Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.Cl[CH2:33][C:34](Cl)=[O:35].Cl.C(N(CC)CC)C.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:28]([C:25]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([NH:1][C:34](=[O:35])[CH2:33][N:49]4[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]4)[N:31]=3)[CH:9]=2)[CH:12]=1)=[O:30])([CH3:27])[CH3:26])#[N:29]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)nn4c3)c2)c1
Reactant: CN1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(CC(=O)Nc2nc3ccc(Oc4cccc(NC(=O)c5cccc(C(C)(C)C#N)c5)c4)cn3n2)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 54.8 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.485 mmol) in N,N-dimethylformamide (5 mL) was added chloroacetyl chloride (116 μL, 1.46 mmol), and the mixture was stirred at room temperature for 21 hr. 1N Hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL, 2×10 mL). The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL) and dried over anhydrous sodium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL). Triethylamine (202 μL, 1.46 mmol) and 1-methylpiperazine (162 μL, 1.46 mmol) were added thereto, and the mixture was stirred at 60° C. for 19 hr. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL, 2×10 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0→94/6), and fractions containing the desired product were concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue. The obtained precipitate was collected by filtration and dried to give the title compound (147 mg, 55%) as a pale-yellow powder.
Reaction SMILES: Cl.Cl.[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:10]=[CH:11][C:12]=1[Cl:13].[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH2:34][C:35](O)=[O:36])[N:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH2:34][C:35]([N:17]2[CH2:18][CH2:19][N:14]([C:9]3[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([O:6][CH2:5][CH2:4][F:3])[CH:8]=3)[CH2:15][CH2:16]2)=[O:36])[N:26]=1
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: FCCOc1cc(N2CCNCC2)ccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1nc(-c2ncc[nH]2)c2cccnc21)N1CCN(c2ccc(Cl)c(OCCF)c2)CC1
Temperature: 20 °C
Yield: 19.7 %

Procedure:
To a vial containing 1-(3-(2-fluoroethoxy)-4-chlorophenyl)piperazine dihydrochloride (70 mg, 0.21 mmol) was added 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (51 mg, 0.21 mmol), HBTU (83 mg, 0.22 mmol), DMF (0.7 mL), and DIPEA (0.20 mL, 1.2 mmol). The reaction mixture was maintained at 20° C. for 24 h. The solution was diluted with EtOAc (30 mL) and washed with 1N HCl (2×10 mL) and sat. aq. NaCl (2×10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resultant residue was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA) and the pure fractions lyophilized to afford the indicated compound (20 mg, 20% yield): MS (ES) [M+H]+ expected 484.2, found 484.4; 1H NMR (CDCl3, 400 MHz) d 9.94 (br s, 1H), 8.78 (dd, J=1.2, 8, 1H), 8.55 (dd, J=1.2, 4.6, 1H), 7.16-7.26 (m, 4H), 6.45-6.53 (m, 2H), 5.44 (s, 2H), 4.77 (dt, J=4.0, 46.8, 2H), 4.26 (dt, J=4.0, 26.8, 2H), 3.69-3.78 (m, 4H), 3.10-3.21 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:3]=1[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Li])CCC.[C:26]([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C:34]1=O)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].[O:40]1CCCC1>>[Si:6]([O:5][CH2:4][C:3]1[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:2]=1[C:36]1([OH:40])[CH2:37][CH2:38][N:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:34][CH2:35]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C(F)(F)F)ccc1Br
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C(F)(F)F)cc2CO[Si](C)(C)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 43.9 %

