Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[F:10][C:11]([F:29])([F:28])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:24]2([OH:27])[CH2:25][CH2:26][N:21]([C:18]3[CH:19]=[CH:20][C:15]4[N:16]([C:12]([C:11]([F:29])([F:28])[F:10])=[N:13][N:14]=4)[N:17]=3)[CH2:22][CH2:23]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reactant: Fc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: OC1(c2cccc(F)c2)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 18 %

Procedure:
3-Fluorophenylmagnesium bromide (1.0M in THF, 1.68 mL, 1.68 mmol) was added dropwise to 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-one (400 mg, 1.40 mmol) in THF (10 mL) cooled to 0° C. over a period of 10 minutes. The resulting mixture was stirred at 0° C. for 20 minutes, then quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate. The extract was washed with saturated brine, dried over MgSO4 and evaporated to a pale orange oil which was triturated with DCM to give a beige solid. The solid was filtered, washed with DCM and dried, then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-(3-fluorophenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (96 mg, 18%) as a colourless 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][CH:8](O)[CH2:7][C:6]=2[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[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][CH:8]=[CH:7][C:6]=2[CH:11]=1
Reactant: OC1Cc2cc(Cl)c(N3CCCCC3)cc2O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cc2ccoc2cc1N1CCCCC1

Procedure:
A solution of 250 mg (1.00 mmole) of crude 5-chloro-2-hydroxy-6-(piperidin-1-yl)-2,3-dihydrobenzofuran in 2.5 g of polyphosphoric acid is maintained at 60° for 20 minutes, then ice and water are added and the whole is adjusted to pH 7 with solid sodium carbonate. The reaction mixture is extracted twice with methylene chloride. The organic phases are washed with water, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. The residue is chromatographed over silica gel using methylene chloride as eluant (Rf =0.63). In that manner, 5-chloro-6-(piperidin-1-yl)-benzofuran is obtained in the form of an oil which distills at 96°-97°/1.5 torr.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3B3OC(C)(C)C(C)(C)O3)[CH2:11][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:33]1[O:34][C:35]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:36][C:37](=[O:39])[CH:38]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:33]3[O:34][C:35]([N:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)=[CH:36][C:37](=[O:39])[CH:38]=3)[CH2:11][C:10]=2[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)Cc1cccc(B3OC(C)(C)C(C)(C)O3)c1S2
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Temperature: 90 °C

Procedure:
[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-9H-thioxanthen-2-yl]-carbamic acid tert-butyl ester (1.02 g, 2.32 mmol), 2-chloro-6-morpholin-4-yl-pyran-4-one (3) (0.60 g, 2.78 mmol) and K2CO3 (0.64 g, 4.64 mmol) were dissolved in dry 1,4-dioxane (ml). The mixture was degassed for 15 minutes and Pd(PPh3)4 (0.13 g, 0.12mol) was then added The dark brown mixture was heated to 90° C. under an atmosphere of N2 for 24 hour. The reaction mixture was concentrated in vacuo and water (50 ml) was added. The brown solid was filtered and washed with water (1.21 g, 88%). m/z (LC-MS, ESP), RT=4.6 minutes, (M++1)=493.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[C:13]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:14][N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:16]=3[CH:17]=[O:18])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[NH:38][N:37]=[N:36][N:35]=1.CC(=CC)C.Cl([O-])=[O:45].[Na+].P([O-])(O)(O)=O.[Na+]>C1COCC1.C(O)(C)(C)C.O>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[C:13]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:14][N:15]([CH2:19][C:20]([F:22])([F:21])[F:23])[C:16]=3[C:17]([OH:45])=[O:18])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[NH:38][N:37]=[N:36][N:35]=1
Reactant: CCCCc1nn(CC(F)(F)F)c(C=O)c1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCc1nn(CC(F)(F)F)c(C(=O)O)c1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
A solution of the product of Example 6 (0.3 g) and 2-methyl-but-2-ene (2M in THF; 4 ml) in a mixture of THF (14 ml) and t-butanol (14 ml) was treated with a solution of sodium chlorite (80% tech. 0.55 g), and sodium dihydrogenorthophosphate (0.65 g) in water (10 ml). The mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and the aqueous residue acidified (pH 4.5) with hydrochloric acid (2M). The product was extracted with a mixture of dichloromethane:ethyl acetate (1:1; 25 ml) and the organic extract dried and evaporated in vacuo. The residue was crystallized from methyl acetate/hexane to give the title compound as a white solid (0.2 g), m.p. 216°-220°.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[C:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:32][CH2:33][CH3:34])=[N:21]4)[CH:16]=[CH:15][N:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.O.C1(C)C=CC=CC=1>[CH2:33]([O:32][C:22]1[C:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:24][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:7]4[CH:8]=3)[CH:18]=2)[N:21]=1)[CH3:34]
Reactant: CCOC(=O)CCc1cn(Cc2ccnc(OCc3cn4c(Cl)cccc4n3)c2)nc1OCC
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccnc(OCc3cn4c(-c5ccccc5)cccc4n3)c2)nc1OCC
Yield: 98.9 %

