Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH3:16])[CH:9]=[C:8]2[C:17]1[N:26](S(C2C=CC(C)=CC=2)(=O)=O)[C:20]2=[N:21][CH:22]=[CH:23][C:24]([CH3:25])=[C:19]2[CH:18]=1>CO.C(OCC)(=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH3:16])[CH:9]=[C:8]2[C:17]1[NH:26][C:20]2=[N:21][CH:22]=[CH:23][C:24]([CH3:25])=[C:19]2[CH:18]=1
Reactant: COc1cc2c(-c3cc4c(C)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2c(-c3cc4c(C)ccnc4[nH]3)cn(C)c2cc1OC

Procedure:
1.3 cm3 of aqueous 5N potassium hydroxide solution are added to a solution of 0.13 g of 2-[5,6-dimethoxy-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-4-methyl-1H-pyrrolo[2,3-b]pyridine in 15 cm3 of methanol, at a temperature in the region of 20° C. The reaction medium is refluxed for about 18 hours. The reaction mixture is evaporated under reduced pressure and the residue thus obtained is dissolved in 100 cm3 of ethyl acetate, transferred into a separating funnel and washed with 50 cm3 of distilled water. The aqueous phase is re-extracted with twice 50 cm3 of ethyl acetate, and the combined organic phases are washed successively with 50 cm3 of saturated aqueous sodium chloride solution and 50 cm3 of distilled water. The organic extract is dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the crude compound, which is purified by chromatography on a Flash Chromabond RS 6 SiOH cartridge (3 g of silica). The elution was performed at a flow rate of 10 cm3/min with a heptane/isopropanol mixture (70/30 by volume). The fractions containing the expected compound are combined and evaporated to give 2-[5,6-dimethoxy-1-methyl-1H-indol-3-yl]-4-methyl-1H-pyrrolo[2,3-b]pyridine in the form of a pasty yellow solid (0.008 g, 8%), the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18](C3C=CC=CN=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:26]1[CH:31]=[CH:30][C:29](C(N2CCN(C(OC(C)(C)C)=O)CC2)C)=[CH:28][CH:27]=1.C(O)(C(F)(F)F)=O.BrC1C(Cl)=C([N+]([O-])=O)C(N)=NC=1>CC(O)C.CCN(C(C)C)C(C)C.C(Cl)Cl>[Br:1][C:2]1[C:3]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]([C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)[CH3:19])[CH2:16][CH2:17]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CC(c1ccncc1)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(c1ccccn1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccncc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1

Procedure:
This was prepared using the same procedure as for 5-bromo-3-nitro-4-(4-(1-(pyridin-2-yl)ethyl)piperazin-1-yl)pyridin-2-amine, but here using tert-butyl 4-(1-(pyridin-4-yl)ethyl)piperazine-1-carboxylate (1.1 eq, 1.12 mmol, 327 mg), TFA (5 mL) and CH2Cl2 (5 mL), then 5-bromo-4-chloro-3-nitropyridin-2-amine (257 mg, 1.02 mmol) in iPrOH (5 mL) and DIPEA (2 mL). Filtration and washing as previously described gave the product (265 mg, 58% for two steps) as a yellow solid; 1H-NMR (500 MHz, DMSO-d6) 1.29 (d, J=6.8 Hz, CH3), 2.46-2.56 (2 m, 4H, piperazine N(CH2)2), 3.05 (s, br, 4H, piperazine N(CH2)2), 3.53 (q, J=6.7 Hz, 1H, CH), 6.96 (s, br, 2H, NH2), 7.34 (dd, J=4.5, 1.5 Hz, 2H, pyridine H-3 & H-5), 8.14 (s, 1H, bromopyridine H-6), 8.52 (dd, J=4.4, 1.5 Hz, 2H, pyridine H-2 & H-6);
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5](=S)[C:4]=2[CH:3]=1.[CH2:17]([O:19][CH2:20][CH2:21][C@H:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1)[CH3:18]>>[CH2:17]([O:19][CH2:20][CH2:21][C@@H:22]1[NH:23][CH2:24][CH2:25][N:26]([C:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[S:11][C:10]=3[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=2)[CH2:27]1)[CH3:18]
Reactant: Cc1cc2c(s1)Nc1ccccc1NC2=S
Reactant: CCOCC[C@H]1CNCCN1
Product: CCOCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1

