Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[CH2:7][C@H:6]1[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)[CH3:3].CC(C)([O-])C.[K+].N#C[Br:25]>C1COCC1>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:7][CH:6]1[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[Br:25])[CH3:1]
Reactant: N#CBr
Reactant: CN(C)C[C@@H]1C[C@H]1c1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CC1CC1c1ccc2[nH]cc(Br)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
A solution of trans N,N-dimethyl-2-(indol-5-yl)cycloprop-1-yl methylamine (75 mg, 0.35 mmol), and potassium t-butoxide (29 mg, 0.35 mmol) in anhydrous THF at 0° C. was stirred at 0° C. for 30 min before cyanogen bromide (37 mg, 0.35 mmol) was added. The reaction was warmed to room temperature and stirred for 16 h. The reaction was concentrated in vacuo, and the residue was dissolved in water, and extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give N,N-dimethyl-2-(3-bromoindol-5-yl)cycloprop-1-yl methylamine (100 mg, 98%) as a colorless oil. 1H NMR (MeOH-d4): δ 7.26 (d, J=8.4 Hz, 1H), 7.22 (s, 1H), 7.16 (s, 1H), 6.94 (dd, J=8.7, 1.5 Hz, 1H), 2.58 (dd, J=6.0, 1H), 2.35 (s, 6H), 2.31 (m, 1H), 1.80 (m, 1H), 1.22 (m, 1H), 1.03 (m, 1H), and 0.88 (m, 1H). FIMS: 293.1 (M−H), reverse-phase HPLC purity: 85%.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:8][C:9]1[N:14]=[N:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>>[CH2:1]([NH:5][C:6]([NH:8][C:9]1[N:14]=[N:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CCCCN=C=O
Product: CCCCNC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 5, making variations only as required to use butylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (92% yield). 1H NMR (500 MHz, CDCl3) δ 7.84, 7.74, 7.63, 7.56, 7.36, 7.08, 4.00-4.07, 3.88-3.94, 3.54-3.66, 3.42-3.46, 3.27-3.36, 1.51-1.57, 1.30-1.40, 0.89. MS (ES+) m/z 451 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]([CH3:18])([CH3:17])[CH2:3]1.[CH3:19][O:20][CH2:21][N:22]=[C:23]=[O:24]>>[CH3:19][O:20][CH2:21][NH:22][C:23]([NH:1][CH:2]1[CH2:3][C:4]([CH3:18])([CH3:17])[N:5]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]([CH3:8])([CH3:9])[CH2:7]1)=[O:24]
Reactant: CC1(C)CC(N)CC(C)(C)N1Cc1ccccc1
Reactant: COCN=C=O
Product: COCNC(=O)NC1CC(C)(C)N(Cc2ccccc2)C(C)(C)C1

Procedure:
51 parts of N-methoxymethyl-N'-1-benzyl-2,2,6,6-tetramethylpiperidin-4-yl urea are obtained by reacting 49.1 parts of 4-amino-1-benzyl-2,2,6,6-tetramethylpiperidine with methoxymethyl isocyanate in the same way as described in Example 23(b).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[NH:5][C:4](=[O:12])[CH:3]=1.[H-].[Na+].I[CH2:16][CH:17]([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH2:16][CH:17]([CH3:19])[CH3:18])[N:5]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:7]=1
Reactant: CC(C)(C)c1cc(Br)cc(=O)[nH]1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)COc1cc(Br)cc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of compound 17b (1.0 g, 4.33 mmol) in dry DMF (10 mL) was added NaH (0.31 g, 13 mmol) under N2 and the mixture was stirred at rt for 1 h. Then 1-iodo-2-methylpropane (1.35 g, 7.3 mmol) was added and the resulting mixture was heated at 80° C. overnight. The mixture was quenched with water (5 mL) and extracted with EA twice. The combined organic layers were washed with brine (3×), concentrated and purified by CC (PE/EA=50/1) to give compound 17c (1.0 g, 91%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O.Cl[C:20]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[N:27]=2)=[CH:24][CH:23]=[CH:22][N:21]=1>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[N:27]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:4][CH:3]=1
Reactant: Nc1nccc(-c2cccnc2Cl)n1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncccc2-c2ccnc(N)n2)cc1
Temperature: 100 °C

