Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[OH:31][C:32]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.Cl.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:31][C:32]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:37][CH2:36][N:35]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][N:5]([C@H:14]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:4]2)[CH2:34][CH2:33]1
Reactant: OC1(CCCc2ccccc2)CCNCC1
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(O)(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 87 mg (0.21 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step I) and 69 mg (0.26 mmol) of 4hydroxy-4-(3-phenylpropyl)-piperidine.HCl in 5 mL of CH2Cl2 at rt was treated with 0.045 mL (0.25 mmol) of DIEA and 86 mg (0.40 mmol) of sodium triacetoxyborohydride and stirred at rt for 1 h. The reaction was diluted with 25 mL of CH2Cl2 and washed with 25 mL of 1.0 N NaHCO3. The layers were separated and the aqueous layer was extracted with 25 mL of CH2Cl2. The combined organic phases were washed with 50 mL of sat'd NaCl, dried over Na2SO4 and concentrated. Flash chromatography on silica gel using 50:1 v/v CH2Cl2/MeOH as the eluant afforded 110 mg (83%) of the title compound: RF: 0.46 (20:1 v/v CH2Cl2/MeOH); 1H NMR (300 MHz) δ 0.91-2.85 (m, 32H), 3.16-3.27 (m, 3H), 5.15 (ABq, J=12.2 Hz, 2H), 7.15-7.41 (m, 15H); NH3-CI-MS 609 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:6]([C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)=[O:7])[CH2:15][CH2:14]1)[CH3:12]
Reactant: CCN1CCNCC1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCN1CCN(C(=O)c2ccc(I)cc2)CC1

Procedure:
Into a 100 mL round bottom flask was placed 4-iodobenzoyl chloride (2.67 g, 0.01 mmol) and dichloromethane (25 mL). The flask was placed in an ice water bath. Then N-ethylpiperazine (2.6 mL, 0.021 mmol) was added dropwise with stirring. The reaction was allowed to stir for 10 days at room temperature. Saturated aqueous potassium carbonate (50 mL) was added, and the product was extracted with ethyl acetate (3×100 mL). The organic layers were dried over sodium sulfate, filtered through a silica plug, and concentrated under reduced pressure to afford the title compound as a yellow oil. Mass found by LC-MS(+): 345 M+H+); calc. for C19H29BN2O3: 344.26.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH2:16][CH2:17][O:18]COCC1C=CC=CC=1)[CH2:3][CH2:4][C:5]12[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:9](=[O:15])[NH:8][C:6]2=[O:7].Cl>CO>[CH3:1][C:2]([CH3:28])([CH2:16][CH2:17][OH:18])[CH2:3][CH2:4][C:5]12[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:9](=[O:15])[NH:8][C:6]2=[O:7]
Reactant: CC(C)(CCOCOCc1ccccc1)CCC12C=CC=CC1C(=O)NC2=O
Agent: Cl
Solvent: CO
Product: CC(C)(CCO)CCC12C=CC=CC1C(=O)NC2=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of 5.70 g (14.9 mmol) of 1-(3,3-dimethyl-5-benzyloxymethoxypentyl)phthalimide in 70 ml of methanol was added 3.75 ml (45 mmol) of conc. HCl. The mixture was stirred for 3 hours at 60° C. The reaction mixture was cooled, and the solvent was distilled off. The residue was dissolved in 100 ml of water, to which was added 30 ml of 1N aqueous solution of sodium hydroxide. The mixture was extracted with dichloromethane. The extract solution was dried, and the solvent was distilled off. The residue was purified by column chromatography (eluent: n-hexane/ethyl acetate=2:1→1:2) to give 3.63 g of the desired compound (93.2%, white solid).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+].Br[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([CH3:31])[CH:25]=[N:24]2>O.C1(C)C=CC=CC=1>[CH3:31][C:26]1[CH:25]=[N:24][C:23]2[C:28]([N:27]=1)=[CH:29][C:30]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)=[CH:21][CH:22]=2
