Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)#[N:2].CC(OC(C)=O)=O.[N+:22]([O-])([OH:24])=[O:23]>O>[C:1]([CH:3]([CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1)#[N:2]
Reactant: CC(=O)Nc1ccc(C(C)C#N)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(C)C#N)cc1[N+](=O)[O-]

Procedure:
To the flask of N-[4-(Cyano-methyl-methyl)-phenyl]-acetamide (12.9 g, 68.5 mmol) was added Ac2O (35 mL) at 5° C. The mixture was stirred and added HNO3 (7.45 g, 70.9 mmol) at 0° C. This reaction was very exothermic. The mixture was stirred for 1 hr at 0° C. and additionally stirred for 3 hrs at room temperature. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:2) as eluant.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.[Br-].[Li+].N1CCNCC1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[CH:24]=4)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4cccc(C(F)(F)F)c4)cc32)cc1Br
Agent: C1CNCCN1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ncc(-c3cccc(C(F)(F)F)c3)cc21

Procedure:
By the same method as in the step d) of Example 45, (3,5-dibromo-4-methoxy-phenyl)-[7-(3-trifluoromethyl-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone (165 mg, 0.29 mmol), lithium bromide (100 mg, 1.15 mmol) and piperazine (37.3 mg, 0.43 mmol) were dissolved in N,N-dimethyl formamide (2 ml) and reacted at 100□ to obtain the target compound 63, i.e., (3,5-dibromo-4-hydroxy-phenyl)-[7-(3-trifluoromethyl-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone, as white solid (90 mg, 56%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[N:4]=[C:3]1[C:22]([O:24]CC)=[O:23].[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:21])[F:20])=[CH:13][CH:12]=2)=[O:9])[N:4]=[C:3]1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1nc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
835 mg (2.13 mmol) of ethyl 1-methyl-4-[({[4-(trifluoromethoxy)phenyl]amino}carbonyl)amino]-1H-imidazole-2-carboxylate (Example 28A) are suspended in 5 ml of ethanol and 12 ml of tetrahydrofuran. While cooling in ice, 2 ml (25 mmol) of 50% strength aqueous sodium hydroxide solution are added. The reaction mixture is stirred at room temperature overnight and then, while cooling in ice, acidified with 1N hydrochloric acid. The solution is extracted with dichloromethane. The organic phase is concentrated in vacuo. The residue is purified by preparative HPLC.
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][C:12](=[O:14])[CH3:13])=[C:6]([CH3:15])[CH:5]=1)=[O:3].[NH2:16][C:17]1[C:22]([C:23](O)=[O:24])=[CH:21][N:20]=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:10][C:8]1[CH:9]=[C:4]([C:2]2[O:3][C:23](=[O:24])[C:22]3[CH:21]=[N:20][CH:19]=[CH:18][C:17]=3[N:16]=2)[CH:5]=[C:6]([CH3:15])[C:7]=1[O:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Oc1c(C)cc(C(=O)Cl)cc1C
Reactant: Nc1ccncc1C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1c(C)cc(-c2nc3ccncc3c(=O)o2)cc1C
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of acetic acid 4-chlorocarbonyl-2,6-dimethylphenyl ester (2.32 g, 10.0 mmol) in anhydrous CH2Cl2 (30 mL) were added 4-amino-nicotinic acid (4) (1.10 g, 8.00 mmol) and pyridine (2.37 g, 30.0 mmol). The reaction mixture was stirred at room temperature under nitrogen for 40 hours. Solvent was evaporated. The residue was diluted with methanol (20 mL). The solid separated was filtered, washed with methanol (2×10 mL) and dried under vacuum to give acetic acid 2,6-dimethyl-4-(4-oxo-4H-pyrido[4,3-d][1,3]oxazin-2-yl)-phenyl ester (6) as yellow solid. Yield: 1.99 g (64%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@:5]([CH3:10])([CH2:7][CH2:8][OH:9])[CH2:4][O:3]1.[Cr](Cl)(O)(=O)=O.N1C=CC=CC=1.CCOCC>C(Cl)Cl>[CH3:1][C:2]1([CH3:11])[O:6][C@@:5]([CH3:10])([CH2:7][CH:8]=[O:9])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@](C)(CCO)O1
Agent: O=[Cr](=O)(O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC[C@](C)(CC=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