Procedure:
A mixture of ethyl 3-[1-[2-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridylmethyl]-3-ethoxy-1H-pyrazol-4-yl]propionate (968 mg), phenylboronic acid (280 mg), tetrakis(triphenylphosphine)palladium (57.8 mg), sodium carbonate (488 mg), ethanol (3 ml), water (3 ml) and toluene (15 ml) was refluxed overnight under an argon atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[2-(5-phenylimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridylmethyl]-1H-pyrazol-4-yl]propionate (1040 mg, yield: 99%) as a colorless oily substance from the fraction eluted with ethyl acetate.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][C:4](=[O:6])[NH2:5].CC[N+]1OC(C2C=CC=C(S([O-])(=O)=O)C=2)=CC=1.C(N(CC)CC)C.[NH2:41][C@H:42]([C:47]([NH:49][C@H:50]([C:53]([NH:55][C@H:56]([C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61])[C@@H:57]([CH3:59])[OH:58])=[O:54])[CH2:51][OH:52])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45].FC(C(O)=O)(F)F>C(#N)C.CN(C)C=O>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:41][C@H:42]([C:47]([NH:49][C@H:50]([C:53]([NH:55][C@H:56]([C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61])[C@@H:57]([CH3:59])[OH:58])=[O:54])[CH2:51][OH:52])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:9])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)O
Agent: CC[n+]1ccc(-c2cccc(S(=O)(=O)[O-])c2)o1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)O
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
20.8 g of BOC-Asn-OH are suspended in 208 ml of acetonitrile, mixed with 22.7 g of Woodward's Reagent K and the mixture stirred for 30 minutes at 20°C. 12.6 ml of triethylamine are then added dropwise, whilst stirring, in such a way that the internal temperature does not exceed +32°C, and the mixture is cooled to 20°C and stirred for a further 50 minutes at this temperature. The almost clear solution is cooled to 0°C and is mixed with a solution, also cooled to 0°C, of 39.1 g of H-Leu-Ser-Thr-OBzl.TFA and 10.5 ml of triethylamine in 257 ml of dimethylformamide. The reaction mixture, which soon solidifies, is stirred overnight at room temperature, cooled to -10°C and stirred for a further 2 hours at -10°C. Thereafter the crystalline precipitate is filtered off and the tetrapeptide derivative is washed once with cold acetonitrile, once with ethyl acetate and three times with water it is free of chloride. The resulting product is crystallised from 370 ml of dimethylformamide, 3.7 ml of glacial acetic acid and 370 ml of acetonitrile. Melting point 225-226°C; [α]D = -36° c = 2 in dimethylformamide); Rf6 = 0.85 (on silica gel).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[CH:5]=[N:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(O)C>[N:18]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=3)[C:13]#[N:14])[N:7]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: C1CNCCN1
Reactant: N#Cc1cccc(COc2cncc(Cl)n2)c1
Solvent: CCO
Product: N#Cc1cccc(COc2cncc(N3CCNCC3)n2)c1

Procedure:
A mixture of 3-(6-chloro-pyrazin-2-yloxymethyl)-benzonitrile I-3a (3.53 g, 14.4 mmol) and piperazine (12.4 g, 143.70 mmol) in ethanol (144 mL) was stirred under reflux for 48 h. The reaction mixture was concentrated to dryness and the residue was dissolved in ethyl acetate (300 mL). The ethyl acetate solution was washed with H2O (4×125 mL), brine (125 mL), dried (Na2SO4), filtered, and concentrated to dryness. The crude material was chromatographed over Silica Gel (40 g) using 5% methanol/methylene chloride with 1% NH4OH as the eluant to give 3.03 g of the desired product (I-3b) as a white solid.
Reaction SMILES: [NH4+].[O-][V:3](=O)=O.[CH2:6]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([O-:11])=[O:10])[CH3:7]>O>[CH2:6]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([O-:11])=[O:10])[CH3:7].[V+5:3].[CH2:6]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([O-:11])=[O:10])[CH3:7].[CH2:6]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([O-:11])=[O:10])[CH3:7].[CH2:6]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([O-:11])=[O:10])[CH3:7].[CH2:6]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([O-:11])=[O:10])[CH3:7]
Reactant: O=[V](=O)[O-]
Agent: CCCCC(CC)C(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: [V+5]
Temperature: 95 °C