Reactant: Cc1cnc2cc(Br)ccc2n1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cnc2ccc(-c3ccc(C#N)cc3)cc2n1
Temperature: 80 °C

Procedure:
4-Cyanophenylboronic acid (588 mg, 4.0 mmol), cesium carbonate (2.2 g, 7.0 mmol), and cesium fluoride (608 mg, 4.0 mmol) were combined in H2O (15 mL) and treated with the products from Example 61B (446 mg, 2.0 mmol) in toluene (10 mL) and heated at 80° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and filtered through a pad of celite. The filtrate was partitioned between IPAc (60 mL) and H2O (50 mL). The organic layer was separated, washed with 20% brine, dried with Na2SO4, filtered, and the filtrate was concentrated under vacuum to provide the title compounds which were used in the next step without further purification. MS 246 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.69 (s, 1H), 8.02–8.20 (m, 4H), 7.84–7.90 (m, 2H), 7.70–7.76 (m, 8H), 2.73 (s, 6H); 13C NMR (400 MHz, CDCl3) δ 154.34, 154.10, 146.47, 147.17, 143.80, 142.93, 141.74, 140.62, 140.39, 140.18, 139.16, 132.49, 130.16, 129.74, 129.25, 128.71, 128.63, 128.06, 127.77, 127.74, 127.66, 127.59, 127.22, 126.73, 118.39, 118.37, 111.61, 111.51, 22.96.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[I:7][CH2:8][CH2:9][OH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CCOCC>[I:7][CH2:8][CH2:9][O:10][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: OCCI
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: ICCOC1CCCCO1
Reaction time: 1 h

Procedure:
Freshly distilled dihydropyran (Aldrich, 59.0-g, 0.7 mol) was added dropwise to a cooled solution of 2-iodoethanol (Aldrich, 98 g, 0.57 mol) in Et2O (1 L) containing 0.1 g of p-toluenesulfonic acid (Eastman). The solution was then stirred for 1 h at 5°. Solid K2CO3 (Mallinckrodt, 5 g) was then added to the reaction mixture and the resulting suspension stirred an additional 1 h at RT. The reaction was then filtered and the remaining solid washed with Et2O (1 L). The organic solutions were combined and concentrated rotary evaporation (in a flask washed with 1% NEt3 in H2O). The crude 2-(2-iodoethoxy)tetrahydro-2-H-pyran (~100 g, 68.9%) was used without further purification.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1.[CH3:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=1)=O.Cl>O1CCCC1>[Br:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=2)=[CH2:17])[CH:21]=1
Reactant: CC(C)Oc1ccc(Br)cc1
Reactant: CC(=O)c1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(OC(C)C)cc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
n-Butyllithium (1.6 M solution in hexane, 12.0 mL, 0.9 eq) was added dropwise to a solution of 1-bromo-4-isopropoxy-benzene (4.8 g, 22 mmol, 1.0 eq) in tetrahydrofuran (20 mL) at −78° C. After stirring 30 min 3-bromoacetophenone (3.3 mL, 1.1 eq) in tetrahydrofuran (20 mL) was added dropwise. The mixture was allowed to warm up to room temperature and stirred for 2 h, then treated with 1 N HCl (10 mL), extracted with ethyl acetate, dried (sodium sulfate) and concentrated in vacuo. The crude material was dissolved in acetic acid (50 mL) and sulfuric acid (10 mL) and the mixture was warmed to 75° C. for 30 min, cooled at room temperature and 1 N NaOH was added up to pH=7. The aqueous phase was extracted with dichloromethane (3×10 mL), dried (sodium sulfate) the solvent was removed and the residue was purified by column chromatography (cyclohexane) to afford the title compound as a colourless oil (1.8 g, 25%);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:9](=[O:18])[CH2:8][O:7][C:6]=2[CH:19]=1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>C(O)C.C([O-])(O)=O.[Na+]>[O:18]=[C:9]1[CH2:8][O:7][C:6]2[CH:19]=[C:2]([NH:1][C:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[NH:27])[CH:3]=[CH:4][C:5]=2[N:10]1[CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Nc1ccc2c(c1)OCC(=O)N2CCN1CCCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)OCC(=O)N2CCN1CCCC1)c1cccs1
