Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1.B([O-])([O-])O[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.[Cl-].[Na+].O.O.C(OCC)(=O)C>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([C:2]2[N:7]=[C:6]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(OB([O-])[O-])cc1
Reactant: CCOC(=O)C=Cc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)C=Cc1cccc(-c2ccc(C)cc2)n1
Temperature: 80 °C
Reaction time: 10 h
Yield: 92.5 %

Procedure:
In 1,2-dimethoxyethane (4 ml) were dissolved ethyl 6-bromo-2-pyridineacrylate (512 mg, 2.00 mmol) and 4-methylphenyl borate (299 mg, 2.20 mmol), and to the mixture were added sodium carbonate (424 mg, 4.00 mmol), water (2 ml) and tetrakis-(triphenylphosphine)palladium (116 mg, 0.10 mmol). The mixture was stirred at 80° C. for 10 hours. To complete the reaction, 4-tolyl borate (150 mg, 1.10 mmol) and tetrakis(triphenyl-phosphine)palladium (116 mg, 0.10 mmol) were added at 80° C. to the mixture, and the mixture was stirred for 14 hours. To the mixture was added ethyl acetate (30 ml), and the mixture was water (5 ml×2) and saturated brine (5 ml). The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 15 g, ethyl acetate/hexane=1/19), and the desired fraction was concentrated under reduced pressure to give ethyl 6-(4-methylphenyl)-2-pyridineacrylate (495 mg, 1.85 mmol, 93%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:16][C:17]1[N:21]=[CH:20][N:19]([CH2:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[N:18]=1>>[C:27]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:19]2[CH:20]=[N:21][C:17]([NH:16][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([CH:9]=3)[C:7]#[N:8])=[N:18]2)=[CH:30][CH:29]=1)#[N:28]
Reactant: N#Cc1ccc(Cn2cnc(N)n2)cc1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ncn(Cc4ccc(C#N)cc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 4-(3-amino-[1,2,4]triazol-1-ylmethyl)-benzonitrile. The title compound was obtained as an off-white solid (Yield=36%). MS ISP (m/e): 381.2 (100) [(M+H)+].
Reaction SMILES: [NH2:1]/[C:2](/[C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:3]\[C:4](=[S:6])[NH2:5].C(=O)([O-])[O-].[K+].[K+].II.O>C(OCC)C>[C:7]([C:2]1[CH:3]=[C:4]([NH2:5])[S:6][N:1]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)/C(N)=C/C(N)=S
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1cc(N)sn1
Yield: 53 %

Procedure:
To a stirred solution of (Z)-3-amino-4,4-dimethyl-pent-2-enethioic acid amide (8.3 g, 525 mmol) and potassium carbonate (14.4 g, 105 mmol) in 140 mL of diethyl ether is added a solution of iodine (13.2 g, 52.5 mmol) in 20 mL of diethyl ether at reflux. The mixture is refluxed for 2 h and cooled. Water is added and the layers separated. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture is purified by flash chromatography to afford title compound in 53% yield. ESI m/z 157=MH+
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([CH2:14][N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([O:24]CC)=O)=[CH:5]2)[CH2:3][CH2:2]1.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.C(OCC)C>ClCCl>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:22]([C:6]2[C:7](=[O:21])[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([CH2:14][N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)[CH:9]=3)[N:4]([CH:1]3[CH2:3][CH2:2]3)[CH:5]=2)=[O:24])=[CH:30][CH:29]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C2CC2)c2ccc(CN3CCOCC3)cc2c1=O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cn(C2CC2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 165 °C

