc1ccc2c(O)c(C(=O)O)nc(Cl)c2c1
Agent: Cl
Product: CC(C)Oc1ccc2c(O)c(C(=O)C(C)(N)C(=O)O)nc(Cl)c2c1

Procedure:
Analogously to Example A-56, 0.040 g of 7-isopropoxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid were allowed to react with 0.020 g of L-Alanine methyl ester hydrochloride to give, after hydrolysis of the intermediate ester, 0.047 g of a white solid: MS-(−)-ion, M−1=353.1 amu.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[C:14]1([C:20]2[C:28]([CH:29]=O)=[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]3[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:14]1([C:20]2[C:28]([CH:29]=[CH:5][C:3]([O:2][CH3:1])=[O:4])=[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]3[N:21]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=Cc1c(-c2ccccc2)nn2ccccc12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Temperature: 60 °C
Yield: 53.5 %

Procedure:
A solution of trimethyl phosphonoacetate (4.0 g) in toluene (10 ml) was added to a mixture of sodium hydride (63%, 880 mg) in toluene (45 ml) with stirring and cooling and then heated at 60° C. for 20 minutes. To the mixture 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (2.0 g) was added and heated at 60° C for 8 hours. A saturated sodium bicarbonate solution (30 ml}was added to the reaction mixture and extracted with ethyl acetate (30 ml, 2 times). The extract was washed with brine (30 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and isopropyl alcohol to give crystals of methyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylate (trans isomer) (1.34 g).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37]>>[CH:1]1([CH2:7][NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnn2c(NCC3CCCCC3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCC3CCCCC3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12

Procedure:
In the same manner as in Example 1, step 6 and using 7-cyclohexylmethylamino-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.08 g, 0.17 mmol) obtained in step 2 and methanesulfonamide (0.11 g, 0.87 mmol), compound a-8 (80 mg, 32%) was obtained.