Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl>[N:26]1([C:24]2[N:25]=[C:20]([C:9]3[CH:10]=[C:11]4[CH:17]=[CH:16][NH:15][C:12]4=[N:13][CH:14]=3)[CH:21]=[N:22][CH:23]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Clc1cncc(N2CCc3ccccc32)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)CCN2c1cncc(-c2cnc3[nH]ccc3c2)n1
Temperature: 90 °C

Procedure:
The starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.205 mmol, 1 eq) and 1-(6-chloropyrazin-2-yl)indoline (88) 423 mg, 0.185 mmol, 0.9 eq) in DME (7 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (133 mg, 0.410 mmol, 2 eq) followed by addition of Pd(dpp)Cl2 (6 mg, 0.00819 mmol, 0.04 eq) and degassing and purging under argon for additional 10 minutes was performed. The reaction mixture was heated at 90° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1% MeOH/CHCl3 to obtain pale yellow solid compound 5-(6-(indolin-1-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine 134 in 12 mg quantity. The compound 134 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 9.06 (s, 2H), 8.59 (s, 1H), 8.60 (s, 1H), 8.55 (s, 1H), 8.44 (m, 1H), 8.16 (s, 1H), 7.41 (m, 1H), 6.99 (m, 1H), 4.21 (m, J=8.53, 2H), 3.33 (m, J=341.82, 2H); MS m/z 313.9 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1.[F:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([F:22])[C:20]=1F>CN(C=O)C>[F:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([F:22])[C:20]=1[N:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: O=C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCN(c2c(F)cc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
To a suspension of anhydrous potassium carbonate (11.80 g, 85.90 mmol) in DMF (30 ml) was added a solution of 4-piperidinone (7.20 g, 47.2 mmol) in DMF (5 ml) followed by the addition of 3,4,5-trifluoronitrobenzene (7.00 g, 42.8 mmol) and stirred at room temperature for 3 h. The reaction mixture was poured onto ice water and the resulting solid was filtered off. Drying the solid under vacuum yielded the title compound as yellow powder (4.50 g, 45%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CON(C)[C:8](=[O:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1>C1COCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][C:8](=[O:19])[CH2:1][CH3:2])=[CH:12][CH:13]=1
Reactant: COc1ccc(CCC(=O)N(C)OC)cc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)CCc1ccc(OC)cc1
Reaction time: 1 h
Yield: 50 %

Procedure:
Ethylmagnesium bromide (10.8 mL, 10.8 mmol, 1M soln in THF) was added to a cooled −78° C. solution of N-Methoxy-3-(4-methoxy-phenyl)-N-methyl-propionamide (2 g, 8.96 mmol, from Step 1) dissolved in THF (20 mL). The reaction mixture was stirred for 60 min. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed brine, dried over Na2SO4 and concentrated to a clear oil. The residue was purified by silica gel chromatography (5% EtOAc in hexanes) to give the title compound as a clear oil (0.87 g, 50%).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:30])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[NH:27][CH:28]=[CH:29][C:22]=34)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.C(OC([N:39]1[CH2:42][CH2:41][C@H:40]1[C:43](O)=[O:44])=O)(C)(C)C>>[NH:39]1[CH2:42][CH2:41][C@H:40]1[C:43]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12](=[O:30])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[NH:27][CH:28]=[CH:29][C:22]=34)[CH:6]=2)[C:2]([CH3:31])([CH3:1])[CH2:3]1)=[O:44]
Reactant: CC1(C)CNc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc21
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Product: CC1(C)CN(C(=O)[C@@H]2CCN2)c2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc21

Procedure:
The titled compound was prepared from N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)amino]nicotinamide (Example 16) and (2S)-azetidine-1,2-dicarboxylic acid-1-tert-butyl ester by the method described in Example 13. MS (ES+): 496 (M+H). Calc'd. for C28H29N7O2—495.58.
Reaction SMILES: [CH3:1][NH2:2].[N:3]([C:6]1[CH:7]=[C:8]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:9]=[CH:10][CH:11]=1)=[C:4]=[O:5]>O1CCCC1.C(OCC)(=O)C>[CH3:1][NH:2][C:4]([NH:3][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:7]=1)=[O:5]
Reactant: CN
Reactant: CC1(C)OB(c2cccc(N=C=O)c2)OC1(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reaction time: 0.08 h