Procedure:
To a flask containing ethyl 1-cyclopropyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.38 g) from Preparation No. 25 is added 4-chlorobenzylamine (2.0 mL). The reaction is tightly capped and heated to 165° C. overnight. The reaction is cooled to room temperature, adsorbed onto silica and chromatographed on silica eluting with 1% to 6% methanol in dichloromethane. The product-containing fractions are evaporated to give a solid which is dissolved in a minimal amount of dichloromethane. The solution is added to 1:1 diethyl ether:pentane to precipitate the title compound as a white solid. This solid is collected by filtration and dried in vacuo to afford 0.36 g of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=C(C=C)[N:26]=2)[N:4]=1)[CH3:2].C[N+]1([O-])CC[O:37]CC1.[CH3:41][C:42]([CH3:44])=[O:43].O>[Os](=O)(=O)(=O)=O>[OH:43][CH:42]([C:44]1[N:26]=[C:25]([CH2:24][N:5]2[C:6]3[C:11](=[C:10]([NH:12][C:13]([C:15]4[N:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]5=[N:17][CH:16]=4)=[O:14])[CH:9]=[CH:8][CH:7]=3)[C:3]([CH2:1][CH3:2])=[N:4]2)[CH:30]=[CH:29][CH:28]=1)[CH2:41][OH:37]
Reactant: C=Cc1cccc(Cn2nc(CC)c3c(NC(=O)c4cnc5ccccn45)cccc32)n1
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CCc1nn(Cc2cccc(C(O)CO)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 1 h

Procedure:
To a solution of N-(3-ethyl-1-((6-vinylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 24, Step B; 40 mg, 0.095 mmol) in acetone/water (2 mL/0.5 mL) was added N-methylmorpholine N-oxide (44 mg, 0.19 mmol), followed by osmium tetroxide (2.5% in tert-butanol, 15 μL). The mixture was stirred for 1 hour and then quenched by the addition of a saturated solution of sodium thiosulfate (1 mL). The mixture was concentrated under reduced pressure to remove acetone and diluted with dichloromethane and saturated sodium chloride solution (5 mL). The phases were separated and the aqueous was extracted with dichloromethane/isopropanol (10:1; 2×10 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product (40 mg).
Reaction SMILES: O.[OH-].[Li+].C([O:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:26][C:25]([CH2:49][C:50]#[N:51])([N:27]4[CH:31]=[C:30]([C:32]5[C:33]6[CH:40]=[CH:39][N:38](COCC[Si](C)(C)C)[C:34]=6[N:35]=[CH:36][N:37]=5)[CH:29]=[N:28]4)[CH2:24]3)[CH2:19][CH2:18]2)=[O:16])[N:12]=[C:11]([C:52]([F:55])([F:54])[F:53])[N:10]=1)(=O)C>O.O1CCCC1>[OH:7][CH2:8][C:9]1[N:10]=[C:11]([C:52]([F:55])([F:54])[F:53])[N:12]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:26][C:25]([CH2:49][C:50]#[N:51])([N:27]4[CH:31]=[C:30]([C:32]5[C:33]6[CH:40]=[CH:39][NH:38][C:34]=6[N:35]=[CH:36][N:37]=5)[CH:29]=[N:28]4)[CH2:24]3)[CH2:19][CH2:18]2)=[O:16])[CH:14]=1
Reactant: CC(=O)OCc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6c5ccn6COCC[Si](C)(C)C)cn4)C3)CC2)nc(C(F)(F)F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3cc(CO)nc(C(F)(F)F)n3)CC2)C1
Reaction time: 0.08 h

Procedure:
Lithium hydroxide monohydrate (3.6 mg, 0.085 mmol) in water (0.10 mL) was added to a solution of [6-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-(trifluoromethyl)pyrimidin-4-yl]methyl acetate (21 mg, 0.028 mmol, from Example 376, Step D) in tetrahydrofuran (0.40 mL). The mixture was stirred for 5 minutes and was then treated with 1N HCl to neutralize. Solvent was then removed in vacuo. The residue was stirred in a solution of 1:1 TFA/DCM for one hour, then solvents were removed in vacuo again. The residue was redissolved in MeOH (1 mL) and ethylenediamine (0.2 mL) was added. When deprotection was complete, the product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: 0.004 g (25%); LC-MS: 567.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.14 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.90 (s, 1H), 7.61 (d, 1H), 7.06 (d, 1H), 5.94 (br s, 1H), 4.71 (s, 2H), 4.12-4.02 (m, 1H), 3.75 (dd, 2H), 3.63-3.46 (m, 5H), 3.31-3.22 (m, 1H), 3.17-3.07 (m, 1h), 2.61-2.53 (m, 1H), 1.84-1.75 (m, 1H), 1.71-1.61 (m, 1H), 1.37-1.18 (m, 2H). 19F NMR (400 MHz, DMSO-d6): δ −69.46 (s, 3F).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH2:21](I)[CH3:22].C1CCN2C(=NCCC2)CC1>ClCCl.CCOC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([O:17][CH2:21][CH3:22])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Reactant: CCI
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 2 h
Yield: 61.2 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.015 g, 0.043 mmol) in dichloromethane (1 mL) was treated with ethyl iodide (0.016 g, 0.102 mmol), DBU (0.016 g, 0.102 mmol) and stirred 2 hours at 20 C. The product mixture was diluted with EtOAc (10 mL), washed with 5% aqueous HCl (5 mL), brine (5 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 0.010 g of a clear oil.
Reaction SMILES: [C:1](O)(=O)C=C.[OH:6][C:7]([CH:9]([C:11]1C=CC(CC(C)C)=CC=1)[CH3:10])=[O:8]>>[C:7]([OH:8])(=[O:6])[C:9]([CH3:11])=[CH2:10].[CH3:1][O:6][C:7](=[O:8])[C:9]([CH3:11])=[CH2:10]
Reactant: C=CC(=O)O
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Product: C=C(C)C(=O)O
Product: C=C(C)C(=O)OC