4.33 g of (S)-2,2,4-trimethyl-1,3-dioxolan-4-ethanol dissolved in 7 ml of absolute methylene chloride were added dropwise to a suspension of 7.59 g of pyridine chlorochromate in 30 ml of absolute methylene chloride. The reaction mixture was stirred at room temperature for 3 hours. By addition of 75 ml of ether, the chromium salt was precipitated and separated by filtration over 120 g of Kieselgel. After removal of the solvent on a rotary evaporator and distillation of the residue at 90°-100°/10 mmHg, there were obtained 3.00 g of (S)-2,2,4-trimethyl-1,3-dioxolan-4-acetaldehyde. [α]D20 =-35.5° (c=1.50; n-hexane).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.Br[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[N:19][CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[N:19][CH:18]=3)[C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: Brc1cncc2ccccc12
Reactant: O=C1NCCc2ccc(C(F)(F)F)cc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2cc(C(F)(F)F)ccc2CCN1c1cncc2ccccc12
Yield: 10.5 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-16c: 150 mg, 0.698 mmol) was reacted with 4-bromo-isoquinoline (145 mg, 0.698 mmol), 1,4-dioxane (10 mL), copper iodide (13.29 mg, 0.0698 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (29.74 mg, 0.209 mmol) and potassium phosphate (369.94 mg, 1.745 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in DCM) afforded 25 mg of the product (10.50% yield).
Reaction SMILES: [CH2:1]([C@H:8]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C@@H:9]([OH:26])[CH2:10][N:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[O:40]=C1C=CC=CN1OC(N(C)C)=[N+](C)C.C(N(C(C)C)CC)(C)C.[CH3:64][O:65][C:66]([NH:68][C@H:69]([C@@H:74]([CH3:77])[CH2:75][CH3:76])[CH2:70]C(O)=O)=[O:67]>ClCCl>[CH2:1]([C@H:8]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C@@H:9]([OH:26])[CH2:10][N:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)[NH:12][C:70](=[O:40])[C@@H:69]([NH:68][C:66]([O:65][CH3:64])=[O:67])[C@@H:74]([CH3:77])[CH2:75][CH3:76])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(On1ccccc1=O)=[N+](C)C
Reactant: CC[C@H](C)[C@H](CC(=O)O)NC(=O)OC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2ccccn2)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
A solution of Example 7B (0.36 g, 0.77 mmol) in dichloromethane (5 mL) was treated with O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TPTU) (0.344 g, 1.5 equivalent), and diisopropylethyl amine (0.4 μL, 3 equivalents) at 0° C. over 20 min. A solution of Example 3A (0.22 g, 1.5 equivalent) in dichloromethane (5 mL) was added at 0° C. and the mixture was stirred at 25° C. for 16 hrs. The mixture was washed with water, 10% sodium bicarbonate, brine, the organic layer was separated, dried over sodium sulfate, filtered and the solvents were evaporated. The crude residue was purified using 1% methanol/chloroform to give 0.37 g (76%) of the title compound.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18]2[C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=[C:20]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[N:19]=2)[CH2:12][CH2:11]1)=O)(C)(C)C.CCO.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[NH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][CH:13]([CH2:16][NH:17][C:18]2[C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=[C:20]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[N:19]=2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(CNc2nc(NCc3ccccc3Cl)ncc2C(=O)O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: NCC1CCC(CNc2nc(NCc3ccccc3Cl)ncc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a solution of 4-{[4-(tert-butoxycarbonylamino-methyl)-cyclohexylmethyl]-amino}-2-(2-chloro-benzylamino)-pyrimidine-5-carboxylic acid (80 mg, 0.159 mmol) dissolved in 2:1 CHCl3:EtOH at room temperature was added 4.0 M HCl/dioxane (5.0 mL). The mixture was stirred at room temperature for 2 h then concentrated in vacuo to provide a crude white powder. The crude material was purified by preparative scale reverse phase HPLC using a 0.1% TFA-H2O/CH3CN mobile phase. The product-containing fractions were combined and concentrated in vacuo to provide 34 mg of the title compound as a white solid, 53%, m/z calculated for C20H26ClN5O2: 403.9, found: 404.4 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]2[CH:9]=[N:10][C:11](I)=[C:7]2[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:4]=1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][CH:2]([F:23])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[C:7]2[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:4]=1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc2c(I)ncn12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ncn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