Reaction time: 48 h
Yield: 90.4 %

Procedure:
A solution of 7-amino-4-(2-(pyrrolidin-1-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (0.125 g, 0.478 mmol) in dry ethanol (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.27 g, 0.956 mmol) at room temperature. The resulting mixture was stirred for 2 days. The reaction was then diluted with saturated NaHCO3 solution (20 mL), and the product was extracted into CH2Cl2 (2×20 mL). The combined CH2Cl2 layers were washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (3:97 (2 M NH3 in MeOH):CH2Cl2) to obtain the title compound 3 (0.16 g, 90%) as a solid. 1H NMR (DMSO-d6) δ 1.64-1.72 (m, 4H), 2.46-2.54 (m, 4H, merged with DMSO-d6 resonance), 2.60 (t, 2H, J=7.2 Hz), 3.99 (t, 2H, J=7.2 Hz), 4.58 (s, 2H), 6.47-6.57 (m, 4H), 7.06-7.12 (m, 2H), 7.60 (d, 1H, J=4.2 Hz), 7.73 (d, 1H, J=3.3 Hz); ESI-MS (m/z, %): 371 (MH+, 66), 150 (63), 128 (100); ESI-HRMS calculated for C19H23N4O2S (MH+), calculated: 371.1536, observed: 371.1548; HPLC purity 93.17% by area.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5][CH:4]=1.CC(=CC)C.Cl([O-])=[O:21].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:21])=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)c2ccccc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(C(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
4-Methoxy-1-naphthaldehyde (10 g, 53.72 mmol) was dissolved in t-butanol (75 ml) and 2-methyl-2-butene (35 ml) was added at room temperature. A solution of sodium chlorite (7.99 g, 70.63 mmol) and sodium dihydrogen orthophosphate (9.15 g, 76.27 mmol) in water (50 ml) was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was washed with a solution of 2MHCl (100 ml) and the solid was filtered and washed with dichloromethane (100 ml) and water (100 ml) and dried in vacuo. The solid was recrystallised from methanol to give 5.95 g (55%) of 4-methoxy-1-naphthoic acid as cream crystals.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH:13]([N:16]2[C:25]3[C:20](=[CH:21][C:22]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[NH:28])=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)C(=O)OC(C)(C)C.N1CCC(N2CCCCC3C=C(NC(C4SC=CC=4)=N)C=CC2=3)C1>CO.Cl>[CH3:1][NH:2][CH:10]1[CH2:11][CH2:12][CH:13]([N:16]2[C:25]3[C:20](=[CH:21][C:22]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[NH:28])=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:15]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(N2CCCc3cc(NC(=N)c4cccs4)ccc32)CC1
Agent: Cl
Agent: N=C(Nc1ccc2c(c1)CCCCN2C1CCNC1)c1cccs1
Solvent: CO
Product: CNC1CCC(N2CCCc3cc(NC(=N)c4cccs4)ccc32)CC1
Yield: 79 %

Procedure:
A solution of compound 11 (250 mg, 0.533 mmol) in methanol (10 mL) and 1M HCl (10 mL) was refluxed for 30 minutes and then concentrated. The residue was partitioned between 3N NaOH (50 mL) and CH2Cl2 (25 mL) and the product was extracted into CH2Cl2 (2×25 mL). The combined organic layers were dried (Na2SO4) and concentrated. This residue was subjected to flash chromatography on silica gel: 2% MeOH: 98% CH2Cl2 followed by 2.5% 2M ammonia in methanol; 97.5% CH2Cl2 to give a yellow-brown solid. (156 mg, 79% yield) 1H NMR (DMSO-d6) δ 7.66 (d, J=2.7 Hz, 1H), 7.54 (dd, J=0.9, 5.1 Hz, 1H), 7.06 (dd, J=3.6, 4.8 Hz, 1H), 6.63-6.41 (m, 3H), 6.21 (s, 2H), 3.55-3.46 (m, 1H), 3.35-3.30 (m, 1H) 3.13 (t, J=5.7 Hz, 2H), 2.63 (t, J=6.0 Hz, 2H), 2.26 (s, 3H), 2.10-1.75 (m, 6H), 1.60-1.45 (m, 2H), 1.39-1.32 (m, 2H). ESI-MS (m/z, %): 369 (MH+, 96), 338 (48), 258 (100), 185 (20), 148 (24), 140 (20); ESI-HRMS calculated for C21H29N4S (MH+): 369.2107, Observed: 369.2112; HPLC purity: 