Procedure:
In a manner similar to that described in Example 311, combine 2-methyl-4,9-dihydro-3-thia-4,9-diazabenzo[f]azulene-10-thione (0.487 g, 1.98 mmol) and (S)-2-(2-ethoxyethyl)piperazine (0.313 g, 1.98 mmol) to obtain the title compound: mass spectrum (APCI): m/z=371.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.FC(F)(F)S(O)(=O)=O.[NH2:24][CH2:25][CH2:26][NH:27][C:28]1[N:33]=[C:32]([S:34][CH3:35])[N:31]=[C:30]([NH2:36])[CH:29]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C=O.C(OCC)(=O)C>[NH2:36][C:30]1[N:31]=[C:32]([S:34][CH3:35])[N:33]=[C:28]([NH:27][CH2:26][CH2:25][NH:24][C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH:29]=1
Reactant: CSc1nc(N)cc(NCCN)n1
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nc(N)cc(NCCNC(=O)/C=C/C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 1.8 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (21 mg, 0.15 mmol) was dissolved in DCM (1 ml containing one drop of DMF), oxalyl chloride was added (13 μl, 0.15 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N6-(2-Aminoethyl)-2-methylsulfanyl-pyrimidine-4,6-diamine trifluoromethanesulfonate (20 mg, 0.057 mmol) and diisopropylethylamine (51 μl, 0.3 mmol) dissolved in dimethylformamide (1 ml) and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate, washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate, the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 3.3 mg of a white solid (0.001 mmol, 18%).
Reaction SMILES: [C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:26][NH:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][N:20]=[CH:19]2)[C:11]([O:13]C)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(O)(=O)C>>[C:1]([O:9][C@H:10]1[C:11](=[O:13])[N:27]([CH2:28][C:29]([F:31])([F:32])[F:30])[CH2:26][C:17]2[C:18]3[CH:19]=[N:20][NH:21][C:22]=3[C:23]([Cl:25])=[CH:24][C:16]=2[CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CNCC(F)(F)F)OC(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(O[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)c1ccccc1
Yield: 74 %

Procedure:
(R)-3-(7-chloro-4-((2,2,2-trifluoroethylamino)methyl)-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-yl benzoate (7.75 g, 16.5 mmol) in toluene (70.00 ml, 657 mmol) was added acetic acid (1.2 ml, 20.96 mmol) and refluxed for 12 h. The solvent was evaporated and the crude product was dissolved in EtOAc, washed with aqueous NaHCO3. The solvent was removed and the crude product was purified by flash chromatography using 50% EtOAc in hexane to give (R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl benzoate in 74% yield. MS (ESI) 438 (M+H); Rf=2.60.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1)#[N:22].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:30]=[CH:31][C:32]([CH2:33][N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[N+:18]([O-:20])=[O:19])[C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:35][CH:36]=1)#[N:22]
Reactant: CCCCC(=O)Nc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 4-valerylamino-3-nitrobenzoate (2.1 g), 4-(2-cyanophenyl)benzyl bromide (2.0 g) and K2CO3 (1.1 g) in DMF (20 ml) was stirred for 4 hours at room temperature. To the reaction mixture was added water, the mixture was extracted with ethyl acetate, and the organic layer was washed with water. The resultant solution was dried and concentrated to give a syrup, which was purified by column chromatography on silica gel to afford a yellow syrup (3.5 g, quantitatively).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][C:22]3[N:21]4[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:15][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].[CH3:28][C@H:29]1[CH2:34][N:33]([CH:35]2[CH2:38][O:37][CH2:36]2)[C@H:32]([CH3:39])[CH2:31][N:30]1[C:40]1[CH:41]=[CH:42][C:43]([NH:46][C:47]2[C:48](=[O:63])[N:49]([CH3:62])[CH:50]=[C:51](B3OC(C)(C)C(C)(C)O3)[CH:52]=2)=[N:44][CH:45]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][C:22]3[N:21]4[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:15][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:51]1[CH:52]=[C:47]([NH:46][C:43]2[CH:42]=[CH:41][C:40]([N:30]3[CH2:31][C@@H:32]([CH3:39])[N:33]([CH:35]4[CH2:38][O:37][CH2:36]4)[CH2:34][C@@H:29]3[CH3:28])=[CH:45][N:44]=2)[C:48](=[O:63])[N:49]([CH3:62])[CH:50]=1)(=[O:3])[CH3:2]
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C[C@@H](C)N(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(cc3n2CCCC3)C1=O
Temperature: 100 °C
Yield: 34.5 %