A mixture of 4-difluoromethyl-8-iodo-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (2.45 g, 5.58 mmol), trimethylsilylacetylene (1.24 ml, 8.94 mmol) and triethylamine (2.08 ml, 14.9 mmol) in N,N-dimethylformamide (10 ml) was stirred for 10 min at room temperature while being purged with Argon, then PdCl2(PPh3)2 (105 mg, 0.15 mmol), PPh3 (78 mg, 0.3 mmol) and CuI (9 mg, 0.05 mmol) were added. Stirring was continued at 90° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with ice-water (50 mL) and extracted with ethyl acetate (3×70 ml). The combined organic layers were washed with water (40 ml) and brine (40 ml), dried (MgSO4) and evaporated to give 4-difluoromethyl-2-(4-trifluoromethyl-phenyl)-8-trimethylsilanylethynyl-imidazo[1,5-a]pyrimidine (1.58 g, 69%) as a brown solid, which was dissolved in THF (15 ml) and MeOH (15 ml), while stirring at 0° C. potassium carbonate (51 mg, 0.37 mmol) was added and the mixture was stirred at 0° C. for 5 h. The mixture was diluted with ice water (50 ml) and extracted with TBME (2×80 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/EtOAc) followed by crystallization from diethyl ether/hexane to give 4-difluoromethyl-8-ethynyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (0.61 g, 49%) as a brown solid. MS (EI) 337.1 [(M)+]; mp 135° C.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[C:4]([C:13]2[C:14]([CH3:19])=[N:15][O:16][C:17]=2[CH3:18])[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][C:32](=O)[NH:33]3)O1.C([O-])([O-])=[O:45].[Cs+].[Cs+]>ICCC.COCCOC.O>[CH3:19][C:14]1[C:13]([C:4]2[CH:3]=[C:2]([C:36]3[CH:35]=[C:34]4[C:29]([CH:30]=[CH:31][CH:32]=[N+:33]4[O-:45])=[CH:28][C:37]=3[C:38]([F:41])([F:40])[F:39])[C:7]3[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=3[CH:5]=2)=[C:17]([CH3:18])[O:16][N:15]=1
Reactant: Cc1noc(C)c1-c1cc(Cl)c2c(c1)[nH]c(=O)n2C
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2c(C(F)(F)F)ccc3[nH]c(=O)ccc23)OC1(C)C
Agent: [Cs+]
Solvent: O
Solvent: CCCI
Solvent: COCCOC
Product: Cc1noc(C)c1-c1cc(-c2cc3c(ccc[n+]3[O-])cc2C(F)(F)F)c2c(c1)[nH]c(=O)n2C
Temperature: 120 °C

Procedure:
To a microwave vial containing 7-chloro-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one (100 mg, 0.36 mmol, 1 equiv.) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)quinolone (350 mg, 1.08 mmol, 3 equiv.), Cs2CO3 (704 mg, 2.16 mmol, 6 equiv.) and PEPPSI™-IPr catalyst (98 mg, 0.14 mmol, 0.4 equiv.) and dissolved in DME-H2O (4 mL, 0.2 M, 2/1, v/v). The mixture was heated to 120° C. for 30 min in microwave. The reaction was concentrated in vacuo and purification was carried out by reverse phase HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@@:8]([NH:18][S@@](C(C)(C)C)=O)([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][F:10])[CH:7]=1.CO.Cl>C(Cl)Cl>[NH2:18][C@@:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:25])([CH2:9][F:10])[CH2:11][C@H:12]([OH:17])[C:13]([F:15])([F:16])[F:14]
Reactant: CC(C)(C)[S@@](=O)N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cc(Br)ccc1F
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cc(Br)ccc1F
Reaction time: 1 h

Procedure:
To a solution of (R)—N-((2S,4S)-2-(5-bromo-2-fluorophenyl)-1,5,5,5-tetrafluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (1.6 g, 3.54 mmol, step 6) in DCM (20 mL)/MeOH (10 mL) was added HCl (4.0M in dioxane; 1.075 ml, 35.4 mmol, Aldrich) at RT. The reaction was stirred for one hour. The reaction was concentrated under reduced pressure and the crude residue was taken up in EtOAc. The solution was washed sequentially with water, saturated aqueous sodium bicarbonate solution, and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound as yellow oil, used without further purification. MS m/z=347.9 M+. Calculated for C11H11BrF5NO: 348.11
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH3:10])[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[F:17][C:13]1[CH:12]=[C:11]([CH:9]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:3]=2)[CH3:10])[CH:16]=[CH:15][CH:14]=1