Procedure:
To a solution of (2-bromo-5-(trifluoromethyl)benzyloxy)(tert-butyl)dimethylsilane (904 mg; 2.45 mmol) in tetrahydrofuran (6.0 mL) at −78° C. was added dropwise n-butyllithium (1.5 mL; 3.75 mmol: 2.5M in hexanes). The reaction was stirred at −78° C. for 5 minutes. Then a solution of Boc-piperidone (831 mg; 4.17 mmol) in tetrahydrofuran (3 mL) was added dropwise into reaction. During addition reaction turned yellow in color. The reaction was stirred at −78° C. allowing it to warm to −40° C. within 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, water and brine. The organic layer was dried sodium sulfate and concentrated under reduced pressure. The residue was purified over 40 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-15% ethyl acetate in heptane) to give 526 mg (43.9% yield) of a white solid. MS (ES+): Calc. 489.6, Found: 534.6 (M−HCO3). 1H NMR (400 MHz, CDCl3) δ ppm 7.54 (dd, J=8.30, 8.71 Hz, 1H), 7.49 (d, J=1.66 Hz, 1H), 7.40 (d, J=8.30 Hz, 1H), 5.02 (s, 2H), 4.78 (s, 1H), 4.04 (d, J=16.18 Hz, 2H), 3.28 (dt, J=12.86, 2.90, 13.28, 2H), 2.00 (dt, J=12.86, 13.28, 4.98, 4.56, 2H), 1.84 (d, J=12.45 Hz, 2H), 1.50 (s, 9H), 0.92 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCOC(C)=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]1)(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc([N+](=O)[O-])ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A solution of compound 37 (0.600 g, 2.34 mmol) in DCM (20.00 mL) was added tert-butyl 1-piperazinecarboxylate (0.566 g, 3.04 mmol) and TEA (0.422 mL, 3.04 mmol). The reaction was monitored with TLC (25% EtOAc in hexanes, Rf=0.53). The reaction mixture was complete after stirring at room temperature for 1 hr, as indicated by the absence of the starting material (TLC). Water was added and aqueous layer was extracted twice with DCM. Combined extracts were sequentially washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo to afford a yellow solid. The solid was triturated with DCM and hexanes, and then filtered to yield compound 38 as a yellow solid (0.789 g, 100% HPLC purity, 83% yield). 1H NMR (500 MHz, DMSO-d6): δ 8.60 (d, J=3 Hz, 1H), 8.47 (dd, J1=3 Hz, J2=8 Hz, 1H), 8.01 (d, J=8 Hz, 1H), 3.37 (m, 4H), 3.23 (m, 4H), 1.37 (s, 9H).
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].C(N(CC)CC)C.[Cl-].[C:22]([O:33][CH3:34])(=[O:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=1>CN(C)C=O.Cl>[C:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[O:5][CH2:4][CH2:3][NH:2][C:27]([C:26]1[CH:30]=[CH:31][C:23]([C:22]([O:33][CH3:34])=[O:32])=[CH:24][CH:25]=1)=[O:28])#[N:10]
Reactant: N#Cc1cccc(OCCN)c1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: Br
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NCCOc2cccc(C#N)c2)cc1
Reaction time: 3 h

Procedure:
1.50 g (6.2 mmol) of 3-(2-aminoethoxy)benzonitrile hydrobromide and 3 ml of triethylamine were stirred in 15 ml of dimethylformamide under cooling with ice. 1.23 g (6.2 mmol) of monomethyl terephthalate chloride was slowly added thereto, and they were stirred for 3 hours. The temperature was elevated to the room temperature, and the reaction liquid was diluted with 1 N hydrochloric acid. After the extraction with ethyl acetate, the organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and then with saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])#[CH:15]>>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]#[C:15][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: C#Cc1ccccc1OC
Reactant: COC(=O)CCc1ccc(I)cc1
Product: COC(=O)CCc1ccc(C#Cc2ccccc2OC)cc1

Procedure:
The title compound was prepared from methyl 3-(4-iodophenyl)propanoate (90 mg, 0.31 mmol) and 1-ethynyl-2-methoxybenzen (40 μL, 0.31 mmol) according to the general procedure IC to give 86 mg (94%) of a pure orange-brown oil. Rf=0.44 (EtOAc:PE; 1:2); 1H NMR (CDCl3): δ 7.48 (d, J=8.1 Hz, 3H) 7.29-7.22 (m, 1H) 7.16 (d, J=8.2, 2H) 6.95-6.88 (m, 2H) 3.90 (s, 3H) 3.66 (s, 3H) 2.95 (t, J=7.6 Hz, 2H) 2.63 (t, J=7.6 Hz, 2H); 13C NMR (CDCl3): δ 173.3, 160.1, 140.8, 133.7, 132.0, 129.8, 128.4, 121.7, 120.6, 112.7, 110.9, 93.5, 85.6, 56.0, 51.8, 35.6, 31.0; ESI-MS m/z 317.0 (M+Na+).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](Cl)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:19]1([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC>C(Cl)Cl>[N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:28]2[CH2:27][CH:26]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 40.6 mg (0.15 mmol) of 2-morpholin-4-yl-5-nitro-benzoyl chloride, 29 mg (0.18 mmol) 4-phenyl-1,2,3,6-tetrahydro-pyridine (commercial) and 62.5 ul (0.45 mmol) NEt3 in 1 ml DCM was stirred at room temperature for 16 h. After evaporation of the volatiles the residue was taken up in 1 ml CH3CN/DMF/HCOOH 3/5/2 and subjected to preparative HPLC purification on reversed phase eluting with an acetonitrile/water gradient to yield after evaporation the title compound.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH3:12])=[N:3][CH:4]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccccc1-c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 7 h

