Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][C:5]1[S:6][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:12]=2[N:13]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:54]([Si:57]([CH:62]([CH3:64])[CH3:63])([CH:59]([CH3:61])[CH3:60])[SH:58])([CH3:56])[CH3:55]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[F:22][C:21]([F:24])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:11]2[C:12]3[N:13]=[C:5]([CH2:4][C:3]4[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=4[S:58][Si:57]([CH:59]([CH3:61])[CH3:60])([CH:62]([CH3:64])[CH3:63])[CH:54]([CH3:55])[CH3:56])[S:6][C:7]=3[N:8]=[CH:9][N:10]=2)=[CH:16][CH:17]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3sc(Cc4ccccc4I)nc23)cc1
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)[Si](Sc1ccccc1Cc1nc2c(Nc3ccc(C(F)(F)F)cc3)ncnc2s1)(C(C)C)C(C)C
Temperature: 100 °C
Yield: 52.2 %

Procedure:
[2-(2-Iodo-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (0.26, 0.50 mmol), palladium acetate (5.7 mg, 0.03 mmol), PPh3 (0.03 g, 0.10 mmol), and Cs2CO3 (0.21 g, 0.65 mmol) were combined in a sealed tube and placed under N2 atmosphere. Toluene (5 mL) was added followed by triisopropylsilanethiol (0.11, 0.55 mmol) and the resulting suspension was heated to 100° C. for 8 h. The reaction mixture was cooled to rt and filtered through a pad of diatomaceous earth. The filtrate was concentrated and purified by FCC to provide the title compound as a colorless solid (0.15 g, 60%). MS (ESI): mass calcd. for C28H33F3N4S2Si, 574.8; m/z found, 575.2 [M+H]+. 1H NMR (CDCl3): 8.65-8.60 (m, 1H), 8.14 (s, 1H), 7.99 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.6 Hz, 2H), 7.57-7.53 (m, 1H), 7.35-7.32 (m, 1H), 7.25-7.18 (m, 2H), 4.79 (s, 2H)
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[C:14]([CH:24]=1)[C:15]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)=[O:16].O>C1COCC1>[OH:23][C:20]1([CH3:4])[CH2:19][CH2:18][N:17]([C:15]([C:14]2[CH:24]=[C:10]([CH3:9])[CH:11]=[CH:12][C:13]=2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[O:16])[CH2:22][CH2:21]1
Reactant: CCOCC
Reactant: Cc1ccc(-c2ccncc2)c(C(=O)N2CCC(=O)CC2)c1
Agent: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccncc2)c(C(=O)N2CCC(C)(O)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3 M methylmagnesium bromide-diethyl ether solution (0.84 mL) was added to a solution of 1-(5-methyl-2-(pyridin-4-yl)benzoyl)piperidin-4-one (0.37 g) in THF (10 mL) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water at 0° C., 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. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.19 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[O:11]([CH2:18][CH2:19][C:20](O)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:20](=[O:21])[CH2:19][CH2:18][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)CCOc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)CCOc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
Proline methyl ester hydrochloride (3.4 g), 3-phenoxypropionic acid (3.4 g) and triethylamine (2.8 ml) were suspended in dry methylene chloride (30 ml). To the cooled suspension, WSCD HCl (N-ethyl-N',N'-dimethylaminopropyl-carbodiimide hydrochloride) (3.9 g) was added. Under cooling, the mixture was stirred for 1 hour, and after allowing the mixture to warm to room temperature, it was again stirred for 18 horus. The stirred mixture was washed successively with water, 1N HCl, water, saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under vacuum. The resulting crude product was purified by medium-pressure liquid column chromatography on silica gel (solvent: chloroform) to obtain the end compound as an oil (3.7 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10]CC2C=CC=CC=2)[CH:7]=[CH:6][C:5]=1[OH:18])=[CH:2][CH3:3]>CO.[Pd]>[CH2:1]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:18])[CH2:2][CH3:3]
Reactant: CC=Cc1cc(OCc2ccccc2)ccc1O
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(O)ccc1O

