Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[S:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:38][C:39]#[N:40].C(O)(=O)C.N1CCCCC1>C(O)C>[C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH:21]=[C:38]([C:34]4[S:33][CH:37]=[CH:36][N:35]=4)[C:39]#[N:40])=[CH:23][CH:24]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:32])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Reactant: N#CCc1nccs1
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)c4nccs4)cc3)nc12
Yield: 72.9 %

Procedure:
To a 25 ml three necked round bottom flask, 4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzaldehyde (0.1 g, 0.000221 mol) and 2-(thiazol-2-yl)acetonitrile (0.082 g, 0.000663 mol) were taken in ethanol (5 ml). Piperidine acetate (3.3 M solution in water) (0.2 ml) was added dropwise at RT. After completion of the addition, reaction mixture was refluxed overnight and ethanol was distilled out and water was added to residue. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, dried over Na2SO4, filtered and concentrated to afford crude product. The crude compound was triturated with n-pentane, the pentane layer was decanted and solid was dried under vacuum to yield 0.090 g of 3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)-2-(thiazol-2-yl)acrylonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]([NH:10][CH3:11])=[O:9].ON1C2C=CC=CC=2N=N1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][C:5]([C:12]2[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([NH:37][CH2:36][C:35]3[CH:38]=[CH:39][C:32]([Cl:31])=[CH:33][CH:34]=3)=[O:17])[CH:13]=2)=[CH:4][N:3]=1
Reactant: CNC(=O)c1nc(-c2cccc(C(=O)O)c2)cnc1N
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1nc(-c2cccc(C(=O)NCc3ccc(Cl)cc3)c2)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
A flask was charged with 3-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}benzoic acid (48.9 mg, 0.18 mmol), 1-hydroxybenzotriazole (HOBT, 39.7 mg, 0.294 mmol), 2.00 mL of tetrahydrofuran, 4-chlorobenzylamine (28.2 mg, 0.2 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (66.2 mg, 0.353 mmol). The reaction was stirred at room temperature for 2 h. The reaction was diluted with ethyl acetate, washed sequentially saturated aqueous NaCl, saturated aqueous sodium carbonate, 1.0 M aqueous hydrochloric acid, and saturated aqueous sodium bicarbonate The organic layer was dried over sodium sulfate, filtered, and concentrated on a rotary evaporator under reduced pressure. The crude product was purified by chromatography on silica gel using EtOAc as the eluent. After concentration, the product was triturated in 5% ethyl acetate in hexanes. The solid product was filtered, and after drying afforded 3-amino-6-[3-({[(4-chlorophenyl)methyl]amino}carbonyl)phenyl]-N-methylpyrazine-2-carboxamide (39.8 mg, 50% yield). 1H NMR (400 MHz; DMSO-d6): 9.15 (m, 1H); 8.87 (s, 1H); 8.80 (m, 1H); 8.50 (s, 1H); 8.35 (d, 1H); 7.85 (d, 1H); 7.53 (d, 1H); 7.37 (m, 2H); 4.51 (d, 2H); 2.83 (s, 3H): MS (EI) for C20H18N5O2Cl: 396 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][S:6][C:5]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:4]=2[NH:3]1.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(OCC)(=O)C.C(O)C>[O:1]=[C:2]1[CH2:7][S:6](=[O:20])[C:5]2[S:8][C:9]([S:11](=[O:13])(=[O:14])[NH2:12])=[CH:10][C:4]=2[NH:3]1
Reactant: NS(=O)(=O)c1cc2c(s1)SCC(=O)N2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: NS(=O)(=O)c1cc2c(s1)S(=O)CC(=O)N2
Reaction time: 8 h