Procedure:
Acrylic acid, ibuprofen and poly(acrylic acid) (MW 2,000) and (MW 5,000) were purchased from Aldrich. Poly(methacrylic acid-methylmethacrylate) (Eudragit L) was provided by Rhom Pharma (Germany). Thionyl chloride, oxalyl chloride, and acetic anhydride were freshly distilled under nitrogen prior to use. All solvents were analytical grade.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O1CCOCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:11][C:12](=[O:15])[CH2:13][CH2:14][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)([CH3:9])[CH3:10])=[CH:16][CH:17]=1
Reactant: c1c[nH]cn1
Reactant: C=CC(=O)NC(C)(C)COc1ccc(Cl)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(COc1ccc(Cl)cc1)NC(=O)CCn1ccnc1
Temperature: 95 °C

Procedure:
A mixture of N-[2-(4-chlorophenoxy)-1,1-dimethylethyl]acrylamide (4.5 g), imidazole (1.24 g), benzyltrimethylammonium hydroxide (0.62 ml of a 40% solution in methanol, Triton®B) and 1,4-dioxane (40 ml) was heated at 95° C. for 7 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. This solution was extracted with 5M hydrochloric acid. The combined acid extracts were basified with 10M sodium hydroxide solution and extracted with dichloromethane to give N-[2-(4-chlorophenoxy)-1,1-dimethylethyl]-3-(imidazol-1-yl)propionamide.
Reaction SMILES: C[C:2]([C:4]([O:6][CH2:7]CO)=O)=[CH2:3].[CH3:10][CH:11](O)[CH2:12][O:13]C(C(C)=C)=O>[Sn]>[CH3:7][O:6][C:4]1[CH:2]=[CH:3][C:12]([OH:13])=[CH:11][CH:10]=1
Reactant: C=C(C)C(=O)OCCO
Reactant: C=C(C)C(=O)OCC(C)O
Agent: [Sn]
Product: COc1ccc(O)cc1

Procedure:
The aliphatic prepolymer was reacted with 66-⅔% HEMA (or HPMA) to 33-⅓% of the prepolymer in the presence of a tin catalyst (UL22) and a stabilizer (MEHQ) for 4 hours at 150° F. to provide a aliphatic methyl methacrylate-urethane oligomer (HP 1516) with the following specifications:
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]3[CH:48]=[CH:47][C:12]([CH2:13][N:14]([C:32]4[N:36]=[C:35]([C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=5)[O:34][N:33]=4)[CH2:15][CH2:16][C:17]4[CH:31]=[CH:30][C:20]([O:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=4)=[CH:11][CH:10]=3)[N:8]=2)[CH2:3][CH2:2]1.CCO.O.[Li+].[OH-]>C1COCC1>[CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]3[CH:48]=[CH:47][C:12]([CH2:13][N:14]([C:32]4[N:36]=[C:35]([C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:44])([F:45])[F:46])[CH:38]=5)[O:34][N:33]=4)[CH2:15][CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:21][C:22]([CH3:29])([CH3:28])[C:23]([OH:25])=[O:24])=[CH:30][CH:31]=4)=[CH:11][CH:10]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(-c3coc(C4CC4)n3)cc2)c2noc(-c3cccc(C(F)(F)F)c3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(-c3coc(C4CC4)n3)cc2)c2noc(-c3cccc(C(F)(F)F)c3)n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.5 %

