Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[NH2:9][C:4]1[N:3]=[C:2]([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
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: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cc(C)nc(N)n3)cc2s1
Temperature: 90 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a suspension of tetrakis(triphenylphosphine)palladium (0) (0.115 g, 0.0999 mmol), 4-chloro-6-methylpyrimidin-2-amine (0.142 g, 0.999 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.318 g, 0.999 mmol) under nitrogen was added sodium carbonate (1 mL, 2M in water, 2 mmol) and then 1,4-dioxane (6 mL). The flask was heated in a pre-heated (90° C.) bath and stirred under an inert atmosphere overnight. The mixture was allowed to cool to ambient temperature and concentrated. The crude material was diluted with DCM and washed with brine. The organic layer was dried over sodium sulfate, concentrated, and purified by silica gel chromatography (0-10% MeOH in DCM) to give N-(6-(2-amino-6-methylpyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (200 mg, 67%) as a brown solid. MS (ESI pos. ion) m/z: 300 (MH+). Calculated exact mass for C14H13N5OS: 299.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:27]([O:34][C:35](=[O:43])[CH2:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>C(Cl)Cl>[CH2:27]([O:34][C:35](=[O:43])[CH2:36][CH:37]1[CH2:38][CH2:39][N:40]([C:11](=[O:13])[C:10]([CH3:15])([CH3:14])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:41][CH2:42]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(CC1CCNCC1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(C)(C)C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(C)(C)C(=O)N1CCC(CC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Methyl 2,2-dimethyl-cyanoacetate (2.0 g) was stirred under a hydrogen atmosphere in a 1N ammonium-containing methanol/ethanol (1:1) mixed solution under the presence of rhodium-alumina catalyst at a room temperature for 6 hours. The catalyst was removed from the reaction solution by filtration and the solvents were distilled off. To the residue were added 4N caustic soda (3 ml) and dioxane (3 ml) and the mixture was stirred at a room temperature for 6 hours. To the resulting mixture were added a 2N aqueous solution of sodium carbonate (25 ml) and di-t-butyl carbonate (2.9 g) dissolved in dioxane (20 ml) and the mixture was stirred for 12 hours. After the solvents were distilled off from the reaction solution, the residue was dissolved in water, washed with ether and adjusted to pH 3 with citric acid under cooling with ice, followed by extraction three times with ethyl acetate. The organic layer was washed with saturated NaCl three times and dried over sodium sulfate. The solvents were distilled off to yield N-t-butoxycarbonyl-α,α-dimethyl-β-alanine (2.5 g). The obtained N-t-butoxycarbonyl-α,α-dimethyl-β-alanine (1.1 g), 4-piperidineacetic acid benzyl ester tosylate (1.52 g), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate (PyBrop, 2.20 g) and triethylamine (1.7 ml) were dissolved in methylene chloride (15 ml) and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off, the residue was applied to a silica gel column (φ 2.5×40 cm, Si-60, eluent: 30% ethyl acetate/hexane) for purification to yield N-(N-t-butoxycarbonyl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid benzyl ester (1.55 g, 96.0%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][C:26]([N:28]([CH3:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][C:26]([N:28]([CH3:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:27])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CN(C(=O)CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)CCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1)c1ccccc1
Yield: 71.8 %

Procedure:
A mixture of 10.0 g (0.033 mole) of α,α-bis(4-fluorophenyl)-4-piperidine-methanol, 6.5 g (0.033 mole) of 3-chloro-N-methyl-N-phenylpropanamide, 14.0 g (0.132 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in 100 ml of N,N-dimethylformamide was heated on a steam bath for 16 h. The mixture was poured into 2 L of water and extracted three times with 500 mL portions of ethyl acetate. The ethyl acetate fractions were combined, washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give a yellow glass. The glass was purified by column chromatography using 250 g of silica gel on a 65 cm×4 column, eluted with ethyl acetate. The fractions containing the desired product were combined and concentrated under reduced pressure to yield 11.0 g (72%) of a white solid. A portion of this solid was recrystallized from ethyl ether to give a white solid, mp 73°-75° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:51])[N:23]([C:27]2[C:32]([CH3:33])=[CH:31][C:30]([NH:34][CH2:35][C@@H:36]([OH:49])[CH2:37][N:38]3[C:46](=[O:47])[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:39]3=[O:48])=[CH:29][C:28]=2[CH3:50])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:52](N1C=CN=C1)(N1C=CN=C1)=[O:53].O.ClCCl>C1(C)C=CC=CC=1>[Si:1]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:51])[N:23]([C:27]2[C:28]([CH3:50])=[CH:29][C:30]([N:34]3[CH2:35][C@H:36]([CH2:37][N:38]4[C:46](=[O:47])[C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[C:39]4=[O:48])[O:49][C:52]3=[O:53])=[CH:31][C:32]=2[CH3:33])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(NC[C@@H](O)CN2C(=O)c3ccccc3C2=O)cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(N2C[C@H](CN3C(=O)c4ccccc4C3=O)OC2=O)cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Temperature: 25 °C

Procedure:
190 g (204 mmol) of the compound from Example 66A are dissolved in 1.01 l of toluene. 66.0 g (407 mmol) of 1,1′-carbonyldiimidazole are then added, and the mixture is heated at reflux for one hour. The mixture is then cooled to room temperature, and water and dichloromethane are added. The phases are separated and the organic phase is dried over sodium sulphate. After filtration, the mixture is evaporated to dryness under reduced pressure. The residue is triturated with methanol, and the solid which remains is filtered off and washed with methanol. This gives 130 g (87% of theory) of the desired product.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Mg]Br)C.[CH3:16][Si:17]([CH3:34])([CH3:33])[CH2:18][CH2:19][O:20][CH2:21][N:22]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27]([CH:31]=[O:32])=[CH:28]2)=[N:23]1.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([CH:31]([C:27]3[CH:26]=[CH:25][C:24]4[C:29](=[CH:30][N:22]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:34])([CH3:33])[CH3:16])[N:23]=4)[CH:28]=3)[OH:32])=[CH:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: C[Si](C)(C)CCOCn1cc2cc(C=O)ccc2n1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)CCOCn1cc2cc(C(O)c3cnc4ccc(Cl)nn34)ccc2n1
Reaction time: 0.25 h

Procedure:
To a solution of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine (465 mg, 2.0 mmol) in THF (60 mL) was added dropwise at rt a solution of ethylmagnesium bromide in Et2O (3 M, 1.0 mL). The temperature rose slightly (up to 27° C.) and the RM was stirred 15 min. Then a solution of 2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazole-5-carbaldehyde (Stage 150.4, 829 mg, 3.00 mmol) in THF (8 mL) was added dropwise and the RM was then stirred 2 h at rt. The RM was then taken into a solution of NH4Cl and extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2SO4 and the solvent was removed. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, n-hexane/EtOAc=95:5->0:100) to afford the title compound as a light brown thick oil (tR 5.35 min (conditions 3), MH+=430).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([Cl:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:19])=[O:18])=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCCC(C)C>C(Cl)Cl.C(OCC)(=O)C.COCCOC>[Cl:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:12]2[CH:13]=[C:14]([S:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)(=[O:19])=[O:18])[CH:15]=[CH:16][C:11]=2[CH3:10])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1B(O)O
Reactant: Nc1ncc(Br)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCC(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1-c1cnc(N)c(Cl)n1

Procedure:
