Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(OB=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:19]1[CH:20]=[CH:21][C:22]([C:40]#[N:41])=[C:23]([NH:25][C:26]([C:28]2[CH:29]=[N:30][CH:31]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:33]=2)=[O:27])[CH:24]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:40]([C:22]1[CH:21]=[CH:20][C:19]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:24][C:23]=1[NH:25][C:26]([C:28]1[CH:29]=[N:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:33]=1)=[O:27])#[N:41]
Reactant: O=BOc1ccccc1
Reactant: N#Cc1ccc(Cl)cc1NC(=O)c1cncc(-c2ccccc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccccc2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 102.2 %

Procedure:
Phenylboranic acid (88 mg), tripotassium phosphate (0.28 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.5 mg), and palladium(II) acetate (2.7 mg) were added to a toluene (3.0 mL) suspension of N-(5-chloro-2-cyanophenyl)-5-phenylpyridine-3-carboxamide (0.20 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.5 mg) and palladium(II) acetate (2.7 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 6 hours. After cooling the reaction mixture to room temperature, ethyl acetate and a 10% aqueous solution of citric acid were added thereto, and the insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.23 g of N-(2-cyano-5-phenylphenyl)-5-phenylpyridine-3-carboxamide as a light yellow solid.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:11]([F:12])=[CH:10][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32]([NH:34][CH3:35])=[O:33])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:7]=1[F:41].[BrH:42]>C(#N)C.CCOC(C)=O.O.[Cu]Br>[Br:42][C:6]1[C:11]([F:12])=[CH:10][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32]([NH:34][CH3:35])=[O:33])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:7]=1[F:41]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(N)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(Br)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
Sodium nitrite (0.034 g, 0.49 mmol) was added to a 0° C. solution of 6-(N-(4-amino-3,5-difluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.235 g, 0.444 mmol) in Acetonitrile (3 ml) and aq HBr (48%) (3 mL). The reaction mixture was stirred for 30 min at 0° C. and copper (I) bromide (0.076 g, 0.53 mmol) was added. The reaction mixture was stirred at 90° C. for 2 h and diluted with EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford the title compound (0.094 g, 36%) as a white foam. LCMS (m/z, ES+)=593.2, 595.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([C@@H:13]([CH3:15])[OH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])(=O)=O.Cl>C(Cl)Cl>[C:9]([O:8][C:6]([NH:5][C@@H:4]([C@H:13]([O:14][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH3:15])[C:3]([O:2][CH3:1])=[O:16])=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
A solution of N-(tert-butoxycarbonyl)-L-threonine methyl ester (Aldrich) (717 mg, 3.07 mmol) in DCM (10 mL) was cooled in an ice-water bath and treated with 2,6-dimethylpyridine (Aldrich) (1.07 mL, 9.22 mmol) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (Fluka) (0.85 mL, 3.69 mmol). The solution was stirred for 16 h, poured into 1 M aq. HCl (100 mL), and extracted with DCM (2×50 mL). The organic extracts were washed with saturated aq. NaHCO3 (100 mL), dried (MgSO4), filtered, and concentrated to give (2S,3R)-methyl 2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)butanoate (614a) (1.07 g, 3.08 mmol, 100% yield) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][CH2:49][C:50]1[CH:54]=[N:53][N:52]([CH2:55][C@@H:56]2[C@H:59]([NH:60][C:61](=[O:97])/[C:62](=[N:76]\[O:77][C:78]3([C:81]([O:83][CH:84]([C:91]4[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=4)[C:85]4[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=4)=[O:82])[CH2:80][CH2:79]3)/[C:63]3[N:64]=[C:65]([NH:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[S:66][CH:67]=3)[C:58](=[O:98])[NH:57]2)[N:51]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([NH:48][CH2:49][C:50]1[CH:54]=[N:53][N:52]([CH2:55][C@@H:56]2[C@H:59]([NH:60][C:61](=[O:97])/[C:62](=[N:76]\[O:77][C:78]3([C:81]([O:83][CH:84]([C:91]4[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=4)[C:85]4[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=4)=[O:82])[CH2:80][CH2:79]3)/[C:63]3[N:64]=[C:65]([NH:68][C:69]([O:71][C:72]([CH3:73])([CH3:75])[CH3:74])=[O:70])[S:66][CH:67]=3)[C:58](=[O:98])[NH:57]2)[N:51]=1)=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(CN)n2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCC(=O)NCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c2csc(NC(=O)OC(C)(C)C)n2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.6 %