Procedure:
To a resealable tube was added 4-aminophenol (1.3 g, 12 mmol), cesium carbonate (7.8 g, 24 mmol), and DMSO (16 ml, 0.75 M). The mixture was heated to 100° C. for 5 minutes, and then 4-(2-chloropyridin-3-yl)pyrimidin-2-amine (2.5 g, 12 mmol) was added, and the reaction mixture was heated to 130° C. overnight. Upon completion, as judged by LCMS, the reaction mixture was allowed to cool to RT and diluted with water. The resulting precipitate was filtered, and the solid washed with water and diethyl ether. The solid was then taken up in 9:1 CH2Cl2:MeOH and passed through a pad of silica gel with 9:1 CH2Cl2:MeOH as eluent. The solvent was concentrated in vacuo to provide the desired product, 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine. MS m/z=280 [M+1]+. Calc'd for C15H13N5O: 279.30.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[CH3:16])C.O.[Li+].[OH-].Cl>CO>[CH3:13][O:12][C:10]([C:9]1[CH:14]=[CH:15][C:6]([CH2:5][C:4]([OH:17])=[O:3])=[C:7]([CH3:16])[CH:8]=1)=[O:11]
Reactant: CCOC(=O)Cc1ccc(C(=O)OC)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(CC(=O)O)c(C)c1
Yield: 91.5 %

Procedure:
Methyl 4-(2-ethoxy-2-oxoethyl)-3-methylbenzoate (366 mg) was suspended in MeOH (10 ml) and H2O (2 ml) and treated with LiOH (48 mg) over 3 days. After the reaction mixture was acidified with 1N HCl, the product was extracted with EtOAc. Evaporation and drying in vacuum afforded the desired product (295 mg).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=O>>[NH:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc[nH]1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc[nH]4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1H-pyrrole-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1H-pyrrol-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]([O:19]CC)=[O:18])[C:6]=2[CH:22]=1.O[Li].O>O1CCOCC1.O>[Br:1][C:2]1[C:3]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]([OH:19])=[O:18])[C:6]=2[CH:22]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)Nc1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1Br
Temperature: 100 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
To a solution of ethyl 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylate (53 g, 0.23 mol) in dioxane/H2O (5/1, 600 mL) was added LiOH.H2O (25 g, 1.17 mol), and the mixture was stirred at 100° C. for 3 hours. After concentrated, the resulting residue was dissolved in H2O, 1 N HCl was added until pH reached 3, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and filtered. The solvent was removed to provide the product of 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (48 g, yield: 96%). 1H-NMR (DMSO-d6, 400 MHz) δ 13.49 (s, 1H), 9.67 (s, 1H), 8.30 (s, 1H), 8.12˜8.17 (m, 2H), 7.87 (s, 1H), 7.45˜7.50 (m, 2H), 3.16 (s, 3H). MS (M+H)+: 428/430.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].C(N(CC)CC)C.Cl[Si:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][Si:18](Cl)([CH3:20])[CH3:19]>ClCCl>[CH3:5][C:2]([N:1]1[Si:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][Si:15]1([CH3:23])[CH3:22])([CH3:6])[C:3]#[CH:4]
Reactant: C#CC(C)(C)N
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Temperature: 15 °C
Reaction time: 3 h