Procedure:
6.8 grams (28.4 mmole, 1.0 eq.) of product from step B was dissolved in 60 ml of methanol. 680 mg of 10% palladium on carbon (0.64 mmole, 0.023 eq.) was added and the stirring suspension was evacuated and charged with hydrogen. After 16 hours the catalyst was filtered over celite and the filtrate evaporated. The title compound (4.3 grams) was recovered by recrystallization from dichloromethane/hexanes.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([N:15]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:21]4[C:16]3=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:12]=[CH:13][CH:14]=2)O1.Br[C:30]1[CH:31]=[C:32]([C:36]2[N:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:39]3[CH:47]=[CH:48][CH:49]=[CH:50][C:38]=3[N:37]=2)[CH:33]=[N:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[C:41]1([N:40]2[C:39]3[CH:47]=[CH:48][CH:49]=[CH:50][C:38]=3[N:37]=[C:36]2[C:32]2[CH:31]=[C:30]([C:13]3[CH:12]=[C:11]([N:15]4[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[C:22]5[C:27]4=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH:10]=[CH:9][CH:14]=3)[CH:35]=[N:34][CH:33]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Brc1cncc(-c2nc3ccccc3n2-c2ccccc2)c1
Reactant: CC1(C)OB(c2cccc(-n3c4ccccc4c4ccccc43)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(-n2c(-c3cncc(-c4cccc(-n5c6ccccc6c6ccccc65)c4)c3)nc3ccccc32)cc1
Temperature: 80 °C
Yield: 56 %

Procedure:
A mixture of compound 1C (3.0 g, 8.15 mmol), compound 1F (2.85 g, 8.15 mmol), tetrakistriphenylphosphine palladium (471 mg, 0.408 mmol), and sodium carbonate (3.09 g, 29.2 mmol) in tetrahydrofuran (THF)/water (50 mL/30 mL) was degassed for about 45 minutes. The mixture then heated to reflux (about 80° C.) overnight under argon. After cooling to RT, the reaction mixture was poured into DCM (300 mL) then washed with saturated sodium bicarbonate (200 mL), water (200 mL), and brine (200 mL). The organic phase was then collected, dried over magnesium sulfate, and loaded onto silica gel. A flash column (gradient of 25% to 40% ethyl acetate in DCM) and precipitation from ethyl acetate/methanol gave 2.34 g of HTH-1; 56% yield, pure by HNMR.
Reaction SMILES: [CH2:1]([OH:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(=O)CCCCC1.CCCCCCCCCCCC>>[CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCC=Cc1ccccc1
Solvent: CCCCCCCCCCCC
Solvent: O=C1CCCCC1
Product: O=CC=Cc1ccccc1

Procedure:
1.5 g (11.2 mmol) of cinnamyl alcohol (trans-3-phenyl-2-propen-1-ol), 36 g (367 mmol) of cyclohexanone, 0.5 g of catalyst and 1.5 g of dodecane (as GC standard) were heated under argon. After the end of the reaction time, the reaction mixture was analyzed by gas chromatography and the yield was determined. The results are summarized in Table 5 below:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH3:25])[CH:13]=3)=[CH:11][C:4]=12.[NH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1>>[CH3:24][O:23][C:18]1[N:17]=[C:16]2[C:12]([C:10]3[N:9]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)(=[O:28])=[O:27])[C:5]4=[N:6][CH:7]=[CH:8][C:3]([CH2:2][NH:36][CH2:37][CH:38]5[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]5)=[C:4]4[CH:11]=3)=[CH:13][N:14]([CH3:25])[C:15]2=[CH:20][C:19]=1[O:21][CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CCl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNCC4CCN(C(=O)OC(C)(C)C)CC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 48.7 %

Procedure:
The product is prepared by following the procedure described in example 52c, starting with 0.3 g of 3-[4-chloromethyl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridine and 0.315 g of 4-(aminomethyl)-1-N-Boc-piperidine instead of the N-Boc-ethylenediamine used in example 52c. 0.197 g of tert-butyl 4-({[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}methyl)piperidine-1-carboxylate is obtained with the following characteristics:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[C:3]=1[CH3:12].I[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]([O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])=[CH:19][CH:20]=2)=[C:3]([CH3:12])[C:4]=1[OH:11])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(N)c(C)c1O
Reactant: N#Cc1cccc(C(OC2CCCCO2)c2ccc(CI)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(NCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)c(C)c1O
Temperature: 50 °C
Yield: 63.5 %

