Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:3])=[O:2].Br[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=O>C(OCC)(=O)C>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:3]=[CH:1][O:2][CH:5]=2)=[CH:9][CH:10]=1
Reactant: NC=O
Reactant: COc1ccc(C(=O)CBr)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cocn2)cc1
Temperature: 180 °C
Reaction time: 0.33 h

Procedure:
10 ml of formamide was added to 2 g of 2-bromo-4′-methoxyacetophenone, and stirred at 180° C. for 20 minutes. This was restored to room temperature, diluted with ethyl acetate, and washed with water and saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane to hexane/ethyl acetate=7/3) to obtain 0.76 g of the entitled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[CH3:27][C:28]1[N:33]=[C:32]2[NH:34][CH:35]=[C:36]([CH:37]=O)[C:31]2=[CH:30][CH:29]=1>CO.N1CCCCC1>[Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9]/[C:8](=[CH:37]\[C:36]3[C:31]4[C:32](=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=4)[NH:34][CH:35]=3)/[C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: Cc1ccc2c(C=O)c[nH]c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: Cc1ccc2c(/C=C3\Oc4c(cc(Cl)c(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c2n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
A solution of tert-butyl 4-[(5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.012 g, 0.031 mmol) obtained in Example A12, Step 2 in methanol (2.0 mL) was added with 6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.005 g, 0.028 mmol) obtained in Example A48, Step 4. Then, the mixture was added with 5 drops of piperidine, and then the mixture was stirred at 50° C. for 3 hours. The solvent was evaporated under reduced pressure, and then the residue was suspended in diethyl ether and thereby washed to obtain tert-butyl (Z)-4-({5-chloro-6-hydroxy-2-[(6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.010 g, 68%).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:15][O:16][C:17](=[O:26])[C:18]([NH:20][CH2:21][C:22]([O:24][CH3:25])=O)=[O:19]>C(#N)C>[CH3:25][O:24][C:22]1[O:19][C:18]([C:17]([O:16][CH3:15])=[O:26])=[N:20][CH:21]=1
Reactant: COC(=O)CNC(=O)C(=O)OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CC#N
Product: COC(=O)c1ncc(OC)o1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a warm (35-40° C.) suspension of phosphorous pentoxide (77.7 g, 109 mmol) in anhydrous acetonitrile (200 mL) was added methyl[(2-methoxy-2-oxoethyl)amino](oxo)acetate (19.19 g, 109.6 mmol). The reaction mixture was heated to 65° C., then stirred overnight at room temperature. The product mixture was cooled to 0° C. and carefully quenched with ice and brine keeping the reaction from generating an unsuitable exotherm. The resultant mixture was extracted with ethyl acetate (600 mL). The organic extract was washed with brine, dried with Na2SO4, then concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 100% CH2Cl2. The appropriate fractions were combined and concentrated to afford the title compound as a light yellow solid that was used without further purification.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:46][C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1>CN(C)C=O>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:51][C:50]4[CH:52]=[CH:53][C:47]([F:46])=[CH:48][CH:49]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1ccc(F)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(F)cc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2S,4S)-1-[[N-(4-Carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg), along with 1-hydroxybenzotriazole, was dissolved in N,N-dimethylformamide (1.0 mL). While the solution was chilled in an ice bath, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53.4 mg) was added and the mixture was allowed to warm to room temperature and was stirred for 1 hour. Subsequently, 4-fluoroaniline (17.8 μL) was added and the mixture was stirred for additional 2 hours. The solvent was evaporated under reduced pressure and the resulting residue was purified by preparative thin-layer chromatography (solvent:dichloromethane:methanol=4:1) to give (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-fluorophenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (14.6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH:21]1[N:25]=[C:24]([NH2:26])[S:23][CH:22]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][C:24]2[S:23][CH:22]=[CH:21][N:25]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1nccs1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1nccs1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and aminothiazole (51.2 mg, 0.51 mmol). The title compound was obtained as a brown solid (77.0 mg, 42% yield). 1H NMR (400 MHz, d6-DMSO) δ: 13.12 (1H, br), 9.02 (2H, s), 7.73 (1H, m), 7.24 (1H, m). MS m/z: 431.20, 433.13 [M+H]+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=4)[CH:24]=[C:23]([CH3:38])[N:22]=3)[CH:18]=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:38][C:23]1[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=3)[N:20]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(OC(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(OC(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)n2)n1
Temperature: 23 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
To N-tert-butyl-3-{6-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide (Example 436) (0.100 g, 0.185 mmol) was added TFA (3 mL) and the reaction mixture was stirred at 23° C. for 3 h. The mixture was partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over MgSO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as an off-white solid (0.068 g, 76%). MS (ISP) 486.0 [(M+H)+]; mp 231° C. (dec.).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11]2.CN([CH:24]=[O:25])C>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([F:20])([F:18])[F:19])=[C:11]2[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: COc1ccc2[nH]c(C(F)(F)F)cc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c(C(F)(F)F)c(C=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
DMF (1 mL) was cooled to 0° C. and POCl3 (0.25 mL) was added and stirred for 10 min Compound 203 (336 mg, 1.69 mmol) in DMF (2 mL) was added drop-wise over 10 min. The solution was stirred for an additional 1 h warming to rt then heated to 85° C. and allowed to react for an additional 4 h. The solution was poured into ice-cold 1 N NaOH (40 mL) and stirred for 30 minutes in an ice-bath resulting in the formation of a precipitate. The precipitate was collected, washed with cold H2O and dried overnight at 40° C. in a vacuum desiccator to yield a cream-colored solid. The sample was further purified by chromatography (7% to 20% EtOAc/hexanes) to obtain a white solid (178 mg, 43%): mp 236-239° C. TLC Rf 0.51 (30% EtOAc/hexanes). 1H NMR (600 MHz, d4-MeOH) δ 10.22 (s, 1H), 7.79 (d, 1H, J=2.46 Hz), 7.45-7.43 (d, 1H, J=9 Hz), 7.06-7.04 (dd, 1H, J1=8.94 Hz, J2=2.52 Hz), 3.86 (s, 3H). 13C NMR (150 MHz, d4-MeOH) δ 186.2, 159.0, 132.0, 127.1, 123.4, 121.6, 118.2, 117.2, 114.8, 104.1, 56.2. 19F NMR (376 MHz, CDCl3) δ −58.7 (s, 3F). Elemental analysis calculated for C11H8F3NO2: C, 54.33; H, 3.32; N, 5.76. Found: C, 54.53; H, 3.32; N, 5.76.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3Cl)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[NH:40][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C)CCN
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2Cl)[C@H](c2ccccc2)C1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: CN(C)CCNc1ccccc1[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1c1ccccc1