Procedure:
To a mixture of 2,3-dihydro-2-oxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazine (0.25 g, 1 mmol) in ethyl acetate (8 ml) and ethanol (8 ml) was added 3-chloroperoxybenzoic acid (0.43 g, 80-85% pure, 2 mmol). The reaction mixture was stirred overnight and the resulting solid collected, triturated with hot ethyl acetate and dried to give 0.25 g, 2,3-dihydro-2,4-dioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazine, mp 222°-223° C.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[C:60]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][N:66]=3)[CH:61]=[CH:62][CH:63]=2)[N:58]=[C:57]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][N:72]=2)[C:56]=1[CH3:77].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.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]>[N:38]1([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[C:60]([C:65]5[CH:70]=[CH:69][CH:68]=[CH:67][N:66]=5)[CH:61]=[CH:62][CH:63]=4)[N:58]=[C:57]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][N:72]=4)[C:56]=3[CH3:77])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:39][CH2:40][O:35][CH2:36][CH2:37]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2c(-c3ccccn3)cccc2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2c(-c3ccccn3)cccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.019 g, 0.040 mmol), 2,5-dimorpholinopyridin-3-amine (0.078 g, 0.30 mmol), 4-chloro-3-methyl-2,8-di(pyridin-2-yl)quinoline (0.082 g, 0.25 mmol) and Pd2dba3 (9.05 mg, 9.89 μmol) in toluene (2.5 mL) was added sodium t-butoxide (0.059 g, 0.62 mmol). The reaction mixture was heated to 120° C. and stirred for 45 min. The reaction was then cooled to rt and diluted with water (10 mL). The mixture was extracted with EtOAc (3×10 mL) and DCM (10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on basic alumina (0 to 100% EtOAc/DCM) to give the desired product N-(2,5-di-4-morpholinyl-3-pyridinyl)-3-methyl-2,8-di-2-pyridinyl-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.75-8.84 (1H, m), 8.69 (1H, br m), 8.28 (1H, d, J=7.6 Hz), 8.21 (1H, d, J=7.6 Hz), 7.97 (1H, d, J=7.6 Hz), 7.84 (2H, br. m.), 7.78 (1 h, m), 7.62 (2H, dd, J=16.0, 7.8 Hz), 7.28-7.35 (2H, br. m.), 6.82 (1H, br. s.), 6.25 (1H, br. s.), 3.95 (4H, br. s.), 3.73 (4H, br. s.), 3.27 (4H, br. s.), 2.93 (4H, br. s.), 2.52 (3H, s). Mass Spectrum (ESI) m/e=560.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH:7]=[CH:8][O:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:32]1([CH2:37][CH2:38]O)[CH:36]=[CH:35][N:34]=[CH:33]1.N(C(OCC)=O)=NC(OCC)=O>CCOC(C)=O.C1COCC1>[N:32]1([CH2:37][CH2:38][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:12])[CH:7]=[CH:8][O:9]3)=[CH:4][CH:3]=2)[CH:36]=[CH:35][N:34]=[CH:33]1
Reactant: O=c1ccoc2cc(O)ccc12
Reactant: OCCn1ccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1ccoc2cc(OCCn3ccnc3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
Under N2, a solution of 0.75 g (4.6 mmol) of 7-hydroxy-4H-4-chromenone (J. Med. Chem., 1991;34:248) in 20 ml, of THF was treated with 1.21 g (4.6 mmol) of triphenylphosphine and 0.5 g (5.1 mmol) of 2-(1H-1-imidazolyl)-1-ethanol and the solution cooled in ice. This was then treated over 10 minutes with 0.72 mL (4.6 mmol) of diethyl azodicarboxylate, and the solution stirred at room temperature overnight. The solution was diluted with EtOAc, washed twice with H2O, twice with saturated NaHCO3, and then with saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure gave the crude product. Chromatography on silica gel, eluting with a gradient of CH2Cl2 to CH2Cl2/MeOH (96/4) gave 0.12 g (10% yield) of the product as a pink solid, mp 131-133° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 257 (M+H+).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].[CH3:11][O:12][CH2:13][C:14]#[C:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]2[O:23][CH2:24][O:25][C:17]=12.[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:39][CH2:40][CH3:41])=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][C:28]=1[C:42]#[N:43].Cl>O.C(Cl)Cl.C(OCC)C.CN(C=O)C>[ClH:26].[C:42]([C:28]1[CH:29]=[N:30][C:31]2[C:36]([C:27]=1[NH:20][C:19]1[CH:21]=[CH:22][C:16]([C:15]#[C:14][CH2:13][O:12][CH3:11])=[C:17]3[O:25][CH2:24][O:23][C:18]=13)=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH2:40][CH3:41])[CH:32]=2)#[N:43]
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: COCC#Cc1ccc(N)c2c1OCO2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(C#CCOC)c4c3OCO4)c2cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
Sodium hexamethyldisilazane (1M solution in THF; 1.17 ml) was added to a stirred mixture of 4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyaniline (0.12 g), 4-chloro-3-cyano-7-ethoxy-6-methoxyquinoline (0.146 g) and DMF (8 ml) that had been cooled to 0° C. and the resultant mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and with a saturated brine solution, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica increasingly polar mixtures of methylene chloride and methanol as eluent. The material so obtained was dissolved in the minimum quantity of methylene chloride. The solution was diluted with diethyl ether and a solution of hydrogen chloride in diethyl ether (1M) was added. The resultant solid was isolated, washed with diethyl ether and dried. Thereby, the product was obtained the title compound (0.18 g); NMR Spectrum: (DMSOd6) 1.44 (t, 3H), 3.33 (s, 3H), 4.0 (s, 3H), 4.24 (q, 2H), 4.36 (s, 2H), 6.12 (s, 2H), 6.96 (d, 1H), 7.03 (d, 1H), 7.45 (s, 1H), 8.11 (s, 1H), 8.96 (s, 1H); Mass Spectrum: M+H+ 432.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][C@@H:12]1[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:13]1[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:5][NH:6]2.[CH3:47][Si:48]([C:51]#[CH:52])([CH3:50])[CH3:49]>C(N(CC)CC)C.C(OCC)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.[Cu]I>[CH3:47][Si:48]([CH3:50])([CH3:49])[C:51]#[C:52][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][C@@H:12]1[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])[C@H:21]([O:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])[C@H:13]1[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:5][NH:6]2
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(Br)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(C#C[Si](C)(C)C)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (0.5 g) in triethylamine (5 mL) were added trimethylsilylacetylene (0.2 mL), tetrakis(triphenylphosphine)palladium (0) (81 mg) and copper (I) iodide (27 mg), and the mixture was stirred at 80° C. under an argon atmosphere overnight. The reaction mixture was cooled to room temperature and diluted with diethyl ether. The insoluble material was removed by filtration. The filtrate was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-3/1-2/1) to give 4-(2-trimethylsilylethynyl)-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (0.4 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution was added tetra(n-butyl)ammonium fluoride (0.15 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound (0.33 g).
Reaction SMILES: C([NH:4][CH2:5][C:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH:11]=1)(=O)C.[OH-].[Na+].Cl>CO>[NH2:4][CH2:5][C:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[CH2:8][CH:7]=1
Reactant: CCN1CC=C(CNC(C)=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN1CC=C(CN)CC1
Yield: 92.6 %