Procedure:
Methyl amine (2.0 M in THF) was added to a solution of 2-(3-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.49 g, 2.0 mmol) and in tetrahydrofuran (6.0 mL) at 0° C. The mixture was stirred at this temperature for 5 min, then at r.t. for 2 h. The mixture was diluted with ethyl acetate, washed with water, 1N HCl aq. and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the desired product which was directly used in next step without further purification. LCMS (M+H)+: m/z=277.1
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:17]=2[S:18][CH2:19][CH3:20])=O)=[CH:7][C:6]([C:25]([F:28])([F:27])[F:26])=[CH:5][N:4]=1.CN(C=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:19]([S:18][C:17]1[CH:16]=[C:15]([C:21]([F:24])([F:23])[F:22])[N:14]=[CH:13][C:12]=1[C:10]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:25]([F:28])([F:27])[F:26])[CH:7]=[C:8]2[N:9]=1)[CH3:20]
Reactant: CCSc1cc(C(F)(F)F)ncc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCSc1cc(C(F)(F)F)ncc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 150 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A mixture of 786 mg of 4-ethylsulfanyl-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide, 704 mg of p-toluenesolufonic acid-hydrate, 2.5 ml of DMF and 0.5 ml of toluene was heated and stirred at 150° C. for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 716 mg of 2-(4-ethylsulfanyl-6-trifluoromethylpyridin-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound of Present Invention 12).
Reaction SMILES: [Al](C)(C)C.C(O[C:8]([C:10]1[C:15]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=[C:12]([CH:23]2[CH2:25][CH2:24]2)[N:11]=1)=[O:9])C.[NH2:26][C:27]1[CH:31]=[CH:30][N:29]([CH3:32])[N:28]=1>>[CH3:32][N:29]1[CH:30]=[CH:31][C:27]([NH:26][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH:23]3[CH2:24][CH2:25]3)[N:11]=2)=[O:9])=[N:28]1
Reactant: CCOC(=O)c1nc(C2CC2)ccc1Nc1cccnc1
Reactant: Cn1ccc(N)n1
Agent: C[Al](C)C
Product: Cn1ccc(NC(=O)c2nc(C3CC3)ccc2Nc2cccnc2)n1

Procedure:
The Al(Me)3-catalyzed reaction of 6-Cyclopropyl-3-(pyridin-3-ylamino)-pyridine-2-carboxylic acid ethyl ester and 3-Amino-1-methylpyrazole in accordance with the general method of Example 78, step 2 yielded the title compound as a light yellow cristalline solid, MS (ISP): m/e=335.4 (M+H+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[CH3:26]I.O>C1COCC1>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(C(C)(C)C)cc1
Yield: 101 %

Procedure:
23.3 mL of lithium bis (trimethylsilyl) amide (1.0 M, 23 mmols) was added dropwise to 4.75 g (23 mmols) of methyl 4-tert-butylphenylacetate in 100 mL of dry THF at −78° C. while stirring under nitrogen. The mixture was stirred at this temperature for 45 minutes, then 1.5 mL (24 mmol) methyl iodide was added dropwise and the solution was stirred for an additional 1 hour at −78° C. The mixture was poured into 200 mL of H2O and the desired product was extracted with 500 mL diethyl ether. The organic layer was backwashed once with 500 mL H2O, dried over K2CO3, and concentrated under reduced pressure to yield 5.12 g of a dark oil. The oil was purified via silica gel chromatography eluting with a solvent gradient of hexane to hexane/ethyl acetate 19:1. The fractions containing the desired product were combined and concentrated under reduced pressure to yield the title compound 2.65 g (53%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[C:11]([NH:1][C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ncc([N+](=O)[O-])cn1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
To stirred solution of 2-amino-5-nitropyrimidine (1.0 g, 7.14 mmol) in pyridine (20 ml) was added benzoyl chloride (0.92 ml, 7.93 mmol). The mixture was refluxed for 4 hr under nitrogen atmosphere. The reactant mixture was cooled to the room temperature and poured into 200 ml water. The resulting mixture was stirred overnight and then filtered in vacuo. The filter cake was washed with water (20 ml*3) and dried in vacuo to give 2-(N-benzoyl)amino-5-nitropyrimidine as a white solid (790 mg).
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:44]([CH3:47])(=[O:46])=[O:45])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C@H:30]3[CH2:35][CH2:34][C@@H:33]([O:36]C4CCCCO4)[CH2:32][CH2:31]3)=[CH:24][CH:23]=2)=[CH:18][C:17]1=[O:43])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>O1CCOCC1>[OH:7][NH:6][C:4](=[O:5])[C@:3]([CH3:2])([S:44]([CH3:47])(=[O:46])=[O:45])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C@H:30]3[CH2:31][CH2:32][C@@H:33]([OH:36])[CH2:34][CH2:35]3)=[CH:24][CH:23]=2)=[CH:18][C:17]1=[O:43]
Reactant: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@@H](OC4CCCCO4)CC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@@H](O)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O

