Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][C:21]1[C:22]([C:27]([OH:31])([C:29]#[CH:30])[CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=1>>[F:19][C:3]1[C:2]([C:30]#[C:29][C:27]([OH:31])([C:22]2[C:21]([CH3:20])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH3:28])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)c1ncccc1C
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: Cc1cccnc1C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Yield: 7 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(3-methylpyridin-2-yl)but-3-yn-2-ol to give the titled compound as a yellow solid (15.0 mg, 7%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][NH:18][CH3:19]>>[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][N:18]([CH3:19])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: CNCCN(C)C
Reactant: N#Cc1ccc(Cl)c(C(F)(F)F)c1
Product: CN(C)CCN(C)c1ccc(C#N)cc1C(F)(F)F

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 4-chloro-3-(trifluoromethyl)-benzonitrile (Lancaster Synthesis GmbH) and N,N,N′-trimethyl-1,2-ethanediamine (Fluka, Buchs, Switzerland).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C:16]1[C:25]([CH3:26])=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[CH3:27].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:15][C:16]2[C:17]([CH3:27])=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][C:25]=2[CH3:26])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Reactant: O=C(O)c1cc(Cl)nc2ccccc12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(Cl)nc3ccccc23)c(C)c1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 960.3 %

Procedure:
To a solution of 2-chloroquinoline-4-carboxylic acid (5.00 g, 0.0024 mol) in CH2Cl2 (50 mL) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (3.88 g, 0.02167 mol, see preparation 12) and N,N-diisopropylethylamine (12.5 ml, 0.07225 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 31.0 ml, 0.048 mol) is added via syringe and heated at 40° C. After 5 hours, the reaction mixture is diluted with water and extracted with dichloromethane. The organic layers are combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using a gradient of 0-40% ethyl acetate in hexanes. After purification the solid is triturated with 20% diethyl ether in pentane and dried to give the title compound as a white solid (8.50 g, 96%). Mass spectrum (m/z): 369.1 (M+1).
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[CH3:5][P:6]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:24]=[C:23](I)[N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH:26]=[CH2:27])=[CH:11][CH:10]=1)([CH3:8])=[O:7].[I-].C([Zn+])(C)C.C1COCC1>CN(C=O)C.[Zn].C1COCC1.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>[CH3:5][P:6]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:24]=[C:23]([CH:1]([CH3:3])[CH3:2])[N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH:26]=[CH2:27])=[CH:11][CH:10]=1)([CH3:8])=[O:7]
Reactant: CC(C)I
Reactant: C=Cn1cnc2c(Nc3ccc(P(C)(C)=O)cc3)nc(I)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[Zn+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=Cn1cnc2c(Nc3ccc(P(C)(C)=O)cc3)nc(C(C)C)nc21
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
In a dry Argon atmosphere Reike Zinc/THF suspension (5 g/100 mL) (2.54 mL, 2.0 mmol) was transferred into a round-bottom flask via syringe with a 12 gauge needle. Then isopropyl iodide (0.18 mL, 1.82 mmol) was added and stirring was started right away. The content turned warm and stirring was continued at rt for 4-5 hours. In a 10 mL CEM microwave tube was dissolved N-(4-(dimethylphosphoryl)phenyl)-2-iodo-9-vinyl-9H-purin-6-amine (0.20 g, 0.46 mmol), PdCl2(PPh3)2 (19 mg, 0.027 mmol) in 1 mL dry DMF. Isopropylzinc iodide/THF solution was transferred to the microwave tube via syringe. The reaction was heated on microwave (60° C./5 min). The reaction mixture was filtered through celite, washed with EtOAc, the filtrate was concentrated, purified on ISCO combiFlash Column (SiO2, 12 g).