Procedure:
A mixture of 2,5-dibromo-3-nitropyridine (0.533 g, 1.89 mmol), 2-methoxyphenylboronic acid (0.29 g, 1.91 mmol), trans-dichlorobis(triphenylphosphine)-palladium (II) (68.9 mg, 0.098 mmol), and 2.0M sodium carbonate (2.9 mL, 5.8 mmol) in 1,4-dioxane (6 mL) was degassed by nitrogen. The mixture was heated to 90° C. After 7 h, the reaction was cooled to rt, then treated with water. After extracting twice with EtOAc, the organic layer was combined and dried over anhydrous magnesium sulfate. After filtration and concentration the residue was purified on silica gel (0-15% EtOAc in hexanes) to afford a yellow solid as 5-bromo-2-(2-methoxyphenyl)-3-nitropyridine. 1H NMR (400 MHz, CDCl3) δ ppm 8.93 (1H, d, J=2.2 Hz), 8.37 (1H, d, J=2.0 Hz), 7.66 (1H, dd, J=7.6, 1.8 Hz), 7.51 (1H, m), 7.16 (1H, td, J=7.5, 1.0 Hz), 6.92 (1H, dd, J=8.3, 0.9 Hz), 3.72 (3H, s).
Reaction SMILES: C[Mg]Br.[N:4]1(C(OC(C)(C)C)=O)[CH2:9][CH2:8][CH2:7][CH:6](C(OCC)=O)[CH2:5]1.[C:22]([OH:28])([C:24](F)(F)F)=O.[CH2:29](Cl)[Cl:30]>C(OCC)C.C1COCC1>[ClH:30].[NH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:22]([OH:28])([CH3:29])[CH3:24])[CH2:5]1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: ClCCl
Reactant: O=C(O)C(F)(F)F
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)C1CCCNC1
Product: Cl
Reaction time: 0.5 h

Procedure:
Methyl magnesium bromide (5 mL, 3M in diethyl ether, 15 mmol) was added dropwise to a solution of the 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (1.29 g, 5 mmol) in diethyl ether (20 mL) and THF (20 mL) during 10 min. The mixture was stirred for 30 min and thereafter slowly quenched with NH3Cl solution (10 mL, 3M). The phases were separated and the organic phase was evaporated to yield a yellow oil. The oil was dissolved in DCM (2 mL) and TFA (2 mL) was added and the reaction was left at room temperature for 15 min. The solvents were evaporated and the residue dissolved in EtOAc. HCl was bubbled through the solution in a gentle stream for 10 minutes. The solvent was evaporated and the residue dried in vacuum. Dissolution in EtOAc (100 mL) and stirring for 1 h at room temperature yielded the solid product, which was filtered off and dried in vacuum to produce white crystals. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.01 (d, J=15.87 Hz, 6 H) 1.08-1.26 (m, 1 H) 1.46-1.68 (m, 2 H) 1.74 (d, J=10.99 Hz, 2 H) 2.47-2.56 (m, 1 H) 2.55-2.75 (m, 1 H) 3.11 (d, J=12.45 Hz, 1 H) 3.24 (d, J=12.45 Hz, 1 H) 8.81 (s, 1 H) 9.18 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]([CH3:6])(O)[C:3]#[N:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]>C(Cl)Cl>[OH:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:2]([CH3:6])([CH3:1])[C:3]#[N:4]
Reactant: NCCCCO
Reactant: CC(C)(O)C#N
Solvent: ClCCl
Product: CC(C)(C#N)NCCCCO
Temperature: 20 °C
Reaction time: 16 h

Procedure:
220 μl of acetone cyanohydrin and 200 μl of 4-amino 1-butanol were mixed together with stirring for 16 hours at 20° C. and then was diluted with 2 ml of methylene chloride, dried, filtered and the filtrate was concentrated under reduced pressure to obtain the propanonitrile which was used as is for the following stage.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16]([OH:20])(=[O:19])[CH:17]=O.[ClH:21]>C(O)(=O)C.C(O)C>[C:11]([C:7]1[CH:8]=[C:9]([CH:17]([Cl:21])[C:16]([OH:20])=[O:19])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=CC(=O)O
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C(Cl)C(=O)O)cc(C(C)(C)C)c1O
Temperature: 180 °C
Reaction time: 8 h