Procedure:
To a solution of 4-((tert-butoxycarbonyl)amino)butanoic acid (30.7 mg, 0.15 mmol) in DCM (2 mL) at 0° C. was added DIPEA (35 μL, 0.20 mmol) and HATU (65 mg, 0.17 mmol). After 10 min, benzhydryl 1-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (90 mg, 0.10 mmol) was added. After stirring at 0° C. for 1 h, the reaction mixture was diluted with DCM (40 mL), washed with 2M aq. Na2CO3 (20 mL), brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (MeOH-DCM, 5-10%) to afford the title compound (42 mg, 46%). LCMS: Rt=1.07 min, m/z=901.5 (M+1) Method 2m_acidic.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].CCN(C(C)C)C(C)C.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC#N>[O:12]=[C:3]1[CH:2]([NH:1][S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1Cc2ccccc2NC1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2ccccc2CC1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.5 %

Procedure:
To a suspension of 3-amino-3,4-dihydro-1H-quinolin-2-one (177.6 mg, 0.59 mmol) (prepared according to the procedures by Davis, A. L.; et al, Arch. Biochem. Biophys., 102, 48 (1963)) in CH3CN (5 mL) was added DIPEA (0.24 mL, 1.44 mmol), followed by addition of benzene sulfonylchloride (0.09 mL, 0.71 mmol). The mixture was stirred at RT for 1.5 h, then concentrated in vacuo. The residue was taken into EtOAc (30 ml), washed with water, brine, dried (MgSO4) and concentrated. The residue was chromatographed (silica gel) eluting with EtOAc (50-90%) in hexane to give the title compound (140 mg, 78%).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[CH2:4][CH2:5][CH3:6].[CH2:8]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])[CH2:9][CH2:10][CH3:11]>C1(C)C=CC=CC=1>[CH2:3]([O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCBr
Reactant: CCCCOCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCOCCOCCOCCCC

Procedure:
Into 120 g of 60% NaH and 500 ml of toluene were added dropweise 329 g of butyl bromide and 486 g of diethylene glycol butyl ether at 50° C. Diethylene glycol dibutyl ether (abbreviated as “DEG-DB” hereafter) was obtained by distillation (b.p.: 256° C. under normal pressure) from the reaction mixture. The solubility of glycolide in this compound at 25° C. was 1.8%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[CH3:25][O:26][C:27](=[O:32])[CH2:28][C:29](Cl)=[O:30]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[C:29](=[O:30])[CH2:28][C:27]([O:26][CH3:25])=[O:32])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)CC(=O)Cl
Reactant: COC(=O)c1cc(Cl)cn1NCc1ccc(-c2ccccc2)cc1
Product: COC(=O)CC(=O)N(Cc1ccc(-c2ccccc2)cc1)n1cc(Cl)cc1C(=O)OC

Procedure:
Prepared according to the acylation condition used in Example 2 step f) from 1-[(biphenyl-4-ylmethyl)-amino]-4-chloro-1H-pyrrole-2-carboxylic acid methyl ester and chlorocarbonyl-acetic acid methyl ester (1.5 eq.). ESI (m/z): 441 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[NH2:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1>C(O)C>[Cl:1][CH2:2][C:3]1[N:7]=[C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]2[CH:5]=1
Reactant: O=C(CCl)CCl
Reactant: Cc1cccnc1N
Solvent: CCO
Product: Cc1cccn2cc(CCl)nc12
Temperature: 25 °C
Yield: 28.1 %