Procedure:
3-Amino-3-methylbutyne (commercially available as 90% aqueous solution; 16.6 g) was dissolved in dichloromethane (150 ml), dried over sodium sulphate and filtered to give a solution containing 14.9 g of amine. To the stirred solution of amine under an atmosphere of nitrogen at ambient temperature was added dry triethylamine (48.4 ml). 1,2-Bis-(chlorodimethylsilyl)ethane (38.98 g) in dichloromethane (100 ml) was then added dropwise, maintaining the reaction temperature at 15° C. by cooling. The mixture was stirred for 3 hours, the colourless solid, which had formed during the reaction, was filtered from solution and the filtrate was evaporated under reduced pressure to give a paste. The paste was extracted into hexane and refiltered. The filtrate was evaporated under reduced pressure and the oil obtained was distilled to give 1-(1,1-dimethyl-2-propynyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane, 21.5 g, b.p. 41° C. at 0.06 mm Hg pressure.
Reaction SMILES: N[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:10]=2)[CH2:5][CH2:4]1.N1CCC(C[C:39]([NH2:41])=[O:40])CC1>>[C:29]([N:26]1[CH2:27][CH2:28][N:23]([C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:11]3[N:10]=[C:9]([N:6]4[CH2:5][CH2:4][CH:3]([CH2:2][C:39]([NH2:41])=[O:40])[CH2:8][CH2:7]4)[C:14]([F:15])=[CH:13][N:12]=3)=[CH:18][CH:19]=2)[CH2:24][CH2:25]1)(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(CN)CC4)n3)cc2)CC1
Reactant: NC(=O)CC1CCNCC1
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(CC(N)=O)CC4)n3)cc2)CC1

Procedure:
The titled compound was synthesized analogously as compound 1-(4-(4-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone, by using 2-(piperidin-4-yl)acetamide. MS 456.3 (M+H); UV 203.8, 269.8 nm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[O:19][CH3:20].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=[S:31])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[O:19][CH3:20]
Reactant: COC(=O)c1cc(NC(=O)c2ccccc2)ccc1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NC(=S)c2ccccc2)ccc1OC
Yield: 89.3 %

Procedure:
A 2 liter round bottom flask was charged with 15.7 grams (55 mmol) methyl-2-methoxy-5-benzamidobenzoate and 22.2 grams (55 mmol) of Lawesson's reagent followed by 500 mL of toluene. The reaction mixture was heated under reflux for 1.5 hours. The mixture was diluted with 500 mL of ethyl acetate, and washed with 250 mL of saturated aqueous bicarbonate solution, followed by washes with water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on silica eluting with 96/4 methylene chloride-ether. There was obtained 14.8 grams (89%) of desired material.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:47]([CH3:49])[CH3:48])[C:10]([O:12][CH2:13][N:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([C:21]2[CH:26]=[C:25](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=3)[C:24]([O:40][CH3:41])=[C:23]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:22]=2)[C:15]1=[O:46])=[O:11])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[C:42]([C:23]1[CH:22]=[C:21]([C:16]2[C:15](=[O:46])[N:14]([CH2:13][O:12][C:10](=[O:11])[C@@H:9]([NH2:8])[CH:47]([CH3:48])[CH3:49])[CH:19]=[C:18]([F:20])[CH:17]=2)[CH:26]=[C:25](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=2)[C:24]=1[O:40][CH3:41])([CH3:43])([CH3:45])[CH3:44]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(-c2cc(F)cn(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)c2=O)cc1C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(-c2cc(F)cn(COC(=O)[C@@H](N)C(C)C)c2=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
step 3—To a solution of 342 (0.886 g, 1.266 mmol and DCM (10 mL) at RT was added a HCl/dioxane solution (1.899 mL, 7.60 mmol, 4M solution) and the resulting solution stirred at RT for 3 h. The resulting solution was poured into DCM (150 mL) which produced a gummy oil. When the mixture was sonicated a white powder formed which was filtered, washed with DCM and air-dried. The solid was dried under high vacuum to remove all traces of solvent which afforded 698 g of II-7 as a white powder: MS (M+H)=600.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=1[F:20].[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[N:32]=1)[C:27](O)=[O:28]>>[F:20][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=1[C:11]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:21])[C:27](=[O:28])[C:26]1[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[N:32]=[C:24]([C:23]([F:38])([F:22])[F:37])[CH:25]=1
Reactant: COC(=O)CNc1cnccc1-c1c(F)cccc1OC
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1)c1cnccc1-c1c(F)cccc1OC