Procedure:
A 100-mL single-neck round-bottomed flask was charged with 2-bromo-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)benzyl acetate 101h (347 mg, 0.80 mmol), 3-(5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 121g (792 mg, 1.6 mmol), Pd(dppf)Cl2 (32.7 mg, 0.040 mmol), K3PO4 (340.0 mg, 1.6 mmol), sodium acetate trihydrate (217.6 mg, 1.6 mmol), water (0.5 mL), and acetonitrile (50 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 126a (200 mg, 34.6%) as a yellow brown solid. MS: [M+H]+ 724.5.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:30]([O:32][C:33](=[O:53])[CH2:34][C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)[CH3:31]>>[CH2:30]([O:32][C:33](=[O:53])[CH2:34][C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:6][CH:7]=3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)[CH3:31]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(CCc1ccccc1)c1ccccc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(CCc4ccccc4)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1,3-diphenyl-propyl)-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1([CH2:22][CH3:23])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[N:20][OH:21])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19].C([O-])([O-])=O.[K+].[K+].CO>O>[CH2:22]([C:5]1([CH2:4][C:3]([OH:24])=[O:2])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[N:20][OH:21])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19])[CH3:23]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3=NO
Temperature: 25 °C

Procedure:
The product of Step A (0.182 g, 0.55 mmol), K2CO3 (0.1 g, 0.71 mmol) and a MeOH--H2O mixture (10 ml-1 ml) were refluxed for 3 h. The reaction mixture was cooled to room temperature and the methanol was removed. To the reaction mixture was added 10 ml H2O, which was then acidified using 1N HCl. The aqueous phase was extracted with EtOAc, which was dried (MgSO4), evaporated and triturated using hexane to yield a solid, m.p. 165°-168° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[CH:10][C@H:9]1[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[CH:10][C@H:9]1[C:13]([O:15][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C[C@H]1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (10 g, 46.9 mmol) in DMF (249 mL) cooled at 0° C. were added cesium carbonate (16.8 g, 51.6 mmol) then benzyl bromide (6.69 mL, 56.3 mmol) and the mixture was allowed to warm up to RT overnight. The reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (3×200 mL). The organic layers were combined and washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 4:1) to give the desired material. TLC, Rf (c-hexane/EtOAc 4:1)=0.25; MS (UPLC): 326 [M+Na]+, 204 [MH−Boc]+; tR (HPLC conditions f): 2.35 min.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:13][C:14](=[O:34])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH:22][CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[O:36]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.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>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([NH:22][CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[C:15]([CH:20]=1)[C:14]([NH:13][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:46]2[CH:47]=[CH:48][C:43]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:44][CH:45]=2)=[CH:10][CH:11]=1)[C:3]([OH:2])=[O:35])=[O:34]
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1NCc1cccc2ccccc12
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: Cc1ccccc1
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1)C(=O)O)c1cc(Cl)ccc1NCc1cccc2ccccc12
Temperature: 80 °C
Yield: 52.3 %