Procedure:
3.81 g of 1,3-dichloroacetone and 3.24 g of 2-amino-3-methylpyridine were dissolved in 30 ml of ethanol, and the solution was heated to reflux for 5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. To the residue, 50 ml of aqueous saturated sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and then recrystallized from hexane-methyl-t-butyl ether to obtain 1.52 g of 2-(chloromethyl)-8-methylimidazo[1,2-a]pyridine.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[C:14]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O1CCOCC1>[CH3:14][N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH:10]=[O:11])=[CH:12][CH:13]=2)=[N:4]1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(-c2nnn[nH]2)cc1
Agent: [K+]
Solvent: CI
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccc(C=O)cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
With ice-cooling, a solution of 75.5 g (0.434 mol) of 4-(tetrazol-5-yl)-benzaldehyde (Example 25a) in 550 ml of DMF/dioxane 1:1 is added dropwise to 179.7 g (1.30 mol) of K2CO3 in 200 ml of DMF/dioxane 1:1; the mixture is stirred for 30 min and then 40 ml (0.64 mol) of methyl iodide are added. The mixture is stirred in an ice bath for 3 hours and, finally, at room temperature for 15 hours; the reaction mixture is poured into 2.8 liters of ice-water and stirred for 10 min; the title compound is filtered off and washed with water: m.p.: 137-139° C.; 1H-NMR (CD3OD/CDCl3) d 10.05(S, HCO), 8.29 and 8.03 (2d, J=8, each 2H), 4.43(S, 3H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=2)[CH2:4]1.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].CO>CN(C)C=O>[Si:22]([O:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=2)[CH2:4]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: COC(=O)c1ccc2c(c1)CCC(CO)C2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)CCC(CO[Si](C)(C)C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In N,N-dimethylformamide (5 ml), (2RS)-2-hydroxymethyl-6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene (1.71 g) was dissolved, followed by the addition of imidazole (0.81 g) and tert-butyldimethylsilyl chloride (1.81 g) under ice cooling. The resulting mixture was stirred at room temperature for 14 hours. After the addition of methanol, the mixture was concentrated under reduced pressure. The concentrate was diluted with ethyl acetate, washed with water and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (hexane:ethyl acetate=50:1), whereby a yellow solid (2.20 g, 85%) was obtained.
Reaction SMILES: [CH:1]([Si:4]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[O:5][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:18]3[CH:19]=[C:20]([O:23][C@H:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C@@H:27]([NH2:34])[CH2:26][CH2:25]4)[CH:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH2:10][CH2:9]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:44][C:45](=O)[NH:46][C:47]1[N:48]([C:56]2[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][CH:57]=2)[N:49]=[C:50]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:51]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:52]([C:50]1[CH:51]=[C:47]([NH:46][C:45]([NH:34][C@@H:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:24]([O:23][C:20]3[CH:21]=[CH:22][C:17]4[N:18]([C:14]([N:11]5[CH2:10][CH2:9][CH:8]([CH2:7][CH2:6][O:5][Si:4]([CH:35]([CH3:37])[CH3:36])([CH:1]([CH3:2])[CH3:3])[CH:38]([CH3:40])[CH3:39])[CH2:13][CH2:12]5)=[N:15][N:16]=4)[CH:19]=3)[CH2:25][CH2:26]2)=[O:44])[N:48]([C:56]2[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][CH:57]=2)[N:49]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)[Si](OCCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(CCO[Si](C(C)C)(C(C)C)C(C)C)CC5)n4c3)c3ccccc32)cc1
Yield: 81 %