Procedure:
The title compound, MS: m/e=564.3 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(2-chloro-phenyl)-3-phenyl-piperidin-1-yl]-methanone, N,N-dimethyl-ethylendiamine and biphenyl-2-yl-dicyclohexyl-phosphane as ligand.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:20][CH2:21]OC(C)=O>CN(C=O)C.[Cu]I.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>[C:20]([C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1)#[CH:21]
Reactant: CC(=O)Nc1ccc(Oc2ccnc(Cl)c2)c(C)n1
Reactant: CCOC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: C#Cc1cc(Oc2ccc(NC(C)=O)nc2C)ccn1
Temperature: 75 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of Example A5 (0.35 g, 1.260 mmol) in DMF (5 mL) was sparged with argon, treated with TEA (1 mL) trimethylsilylacetylene (0.531 mL, 3.78 mmol), copper(I) iodide (0.024 g, 0.126 mmol) and dichlorobis(triphenylphosphine)palladium(II) [Pd(PPh3)2Cl2](0.088 g, 0.126 mmol) and heated at 75° C. under argon for 16 h. The mixture was cooled to RT, treated with EtOAc, solids removed via filtration through diatomaceous earth, rinsed well with EtOAc and H2O and the layers of the filtrate separated. The aqueous layer was extracted with EtOAc (1×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The resulting material was dissolved in MeOH (20 mL), treated with K2CO3 (300 mg) and stirred at RT for 1 h. The mixture was concentrated to dryness, treated with EtOAc, sonicated, the solids removed via filtration through diatomaceous earth, rinsed well with EtOAc and the filtrate concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(5-((2-ethynylpyridin-4-yl)oxy)-6-methylpyridin-2-yl)acetamide (102 mg, 30%) as a light red solid. 1H NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H); 8.40 (d, J=5.8 Hz, 1H); 8.01 (d, J=8.8 Hz, 1H); 7.60 (d, J=6.0 Hz, 1H); 7.04 (d, J=2.5 Hz, 1H); 6.89 (dd, J=5.8, 2.6 Hz, 1H); 4.34 (s, 1H); 2.22 (s, 3H); 2.07 (s, 3H); MS (ESI) m/z: 268.1 (M+H+).
Reaction SMILES: OC[C@@H](N[C:11](=[O:26])[C@@:12]([CH3:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])C1C=CC=CC=1.S(=O)(=O)(O)[OH:28]>O1CCOCC1>[CH3:25][C@:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH2:13][CH2:14][C:15]([CH3:16])([CH3:17])[CH3:18])[C:11]([OH:26])=[O:28]
Reactant: CC(C)(C)CC[C@@](C)(C(=O)N[C@H](CO)c1ccccc1)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)CC[C@@](C)(C(=O)O)c1ccccc1
Yield: 98 %