Procedure:
65 g of still wet (3,5-di-tert-butyl-4-hydroxy-phenyl)-chloroacetic acid are prepared from 41.2 g (0.2 mol) of 2,6-di-tert-butylphenol, 35.4 g (0.24 mol) of 50% aqueous glyoxylic acid and 44 g of hydrogen chloride in 200 ml of acetic acid as described in Example 2A. This acid is dissolved in 200 ml of absolute ethanol and allowed to stand overnight. The solvent is then evaporated in vacuo, 1.0 g of p-toluenesulfonic acid is added, followed by another 200 ml of absolute ethanol. The mixture is then heated for three hours, and the ethanol is then evaporated. The residue is then stirred at 0.1 mm Hg vacuum with the bath temperature slowly increasing up to 180° C. The title compound distills at a temperature between about 140°-160° C. as a viscous orange liquid in a yield of 27 g.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](/[C:13](=[CH:25]\[CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)/[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:36]>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10](/[C:13](/[C:14]3[NH:36][C:17]([C:19]4[S:20][CH:21]=[CH:22][N:23]=4)=[CH:16][CH:15]=3)=[CH:25]\[CH:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(CCC(=O)c1nccs1)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(/C(=C\C2CCOCC2)c2ccc(-c3nccs3)[nH]2)cc1)C1CC1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 49.9 %

Procedure:
To a solution of (5E)-5-[4-(cyclopropylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)-1-(1,3-thiazol-2-yl)hex-5-ene-1,4-dione (278 mg) in acetic acid (5 mL) was added ammonium acetate (750 mg), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (133 mg, yield 50%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 441 (MH+).
Reaction SMILES: O=[C:2]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3]1.[NH2:26][OH:27].Cl.CC([O-])=O.[Na+]>CCO>[OH:27][N:26]=[C:2]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3]1
Reactant: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)c2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CC(=NO)c1ccccc12
Yield: 87 %

Procedure:
A solution of benzyl 3-oxo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (3 g, 10.3 mmol) in EtOH (30 mL) containing NH2OH.HCl (1.43 g, 20.6 mmol) and NaOAc (1.52 g, 18.53 mmol) was heated under reflux for 1.5 h. The solvent was removed by evaporation and the residue was partitioned between CH2Cl2 and water. The organic phase was washed with brine, dried over Na2SO4, and concentrated to provide benzyl 3-(hydroxyimino)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (3.14 g, yield 99%), which was used directly in the next step.
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C(N(CC)CC)C.[H][H]>CO.[Ni]>[NH2:2][CH2:1][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(F)n2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CN)(c2cccc(F)n2)CC1

Procedure:
A solution of tert-butyl 4-cyano-4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate (250 mg, 0.82 mmol) in methanol (20 mL) with triethylamine (1 mL) was reacted with Raney nickel (0.5 mL of 50% slurry in water) under 40 psi hydrogen for 5 hours. The catalyst was filtered off and washed thoroughly with methanol. Evaporation of the solvent afforded the desired product: tert-butyl 4-(aminomethyl)-4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate: m/z (ES) 310 (M+H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:14][O:15][C:16]([C:18]12[CH2:23][CH:22]1[CH:21]([O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:19]2=[O:29])=[O:17]>>[CH3:14][O:15][C:16]([CH:18]1[CH:22]([CH2:23][S:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:21]([O:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[CH2:20][C:19]1=[O:29])=[O:17]
Reactant: Sc1ccccc1
Reactant: COC(=O)C12CC1C(O[Si](C)(C)C)CC2=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COC(=O)C1C(=O)CC(O[Si](C)(C)C)C1CSc1ccccc1
Yield: 66.7 %

Procedure:
In accordance with the process of Preparation 3, potassium t-butoxide (246 mg; 2.2 mmol), thiophenol (220 mg; 2 mmol) and 2-oxo-4-trimethylsilyloxy-bicyclo[3.1.0] hexane-1-carboxylic acid methyl ester (484 mg; 2 mmol) were used to obtain 470 mg of 2-oxo-5-phenylthiomethyl-4-trimethylsilyloxy-cyclopentanecarboxylic acid methyl ester as a viscous oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[F:22])=[O:4].[OH-].[Na+].Cl>CO.O>[Br:11][C:9]1[C:8](=[O:12])[N:7]([CH3:13])[C:6]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[F:22])=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=1
Reactant: COC(=O)c1cc(Br)c(=O)n(C)c1Nc1ccc(Br)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)O)cc(Br)c1=O
Temperature: 60 °C
Yield: 72.5 %

Procedure:
To a suspension of 5-bromo-2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.030 g, 0.069 mmol) in methanol (1 mL) was added 1 M NaOH (0.346 mL, 0.346 mmol). The reaction mixture was heated to 60° C. for 12 hours. The reaction mixture was diluted with H2O and the pH was adjusted with 1 M HCl until 1-2. Solids precipitated out of solution, which were collected, washed with H2O and dried under vacuum to yield 0.021 g (72%) pure desired product as a pale yellow solid. MS ESI (+) m/z 421, 423 (M+, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 13.3 (br s, 1H), 9.93 (s, 1H), 8.21 (s, 1H), 7.66 (d, 1H), 7.34 (d, 1H), 7.05 (t, 1H), 3.18 (s, 3H).