Procedure:
A mixture of Intermediate 66c (178 mg, 0.316 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 128 mg, 0.316 mmol) in 1,4-dioxane (3 mL) and DIPEA (83 μL, 0.474 mmol) was stirred at 95° C. for 4 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as a brown foam (208 mg, 81%). LCMS (Method 3): Rt 5.96 min, m/z 819 [MH+].
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:14]3[N:15]=[CH:16][N:17]=[C:13]3[C:12]([NH:18][C:19]3[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:24])=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.Cl.N1C=CC=CC=1>O>[O:2]=[C:3]1[CH:8]=[C:7]([C:9]2[N:14]3[N:15]=[CH:16][N:17]=[C:13]3[C:12]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:24])=[CH:33][CH:34]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][NH:4]1
Reactant: COc1cc(-c2ccc(Nc3ccc(C(=O)NCc4cccnc4)cc3)c3ncnn23)ccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(NCc1cccnc1)c1ccc(Nc2ccc(-c3cc[nH]c(=O)c3)n3ncnc23)cc1
Yield: 62.8 %

Procedure:
4-[5-(2-Methoxy-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-N-pyridin-3-ylmethyl-benzamide (46 mg, 51 μmol) is treated in a sealed tube with pyridine hydrochloride (153 mg, 1.32 mmol) and one drop of water at 150° C. for two hours. The reaction mixture is evaporated and the residue purified by flash chromatography (silica gel, dichloromethane/7N NH3 in methanol 96:4 then 85:15) affording the title compound (14 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][CH2:8][CH:7](O)[C:6]=2[CH:11]=1>C(O)C.[Pt]=O>[Cl:1][C:2]1[C:3]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:11]=1
Reactant: OC1COc2cc(N3CCCCC3)c(Cl)cc21
Agent: O=[Pt]
Solvent: CCO
Product: Clc1cc2c(cc1N1CCCCC1)OCC2

Procedure:
200 mg of platinum oxide are added to a solution of 1.42 g (5.60 mmole) of 5-chloro-3-hydroxy-6-(piperidin-1-yl)-2,3-dihydrobenzofuran in 20 ml of ethanol and the whole is hydrogenated at 3 atmospheres. The catalyst is filtered off and the filtrate is concentrated in a vacuum rotary evaporator. The residue is chromatographed over silica gel using methylene chloride as eluant. Recrystallisation from petroleum ether yields 5-chloro-6-(piperidin-1-yl)-2,3-dihydrobenzofuran having a melting point of 38°-40°.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:21])=[C:6]([O:19][CH3:20])[CH:7]=[C:8]2/[CH:13]=[C:14](\[CH3:18])/[C:15]([OH:17])=[O:16])[CH3:2].[C:22](OC(=O)C)(=[O:24])[CH3:23].O>N1C=CC=CC=1>[C:22]([O:21][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[CH2:1][CH3:2])[C:8](/[CH:13]=[C:14](\[CH3:18])/[C:15]([OH:17])=[O:16])=[CH:7][C:6]=1[O:19][CH3:20])(=[O:24])[CH3:23]
Reactant: CCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(OC(C)=O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
440 mg of (E)-3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthyl)-2-methylpropenoic acid was dissolved in 2.4 ml of pyridine and 0.42 ml of acetic anhydride was added, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and water in this order, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant crystals were washed with hexane to obtain 390 mg of the titled compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]([CH3:17])([CH3:16])[CH:6](Cl)[CH2:7][C:8]([Cl:14])(Cl)[C:9]([F:12])([F:11])[F:10].[Na].[CH2:20](O)C>>[CH2:1]([O:2][C:3]([CH:4]1[CH:6]([CH:7]=[C:8]([Cl:14])[C:9]([F:10])([F:11])[F:12])[C:5]1([CH3:17])[CH3:16])=[O:18])[CH3:20]
Reactant: CCO
Reactant: COC(=O)CC(C)(C)C(Cl)CC(Cl)(Cl)C(F)(F)F
Agent: [Na]
Product: CCOC(=O)C1C(C=C(Cl)C(F)(F)F)C1(C)C
Temperature: 45 °C