Reaction SMILES: CC1(C)C(=O)C=C([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)CC1.[CH3:21][C:22]1([CH3:30])[CH2:27][C:26](=O)[CH2:25][C:24](=[O:29])[CH2:23]1>>[CH3:30][C:22]1([CH3:21])[CH2:23][C:24](=[O:29])[CH:25]=[C:26]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH2:27]1
Reactant: CC1(C)CCC(Nc2cccc(C(F)(F)F)c2)=CC1=O
Reactant: CC1(C)CC(=O)CC(=O)C1
Product: CC1(C)CC(=O)C=C(Nc2cccc(C(F)(F)F)c2)C1

Procedure:
The title compound is prepared in analogy to 6,6-dimethyl-3-(3-(trifluoromethyl)phenyl-amino)cyclohex-2-enone (intermediate 6), using 5,5-dimethylcyclohexane-1,3-dione (1.13 g, 8.04 mmol) as starting material. Yield: 1.73 g, ESI mass spectrum [M+H]+=284, Retention time HPLC: 1.18 min (Z005—001).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][C:16]([CH2:18][O:19]CC)=[N:15][CH:14]=2)=[CH:9][CH:8]=1>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:17][C:16]([CH2:18][OH:19])=[N:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: CCOCc1ncc(-c2ccc(Cl)cc2)o1
Agent: O=S(=O)(O)O
Solvent: O
Product: OCc1ncc(-c2ccc(Cl)cc2)o1
Temperature: 140 °C
Yield: 64.7 %

Procedure:
7.5 ml of concentrated sulphuric acid were added carefully to a suspension, cooled in ice, of 1.4 g (5.9 mmol) of 5-(4-chlorophenyl)-2-ethoxymethyl-oxazole in 4.5 ml of water. The resulting solution was stirred and heated at 140° C. under reflux for 4 hours, then cooled and poured on to 140 ml of ice/water. The mixture was extracted three times with 30 ml of dichloromethane each time. The combined dichloromethane extracts were washed with 50 ml of saturated sodium hydrogen carbonate solution, dried over sodium sulphate, filtered and evaporated. Recrystallization of the product from toluene yielded 0.80 g (65%) of 5-(4-chlorophenyl)-2-oxazolemethanol of melting point 100°-103.5° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C([O-])(=O)C([O-])=O.[K].[NH:24]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[C@H:25]([C:35](ON1C(=O)CCC1=O)=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CCOCC.CN(C=O)C>[NH:24]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[C@H:25]([C:35]([NH:1][C@H:2]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:7])([CH3:8])[CH3:6])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32]
Reactant: C[C@@H](OC(C)(C)C)[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])C(=O)[O-]
Agent: [K]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
After suspending 3.3 g (11.0 mmol) of H-Thr(tBu)-OtBu.oxalate in 60 ml of ether, the suspension is shaken with 30 ml of 5% aqueous potassium hydrogenocarbonate solution until dissolving. The organic phase is separated, washed with an additional 20 ml of 5% aqueous potassium hydrogenocarbonate solution and then with 20 ml of water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. To the solution of the oily residue in 20 ml of DMF, 4.12 g (9.5 mmol) of Z-Glu(OtBu)-OSu are added. The mixture is stirred at room temperature for 2 hours then evaporated under reduced pressure. The residue is dissolved in 50 ml of ethyl acetate and successively washed three times, three times with 15 ml of 10% aqueous citric acid solution each, twice with 15 ml of 5% aqueous sodium hydrogenocarbonate solution each, and finally with 15 ml of water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. 4.4 g (8.0 mmol) of oily Z-Glu(OtBu)-Thr(tBu)-OtBu protected dipeptide (Rf1 =0.85) are obtained which is dissolved in 50 ml of methanol and hydrogenated as described in Example 1. After filtering off the catalyst, the filtrate is evaporated to yield the free H-Glu(Ot -Bu)-Thr(tBu) -OtBu dipeptide (Rf2 =0.22) which is then dissolved in 20 ml of DMF and after adding 4.77 g (10 mmol) of Z-Lys(Boc) -OSu, the reaction mixture is stirred at room temperature for 2 hours and evaporated under reduced pressure. After dissolving the oily residue in 50 ml of ethyl acetate, the solution is purified by several washings in the usual manner, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The oily evaporation residue is recrystallized in ether to yield 4.75 g (74%) of Z-Lys(Boc)-Glu(OtBu)-Thr(tBu)-OtBu protected tripeptide, m.p.: 114°-115° C.; Rf2 =0.80; /α/D20 = -22.8° (c=1, methanol).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:23]([OH:25])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[F:35][C:36]([F:41])([F:40])[CH2:37][CH2:38]O.C(C=P(CCCC)(CCCC)CCCC)#N.O>C1(C)C=CC=CC=1>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:23]([O:25][CH2:38][CH2:37][C:36]([F:41])([F:40])[F:35])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(O)c2)ncn1)C1CC1