Procedure:
A mixture of 69.6 grams (0.589 mole) of ammonium metavanadate, 342.0 grams (2.356 moles) of 2-ethylhexanoate (acid number 387) and 130 grams of mineral spirits was heated to 95° C. and held for 1 hour without reaction occurring. The temperature was gradually increased to 195° C. in 3.5 hours while the water of reaction was removed. The reaction product solidified at room temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[N:3]=1.[F:24][C:25]([F:31])([F:30])[CH2:26][N:27]=[C:28]=[S:29]>C(#N)C>[F:24][C:25]([F:31])([F:30])[CH2:26][NH:27][C:28](=[S:29])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])[N:3]=1
Reactant: Nc1ccnc(SCCCCN2C(=O)c3ccccc3C2=O)n1
Reactant: FC(F)(F)CN=C=S
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCSc1nccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 48 h
Yield: 69.9 %

Procedure:
A mixture of 4-amino-2-(4-phthalimidobutylthio)pyrimidine (0.49 g.), acetonitrile (5 ml.) and 2,2,2-trifluoroethylisothiocyanate (0.28 g.) was stirred at 70° for 48 hours. A further 0.28 g. of 2,2,2-trifluoroethylisothiocyanate was added and the mixture stirred at 70° for 48 hours. The reaction mixture was cooled and filtered, the residue stirred with N aqueous acetic acid and the undissolved solid collected to give 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(4-phthalimidobutylthio)pyrimidine (0.49 g.), m.p. 201°-202° after recrystallisation from a mixture of ethanol and dimethylformamide.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:11][CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[Cl:1])[CH2:6][CH2:7]2)=[O:30])=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2ccccc2Cl)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3Cl)CC2)cc1
Yield: 43.6 %