Procedure:
To a solution of 1-(4-amino-2-hydroxy-3-methyl-phenyl)-ethanone (300 mg, 1.8 mmol) and 3-[(4-Iodomethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (865 mg, 2.0 mmol)) in anhydrous DMF (1.5 mL) under Ar gas at RT is added K2CO3 (303 mg, 2.2 mmol). The reaction mixture is heated at 50° C. overnight. The reaction mixture is quenched into water and extracted with EtOAc (3×). The organic layers are combined, washed with brine, dried over Na2SO4 and concentrated. The residue is purified by flash chromatography using 25% EtOAc/hexane as eluent. Obtained is the title compound as a yellow foam (538 mg, 64%). LC-MS (m/e): 469 (M−1).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9](OC)=[O:10])=[C:7]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:6]=[C:5]([NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:4]=1)#[N:2].C([O-])(O)=O.[Na+]>[Pd].CO.Cl>[CH:22]1([NH:21][C:5]2[N:6]=[C:7]([NH:13][C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[C:8]3[C:9](=[O:10])[NH:2][CH2:1][C:3]=3[N:4]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COC(=O)c1c(C#N)nc(NC2CCCCC2)nc1Nc1cccc(C)c1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: Cc1cccc(Nc2nc(NC3CCCCC3)nc3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
A mixture of methyl 4-cyano-2-(cyclohexylamino)-6-(m-tolylamino)pyrimidine-5-carboxylate (112.6 mg, 0.308 mmol) and palladium on carbon (26.4 mg, 0.248 mmol) in MeOH (2 mL) and HCl (1N, 2 mL) was stirred at RT for 4 h under a hydrogen atmosphere. Saturated aq NaHCO3 was added and the mixture was stirred for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was extracted with EtOAc. The organic layers were washed with aq NaHCO3, water, and brine, were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, EtOAc) to give a white solid (72.2 mg, 69%). The white solid was recrystallized from EtOH gave the title compound (35.2 mg). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.14-1.17 (m, 1H), 1.24-1.34 (m, 4H), 1.62-1.63 (m, 1H), 1.73-1.78 (m, 2H), 1.89-1.97 (m, 2H), 2.33 (s, 3H), 3.74-3.83 (m, 1H), 4.12-4.17 (m, 2H), 6.86-6.88 (m, 1H), 7.20-7.23 (m, 1H), 7.42-7.52 (m, 2H), 7.76 (s, 1H), 8.00-8.05 (m, 1H), 8.53-8.57 (m, 1H). [M+H] calc'd for C19H24N5O, 338. found, 338.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:13])[CH:4]=1)=O.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15]C([O-])=O.N1CCCCC1>N1C=CC=CC=1>[CH2:21]([O:20][C:14](/[CH:15]=[CH:1]/[C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:13])[CH:4]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1[nH]c(C=O)cc1C
Reactant: CCOC(=O)CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOC(=O)/C=C/c1cc(C)c(C(=O)OCC)[nH]1
Temperature: 100 °C
Reaction time: 38 h
Yield: 47.7 %

Procedure:
Ethyl 5-formyl-3-methyl-1H-pyrrole-2-carboxyate 470 mg, monoethyl malonate 378 mg, piperidine 0.05 mL and pyridine 6 mL were mixed and stirred at 100° C. for 38 hours. Ice water was added to the reaction liquid and the precipitate was recovered by filtration. The precipitate was washed with water and dried in flowing air under heating to provide 311 mg of the title compound.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:19]([O:51][C:52]1[CH:57]=[C:56]([O:58][CH3:59])[C:55]([C:60]([N:62]2[CH2:66][C:65](=[CH2:67])[CH2:64][C@H:63]2[CH2:68][O:69][Si](C(C)(C)C)(C)C)=[O:61])=[CH:54][C:53]=1[N+:77]([O-:79])=[O:78])[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([C:31]([N:33]2[CH2:37][C:36](=[CH2:38])[CH2:35][CH:34]2[CH2:39][O:40][Si](C(C)(C)C)(C)C)=[O:32])=[CH:25][C:24]=1[N+:48]([O-:50])=[O:49].[NH4+].[Cl-]>C1COCC1>[CH2:21]([O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([C:31]([N:33]2[CH2:37][C:36](=[CH2:38])[CH2:35][C@H:34]2[CH2:39][OH:40])=[O:32])=[CH:25][C:24]=1[N+:48]([O-:50])=[O:49])[CH2:20][CH2:19][O:51][C:52]1[CH:57]=[C:56]([O:58][CH3:59])[C:55]([C:60]([N:62]2[CH2:66][C:65](=[CH2:67])[CH2:64][CH:63]2[CH2:68][OH:69])=[O:61])=[CH:54][C:53]=1[N+:77]([O-:79])=[O:78]
Reactant: C=C1CC(CO[Si](C)(C)C(C)(C)C)N(C(=O)c2cc([N+](=O)[O-])c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4CO[Si](C)(C)C(C)(C)C)cc3[N+](=O)[O-])cc2OC)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C=C1CC(CO)N(C(=O)c2cc([N+](=O)[O-])c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4CO)cc3[N+](=O)[O-])cc2OC)C1
Yield: 93.9 %