Reactant: OCCC(F)(F)F
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(OCCC(F)(F)F)c2)ncn1)C1CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(6-((6-(2-fluoro-5-methoxyphenyl)-5-hydroxypyridin-3-yl)methoxy)pyrimidin-4-yl)propanoate (57 mg) in toluene (1.2 mL) were added 3,3,3-trifluoro-1-propanol (21 μL) and cyanomethylenetributylphosphorane (64 uL), and the mixture was stirred at 100° C. for 4 hr. After allowing to cool to room temperature, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (53 mg) as a pale-yellow amorphous solid.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([CH2:16][S:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)([O:13][CH2:14][CH3:15])=[O:12].CN1C[CH2:32][CH2:31]N(C)C1=O.BrCCCl>O1CCCC1>[C:11]([C:16]1([S:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:32][CH2:31]1)([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CN1CCCN(C)C1=O
Reactant: CCOC(=O)CSCc1ccc(OC)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: ClCCBr
Solvent: C1CCOC1
Product: CCOC(=O)C1(SCc2ccc(OC)cc2)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 21 %

Procedure:
Cool lithium hexamethyldisilazane (6 mL of a 1.0M solution in tetrahydrofuran, 6.0 mmol) to -78° C. Add, by cannula transfer, a solution of 1-(carboethoxy)-1-(4-methoxybenzylthio)methane (1.36 g, 5.66 mmol) in tetrahydrofuran (10 mL). Stir for 45 minutes, add 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (0.73 mL, 6.0 mmol) followed by 1-bromo-2-chloroethane (050 mL, 6.0 mmol) and stir to room temperature overnight. Cool to -78° C., add lithium hexamethyldisilazane (6.0 mL, 6.0 mmol) and stir at room temperature for 24 hours. Quench with saturated ammonium chloride (5 mL) and partition between ethyl acetate (30 mL) and water (30 mL). Separate the organic phase, dry (Na2SO4) and evaporate the solvent in vacuo. Purify by chromatography (5:1 hexane/ethyl acetate to 2.5:1 hexane/ethyl acetate) to give 1-(carboethoxy)-1-(4-methoxybenzylthio)cyclopropane (317 mg, 21%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:10])[CH3:9])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C=O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:10])[CH3:9])[CH2:3][CH2:2]2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: CC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of N-(piperidin-4-yl)acetamide (341 mg, 2.4 mmol) in DMF (15 mL) was added K2CO3 (331 mg, 2.4 mmol) and 1-fluoro-4-nitrobenzene (282 mg, 2 mmol) at room temperature. The reaction was stirred at 80° C. for 24 hours. After that, the reaction was poured into 50 mL of water and extracted with EA (3×25 mL), washed with H2O (25 mL) and brine (25 mL), dried over Na2SO4 and concentrated to give yellow solid. MS (m/z): 264 (M+H)+
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:33](O)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[N:6]([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:5]=1)(=[O:3])[CH3:2]
Reactant: OCCc1ccccc1
Reactant: CC(=O)c1c[nH]c2ccc(Cl)cc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1cn(CCc2ccccc2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a mixture of 0.58 g (3 mmol) of 3-acetyl-5-chloroindole, 1.42 g (5.4 mmol) of triphenylphosphine and 0.66 g (5.4 mmol) of phenethyl alcohol in THF (12 ml) was added under ice-cooling, 1.09 g (5.4 mmol) of diisopropyl azodicarboxylate. After stirring for 3 hours at room temperature, the mixture was concentrated under reduced pressure. The obtained residue was chromatographed on silica gel (¼ ethyl acetate/toluene as eluant) to give 0.58 g of the titled compound as an oil. Yield: 65%.