Procedure:
(S)-3-(4-Bromo-phenyl)-2-{5-chloro-2-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-propionic acid methyl ester (150 mg, 0.36 mmol), Pd (PPh3)4 (84 mg, 0.072 mmol), and 4-phenoxyphenylboronic acid (233 mg, 1.09 mmol) were dissolved in 5 mL of toluene, a 1M Na2CO3 solution (0.9 mL, 0.91 mmol) added and the mixture heated at 80° C. for 12 h. The reaction mixture was diluted with 5 mL of CH2Cl2 and filtered, all volatiles are removed under vaccum and the ester product was hydrolyzed according to Procedure C, and purified over silica gel (ethyl acetate:hexanes) to give the title compound(118 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([I:8])=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>CC(O)(C)C>[I:8][C:5]1[N:6]=[CH:7][C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[N:3][CH:4]=1
Reactant: Brc1cnc(I)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(I)cn2)CC1
Temperature: 100 °C
Reaction time: 66 h

Procedure:
2-bromo-5-iodopyrazine (503 mg, 1.77 mmol) and tert-butyl piperazine-1-carboxylate (355 mg, 1.91 mmol) were taken up in tBuOH (8 mL). iPr2NEt (400 μL, 2.3 mmol) was added and the stirred reaction mixture was heated to 100° C. After 66 h, the reaction mixture was cooled and was partitioned between EtOAc, water and brine. The phases were separated, and the organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (10-30% EtOAc in hexanes) to afford tert-butyl 4-(5-iodopyrazin-2-yl)piperazine-1-carboxylate 7.11.
Reaction SMILES: [CH3:1][C:2]1(C)[C:6](C)([CH3:7])OB(C(=C)CC)O1.[C:14]([O:18][C:19]([N:21]1[C:29]2[CH:28]=[C:27](Cl)[N:26]=[CH:25][C:24]=2[C:23]([CH3:32])([CH3:31])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].C([O-])(O)=O.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O.O1CCOCC1>[C:14]([O:18][C:19]([N:21]1[C:29]2[CH:28]=[C:27]([C:2](=[CH2:1])[CH2:6][CH3:7])[N:26]=[CH:25][C:24]=2[C:23]([CH3:32])([CH3:31])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: C=C(CC)B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: C=C(CC)c1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Temperature: 94 °C
Yield: 55.5 %

Procedure:
A mixture of 4,4,5,5-tetramethyl-2-(1-methylene-propyl)-[1,3,2]dioxaborolane (0.793 g, 4.36 mmol), 6-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.821 g, 2.9 mmol), potassium carbonate (1.20 g, 8.7 mmol), tris(dibenzylideneacetone)-dipalladium (0) (0.133 g, 0.145 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos, 0.060 g, 0.145 mmol), 1,4-dioxane (18 mL) and water (45 mL) was heated at 94° C. for 18 h, then poured into saturated aqueous NaHCO3 (100 mL) and extracted with DCM (3×50 mL). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-25% Et2O in 40-60 petroleum ether) gave the title compound (0.487 g) as an oil. MS: [M+H]+=303. Further chromatography of mixed fractions gave further title compound (0.20 g).
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)[C:9](O)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:25][C:26]([O:29][C:30]([NH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:31])([CH3:28])[CH3:27]>>[OH:1][C:2]1([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=2)[C:9]([N:36]2[CH2:35][CH2:34][CH:33]([NH:32][C:30](=[O:31])[O:29][C:26]([CH3:25])([CH3:27])[CH3:28])[CH2:38][CH2:37]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(O)C(c1cccc(Oc2ccccc2)c1)C1(O)CCCCC1
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)C(c2cccc(Oc3ccccc3)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 1′ step 1, tert-butyl (1-{(1-hydroxycyclohexyl)[3-(phenoxy)phenyl]acetyl}piperidin-4-yl)carbamate was prepared from (1-hydroxycyclohexyl)[3-phenoxyphenyl]acetic acid (Reference Example 1-ccc) and 4-N-BOC-aminopiperidine. MS (ESI) m/z 509 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH2:24][CH3:25])[C:3](=[O:23])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11](=[O:22])[CH2:12][CH2:13][CH:14]=[CH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:5].C(OCC)(=O)C.C(O)C.C(O)C.C(OCC)(=O)C>CO.[Pt]=O.[Pd]>[CH3:1][C:2]([CH3:26])([CH2:24][CH3:25])[C:3](=[O:23])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11](=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:5]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC1C(=O)CCC=Cc1cccnc1
Agent: O=[Pt]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(C)(C)C(=O)C(=O)N1CCCC1C(=O)CCCCc1cccnc1
Reaction time: 2.5 h