Procedure:
HCl (1.0 N in water, 1.02 mL) was added to a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(4-{[cis-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)pyridin-1(2H)-yl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (135 mg, 0.204 mmol) in 1,4-dioxane (5.0 mL). After 1 hour the reaction was concentrated to give a white solid. The solid was triturated with ethanol at 50° C., for 30 minutes. After cooling, filtration afforded the title compound as a white solid (90 mg, 90%). LCMS m/z 493.7 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.70 (m, 12H) 1.79 (br. s., 1H) 2.09-2.24 (m, 1H) 2.42 (ddd, J=13.07, 11.12, 4.68 Hz, 1H) 3.12 (s, 3H) 3.68-3.83 (m, 2H) 3.87 (d, J=6.63 Hz, 2H) 4.10 (d, J=6.44 Hz, 1H) 6.55-6.75 (m, 2H) 6.94-7.10 (m, 2H) 7.61-7.80 (m, 3H) 11.15 (br. s., 1H)
Reaction SMILES: C1(O[C:8](=[O:25])[NH:9][CH:10]2[CH2:15][CH2:14][C:13]([N:22]([CH3:24])[CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:36]1[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]1>O1CCOCC1>[CH3:24][N:22]([CH3:23])[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11][CH:10]([NH:9][C:8]([N:38]2[CH2:39][CH2:40][CH2:41][CH:36]([C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([Cl:26])[CH:28]=4)[NH:32][CH:31]=3)[CH2:37]2)=[O:25])[CH2:15][CH2:14]1
Reactant: Clc1ccc2[nH]cc(C3CCCNC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(NC(=O)Oc2ccccc2)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)N2CCCC(c3c[nH]c4ccc(Cl)cc34)C2)CC1

Procedure:
The polar diastereoisomer of (4-dimethylamino-4-phenylcyclohexyl)-carbamic acid phenyl ester (288 mg, 0.85 mmole) was added to a solution of 5-chloro-3-piperidine-3-yl-1H-indole (200 mg, 0.85 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 32 hours. The reaction mixture was worked up by distilling off dioxane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×15 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The polar diastereoisomer of 3-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl)-amide was purified by column chromatography with methanol. It was obtained in a yield of 86 mg (21%) as a colourless solid.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH:32][C:31]4[CH:33]=[CH:34][C:28]([C:27]([F:26])([F:35])[F:36])=[CH:29][CH:30]=4)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 42 %

Procedure:
Using 3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoic acid (30 mg, 0.089 mmol), 4-(trifluoromethyl)aniline (44 mg, 0.27 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 4-(dimethylamino)pyridine (17 mg, 0.14 mmol) and pyridine (1.0 mL) as starting materials and in the same manner as in Example 318, the title compound (18 mg, 42%) was obtained as a white powder.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[N+:23]([O-])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)(=O)C.CO.[Fe]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[NH2:23])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCCNc1c(N)cnc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Iron powder (10 g) was added to a solution of the product from step (ii) (20 g) in acetic acid (200 mL) and MeOH (100 mL). The mixture was stirred at rt for 30 min then evaporated under reduced pressure. The residue was partitioned between DCM and water, the organics separated, washed with aq NaHCO3 solution, water, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 3-5% MeOH in DCM to give a brown oil, 10.1 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[N:11]/[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].B(F)(F)F.CCOCC.[CH2:28]=[C:29]([CH3:31])[CH3:30]>C(#N)C>[CH3:28][C:29]1([CH3:31])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=2)[NH:11][CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:30]1
Reactant: C=C(C)C
Reactant: Cc1ccc(/N=C/c2cccc([N+](=O)[O-])c2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc([N+](=O)[O-])c1)N2

Procedure:
A 2000 mL of autoclave was charged with [1-(3-nitro-phenyl)-meth-(E)-ylidene]-p-tolyl-amine (44.5 g, 0.185 mmol), acetonitrile (500 mL), boron trifluoride etherate (30 mL). The mixture was cooled with liquid nitrogen, and then isobutene was added quickly. The resultant mixture was stirred at room temperature for 60 h. The reaction mixture was washed with brine, water, dried over magnesium sulfate, concentrated. The residue was washed with ethyl acetate and the desired 4,4,6-trimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline was obtained by filtration (53 g).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:37])[CH:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28]2)=[CH:23][CH:22]=1>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][O:20][C:21]2[CH:30]=[C:29]3[C:24]([C:25](=[O:37])[CH:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28]3)=[CH:23][CH:22]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc3c(=O)cc(-c4ccccc4)oc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5, Step A and 7-hydroxyflavone in a manner analogous to that described for Example 5, Step B. MS(ES) for C28H22O6[M+H]+: 455.2.
Reaction SMILES: C(Cl)Cl.[C:4]([NH:12][CH2:13][CH:14]([C:19](=[O:21])[CH3:20])[C:15]([O:17][CH3:18])=[O:16])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCN(CC)CC>[C:4]([NH:12][CH2:13][C@H:14]([C@@H:19]([OH:21])[CH3:20])[C:15]([O:17][CH3:18])=[O:16])(=[O:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)C(CNC(=O)c1ccccc1)C(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNC(=O)c1ccccc1)[C@H](C)O
Temperature: 45 °C
Reaction time: 24 h
Yield: 90.1 %