Reaction SMILES: C(O)(C(F)(F)F)=O.COC1C=CC(C[N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)=[C:18]3[CH:17]=[N:16]2)=CC=1.[Li+].[OH-].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl.O.CCOCC>[NH:15]1[C:19]2=[N:20][CH:21]=[CH:22][C:23]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)=[C:18]2[CH:17]=[N:16]1
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)ccnc32)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
TFA (6 mL) was added to tert-butyl 4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (1.59 g, 3.754 mmol) in DCM (30 mL) and stirred at room temperature for 1 hour. The reaction was then concentrated to dryness and dried under vacuum for 3 hours. TFA (8.68 mL, 112.6 mmol) was added, and the mixture was heated at 65° C. for 2 hours. The reaction was then concentrated to dryness. The resulting residue was added to THF (10 mL), a LiOH solution (3.8 mL, 7.5 mmol, 2N) and Boc2O (0.98 g, 4.50 mmol) and stirred at room temperature for 1 hour. Ether (20 mL) and water (10 mL) were then added. The organic layer was separated, washed with brine, and dried over sodium sulfate. After removal of solvent, the resulting residue was purified by chromatography (hexane:ethyl acetate, 3:1) to give tert-butyl 4-(1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.55 g, 48%) as a solid. MS APCI (+) m/z 304.1 detected. 1H NMR (400 Hz, DMSO-d6) δ 8.21 (s, 1H), 8.08 (d, J=5.6 Hz, 1H), 6.37 (d, J=5.6 Hz, 1H), 3.60 (m, 4H), 3.54 (m, 4H), 2.50 (s, 9H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:35])[CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:29][SH:30]>>[CH3:25][O:26][C:27](=[O:35])[CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:29][S:30][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1
Reactant: COC(=O)C(CS)NC(C)=O
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: COC(=O)C(CSc1cnc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)s1)NC(C)=O
Yield: 30.9 %

Procedure:
2-Acetylamino-3-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl)-propionic acid methyl ester (156 mg, 35%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2-acetylamino-3-mercapto-propionic acid methyl ester (354 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:18]=1[CH2:19]Br>>[F:16][C:17]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:18]=1[CH2:19][N:9]([C:10]1[CH:15]=[N:14][CH:13]=[N:12][CH:11]=1)[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: Fc1cc(F)c(CBr)cc1F
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(Cc2cc(F)c(F)cc2F)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 2,4,5-trifluorobenzyl bromide
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH3:21].[OH-].[K+].O.CO>C1COCC1>[Br:10][C:8]1[CH:7]=[CH:6][C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[CH3:21])=[C:4]([CH:9]=1)[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1cc(Br)ccc1CCc1cccc(OC)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(CCc2ccc(Br)cc2C(=O)O)c1C
Yield: 98 %

Procedure:
The crude 5-bromo-2-[2-(3-methoxy-2-methylphenyl)-ethyl]-benzoic acid methyl ester 6 was stirred with 50% KOH solution (5 mL), water (30 mL), methanol (12 mL), and THF (30 mL), heated at reflux temperature for three hours and concentrated in vacuo to remove the organic solvents. The resultant aqueous suspension was acidified using 1.0 N HCl solution and filtered. The filtercake was dried over night to give the benzoic acid 7 as a white solid, 4.74 g; 98% yield.