Procedure:
To a solution of ethyl 2-{4-[2-([4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]{5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}-2-methylpropanoate (93 mg, 0.14 mmol) in anhydrous THF (1.5 ml) was added EtOH (0.4 ml), water (0.4 ml), and LiOH (31 mg, 1.28 mmol). The mixture was stirred at rt for 12 h. The reaction was quenched with a solution of saturated aqueous KH2PO4, and the aqueous phase was extracted with EtOAc (3×20 ml). The combined organic phases were dried with Na2SO4 and concentrated in vacuo to yield the title compound as a colorless solid (58 mg, 65%). 1H NMR (CDCl3) δ 8.34 (s, 1H), 8.26 (d, 1H, J=7.9), 7.80 (d, 1H, J=7.8), 7.65 (s, 1H), 7.62 (d, 1H, J=8.0), 7.40 (d, 2H, J=8.1), 6.92 (d, 2H, J=8.3), 6.81 (d, 2H, J=8.5), 6.65 (d, 2H, J=8.4), 4.53 (s, 2H), 3.63 (t, 2H, J=6.2), 2.92 (t, 2H, J=6.4), 2.21 (m, 1H), 1.58 (s, 6H), 1.19–1.06 (m, 4H). MS: m/z 633 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(#N)C.CCOCC>C(Cl)(Cl)Cl>[Br-:8].[CH2:9]([N+:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCBr
Reactant: Cc1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CCOCC
Product: CCCCCC[n+]1ccc(C)cc1
Product: [Br-]
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 4.65 g of 4-picoline (50 mmol), 9.90 g of 1-bromohexane (60 mmol) and 30 mL of acetonitrile was refluxed for three hours and then cooled to room temperature. The viscous mixture was then added dropwise into 100 mL of ether with vigorous stirring. The mixture was let to stand for a while and then the upper ether layer was decanted. The residual viscous solution was dissolved in 10 mL of acetonitrile again and dispersed into 100 mL of ether. This procedure was repeated two more times in order to completely remove the unreacted starting materials. The resulting viscous liquid was dried under vacuum to give 11.8 g of off-white wax (92% yield). 1H NMR (DMSO-d6, 400 MHz): 0.89 (t, 3H), 1.26 (m, 4H), 1.85 (m, 4H), 2.64 (s, 3H), 4.81 (t, 2H), 8.0 (m, 2H), 8.9 (m, 2H); IR (CHCl3, cm−1): 1398 (C═C), 1635 (C═N), 2975 (N—C).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:44]=[CH:45][C:46]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:39][O:40][C:41]1[CH:42]=[C:43]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:44]=[CH:45][C:46]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: COc1cc(NS(C)(=O)=O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc(NS(C)(=O)=O)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Yield: 76.7 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (170 mg, 0.29 mmol) was treated with N-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (190 mg, 0.58 mmol, described at WO 2012015723 A1 20120202), sodium carbonate (100 mg, 0.94 mmols) and bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (50 mg, 0.06 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to give 159 mg (71% yield) of the title compound. Purity 91%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[CH2:10]([N:28]=[C:29]=[O:30])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(Cl)(Cl)Cl>[CH2:7]=[CH:6][C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1.[CH2:10]([NH:28][C:29]([NH2:1])=[O:30])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: C=Cc1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: ClC(Cl)Cl
Product: C=Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCNC(N)=O