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-fluoro-6-methoxy-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 20:80). Light yellow solid (48%). MS (ESI): m/z=532.109 [M+H]+.
Reaction SMILES: [NH:1]1[C:10]2[C:9]3[CH2:11][NH:12][CH2:13][CH2:14][C:8]=3[CH:7]=[CH:6][C:5]=2[NH:4][C:3](=[O:15])[C:2]1=[O:16].[N+:17]([O-])([OH:19])=[O:18]>FC(F)(F)C(O)=O>[N+:17]([C:7]1[C:8]2[CH2:14][CH2:13][NH:12][CH2:11][C:9]=2[C:10]2[NH:1][C:2](=[O:16])[C:3](=[O:15])[NH:4][C:5]=2[CH:6]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2ccc3c(c2[nH]c1=O)CNCC3
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2cc([N+](=O)[O-])c3c(c2[nH]c1=O)CNCC3
Reaction time: 19 h
Yield: 58 %

Procedure:
A solution of the quinoxalinedione from Example 30 (50 mg, 0.23 mmol) in 2 mL of trifluoroacetic acid was treated with fuming nitric acid (0.1 mL, 2.3 mmol) and stirred under a nitrogen atmosphere for 19 h. After evaporating to dryness, the residue was triturated with acetone and the precipitant collected by filtration. The solid was suspended in water, heated on a hot plate and basified to pH 8 with an ammonium hydroxide solution. The solid was collected by filtration while hot, and dried in vacuo to give a yellow solid (35 mg, 65% yield). mp=245-240° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([Br:11])[C:6]=1[C:7]([O:9][CH3:10])=[O:8].[N:12]1[C:21]2[C:16](=[C:17]([CH2:22][C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>>[Br:11][C:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([NH:1][C:23](=[O:24])[CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:16]=2[CH:15]=[CH:14][CH:13]=[N:12]3)[S:3][CH:4]=1
Reactant: O=C(O)Cc1cccc2ncccc12
Reactant: COC(=O)c1c(Br)csc1N
Product: COC(=O)c1c(Br)csc1NC(=O)Cc1cccc2ncccc12
Yield: 49 %

Procedure:
The title compound was prepared from methyl 2-amino-4-bromothiophene-3-carboxylate (660 mg, 2.8 mmol) and 2-(quinolin-5-yl)acetic acid using protocol A. 560 mg (49% yield). Method [1]: rt=1.666 min; MH+ 405/407.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21]Cl.O>CN(C=O)C.[I-].[K+]>[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21][O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cccc(OCc2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of 3′-hydroxyacetophenone (19 g) in DMF (400 mL) was added K2CO3 (38.5 g) and the mixture was stirred for 3 hours at room temperature. 3,4-Dichlorobenzyl chloride (32.7 g) and potassium iodide (1.16 g) were added to the reaction mixture and stirred for 48 hours. After completion of the reaction, the mixture was poured into ice and water mixture and stirred for 15 minutes, solid was filtered and washed with water and hexanes. Solid was dissolved in DCM and precipitated by adding hexanes to get pure 1-[3-(3,4-dichloro-benzyloxy)-phenyl]-ethanone (30 g) 1H NMR (400 MHz, CDCl3) 7.53-7.60 (m, 3H), 7.46 (d, 1H), 7.39 (t, 1H), 7.25-7.30 (m, 1H), 7.14-7.19 (m, 1H), 5.07 (s, 2H), 2.60 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.C(N(CC)CC)C.[CH2:17]([Si:19]([C:24]#[CH:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:18]>[Cu](I)I.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.C1COCC1>[Cl:8][C:6]1[N:7]=[C:2]([C:18]#[C:17][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Cl)nc1Br
Reactant: C#C[Si](CC)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[Si](C#Cc1nc(Cl)cnc1N)(CC)CC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 250 ml round bottom flask was charged with 3-bromo-5-chloro-pyrazin-2-ylamine (2) (1 g, 4.8 mmol), THF (10 ml), copper iodide (9 mg, 0.05 mM) and PdCl2(PPh3)2 (34 mg, 0.05 mmol) under nitrogen. To the reaction mixture, triethylamine (2 ml, 14.4 mmol) and triethylsilylacetylene (1 ml, 5.76 mmol) were added. The reaction mixture was stirred at room temperature for 3 h, then concentrated in vacuo and the residue was purified by flash chromatography, using as eluent pentane/EtOAc 10% to 30%, to give the title compound as an off white solid (1.2 g, 100%). 1H NMR (CDCl3): 0.7-0.8 (6H, qd), 1.0-1.1 (9H, t), 5.0-5.1 (2H, brs), 7.95 (1H, s). MS (ES+): 268.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C@H:14]1[CH2:20][N:19]2[C:21]([C:24]([O:27]C)([CH3:26])[CH3:25])=[CH:22][N:23]=[C:18]2[C@H:17]([NH:29]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1>O>[NH2:29][C@@H:17]1[CH2:16][CH2:15][C@@H:14]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=2[F:6])[CH2:20][N:19]2[C:21]([C:24]([OH:27])([CH3:25])[CH3:26])=[CH:22][N:23]=[C:18]12
Reactant: COC(C)(C)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2N
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
Concentrated sulfuric acid (0.335 mL, 5.70 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-(1-methoxy-1-methylethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (310 mg, 0.712 mmol) in H2O (2 mL) and the mixture heated to 60° C. After 2.5 h, the reaction mixture was quenched with saturated aqueous NaHCO3. The mixture was extracted with CH2Cl2 (3×), and the combined organic extracts were washed with water, saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound. MS: m/z=322 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH:10]([OH:15])[CH2:11][CH2:12][CH:13]=[CH2:14].[Br:16]N1C(=O)CCC1=O>C(Cl)Cl>[Br:16][CH2:14][CH:13]1[CH2:12][CH2:11][CH:10]([C:4]2[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[O:15]1
Reactant: C=CCCC(O)c1cc(F)ccc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1ccc(F)cc1C1CCC(CBr)O1
Temperature: 25 °C
Yield: 43.8 %