Reactant: CC(Oc1cncc(Cl)n1)c1cccc(F)c1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(Oc1cncc(N2CCNCC2)n1)c1cccc(F)c1
Yield: 55 %

Procedure:
A mixture of the product from step 1 above (crude, 1.09 g, ˜4.3 mmol), piperazine (1.03 g, 12.0 mmol) and K2CO3 (1.00 g, 7.2 mmol) in acetonitrile (5 mL) was heated under reflux overnight (20 h). After cooling, ethyl acetate (15 mL) and water (5 mL) were added. The ethyl acetate layer was filtered through a short column of silica gel using MeOH/ethyl ether (1:1) as eluent to give 0.72 g (55%) of the title compound as an oil. HRMS m/z calcd for C16H19N4O4F (M)+ 302.1543, found 302.1528. Anal. (C16H19N4OF.0.5 H2O) C, H, N.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#N)=[CH:2]1.[CH3:9]I.[H-].[Na+].C[N:14]([CH:16]=O)C>>[CH3:9][C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)([CH3:7])[C:16]#[N:14]
Reactant: N#CCc1ccsc1
Reactant: CN(C)C=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C#N)c1ccsc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of thiophene-3-acetonitrile (6.15 g, 50 mmol) and MeI (12.5 mL, 4 equiv) in DMF (200 mL) was added sodium hydride (6 g, 60%, 3 equiv) at 0° C. under nitrogen and the reaction mixture was stirred for 3 h at 0° C. It was then quenched with water and extracted with hexane (3×100 mL). The combined organic layer was washed with water and dried over MgSO4. Evaporation of solvent afforded 2-methyl-2-thiophen-3-yl-propionitrile as an oil, which was used in next step without further purification. 1H-NMR(CDCl3): δ 8.02 (1H, m), 7.35 (1H, dd), 7.12 (1H, dd), 2.96 (3H, s), 2.89 (3H, s).
Reaction SMILES: [N:1]1([C:7](=[O:12])[CH2:8][C:9](=[O:11])[CH3:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:13]N1C(=O)CCC1=O>ClCCCl>[Br:13][CH:8]([C:9](=[O:11])[CH3:10])[C:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:12]
Reactant: CC(=O)CC(=O)N1CCOCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Product: CC(=O)C(Br)C(=O)N1CCOCC1
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of 1-morpholin-4-yl-butane-1,3-dione (0.53 g, 3.1 mmol) in 1,2-dichloroethane (30 mL) stirred at 0° C., N-bromosuccinimide (0.55 mg, 3.1 mmol) was added in small portions and the mixture was stirred for 1 h. The solution was washed with brine (3×5 mL), dried over MgSO4 and concentrated below 30° C. 2-Bromo-1-morpholin-4-yl-butane-1,3-dione 0.76 g, 3.04 mmol, 98.1%, LCMS/BB_LCMS01(+)/: M+1=250, 252, Rt: 1.831 min] was obtained as a yellowish oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(S)[CH2:12][S:13]([O-])(=O)=O.[Na+]>CS(C)=O.[Cu]I>[CH3:12][S:13][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: O=S(=O)([O-])CCS
Reactant: Ic1n[nH]c2cnccc12
Agent: [Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1n[nH]c2cnccc12
Temperature: 150 °C
Yield: 49.9 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-c]pyridine 3 (9.5 g, 38.8 mmol) in DMSO (20 mL) was added aq. MeSNa (wt. 20%, 40 mL, 116 mmol), followed by CuI (270 mg, 1.94 mmol). The mixture was degassed and refilled with nitrogen. The reaction was heated at 150° C. overnight. After cooled to RT, the volatiles were removed and the residue was purified by column (PE/EtOAc=2/1 to 1/1) to give 3-(methylthio)-1H-pyrazolo[3,4-c]pyridine (3.2 g, yield: 50%) as a yellow solid. MS obsd. (ESI+) [(M+H)+] 166.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.O>N1C=CC=CC=1>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCOCCO
Solvent: O
Solvent: c1ccncc1
Product: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of diethylene glycol monomethylether (12 g, 100 mmol) in pyridine (70 ml) was added p-toluenesulfonyl chloride (22.8 g, 120 mmol) at 0° C., which was then stirred at room temperature for 2 hours. Water was added thereto, and the mixture was extracted with diethyl ether. The extracted organic layer was washed with 0.5N-HCl, water and saturated sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. The organic solvent was removed under reduced pressure to give the title compound (27 g, stoichiometric yield) as a yellow oil. The compound thus obtained was used in the next reaction without further purification.