Procedure:
1.00 g (8.40 mmol) of p-aminostyrene (99% Tokyo Kasei) was added to a 250 ml round bottom flask containing 10 ml of chloroform. After ten minutes of mixing, 2.52 g (8.41 mmol) of n-octadecyl isocyanate (98% Aldrich) was added dropwise. Within seconds, a yellow precipitate formed. Chloroform (20 ml) was added to aid stirring. The precipitate was filtered to remove the reaction liquid, then washed with 20 ml of chloroform resulting in a pale yellow powder (3.38 g, 96.0% crude yield, mp=109° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under N2, to the solution of 2-chloro-4-fluoro-5-nitro-benzoic acid (1.0 g, 4.56 mmol in 40 mL of DCM at 0° C. are added thionyl chloride (1.0 mL, 13.68 mmol) and 0.1 mL of DMF sequentially. The reaction mixture was warmed gradually to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo to afford 2-chloro-4-fluoro-5-nitrobenzoyl chloride. The crude was dissolved in 40 mL of DCM, and 1-boc-4-aminopiperidine (910 mg, 4.56 mmol) and triethylamine (1.29 mL, 9.12 mmol) were added to the solution sequentially. After stirring at room temperature 1 h, the reaction mixture was washed with 20 mL of water. The organic extract was dried (Na2SO4), followed by concentration in vacuo to afford tert-Butyl 4-(2-chloro-4-fluoro-5-nitrobenzamido)piperidine-1-carboxylate; ESMS m/z 402.1 (M+H+).
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7](=[O:44])[C:8]1[CH:13]=[C:12]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[C:15]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:11]([O:28]CC2C=CC=CC=2)=[CH:10][C:9]=1[O:36]CC1C=CC=CC=1.C(OCC)(=O)C>CO.[Pd]>[CH3:5][O:6][C:7](=[O:44])[C:8]1[CH:13]=[C:12]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[C:15]=2[C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:11]([OH:28])=[CH:10][C:9]=1[OH:36]
Reactant: COC(=O)c1cc(-c2onc(C)c2-c2ccc(OC)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(-c2onc(C)c2-c2ccc(OC)cc2)c(O)cc1O
Temperature: 60 °C
Yield: 15.2 %

Procedure:
Ammonium formate (172 mg, 20 eq) was added to a solution of 2,4-Bis-benzyloxy-5-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-benzoic acid methyl ester (72 mg, 0.13 mmol) in methanol (2 ml)/ethyl acetate (1 ml) under a nitrogen atmosphere. 10% Palladium on carbon (cat.) was added and the suspension heated at 60° C. overnight. The solution was allowed to cool. Ethyl acetate (5 ml) added, solution washed with water (2×5 ml) and saturated aqueous sodium chloride solution (5 ml). The solution was dried over anhydrous magnesium sulphate and concentrated. The crude products were purified by column chromatography, silica, eluting with ethyl acetate in hexane (gradient 25% to 45% ethyl acetate) to give 2,4-dihydroxy-5-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-benzoic acid methyl ester (7.0 mg).
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].I[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:1][C:2]([F:18])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:3][C:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: CCCCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.4 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.0 g of iodopentane were dissolved in 10 ml of dimethyl sulfoxide, 0.70 g of potassium carbonate was added, and the mixture was stirred at room temperature for 3 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.90 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-pentylmalononitrile (hereinafter, referred to as the present compound (51)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17]/[C:18](/[CH3:37])=[CH:19]\[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:35][CH2:34][C:33](=[O:36])[NH:32][N:31]=2)=[CH:26][CH:25]=1)=[O:21].[N+:38]([CH2:41][C:42](=O)[CH3:43])([O-:40])=[O:39]>C(O)(C)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]2[C:41]([N+:38]([O-:40])=[O:39])=[C:42]([CH3:43])[NH:17][C:18]([CH3:37])=[C:19]2[C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH2:35][CH2:34][C:33](=[O:36])[NH:32][N:31]=3)=[CH:28][CH:29]=2)=[O:21])[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: C/C(N)=C/C(=O)OCc1ccc(C2=NNC(=O)CC2)cc1
Reactant: CC(=O)C[N+](=O)[O-]
Solvent: CC(C)O
Product: CC1=C(C(=O)OCc2ccc(C3=NNC(=O)CC3)cc2)C(c2cccc(OCc3ccccc3)c2)C([N+](=O)[O-])=C(C)N1

Procedure:
10 mmol of 3-benzyloxybenzaldehyde and 10 mmol of 4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzyl 3-aminocrotonate are heated at 60° C. for 8 hours in 30 ml of i-propanol, a total of 20 mmol of nitroacetone being added in portions. The product crystallizes after addition of a little petroleum ether and trituration. It is recrystallized from a little i-propanol.