Procedure:
Platinum oxide (12 mg) was added to a solution of 3,3-dimethyl-1-[2-(5-(3-pyridyl)pent-4-enoyl) pyrrolidinyl]pentane-1,2-dione (300 mg; 0.84 mmol) in methanol (8 ml). The mixture was hydrogenated at 1 atm. for 2.5 hours. TLC indicated that the reaction was complete, and it was filtered through Celite and concentrated. Eluting through a plug of silica gel (ethyl acetate) furnished analytically pure material, 260 mg (87%). 1H NMR (CDCl3, 400 MHz): δ 0.87 (t, 3H, J=7.5); 1.21 (s, 6H); 1.64 (m, 4H); 1.69 (m, 2H); 1.78 (m, 1H); 1.96 (m, 2H); 2.15 (m, 1H); 2.53 (m, 1H); 2.63 (m, 2H); 3.49 (m, 1H); 3.53 (m, 1H); 4.57 (dd, 1H, J=8.8, 4.8); 7.20 (m, 1H); 7.49 (m, 1H, J=7.8); 8.44 (m, 2H). Anal. Calcd. for C21H30N2O3: C, 70.36; H, 8.44; N, 7.81. Found: C, 70.15; H, 8.54; N, 7.76. TLC: R1=0.80 (ethyl acetate:ethanol 4:1). Note: this final hydrogenation step may be done using 10% Pd/C, and hydrogenating for 5 hours at 60 psi. Ethanol or ethyl acetate may be used instead of methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2
Reactant: CCS(=O)(=O)Cl
Reactant: COc1cc(O)ccc1-c1nc2ncccc2[nH]1
Product: CCS(=O)(=O)Oc1ccc(-c2nc3ncccc3[nH]2)c(OC)c1

Procedure:
Prepared analogously to Example 1 from 2-(2'-methoxy-4'-hydroxy-phenyl)-imidazo[4,5-b]pyridine and ethanesulfonic acid chloride.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=1.Br[CH:14]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15](OC)OC.Cl.C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[C:20]1([C:14]2[S:11][C:10]([NH:9][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][OH:1])[N:8]=3)=[N:12][CH:15]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=S)Nc1cccc(CO)n1
Reactant: COC(OC)C(Br)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1cccc(Nc2ncc(-c3ccccc3)s2)n1
Reaction time: 7 h

Procedure:
(6-Hydroxymethyl-pyridin-2-yl)-thiourea (6-3) 1.05 g (5.73 mmol) and (1-bromo-2,2-dimethoxy-ethyl)-benzene (2.11 g, 8.60 mmol) were stirred in 18 mL EtOH. Concentrated HCl (aq), 6 mL, was added and the mixture was heated to reflux. After 7 h, additional (1-bromo-2,2-dimethoxy-ethyl)-benzene (1.05 g, 4.30 mmol) and conc HCl (aq), 3 mL were added. The reaction was then heated at reflux for an additional 14.5 h. The reaction was poured into 120 mL water and the pH was adjusted to 7 with Na2CO3 (s). A precipitate formed which was filtered and washed with water. The solid was triurated with 50 mL ether, filtered and washed with ether to provide the titled compound as a white solid. 1H NMR(CD3OD): δ7.72 (t, 1H, J=7.7 Hz), 7.58 (s overlapping with d, 3H), 7.38 (t, 2H, 7.5 Hz), 7.25 (t, 1H, J=7.3 Hz), 7.07 (d, 1H, J=7.5 Hz), 6.90 (d, 1H, J=8.3 Hz), 4.76 (s, 2H). Mp: 196-198° C. M+1: 284.0.