5-Bromo-3-chloro-pyrazin-2-ylamine (0.600 g, 2.88 mmol), 2-methyl-5-(N-morpholinylsulfonyl)phenylboronic acid (0.821 g, 2.88 mmol), 1,1′BIS(Diphenylphosphino-ferrocene)dichloropalladium (II) complex with DCM (0.118 g, 0.14 mmol), 2N Na2CO3 (aq.) (5 ml) and DME (15 ml) are stirred together at 100° C. for 1 hour. Product is purified by reverse phase chromatography and evaporation of the clean fractions yields a cream solid. The solid is dissolved in DCM (100 ml) and washed with 2N NaOH (aq.) (50 ml). The organic phase is dried over magnesium sulphate, filtered and the solvent evaporated to yield an orange semi-solid. This is dissolved ethyl acetate (10 ml) and iso-hexane is added. A precipitate forms and is filtered off to yield the title compound as an off white solid. [M+H]+ 410.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]2[CH2:13][CH2:12]2)[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[CH:11]1([NH:10][C:6]2[C:7]([CH:8]=[O:9])=[C:2]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[F:16])[N:3]=[C:4]([S:14][CH3:15])[N:5]=2)[CH2:13][CH2:12]1
Reactant: OB(O)c1ccccc1F
Reactant: CSc1nc(Cl)c(C=O)c(NC2CC2)n1
Product: CSc1nc(NC2CC2)c(C=O)c(-c2ccccc2F)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-fluorophenylboronic acid to give the title compound 4-cyclopropylamino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.66 (m, 2H), 0.92 (m, 2H), 2.60 (s, 3H), 3.11 (m, 1H), 7.10-7.30 (m, 2H), 7.41-7.57 (m, 2H), 9.10 (br s, 1H), 9.66 (s, 1H). LC MS (m/e)=304 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[F:12].Cl.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][N:15]([CH3:16])[CH3:14]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN(C)Cc1cc([N+](=O)[O-])ccc1F
Temperature: 70 °C

Procedure:
To a solution of 2-bromomethyl-1-fluoro-4-nitro-benzene (131 mg, 0.56 mmol), which was generated in Example 64) and dimethylamine hydrochloride (44 mg, 0.54 mmol) in 4 mL dioxane, was added cesium carbonate (546 mg, 1.68 mmol). The mixture was heated to 70° C. under argon for 12 hours. Work up and RP prep HPLC to give (2-fluoro-5-nitro-benzyl)-dimethyl-amine.
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].[CH3:9][Si:10]([CH3:29])([CH3:28])[O:11][C:12]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](=[O:15])[CH3:14].C(Br)C#C.CCOCC>C1COCC1>[CH3:29][Si:10]([CH3:28])([CH3:9])[O:11][C:12]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:13](=[O:15])[CH2:14][CH2:3][C:1]#[CH:2]
Reactant: CC(=O)C(O[Si](C)(C)C)(c1ccccc1)C1CCCCC1
Reactant: CC(C)[N-]C(C)C
Agent: C#CCBr
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCCC(=O)C(O[Si](C)(C)C)(c1ccccc1)C1CCCCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Lithium diisopropylamide is dissolved in dry THF and the solution cooled to -78° C. A solution containing 1-(trimethylsilyloxy)-1-cyclohexyl-1-phenylpropan-2-one in dry THF is added dropwise to the stirring solution at -78° C. After the addition is complete the reaction mixture is stirred for 1 hour. Then a solution of propargyl bromide in dry THF is added dropwise to the solution at -78° C. The solution is then warmed to 0° C. and stirred for 5 hours. An ether-acetic acid solution (9:1) is slowly added and the resultant mixture warmed to room temperature. Ether is added and the solution transferred to a separatory funnel and washed with water. The ether layer is dried over sodium sulfate and evaporated to dryness to afford the product as a white crystalline solid after recrystallization.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[O:17][C:16]3=[O:25])=[CH:11][CH:10]=2)[CH2:5][C:4]1([F:27])[F:26].CSC.C(Cl)(=O)C>>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[O:17][C:16]3=[O:25])=[CH:11][CH:10]=2)[CH2:5][C:4]1([F:27])[F:26]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@H](CCC(N)=O)OC3=O)cc2)CC1(F)F
Solvent: CSC
Solvent: CC(=O)Cl
Product: NC(=O)CC[C@H]1CN(c2ccc(N3CCC(=O)C(F)(F)C3)cc2)C(=O)O1
Temperature: 40 °C
Reaction time: 96 h
Yield: 71 %

Procedure:
The mixture of (S)-{3-[4-(4,4-dimethoxy-3,3-difluoropiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol), freshly fused zinc chloride (3.1 mmol), dimethyl sulphide (5.1 mmol), acetyl chloride (3.1 mmol) in tetrahydrofuaran (50 ml) was stirred at 40° C. for 4 days. The reaction mixture was extracted with ethyl acetate water mixture and the organic layer was dried over sodium sulfate. The removal of the solvent afforded a residue, which was chromatographed over silica gel to give title compound in 71% yield.