Procedure:
A solution of TBAF (3.98 mL of a 1M solution in THF, 3.98 mmol) was added to the bis-silyl ether 75 (1.41 g, 1.59 mmol) in THF (35 mL) at 0° C. (ice/acetone). The reaction mixture was allowed to warm to room temperature and after a further 30 minutes saturated NH4Cl (120 mL) was added. The aqueous solution was extracted with EtOAc (3×80 mL), washed with brine (80 mL), dried (MgSO4), filtered and evaporated in vacuo to give a dark orange oil which was purified by flash chromatography (97% CHCl3/MeOH) to provide the pure diol 76 as a light orange solid (0.98 g, 94%): [α]19D=−31.9° (c=0.09, CHCl3); 1H NMR (270 MHz, CDCl3) (Rotamers) δ7.75 and 7.71 (s×2, 2Harom), 6.96 and 6.84 (s×2, 2Harom), 5.08, 5.02 and 4.88 (br s×3, 4H, NCH2C═CH2), 4.61-4.50 (m, 2H, NCHCH2OH), 4.35-4.33 (m, 4H, OCH2CH2CH2O), 4.02-3.65 (m, 14H, NCHCH2OH, NCH2C═CH2 and OCH,), 2.88-2.43 (m, 6H, NCH2C═CH2CH2 and OCH2CH2CH2O); 13C NMR (67.8 MHz, CDCl3) (Rotamers) δ167.9 and 166.9 (NC═O), 154.9 and 154.3 (Cquat), 148.4 and 148.2 (Cquat), 143.3 and 142.6 (Cquat), 137.2 and 137.0 (Cquat), 127.6 and 127.3 (Cquat), 109.1 (C—Harom), 108.4 (NCH2C═CH2), 108.2 (C—Harom), 65.6 and 65.4 (OCH2CH2CH2O), 64.5 and 63.3 (NCHCH2OH), 60.5 and 60.0 (NCHCH2OH), 56.8 and 56.7 (OCH3), 52.9 (NCH2C═CH2), 35.0 and 34.3 (NCH2C═CH2CH2), 29.6 and 28.6 (OCH2CH2CH2O); MS (FAB) (Relative Intensity) 657 (M+. +1, 10), 639 (M—OH, 2), 612 (1), 544 (M—NCH2CCH2CH2CHCH2OH, 4), 539 (1), 449 (16), 433(9), 404 (8), 236 (32), 166 (65), 151 (81), 112 (82), 82 (100); IR (NUJOL®) 3600-3200 (br, OH), 2923, 2853, 2360, 1618, 1582, 1522 (NO2), 1459, 1408, 1375, 1335 (NO2), 1278, 1218, 1061, 908, 810, 757 cm−1.
Reaction SMILES: C[O-].[Na+].Br[C:5]1[CH:14]=[C:13]2[C:8]([C:9]([S:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[CH:10][CH:11]=[N:12]2)=[N:7][CH:6]=1>CN(C=O)C.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>[N:12]1[C:13]2[C:8](=[N:7][CH:6]=[CH:5][CH:14]=2)[C:9]([S:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(Sc2ccnc3cc(Br)cnc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccnc3cccnc23)cc1