Procedure:
In a 100 ml-volume autoclave whose atmosphere had been displaced with nitrogen was added a methylene chloride solution of 2.5 g of methyl 2-(N-benzoylamino)methyl-3-oxobutanoate and 84.5 mg (0.05 mmole) of Ru2Cl4 ((-)-BINAP2 (NEt3), and a reaction was conducted by stirring at 45° C. under a hydrogen pressure of 70 kg/cm2 for 24 hours. The reaction mixture was taken out, and the solvent was removed by distillation under reduced pressure of 20 mmHg at 30° C. The residue was purified by silica gel column chromatography using a 7/3 (by volume) mixture of hexane and isopropanol as an eluent to obtain 2.27 g (yield: 91%) of methyl (2R, 3S)-2-(N-benzoylamino)methyl-3-hydroxybutanoate having an optical purity of 97 %ee.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17](=[O:18])[N:16]([CH3:19])[CH:15]=[C:14](Br)[N:13]=2)=[CH:7][CH:6]=1)[CH3:2].[C:22]([C:26]1[CH:50]=[CH:49][C:29]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[C:34]=2[CH3:48])=[O:31])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17](=[O:18])[N:16]([CH3:19])[CH:15]=[C:14]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([NH:32][C:30](=[O:31])[C:29]4[CH:28]=[CH:27][C:26]([C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:50][CH:49]=4)[C:34]=3[CH3:48])[N:13]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1ccc(Nc2nc(Br)cn(C)c2=O)cc1
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: COCCOC
Solvent: O
Product: CCOC(=O)c1ccc(Nc2nc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3C)cn(C)c2=O)cc1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
A mixture of 4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoic acid ethyl ester (2) (340 mg; 0.97 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (5) (457 mg; 1.16 mmol), tetrakis(triphenylphosphine)palladium (56 mg; 0.05 mmol), 1N sodium carbonate (2.9 mL; 2.9 mmol), and 1,2-dimethoxyethane (30 mL) was heated at 100 degrees in a sealed pressure vessel for 16 hr. The mixture was cooled to room temperature, treated with water (70 mL) and extracted with ethyl acetate (3×60 mL). The combined organic extracts were washed with water (2×40 mL) and brine (1×40 mL), dried over magnesium sulfate, and evaporated under reduced pressure. The resulting residue was triturated with diethyl ether/dichloromethane to give 4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic acid ethyl ester (6) as a gray solid (330 mg), MS 539.49 (M+H).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[C:4]([C:3]1[C:2]([O:20][C:17]2[CH:18]=[CH:19][C:11]([F:10])=[C:12]([CH:16]=2)[C:13]([OH:15])=[O:14])=[N:9][CH:8]=[CH:7][CH:6]=1)#[N:5]
Reactant: O=C(O)c1cc(O)ccc1F
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cccnc1Oc1ccc(F)c(C(=O)O)c1
Temperature: 95 °C

Procedure:
To 2-chloronicotinonitrile (900 mg, 6.50 mmol), 2-fluoro-5-hydroxybenzoic acid (1.0 g, 6.4 mmol) and cesium carbonate (4.2 g, 13 mmol) was added DMSO (7 mL). The mixture was heated to 95° C. for 18 hours in a sealed tube. The mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified with 6 N HCl (pH˜2) and then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to yield 5-(3-cyanopyridin-2-yloxy)-2-fluorobenzoic acid. MS m/z 257=[M+H]+. Calc'd for C13H7FN2O3: 258.21.
Reaction SMILES: C([O:5][C:6](=[O:30])[C:7]([C:16]1[CH:29]=[CH:28][C:19]2[CH:20]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:22][C:18]=2[CH:17]=1)([F:15])C(OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:26]([O:25][C:23]([C:21]1[S:22][C:18]2[CH:17]=[C:16]([CH:7]([C:6]([OH:30])=[O:5])[F:15])[CH:29]=[CH:28][C:19]=2[CH:20]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)c1cc2ccc(C(F)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc(C(F)C(=O)O)cc2s1

Procedure:
Di-tert-butyl[2-(ethoxycarbonyl)-1-benzothien-6-yl](fluoro)malonate (9.3 g) was stirred in DCM (40 mL)/TFA (20 mL) at room temperature overnight. The solvent was removed in vacuo and the residue partitioned between saturated NaHCO3-EtOAc. The aqueous phase was acidified with 2N HCl and extracted with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was suspended in H2O (50 mL) and heated to reflux for 2 hours. Room temperature was attained and the products extracted into EtOAc. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give the product as a pale yellow solid. 1H NMR (DMSO-d6) δ 13.60 (br s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 6.14 (d, J=47.4 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H).