95.3%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(#N)C>[CH3:26][S:27]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[N:8]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 6-(hydroxymethyl)pyridin-2-ylcarbamate 80 (3.0 g, 13.4 mmol) and diisopropylethylamine (5.0 g, 40 mmol) in acetonitrile (30 mL) was added methanesulfonyl chloride (2.0 g, 17.4 mmol) over a period of 30 min at 0° C. and the mixture was stirred for 2 h at room temperature. The reaction was quenched by adding saturated aqueous NaHCO3 and extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford quantitative yield of crude 81.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.C1(P(=[CH:33][CH:34]=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[CH:33][CH:34]=[O:35])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH3:13]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)cc(Br)c1OC
Solvent: c1ccccc1
Product: COc1cc(C=CC=O)cc(Br)c1OC
Yield: 45 %

Procedure:
A mixture of 5-bromoveratraldehyde (100 mg, 0.41 mmol) and (triphenylphosphoranylidene)acetaldehyde (137 mg, 0.45 mmol) in dry benzene (2.5 ml) was refluxed for 9 h and the solvent was removed. The crude product was passed through a short silica gel column (bond-elute) (eluents: 10% ethyl acetate in hexane), giving 3-(3-bromo-4,5-dimethoxy-phenyl)-propenal (50 mg, 45%). 1H NMR (CDCl3): 9.68 (d, J=7.6 Hz, 1H), 7.36 (d, J =1.8 Hz, 1H), 7.34 (d, J=15.8 Hz, 1H), 7.03 (d, J=1.9 Hz, 1H), 6.62 (dd, J=7.6, 16.0 Hz, 1H), 3.913 (s, 3H), 3.907 (s, 3H) (the sample contained trace amount of starting material).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][NH:12][CH:13]=2)=[CH:4][CH:3]=1.IC.[C:22]([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:19])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][N:12]([CH3:22])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Product: CCOC(=O)c1cn(C)cc(-c2ccc(F)cc2)c1=O
Yield: 69.9 %

Procedure:
A mixture of Example A7 (1.5 g, 5.7 mmol) and iodomethane (0.9 g, 6.3 mmol) in satd. NaHCO3 (25 mL) was heated at 60° C. overnight. The mixture was filtered. The solid was concentrated under vacuum to afford ethyl 5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (1.1 g, 69.9% yield) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[C:5]([O:7][CH3:8])=[O:6].[NH4+].[Cl-]>CO.O.[Fe]>[NH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[CH3:1]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(N)c(C)c1
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 3-methyl-4-nitrobenzoate (50 g, 1.0 eq) in 1 L MeOH were added at rt a solution of NH4Cl (137 g, 10 eq) in 60 mL H2O and Fe power (96 g, 7 eq), and the resulting mixture is heated at reflux for 4 h. The reaction mixture was allowed to cool to rt, filtered, and water was added. The mixture was extracted with EtOAc. The extract was dried, washed with water, and concentrated to give the desired product directly as a white solid (26 g, 62%).
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(C1C=CC(C)=CC=1)(=O)=O.[Br-:33].[Li+].CCOCC.Cl>CC(C)=O>[Br:33][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCCCCCCOCC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)COCCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To 2 mmol of product 2 in acetone was added lithium bromide (7 mmol) and the solution was stirred at room temperature for 4 hours. Ether (20 ml) and dilute HCl was added, and the organic layer washed successively with water and brine, dried (MgSO4), and evaporated under reduced pressure. The product 3 was isolated as an oil in 85% yield by column chromotography (hexane/ethyl acetate 4:1). TLC (hexane/ethyl acetate 3:1) Rf=0.8. 1H-NMR 1.2-1.65 (m, 20H, CH2), 1.48 (s, 9H, (t-butyl) CH3), 3.41 (t, 2H, C(15)H2), 3.50 (t, 2H, C(4)H2), 3.94 (s, 3H, C(2)H2).