Procedure:
To a mixture of tetrakis(triphenylphosphine)palladium (188 mg, 163 μmol) and sodium methoxide (176 mg, 3251 μmol) was added a solution of 4-(7-bromo-1,5-naphthyridin-4-ylthio)benzenamine (540 mg, 1625 μmol) in DMF (2 mL). The resealable tube was purged with argon, and the mixture was heated to 100° for 1.5 h. The mix was diluted with ethyl acetate, washed with brine twice, dried with sodium sulfate, and concentrated. The residue was purified by silica gel chromatography using 1-10% MeOH:CH2Cl2 w/1% NH4OH to provide 4-(1,5-naphthyridin-4-ylthio)benzenamine. MS m/z=254 [M]+. Calc'd for C14H11N3S: 253.32.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>O1CCCC1>[CH3:17][N:18]([CH3:22])[C:19](=[O:20])[O:14][CH:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: CN(C)C(=O)Cl
Reactant: OC1CCN(c2ccc(Br)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)OC1CCN(c2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(4-Bromophenyl)piperidin-4-ol (200 mg) is dissolved under argon in tetrahydrofurane (4 mL), cooled to 0° C. and treated with NaH (60% in mineral oil, 36 mg). The mixture is stirred for 30 minutes, treated with dropwise with dimethylcarbamoylchloride (110 μL) and stirred for 4 hours at room temperature. Then the mixture is partitioned between water and ethylacetate. The organic phase is washed with water and brine and is dried (MgSO4). The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→50:50) to give the title compound. LC (method 3): tR=1.05 min; Mass spectrum (ESI+): m/z=327 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:20]=[C:19]([OH:21])[CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:23]I>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:20]([CH3:23])[C:19](=[O:21])[CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cccc(O)n1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cccc(=O)n1C

Procedure:
The title compound, yellow cristalline solid, MS: m/e=325.2, 327.1 (M+H+), was prepared in accordance with the general method of example 2 from 6-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-pyridin-2-ol and methyl iodide, along with the O-alkylation product from which it was separated by flash chromatography (gradient: EtOAc to EtOAc/MeOH 95:5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:17]1[N:18]([CH3:34])[C:19](=[O:33])[CH:20]=[CH:21][C:22]=1[NH:23][S:24]([C:27]1([CH2:30][CH:31]=[O:32])[CH2:29][CH2:28]1)(=[O:26])=[O:25])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:17]1[N:18]([CH3:34])[C:19](=[O:33])[CH:20]=[CH:21][C:22]=1[NH:23][S:24]([C:27]1([CH2:30][CH2:31][OH:32])[CH2:29][CH2:28]1)(=[O:26])=[O:25])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: Cn1c(N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)c(NS(=O)(=O)C2(CC=O)CC2)ccc1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1c(N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)c(NS(=O)(=O)C2(CCO)CC2)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of the crude tert-butyl (2-fluoro-4-iodophenyl)[1-methyl-6-oxo-3-({[1-(2-oxoethyl)cyclopropyl]sulfonyl}amino)-1,6-dihydropyridin-2-yl]carbamate (88% UV, 97 mg, 0.160 mmol) in MeOH at 0° C. under a nitrogen atmosphere was added NaBH4 (4 eq, 25 mg, 0.641 mmol). The reaction mixture was stirred at this temperature for 1 hour and then allowed to warm up to room temperature. The solvent was removed under reduced pressure, the residue partitioned between EtOAc (10 ml), H2O (5 ml) and 1N aq HCl (5 ml). The aqueous phase was separated and extracted twice with EtOAc (10 ml). The combined organic layers were washed with brine (20 ml), dried (silicone filter) and concentrated under reduced pressure. The crude material was purified by flash chromatography (Biotage system) to afford the title compound (77 mg, 79%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[CH2:40]([NH:44][CH3:45])[CH2:41][CH2:42][CH3:43]>>[CH2:40]([N:44]([CH3:45])[CH2:1][CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCNC
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Product: CCCCN(C)CCc1ccc(CCCNc2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 17.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and butylmethylamine (22 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (3.2 mg) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[N:9]=1.[NH2:20][C:21]1[C:29]2[C:24](=[CH:25][C:26]([NH2:30])=[CH:27][CH:28]=2)[NH:23][N:22]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:20][C:21]1[C:29]2[C:24](=[CH:25][C:26]([NH:30][C:17]([C:15]3[CH:14]=[CH:13][C:11]4[NH:12][C:8]([NH:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[N:9][C:10]=4[CH:16]=3)=[O:19])=[CH:27][CH:28]=2)[NH:23][N:22]=1
Reactant: O=C(O)c1ccc2[nH]c(Nc3ccccn3)nc2c1
Reactant: Nc1ccc2c(N)n[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1n[nH]c2cc(NC(=O)c3ccc4[nH]c(Nc5ccccn5)nc4c3)ccc12

Procedure:
The carboxylic acid (0.5 mmol) from above was coupled with aforementioned 3,6-diaminoindazole (0.5 mmol) using HBTU as described in general procedure D to afford 2-(pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (3-amino-1H-indazol-6-yl)-amide. MS: m/z 385 (M+H)+.