Procedure:
To a solution of 1-(2′-methoxy-5′-fluorophenyl)pent-4-en-1-ol (3.24 g, 18.0 mmol) in dry CH2Cl2 (50 mL) at 0° C. was added portionwise N-bromosuccinimide (NBS, 3.56 g, 20.0 mmol) portionwise and the reaction was warmed to room temperature for 12 h. Solvent was then removed in vacuo and the residue was purified by flash column chromatography (10% EtOAc in Hexane, Rf=0.28) to give the product (2.28 g, 44%) as an oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH:27]1([CH2:30]Br)[CH2:29][CH2:28]1.O>CN(C=O)C>[CH:27]1([CH2:30][N:13]2[C:14]3=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]3[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[N:12]2)[CH2:29][CH2:28]1
Reactant: BrCC1CC1
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccccc3c1)nn2CC1CC1
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and cyclopropyl methyl bromide (22 μL, 0.25 mmol) were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 316.2, found 316.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([S:11][CH3:12])=[N:8][CH:7]=[N:6]2.C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)(Cl)Cl>[CH3:12][S:11][C:9]1[C:10]2=[C:2]([CH2:1][N:37]3[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]3)[CH:3]=[CH:4][N:5]2[N:6]=[CH:7][N:8]=1
Reactant: OC1CCNCC1
Reactant: CSc1ncnn2ccc(C)c12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ncnn2ccc(CN3CCC(O)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A solution of 5-methyl-4-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (200 mg, 1.12 mmol), NBS (218 mg, 1.23 mmol), and AIBN (spatula tip) in carbon tetrachloride (4 mL) was heated at 80° C. for 1 h. After cooling to rt, the solution was filtered to remove succinimide. To the filtrate was added 4-hydroxypiperidine (126 mg, 1.34 mmol, Aldrich) and DIPEA (214 μL, 1.23 mmol). The reaction was stirred at rt overnight and was then concentrated in vacuo. The residue was suspended in methanol and filtered. The filtrate was concentrated and the crude product was purified by flash chromatography on silica gel (20% MeOH/EtOAc) to give the title compound (229 mg, 74%) as a colorless solid. 1H NMR (DMSO-d6) δ 8.25 (s, 1H), 7.88 (d, 1H, J=2 Hz), 6.81 (d, 1H, J=2 Hz), 4.54 (br s, 1H), 3.76 (s, 2H), 3.48–3.44 (m, 1H), 2.75–2.71 (m, 2H), 2.62 (s, 3H), 2.10–2.08 (m, 2H), 1.70–1.68 (m, 2H), 1.38–1.36 (m, 2H); MS(ESI+) m/z 279.3 (M+H)+.