Reaction SMILES: C[O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:36])[NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[OH:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[CH2:28][NH:27][C:26]([C:19]1[S:18][C:17]([C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[C:3]([OH:37])=[O:2])=[O:16])=[C:21]([C:22]([F:25])([F:24])[F:23])[CH:20]=1)=[O:36]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC[C@H](NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(F)(F)F)C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-2-{[5-(3-Hydroxy-benzylcarbamoyl)-3-trifluoromethyl-thiophene-2-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (40 mg, 0.072 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (30 mg, 0.71 mmol) in water (6 mL). The mixture was then stirred at room temperature 4 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 26.7 mg (68%). MS m/e 542.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:36]=[CH:35][C:12]3[N:13]=[C:14]([C@@H:16]4[CH2:19][C@H:18]([N:20]5[CH2:27][C@@H:26]6[C@@H:22]([N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25]6)[CH2:21]5)[CH2:17]4)[S:15][C:11]=3[CH:10]=2)=[CH:5][N:4]=1.N1C=C(C2C=CC3N=C([C@@H]4C[C@H](N5C[C@@H]6[C@@H](N(C(OC(C)(C)C)=O)CC6)C5)C4)SC=3C=2)C=NC=1>>[NH:23]1[CH2:24][CH2:25][C@@H:26]2[CH2:27][N:20]([C@@H:18]3[CH2:19][C@H:16]([C:14]4[S:15][C:11]5[CH:10]=[C:9]([C:6]6[CH:5]=[N:4][C:3]([O:2][CH3:1])=[N:8][CH:7]=6)[CH:36]=[CH:35][C:12]=5[N:13]=4)[CH2:17]3)[CH2:21][C@H:22]12
Reactant: COc1ncc(-c2ccc3nc([C@H]4C[C@@H](N5C[C@H]6CCN(C(=O)OC(C)(C)C)[C@H]6C5)C4)sc3c2)cn1
Agent: CC(C)(C)OC(=O)N1CC[C@@H]2CN([C@H]3C[C@@H](c4nc5ccc(-c6cncnc6)cc5s4)C3)C[C@@H]21
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@@H](N5C[C@H]6CCN[C@H]6C5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 38C, substituting the product of Example 39A for the product of Example 38B. 1H NMR (500 MHz, CDCl3) δ ppm 8.77 (s, 2H) 8.05 (d, J=8.54 Hz, 1H) 7.97 (s, 1H) 7.58 (dd, J=8.54, 1.83 Hz, 1H) 4.08 (s, 3H) 3.85-3.98 (m, 1H) 3.60-3.70 (m, 1H) 3.08-3.16 (m, 1H) 2.90-3.02 (m, 2H) 2.73-2.81 (m, 1H) 2.61-2.71 (m, 2H) 2.49-2.60 (m, 3H) 2.31-2.47 (m, 3H) 1.93-2.05 (m, 1H) 1.58-1.74 (m, 1H). MS: (M+H)+=408.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])=[CH:10][CH:9]=1.[CH2:22]([C:24]([C:43]1[CH:56]=[CH:55][C:46]([O:47][CH2:48][C@@H:49]2[O:53][C:52](=[O:54])[CH2:51][CH2:50]2)=[C:45]([CH3:57])[CH:44]=1)([C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[C:29]([CH3:42])[CH:28]=1)[CH2:25][CH3:26])[CH3:23].C(OCC)(=O)C>CN(C)C=O>[CH2:22]([C:24]([C:43]1[CH:56]=[CH:55][C:46]([O:47][CH2:48][C@@H:49]2[O:53][C:52](=[O:54])[CH2:51][CH2:50]2)=[C:45]([CH3:57])[CH:44]=1)([C:27]1[CH:32]=[CH:31][C:30]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])=[CH:10][CH:9]=2)=[C:29]([CH3:42])[CH:28]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CC(C)(O[Si](C)(C)C)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(-c2ccc(C(C)(C)O[Si](C)(C)C)cc2)c(C)c1
Temperature: 85 °C
Reaction time: 13.5 h
Yield: 47.8 %

Procedure:
A [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.49 mg, 0.002 mmol), a 2 M sodium carbonate solution (0.1 mL, 0.2 mmol) and [1-(4-bromo-phenyl)-1-methyl-ethoxy]-trimethylsilane (Example 15-(1); 26.25 mg, 0.091 mmol) were added to a solution of (R)-5-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (Example 15-(3); 30 mg, 0.061 mmol) in N,N-dimethylformamide (0.1 mL) at room temperature, and the mixture was stirred at 85° C. for 13.5 hours. Ethyl acetate was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=3/1, developed three times) to give the title compound (16.7 mg, 47.9%).