Procedure:
0.451 g (0.002 mol) of 1-(2-chloro-benzyl)-piperidin-4-ol and 1.23 ml (0.0088 mol) of triethylamine were dissolved in 4 ml of toluene, treated with 0.331 ml (0.0025 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:1→1:2). 0.3 g (44%) of 1-(2-chloro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][OH:14])=[N:10][C:9]=2[C:15]([OH:17])=O)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.[F:40][C:41]1[C:56]([F:57])=[CH:55][C:44]2[NH:45][C:46]([CH2:48][CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][NH:50]3)=[N:47][C:43]=2[CH:42]=1>CN(C=O)C>[F:40][C:41]1[C:56]([F:57])=[CH:55][C:44]2[NH:45][C:46]([CH2:48][CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][N:50]3[C:15]([C:9]3[N:10]=[C:11]([CH2:13][OH:14])[S:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:17])=[N:47][C:43]=2[CH:42]=1
Reactant: Fc1cc2nc(CC3CCCCN3)[nH]c2cc1F
Reactant: O=C(O)c1nc(CO)sc1-c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1nc(CO)sc1-c1ccc(F)cc1)N1CCCCC1Cc1nc2cc(F)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
A stirring solution of 5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazole-4-carboxylic acid (632 mg, 2.0 mmol, 80% pure), EDC.HCl (311 mg, 2.0 mmol) and 1-hydroxybenzotriazole (270 mg, 2.0 mmol) in DMF (20 ml) was treated with (RS)-5,6-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D18 (500 mg, 2.0 mmol). The reaction mixture was stirred at room temperature, under argon for 16 h. The DMF was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 0-10% methanol-ethyl acetate) afforded the title compound as a pale yellow solid (350 mg, 36%).
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:17]/[C:18]2[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[C-]#N.[Na+].[C:33](O)(=[O:35])[CH3:34]>[O-2].[O-2].[Mn+4].CCCCCC>[CH3:1][C:2]1[C:3](/[C:16](/[Si:26]([CH3:28])([CH3:27])[CH3:29])=[CH:17]/[C:18]2[CH:25]=[CH:24][C:21]([C:22]([O:35][CH2:33][CH3:34])=[O:23])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CC(=O)O
Reactant: Cc1cc2c(cc1/C(=C/c1ccc(CO)cc1)[Si](C)(C)C)C(C)(C)CCC2(C)C
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(/C=C(/c2cc3c(cc2C)C(C)(C)CCC3(C)C)[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Manganese dioxide (265 mg, 2.96 mmol) was added to a solution of (Z)-4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trimethylsilyl)vinyl]benzyl alcohol (Compound 3, 60 mg, 0.15 mmol) and 3.65 mL of hexane. The solution was stirred at room temperature for 16 hours, the manganese dioxide filtered off, and the hexane removed in vacuo. The residue was dissolved in 2 mL of ethanol and treated with sodium cyanide (37.5 mg, 0.77 mmol) and acetic acid (13.7 mg, 0.23 mmol). After 15 minutes, the solution was treated with 265 mg (3.0 mmol) of manganese dioxide. The suspension was stirred at room temperature for 6 hours and the manganese dioxide removed by filtration. The solution was poured into a separatory funnel containing water and ether. The layers were separated and the aqueous layer was extracted 3 times with ether. The combined organic layers were washed once with brine, and dried over magnesium sulfate, and the solvents were removed under reduced pressure. The residue was purified by silica gel chromatograhy (97:3, hexane:ethyl acetate) to give the title compound. PNMR (300 MHz, CDCl3)-0.11 (s, 9H), 1.28 (s, 12H), 1.41 (t, 3H, J=7.1 Hz), 1.68 (s, 4H), 2.23 (s, 3H), 4.39 (q, 2H, J=7.1 Hz), 6.86 (s, 1H), 7.08 (s, 1H), 7.17 (s, 1H), 7.41 (d, 2H, J=8.5 Hz), 8.03 (d, 2H, J=8.5 Hz).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([CH2:19][NH:20][OH:21])=[CH:17][CH:16]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N:28]=[C:29]=[O:30])(C)C.O.Cl>O1CCOCC1>[OH:21][N:20]([CH2:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][C:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][N:10]=2)=[CH:23][CH:22]=1)[C:29]([NH2:28])=[O:30]
Reactant: C[Si](C)(C)N=C=O
Reactant: ONCc1ccc(OCCc2noc(-c3ccccc3)n2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)N(O)Cc1ccc(OCCc2noc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of N-[4-[2-(5-phenyl-[1,2,4]-oxadiazol-3-yl)-ethoxy]-benzyl]-hydroxylamine (1.5 g, 4.82 mmol in dioxane (70 mL) was added trimethylsilylisocyanate (o.84 g, 7.23 mmol). After stirring for 2 hours at room temperature the mixture was poured into H2O, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from acetone/ether (after cooling to 0° C.), gave a white solid (1.2 g, 70% yield, m.p. 135°-136° C.).
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1)=[O:20].[N:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[N:34][CH:33]=1>>[CH3:18][N:4]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[C:2]([C:36]2[CH:37]=[N:32][CH:33]=[N:34][CH:35]=2)[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1
Reactant: OB(O)c1cncnc1
Reactant: Cn1c(-c2ccc(OC(F)(F)F)cc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2ccc(OC(F)(F)F)cc2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(4-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 66) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as colorless amorphous solid. MS: 501.1 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([NH2:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Br:67][CH2:68][C:69](O)=[O:70]>CN(C)C=O>[Br:67][CH2:68][C:69]([NH:15][CH:13]1[CH2:14][N:11]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[O:10])[CH2:12]1)=[O:70]
Reactant: NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reactant: O=C(O)CBr
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Yield: 81.6 %

Procedure:
A solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine (100 mg, 0.22 mmol), PyBOP (131 mg, 0.25 mmol), N,N-diisopropylethylamine (80 μL, 0.44 mol) and bromoacetic acid (35 mg, 0.25 mmol) in dimethylformamide (1 mL) was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and the resultant residue was purified by column chromatography eluting with 80% ethyl acetate in hexanes to afford 2-bromo-N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]acetamide (102 mg, 82% yield) as a white foam. MS (EI) for C18H14BrF3IN3O2: 568.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14](O)=[O:15])[CH:5]=[CH:6][C:7]=1[F:8].[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:22])([F:21])[F:23])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(F)c(Cl)c2)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(-c2ccc(F)c(Cl)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(3-chloro-4-fluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BQ) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 97.1%, 497.0259 (M−H)−.