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[CH:18]1([C:24]2[S:25][C:26]([C:30](O)=[O:31])=[C:27]([CH3:29])[N:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>O>[CH:18]1([C:24]2[S:25][C:26]([C:30]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:15])[F:16])=[O:31])=[C:27]([CH3:29])[N:28]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Cc1nc(C2CCCCC2)sc1C(=O)O
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CCOC(=O)c1sc(C2CCCCC2)nc1C)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To 7 ml of N,N-dimethylformamide were dissolved 0.50 g (2.5 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 0.56 g (2.5 mmol) of 2-cyclohexyl-4-methylthiazole-5-carboxylic acid, followed by the addition of 0.42 g (5.0 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 0.64 g (yield: 78%) of 4,4-difluoro-3-methyl-3-butenyl 2-cyclohexyl-4-methylthiazole-5-carboxylate.
Reaction SMILES: [CH3:1][Si:2]([CH3:58])([CH3:57])[O:3][Si:4]([CH2:15][CH2:16][CH2:17][N:18]([CH2:38][CH2:39][CH2:40][Si:41]([O:52][Si:53]([CH3:56])([CH3:55])[CH3:54])([O:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[O:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH2:19][CH2:20][CH2:21][Si:22]([O:33][Si:34]([CH3:37])([CH3:36])[CH3:35])([O:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[O:23][Si:24]([CH3:27])([CH3:26])[CH3:25])([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[O:5][Si:6]([CH3:9])([CH3:8])[CH3:7].C[I:60].[C:61](=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[I-:60].[CH3:61][N+:18]([CH2:38][CH2:39][CH2:40][Si:41]([O:52][Si:53]([CH3:55])([CH3:54])[CH3:56])([O:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[O:42][Si:43]([CH3:46])([CH3:45])[CH3:44])([CH2:17][CH2:16][CH2:15][Si:4]([O:5][Si:6]([CH3:7])([CH3:8])[CH3:9])([O:3][Si:2]([CH3:1])([CH3:57])[CH3:58])[O:10][Si:11]([CH3:12])([CH3:13])[CH3:14])[CH2:19][CH2:20][CH2:21][Si:22]([O:23][Si:24]([CH3:25])([CH3:26])[CH3:27])([O:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[O:28][Si:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C([O-])[O-]
Reactant: C[Si](C)(C)O[Si](CCCN(CCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C)CCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Reactant: CI
Agent: [Na+]
Solvent: CC(C)=O
Product: C[N+](CCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C)(CCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C)CCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Product: [I-]
Reaction time: 15 h

Procedure:
1.42 g of tris(tris(trimethylsiloxy)silylpropyl)amine (30), 1.2 g of methyl iodide and 0.9 g of sodium carbonate are added to 50 ml of acetone. The reaction mixture is stirred for 15 hours at reflux. The solvent is evaporated and the residue taken up in methylene chloride. The organic phase is then washed with water, dried and evaporated. The residue contains the desired product methyl-tris(tris(trimethylsiloxy)silylpropyl)ammonium iodide (31); 1H-NMR (ppm, CDCl3): 3.27 6H t, 3.18 3H s, 1.56-1.50 6H m, 0.37 6H t, 0 81H s.