Procedure:
To a solution of Example 49A (3.78 g, 10.7 mmol) in 1,4-dioxane (60 mL) was added 4 M sulfuric acid (60 mL) and the reaction was stirred at reflux for 48 hours. The solution was concentrated in vacuo, dissolved in 1 N NaOH (250 mL), and washed with hexane (200 mL). The aqueous layer was acidified to pH 1 with 6 N HCl and extracted with ethyl acetate (3× 200 mL). The combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give a clear oil (2.47 g, 98%). 1H NMR (300 MHz, CDCl3): δ ppm 0.86 (s, 9H) 1.09 (m, 2H) 1.56 (s, 3H) 1.99 (m, 2H) 7.33 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])=[CH:4][CH:3]=1.[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:17]([O:13][C:12](=[O:14])[CH2:11][CH2:10][NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc(C(=O)NNCCC(=O)O)cc1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Nc1ccc(C(=O)NNCCC(=O)OCc2ccccc2)cc1

Procedure:
N-(p-Aminobenzamido)-β-alanine is reacted with benzyl alcohol and p-toluenesulphonic acid to give N-(p-aminobenzamido)-β-alanine benzyl ester, m.p. 96°-97° C.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:49])[C:11]2[CH:17]=[C:16]([CH2:18][N:19]([CH2:26][C:27]3[CH:48]=[CH:47][C:30]([C:31]([NH:33][C@H:34]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:32])=[CH:29][CH:28]=3)[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>C(O)(=O)C.[Pt]=O>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:49])[C:11]2[CH2:17][CH:16]([CH2:18][N:19]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:31]([NH:33][C@H:34]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:32])=[CH:47][CH:48]=3)[C:20](=[O:25])[C:21]([F:23])([F:24])[F:22])[CH2:15][NH:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CN(Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)C(=O)C(F)(F)F)cc1)C(=O)OCC
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CN(CC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)C(=O)C(F)(F)F)cc1)C(=O)OCC
Reaction time: 3 h
Yield: 33.1 %

Procedure:
To 3.75 g. (5.43 mmol) of the product of Example 3, diethyl N-[N-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylmethyl)-N-trifluoroacetyl-4-aminomethylbenzoyl]-glutamate, in 60 mL of glacial acetic acid are added 575 mg of platinum oxide. The suspension was hydrogenated in a Parr apparatus at 50 psi at 25° C. for 3 h. The reaction mixture was filtered through Celite and the solvent removed under reduced pressure. The residue was taken up in methylene chloride and extracted twice with a saturated solution of sodium bicarbonate and the organic layers dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed, eluting with 5% methanol in methylene chloride to give 1.25 g (33% yield) of diethyl N-[N-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-ylmethyl)-N-trifluoroacetyl-4-aminomethylbenzoyl)-glutamate; 1H NMR (Me2SO d6) delta 1.11-1.15 (m, 6H), 1.33 (s, 9H), 1.6-2.1 (m, 6H), 2.28-2.33 (m, 2H), 3.07-3.18 (m, 1H), 3.97-4.10 (m, 4H), 4.10-4.20 (m, 1H), 6.64-6.67 (m, 1H), 8.03-8.06, (m, 1H).
Reaction SMILES: [F:1][B-](F)(F)F.[H+].[CH2:7]([C:11]1[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14](N)[N:15]=1)[CH2:8][CH2:9][CH3:10].N([O-])=O.[Na+]>O>[CH2:7]([C:11]1[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([F:1])[N:15]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1nc(N)c(C(=O)OCC)n1Cc1ccccc1Cl
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CCCCc1nc(F)c(C(=O)OCC)n1Cc1ccccc1Cl
Temperature: 0 °C

Procedure:
The 4-amino product was fluorinated using the procedure of K. L. Kirk and L. J. Cohen, JACS, 95 (14), 4619 (1973). Fluoroboric acid (48%, 150 mL) was added to 2-n-butyl-1-{(2-chlorophenyl)methyl}-4-amino-5-carboethoxyimidazole (10.75 g, 0.032 mol) in a quartz flask. The resulting solid mass was sonicated and stirred vigorously to form a suspension. This suspension was cooled to 0° C. and then sodium nitrite (2.80 g, 0.0406 mol) in 5 mL of water was added slowly. The ice bath was removed and then the reaction mixture was irradiated for 20 hours with a 450-watt mercury vapor lamp placed in a quartz immersion well, cooled by circulating water. The reaction mixture was cooled to -20° C. and the pH was adjusted to 6.4 with 50% aqueous sodium hydroxide. The product was extracted into ethyl acetate (3×) and the combined extracts were washed with water and saturated sodium chloride solution. The organic extract was dried with anhydrous sodium sulfate and concentrated to give 8.43 g of a crude product, which was chromatographed on silica gel eluting with chloroform to give 4.31 g of 2-n-butyl-1-{(2-chlorophenyl)methyl}-4-fluoro-5-carboethoxyimidazole.
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][C@@H:16]([CH2:25][CH:26]([CH3:28])[CH3:27])[C@@H:17]([OH:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=O)(C)(C)C.CN1CCOCC1>CN(C)C=O>[NH2:15][C@@H:16]([CH2:25][CH:26]([CH3:27])[CH3:28])[C@@H:17]([OH:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: CCOC(=O)C[C@H](O)[C@@H](N)CC(C)C
Reaction time: 0.33 h