Reaction SMILES: [CH2:1]([N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[SH:17][CH2:18][CH2:19][NH2:20].C(N(CC)CC)C>C(#N)C>[NH2:20][CH2:19][CH2:18][S:17][CH:13]1[CH2:12][C:11](=[O:16])[N:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:14]1=[O:15]
Reactant: CCCCCCCCCN1C(=O)C=CC1=O
Reactant: NCCS
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCN1C(=O)CC(SCCN)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-nonyl maleimide (0.01 M) prepared as described in Example 12 above, mercapto ethylamine (0.01 M) and triethylamine (0.001 M) in acetonitrile (50 ml) was stirred for 24 hours at room temperature. Acetonitrile was evaporated in vacuo and the residue obtained was triturated with ethyl acetate (25 ml). The resultant suspension was filtered and the solid washed with ethyl acetate. The solid was then dried and characterised as the desired product, N-nonyl,3-mercapto ethylamino maleimide.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:15]=[N:16][N:17]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)[CH:18]=3)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.[F-].[Cs+].O1CCOCC1>CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[O:32]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]([C:8]3[N:13]=[CH:12][C:11]([C:14]4[CH:15]=[N:16][N:17]([CH:19]5[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]5)[CH:18]=4)=[CH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)[CH:34]=[N:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(N)c4)nc3)cn2)CC1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(-c5cnoc5)c4)nc3)cn2)CC1
Temperature: 120 °C
Yield: 61.7 %

Procedure:
Tert-butyl 4-4-[2-(3-iodophenyl)pyrimidin-5-yl]-1H-pyrazol-1-ylpiperidine-1-carboxylate (intermediate 5, 150 mg; 0.24 mmol; 1.0 eq.), 4-Isoxazoleboronic acid pinacol ester (47 mg; 0.24 mmol; 1.0 eq.), bis(triphenylphosphine)palladium(II)chloride (17 mg; 0.02 mmol; 0.10 eq.) and cesium fluoride (109 mg; 0.72 mmol; 3.0 eq.) were flushed with nitrogen before the addition of dioxane: water (2.25:1.1 mL). The reaction mixture was heated in MW at 120° C. for 30 min. It was then diluted with EtOAc and water. Aqueous phase was extracted with EtOAc and combined organic phases were dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (cyclohexane:EtOAc, gradient from 80:20 to 30:70) afforded the title compound as a white beige solid (70 mg; 62%). 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.27 (s, 1H), 9.17 (s, 2H), 8.64 (t, J=1.5 Hz, 1H), 8.56 (s, 1H), 8.35 (dt, J=8.0 Hz, 1.5 Hz, 1H), 8.16 (s, 1H), 7.87-7.83 (m, 1H), 7.61 (t, J=8.0 Hz, 1H), 4.47-4.35 (m, 1H), 4.09-4.04 (m, 2H), 2.95 (m, 2H), 2.09-2.06 (m, 2H), 1.87-1.72 (m, 2H), 1.43 (s, 9H). HPLC (Condition A): Rt 4.70 min (purity 97.4%). MS (ESI+): 473.5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1)=[O:10].[O:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:21][N:20]=[CH:19]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:29]([C:26]2[CH:27]=[CH:28][C:23]([C:22]3[O:18][CH:19]=[N:20][CH:21]=3)=[CH:24][CH:25]=2)(=[O:30])=[O:31])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])[CH:4]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ccc2N)ccn1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Product: Cc1cc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(-c3cnco3)cc2)ccn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 123 mg of (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 122 mg of 4-oxazol-5-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 2.78 (s, 3H), 7.29 (d, 1H, J=2.8 Hz), 7.45 (m, 2H), 7.48 (s, 1H), 7.55 (dd, 1H, J=9.2 Hz, 2.8 Hz)), 7.67 (m, 3H), 7.83 (d, 2H, J=8.4 Hz), 8.03 (s, 1H), 8.81 (d, 1H, J=5.6 Hz), 10.10 (s, 1H). MS: m/z 454.9 (M++1).