Procedure:
A solution of 4-acetylaminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine (20.0 g) and 6N aqueous solution of sodium hydroxide (73 ml) in methanol (150 ml) was refluxed for 40 hours. The solution was acidified with concentrated hydrochloric acid under ice cooling and evaporated in vacuo. To the residue was added ethanol (400 ml) and the mixture was refluxed for an hour. The resulting precipitates were filtered off and the filtrate was evaporated in vacuo. The residue was treated with Amberlite IRA-910 (trademark: Rohm & Haas Co.) and purified by vacuum distillation to give 4-aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine (14.25 g).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>>[C:20]1([CH3:23])[CH:21]=[CH:22][C:17]([C:2]#[C:1][C:3]2[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(I)cc1
Reactant: C#Cc1ccc(OCC(=O)OCC)cc1
Product: CCOC(=O)COc1ccc(C#Cc2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from ethyl (4-ethynylphenoxy)acetate (41 mg, 0.20 mmol) and iodo-4-methylbenzene (46 mg, 0.21 mmol) according to the general procedure ID to give 47 mg (79%) of an orange oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:10). Rf: 0.14 (EtOAc:hexanes, 1:10); 1HNMR (CDCl3) δ 7.49-7.37 (m, 4H), 7.17-7.11 (m, 2H), 6.91-6.84 (m, 2H), 4.63 (s, 2H), 4.29-4.26 (dq, 2H, J=7.2 Hz, 2.1 Hz), 2.36 (s, 3H), 1.32-1.27 (tt, 3H, J=7.2 Hz, 1.5 Hz); 13CNMR (CDCl3) δ 168.6, 157.6, 138.1, 133.0, 131.4, 129.1, 120.3, 116.8, 114.7, 88.6, 88.3, 65.4, 61.5, 21.5, 14.1; EI-MS m/z 294 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17](O)[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]([O:32][Si](C)(C)C)=[C:29]([CH3:31])[CH3:30]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:29]([CH3:31])([CH3:30])[C:28]([O:27][CH3:26])=[O:32])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: OC(Cc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(Cc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To a stirred solution of 1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylethanol (290 mg, 0.87 mmol) and (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (0.7 mL, 3.5 mmol) in anhydrous dichloromethane (5 mL) was added titanium(IV) tetrachloride (1M solution in toluene, 1.9 mL, 1.9 mmol) dropwise at 0° C. under argon. The reaction mixture was stirred at 0° C. for 30 min and rt for 2 hr before being quenched by the slow addition of saturated aqueous sodium bicarbonate solution (15 mL). The mixture was filtered through a pad of celite that was then washed with dichloromethane (10 mL). The aqueous filtrate was reextracted with dichloromethane (10 mL). The combined dichloromethane layers were dried (Na2SO4), concentrated and purified by silica gel flash chromatography to give methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-4-phenylbutanoate (216 mg, 0.52 mmol, 60% yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][C:5]=1[S:13]([Cl:12])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Temperature: 130 °C
Reaction time: 26 h
Yield: 59.6 %