Procedure:
Meanwhile, 5 ml of 6N hydrogen chloride/dioxane were added to 152 mg (0.5 mmole) of ethyl 4(S)-t-butoxycarbonylamino-3(S)-hydroxy-6-methylheptanoate. The solution was stirred for 20 minutes under a nitrogen stream, and then concentrated by evaporation under reduced pressure, to give a solid residue. The resulting residue was dissolved in 2 ml of dimethylformamide, and 0.05 g of N-methylmorpholine was added to give a solution of ethyl 4(S)-amino-3(S)-hydroxy-6-methylheptanoate.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.Br[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1>O.C(COC)OC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:10][CH:9]=1
Reactant: Brc1cccs1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1ccc(-c2cccs2)cc1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
A solution of sodium carbonate (1.63 g) in H2O (7.65 ml), 4-fluorobenzeneboronic acid (1.03 g) and tetrakis(triphenylphosphine) palladium(0) (70.9 mg) were added successively to a solution of 2-bromothiophene (1.00 g) in dimethoxyethane (12.3 ml). The mixture was refluxed for 4 hours. The mixture was cooled to ambient temperature and partitioned between AcOEt and H2O. The organic layer was washed with 0.5N aqueous NaOH solution and saturated aqueous NaCl solution, dried over MgSO4 and concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: n-hexane and then AcOEt in n-hexane 10%). The solvent was evaporated in vacuo to give 1.05 g of 2-(4-fluorophenyl)thiophene as a white solid.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15]/[C:16](=[C:23]2\[C:24](=[O:35])[NH:25][C:26]3[C:31]\2=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.C(OCC)(=O)C.Cl>ClCCl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15]/[C:16](=[C:23]2\[C:24](=[O:35])[NH:25][C:26]3[C:31]\2=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 29a from (Z)-3-[1-(4-tert.butoxycarbonylamino-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone and ethyl acetate/hydrogen chloride in dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[Br-].[Mg+2].[Br-].[CH:20](=[O:22])[CH3:21]>O1CCCC1>[OH:22][CH:20]([C:10]1[O:11][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)[CH3:21]
Reactant: COc1cccc2ocnc12
Reactant: CC=O
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COc1cccc2oc(C(C)O)nc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
4-Methoxybenzoxazole (6.0 g) was dissolved in tetrahydrofuran (225 ml) and cooled to −78° C. under nitrogen. n-Butyllithium (26.5 ml of a 1.6M solution in hexanes) was added, and the mixture stirred at −78° C. for 30 minutes before addition of magnesium bromide etherate (11.5 g). The resulting heterogeneous mixture was stirred at −45° C. for 15 minutes, and then cooled to −78° C. A solution of acetaldehyde (2.3 ml) was added from a pre-cooled syringe. The mixture was stirred at −78° C. for 3 h, then allowed to warm to room temperature and stirred overnight. It was quenched with aqueous sodium bicarbonate (50 ml, gradually) and the tetrahydrofuran evaporated in vacuo. The residue was extracted with dichloromethane (3×150 ml). The combined organic phases were dried over magnesium sulphate, evaporated in vacuo and purified by flash chromatography eluting with 30%-50% ethyl acetate in hexane to afford the title compound as a brown solid (6.25 g).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:37])(=O)=O)=CC=1.CCCCCC>C1COCC1>[F:37][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62.5 %

Procedure:
A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (1.50 g, 5.81 mmol) in THF (25.0 mL) was cooled to −78° C. followed by drop wise addition of LDA (1.80 M in THF, 6.50 mL, 11.62 mmol) and the mixture stirred at the same temperature for 45 min followed by addition of N-fluorobenzenesulphonimide (3.60 g, 11.62 mmol) at −78° C. The temperature of the reaction was slowly raised to rt and left to stir for 5-6 h. The reaction was then cooled to 0° C. and quenched by drop wise addition of saturated NH4Cl solution (50 mL), extracted with EtOAc (3×100 mL) and the combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 2% EtOAc:hexane to obtain the product as an orange viscous liquid (1.0 g, 63% yield). MS: 276.27 [M+H]+.