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([O:57][C:58]([N:60]1[CH2:64][CH2:63][CH2:62][C@H:61]1[C:65](=[O:79])[NH:66][C:67]1[S:68][CH:69]=[C:70]([C:72]2[CH:77]=[CH:76][C:75]([NH2:78])=[CH:74][CH:73]=2)[N:71]=1)=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[CH2:50]([O:57][C:58]([N:60]1[CH2:64][CH2:63][CH2:62][CH:61]1[C:65](=[O:79])[NH:66][C:67]1[S:68][CH:69]=[C:70]([C:72]2[CH:73]=[CH:74][C:75]([NH:78][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]3[CH:16]4[CH:11]([NH:12][C:13](=[O:14])[NH:15]4)[CH2:10][S:9]3)=[CH:76][CH:77]=2)[N:71]=1)=[O:59])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: Nc1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCCCC1SCC2NC(=O)NC21)Nc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
70 mg (0.28 mmol) of biotin was dissolved in 5 mL of dry DMF. To this solution were added DIEA (0.34 mmol, 0.06 mL) and HATU (0.28 mmol, 0.1 g). This solution was stirred at room temperature for 2 hours. 80 mg (0.189 mmol) of Compound 5050 was then added to the reaction mixture and stirred at room temperature overnight. Reaction mixture was evaporated to dryness and redissolved in 5 mL of DMF and purified using reverse phase HPLC. MS: 649.2 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]([OH:18])=O)[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:48][C:47]=1[O:58][C:59]([F:62])([F:61])[F:60].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][N:55]([C:16](=[O:18])[CH2:15][N:8]3[C:9]4=[N:10][CH:11]=[CH:12][CH:13]=[C:14]4[C:6]([C:2]4[NH:1][CH:5]=[CH:4][N:3]=4)=[N:7]3)[CH2:54][CH2:53]2)=[CH:48][C:47]=1[O:58][C:59]([F:62])([F:60])[F:61]
Reactant: FC(F)(F)Oc1cc(N2CCNCC2)ccc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1nc(-c2ncc[nH]2)c2cccnc21)N1CCN(c2ccc(Cl)c(OC(F)(F)F)c2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
This compound was prepared by Protocol A. A vial was charged with 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (55 Mg, 0.226 Mmol), HBTU (125 mg, 0.33 Mmol), 1-(4-Chloro-3-trifluoromethoxy-phenyl)-piperazine dihydrochloride (177 mg, 0.50 Mmol), anhydrous DMF (2.0 mL), and DIPEA (0.4 mL). The vial was capped, heated to 45° C., and stirred overnight. The following day, the volatiles were removed in vacuo and separation by preparative hplc (reverse phase, acetonitrile-water gradient) gave 1-[4-(4-Chloro-3-trifluoromethoxy-phenyl)-piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone. MS (ES) [M+H]+ found: 506.4
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:19]([O-:21])=[O:20])=[CH:7][C:6]=2[NH:5][CH2:4]1.Cl.[CH3:23][N:24]([CH3:40])[CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([C:37](O)=[O:38])=[CH:31]2.CCN=C=NCCCN(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.N.Cl>CC(N(C)C)=O.CO.CCOC(C)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:19]([O-:21])=[O:20])=[CH:7][C:6]=2[N:5]([C:37]([C:32]2[NH:33][C:34]3[C:30]([CH:31]=2)=[CH:29][C:28]([O:27][CH2:26][CH2:25][N:24]([CH3:40])[CH3:23])=[CH:36][CH:35]=3)=[O:38])[CH2:4]1
Reactant: O=[N+]([O-])c1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl
Reactant: CN(C)CCOc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CN(C)CCOc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3cc([N+](=O)[O-])ccc43)cc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of amine 135 (100 mg, 0.33 mmol), 5-[2-(dimethylamino)ethoxy]indole-2-carboxylic acid hydrochloride (111 mg, 0.39 mmol), EDCI (249 mg, 1.30 mmol) and anhydrous TsOH (4.0 mg, 0.02 mmol) in dry DMA (8 mL) was stirred at room temperature under N2 for 6 h, then poured into dilute aqueous NH3. The basic mixture was stirred for 1 h, then the precipitate was collected and dissolved in EtOAc (300 mL) at room temperature. The solution was washed with water, dried, and then concentrated to 10 mL under reduced pressure below 30° C. to give crude 9. Treatment of a suspension of the free base in MeOH with HCl(g)/EtOAc, followed by crystallization from MeOH/Me2CO/EtOAc gave 9.HCl (114 mg, 60%) as a yellow solid: mp 263-264° C.; 1H NMR [(CD3)2SO] δ 11.88 (s, 1H), 10.15 (br s, 1H), 9.36 (s, 1H), 9.34 (d, J=2.2 Hz, 1H, 8.48 (d, J=9.3 Hz, 1H), 8.41 (dd, J=9.3, 2.2 Hz, 1H), 7.46 (d, J=8.9 Hz, 1H), 7.26 (s, 2H), 7.03 (dd, J=8.9, 2.3 Hz, 1H), 5.00 (t, J=10.5 Hz, 1H), 4.78-4.65 (m, 2H), 4.36 (t, J=4.9 Hz, 2H), 4.22-4.09 (m, 2H), 3.52 (t, J=4.5 Hz, 2H), 2.80 (s, 6H). Anal. (C26H24ClN5O6.HCl) C, H, N.
Reaction SMILES: CI.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([CH2:15][CH3:16])[CH:5]=1.[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:17])[S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([CH2:15][CH3:16])[CH:5]=1
Reactant: CCc1cc(Br)ccc1NS(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCc1cc(Br)ccc1N(C)S(C)(=O)=O
Reaction time: 24 h
Yield: 71.8 %

Procedure:
Methyl iodide (1.6 g, 0.0256M) was added to a mixture of N-(4-bromo-2-ethylphenyl)methanesulfonamide (4.77 g, 0.0171M) and potassium carbonate (3.5 g, 0.0256M) in dimethylformamide (50 ml) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for a further 24 hrs after which time it was partitioned between diethylether (100 ml) and water (100 ml). The aqueous was extracted further with diethyl ether (2×100 ml). The combined organics were dried over magnesium sulfate, filtered and the solvent concentrated in vacuuo to afford the title compound as a brown oil (3.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:19][OH:20])[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH2:9][CH2:10][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])([CH2:12][CH2:13]2)[O:20][CH2:19]3)=[CH:6][CH:7]=1
Reactant: COC(=O)C=C1CCC(CO)(c2ccc(Br)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)CC12CCC(c3ccc(Br)cc3)(CC1)CO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a round bottom flask containing methyl 2-(4-(4-bromophenyl)-4-(hydroxymethyl)cyclohexylidene)acetate (4.36 g, 12.85 mmol) was added 1,4-dioxane (161 ml). The clear solution was cooled in an ice-bath and sodium hydride (0.67 g, 16.75 mmol) was then added portion-wise. After the addition, the mixture was warmed to room temperature and stirred for 10 minutes. After 10 minutes of stirring, the content was heated to 100° C. in an oil bath (with a reflux condenser) for 30 minutes. The reaction mixture was cooled to room temperature and quenched with a saturated solution of ammonium chloride and subsequently concentrated to remove excess dioxane. The residue was taken in saturated ammonium chloride solution and extracted twice with EtOAc. The combined organic portion was dried over sodium sulfate and concentrated to afford a crude product. Column purification afforded the title compound as white solid (3.4 g, 78% yield). LC/MS, ESI-MS: 341.2 (M+H+), RT: 1.40 (Condition E).