Procedure:
135 g of 3,3-dimethyl-4,6,6-trichloro-7,7,7-trifluoroenanthic acid methyl ester were added dropwise to a solution of 20.7 g of sodium in 300 ml of ethanol at room temperature in the course of 3 hours, while stirring. The mixture was subsequently stirred at room temperature for 1 hour and then heated to 45° C. for 7 hours. After cooling, sodium chloride which had separated out was filtered off, the filtrate was concentrated somewhat in vacuo, the residue was added to 500 ml of water and the mixture was rendered neutral. Extraction with methylene chloride and fractional distillation gave 90 g of 2,2-dimethyl-3-(2'-chloro-3',3',3'-trifluoropropenyl)-cyclopropanecarboxylic acid ethyl ester (isomer mixture) of boiling point: 55°-57° C./0.2 mm Hg.
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:3]2[C:4](=[O:6])[CH2:5][NH:1][C:2]2=[O:7])=[CH:12][CH:11]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CNC(=O)N1
Product: COc1ccc(CN2C(=O)CNC2=O)cc1

Procedure:
Using imidazolidine-2,4-dione (1.00 g) and 4-methoxybenzyl chloride (1.63 mL) and by the reaction and treatment in the same manner as in Preparation Example 51, the title compound (1.68 g) was obtained.
Reaction SMILES: [CH:1]([N:4]1[C:13](OS(C(F)(F)F)(=O)=O)=[C:12]2[C:6]([CH2:7][C:8]([CH3:25])([CH3:24])[NH:9][C:10]([CH3:23])([CH3:22])[CH2:11]2)=[N:5]1)([CH3:3])[CH3:2].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:1]([N:4]1[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:12]2[C:6]([CH2:7][C:8]([CH3:25])([CH3:24])[NH:9][C:10]([CH3:23])([CH3:22])[CH2:11]2)=[N:5]1)([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CC(C)(C)NC(C)(C)C2
Product: CC(C)n1nc2c(c1-c1ccccc1)CC(C)(C)NC(C)(C)C2
Yield: 61.6 %

Procedure:
The title compound (98 mg) was prepared as in Step B of Example 294 using 196 mg trifluoro-methanesulfonic acid 2-isopropyl-5,5,7,7-tetramethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl ester and 87 mg of phenylboronic acid. MS (ESI): exact mass calculated for C20H29N3, 311.24; found, m/z 312.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.57-7.52 (m, 3H), 7.32-7.31 (m, 2H), 4.34 (m, 1H), 3.11 (s, 2H), 2.71 (s, 2H), 1.49-1.34 (m, 18H).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:31])[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1.[CH2:38]([NH2:46])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[C:5]([O:9][C:10](=[O:11])[NH:12][CH:13]1[CH2:14][CH2:15][N:16]([S:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26](=[O:28])[NH:46][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:24]([F:31])[CH:23]=2)(=[O:20])=[O:21])[CH2:17][CH2:18]1)([CH3:7])([CH3:8])[CH3:6]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)O)c(F)c2)CC1
Reactant: NCCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)NCCc3ccccc3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
Thionyl chloride (0.16 g, 2.2 mmol) was added dropwise to a stirred solution of 4-(4-tert-butoxycarbonylamino-piperidine-1-sulfonyl)-2-fluoro-benzoic acid (0.3 g, 0.75 mmol) and pyridine (0.36 ml, 4.5 mmol) in DCM (10 ml). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours, after this time phenethylamine (0.19 ml, 1.5 mmol) was added in one portion and stirring was continued for a further 12 hours. The mixture was then diluted with DCM (10 ml) before being washed sequentially with HCl (1M solution, 10 ml) and NaOH (1M solution, 10 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (0.38 g, 74%) as a white foam which was taken on without further purification. Tr=2.16 min m/z (ES+) (M+Na+) 528.