Procedure:
2,4-Dichloronitrobenzene (10 g, 52 mmol) was added ClSO3H (8 ml, 120 mmol) dropwise under ice-water bath. The mixture was stirred at 130° C. for 26 h. The mixture was cooled to rt and poured onto ice-water. The resulting precipitates were collected by filtration and dried under reduced pressure to give 9 g (60%) of the title compound as brown solids.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:15])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O.CCOCC>[C:9]1([CH2:8][CH2:7][C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)CNC(=O)CCc1ccccc1
Yield: 85.2 %

Procedure:
Glycine (1.5 g, 20 mmol) and hydrocinnamoyl chloride (3.37 g, 22 mmol) were reacted in the presence of NaOH (40 mmol) in a mixture of water and ether using the method described in Example 5 Part A. The crude product was extracted into chloroform, dried (MgSO4) and freed of solvent in vacuo leaving a near white solid (3.53 g, 85%). This was recrystallized from EtOAc (13 ml) to give title compound (2.66 g, 64%) m.p. 112°-114° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11]2)[CH:5]=[N:6][C:7]=1[C:8]#[N:9].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])=[CH:27][CH:26]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[C:8]([C:7]1[N:6]=[CH:5][C:4]([N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11]2)=[CH:3][C:2]=1[NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[O:32])=[CH:29][CH:30]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Br)c2)C1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Nc3ccc(C(=O)N4CCOCC4)cc3)c2)C1
Temperature: 115 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of (R)-tert-butyl 1-(5-bromo-6-cyanopyridin-3-yl)piperidin-3-ylcarbamate (95) (300 mg, 0.78 mmol), (4-aminophenyl)(morpholino)methanone (322 mg, 1.56 mmol), Pd2(dba)3 (73 mg, 0.08 mmol), XantPhos (93 mg, 0.16 mmol), fine powder Cs2CO3 (765 mg, 2.34 mmol) in dioxane (50 mL) was degassed with nitrogen stream for 3 min. The mixture was stirred in a nitrogen atmosphere at 115° C. for 2 h. The mixture was cooled, diluted with 200 mL EtOAc, filtered through celite, and concentrated in vacuo. The residue was subjected to flash column chromatography with 20 to 100% EtOAc in DCM to isolate (R)-tert-butyl 1-(6-cyano-5-(4-(morpholine-4-carbonyl)phenylamino)pyridin-3-yl)piperidin-3-ylcarbamate (96) (yield >80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: ClCc1nc2ccccc2s1
Reactant: O=[N+]([O-])c1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCc2nc3ccccc3s2)ccc1F
Temperature: 25 °C

Procedure:
A solution of 4-fluoro-3-nitrophenol (2.1 g, 13 mmol), potassium carbonate (2.2 g, 16 mmol), 2-(chloromethyl)benzo[d]thiazole (2.4 g, 13 mmol) and DMF (15 mL) was stirred at 80° C. for 6 h. The reaction mixture was cooled to RT and poured onto ice water (300 mL). Solid precipitate was collected by vacuum filtration and dried in a vacuum oven at 60° C. to provide the title product, which was used without purification. MS (ESI): mass calcd. for C14H9FN2O3S, 304.1; m/z found, 305.1 [M+H]+. 1H-NMR (500 MHz, DMSO-d6) δ 8.15 (t, J=6.7, 1H), 8.08-8.01 (m, 1H), 7.90-7.84 (m, 1H), 7.63-7.53 (m, 3H), 7.52-7.45 (m, 1H), 5.75 (s, 2H).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=3[OH:26])[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=3[OH:26])[C:9]2=[O:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc(O)c(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
To a stirred mixture of 1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one (15.4 g, 34.1 mmol) and triethylsilane (15 mL) was added trifluoroacetic acid (15 mL) at 0° C. The solution was stirred at ambient temperature for 16 h and concentrated in vacuo to dryness. The residue was recrystallized from diethyl ether (25 mL) in a Branson ultrasonic bench top water bath to afford 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one (11.0 g, 74%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.42-7.16 (m, 12H), 7.11-7.01 (m, 2H), 6.94 (s, 1H), 6.61 (s, 1H), 6.57-6.49 (m, 1H), 6.45 (s, 1H), 5.08 (s, 1H), 3.63 (s, 3H), 2.03 (s, 3H); MS (ES+) m/z 436.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([OH:12])=O)=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH:26]1[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1>>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:25][CH:26]2[CH:31]3[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]3)[CH2:27]2)=[O:12])=[CH:4][N:3]=1
Reactant: NC1CN2CCC1CC2
Reactant: COc1nc(N)ncc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1nc(N)ncc1C(=O)NC1CN2CCC1CC2

Procedure:
Following the procedure of Example 22, 2-amino-4-methoxy-5-pyrimidinecarboxylic acid, 1,1'-carbonyldiimidazole and 3-aminoquinuclidine are reacted to give the title compound.