Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@H:10]([C:18](CCC)=S)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.CC(C)=[O:32]>[Pd]>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@H:10]([CH:18]=[O:32])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: CCCC(=S)[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)OCC
Agent: [Pd]
Agent: CC[SiH](CC)CC
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C=O
Reaction time: 0.75 h

Procedure:
To a mixture of 0.375 g of 10% Pd/C and 6.5 g (19.4 mmol) of 1-benzyl-3-(S)-(n-propanethiocarbonyl)-4-(S)-(ethoxycarbonyl)pyrrolidine in 30 mL acetone was added dropwise 7.5 mL (47.0 mmol) of triethylsilane over 15 min. The mixture was allowed to stir for 45 min after addition was complete. The reaction mixture was filtered through a thin pad of celite and the filtrate was concentrated. The residue was purified by chromatography (silica, acetone:hexanes, 1:4) to give 4.2 g of title compound; 1H NMR (CDCl3) δ9.69 (s, 1H), 7.25-7.33 (m, 5H), 4.18 (q, 2H, J=7.1 Hz), 4.44-4.48 (m, 1H), 3.61 (d, 1H, J=13.5 Hz), 3.64 (d, 1H, J=13.5 Hz), 3.32 (m, 1H), 3.46 (m, 1H), 1.27 (t, 7.1 Hz); Mass spectrum (ESI) m/e=262 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15][Si](C(C)C)(C(C)C)C(C)C)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F-].[Cs+]>CN1CCCC1=O>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([SH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2cc(S[Si](C(C)C)(C(C)C)C(C)C)ccc21
Agent: [Cs+]
Agent: [F-]
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cn1ccc2cc(S)ccc21
Temperature: 25 °C

Procedure:
(5-Triisopropylsilanylsulfanyl-indol-1-yl)-acetic acid ethyl ester (60 mg, 0.1621 mmol) is dissolved in n-methylpyrrolidinone (NMP) (5 mL) and cesium fluoride (0.243 mmol) is added. The reaction is allowed to stir at room temperature until complete. This solution may be used in the coupling step (next) without further purification.
Reaction SMILES: C(N=C=NCCCN(C)C)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:30][C:31]([OH:33])=O)[C:20](=[O:29])/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][CH:14]=1.[C:34]([O:38][C:39]([NH:41][C@H:42]1[CH2:46][CH2:45][NH:44][CH2:43]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]([C:20](=[O:29])/[CH:21]=[CH:22]/[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:30][C:31]([N:44]2[CH2:45][CH2:46][C@H:42]([NH:41][C:39](=[O:40])[O:38][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:43]2)=[O:33])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C(O)CN(C(=O)/C=C/c1ccccc1)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide (9.39 g, 0.049 mol) was added to a solution of {(4-Bromophenyl)-[(E)-(3-phenylacryloyl)]amino}acetic acid 2 (13.82 g, 0.038 mol), (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (9.13 g, 0.049 mol), 1-hydroxy-7-azabenzotriazole (6.67 g, 0.049 mol) and N-methylmorpholine (8.4 mL, 0.08 mol) in DMF (150 ml). The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 10% hydrochloric acid (×3), brine, saturated aqueous sodium bicarbonate (×2) and brine. The title compound began to crystallize during work-up and was collected by filtration. The mother liquor was concentrated to provide a further quantity of product. Total yield of title compound: 17.43 g, 86%. 1HNMR (300 MHz) (CDCl3) δ 1.45 (6H, s), 1.60 (3H, s), 1.7-2.3 (2H, m), 3.4-3.8 (4H, m), 4.1-4.9 (3H, m), 6.36 (1H, d, J=16 Hz), 7.36 (2H, d), 7.2-7.4 (5H, m), 7.55 (2H, d) and 7.70 (1H, d, J=16 Hz).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=1[F:22].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:16]1[CH:17]=[C:18]([OH:21])[CH:19]=[CH:20][C:15]=1[C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Oc1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cc2F)cc1
Yield: 71.4 %

Procedure:
2-Fluoro-4′-(methylsulfonyl)-4-biphenylol (0.58 g, 71%) was prepared as a white solid from [4-(methylsulfonyl)phenyl]boronic acid (0.69 g, 3.38 mmol), 4-bromo-3-fluorophenol (0.6 g, 3.05 mmol), 2M Na2CO3 (18 mL) and Pd(PPh3)4 (30 mg, 0.03 mmol) in DME (18 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CDCl3): δ 7.98 (d, 2H, J=8.3 Hz), 7.69 (d, 2H, J=7.4 Hz), 7.40-7.30 (m, 1H), 6.80-6.65 (m, 2H), 5.10 (s, 1H), 3.09 (s, 3H); LRMS (ESI), m/z 267 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([CH2:12][CH2:13][CH3:14])[N:4]=1)#[N:2].[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].O>CC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([CH2:12][CH2:13][CH3:14])[N:4]=1)#[N:2]
Reactant: CCCc1nc(C#N)c(C#N)nc1Cl
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCc1nc(C#N)c(C#N)nc1Oc1ccccc1
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
2,3-Dicyano-5-chloro-6-n-propylpyrazine (0.207 g; 0.001 mole) was dissolved in 15 ml of acetone, and a solution prepared from 0.094 g (0.001 mole) of phenol, 0.040 g (0.001 mole) of sodium hydroxide, 0.7 ml of water and 5 ml of acetone was added dropwise over the period of 5 minutes. Then, the mixture was stirred at 5° to 10° C. for 10 minutes. The reaction mixture was worked up in the same way as in Example 9, and recrystallized from benzene to afford 0.150 g (yield 57%) of 2,3-dicyano-5-phenoxy-6-propylpyrazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][CH2:5]2.[Br:12]Br>BrC1C=CC=CC=1>[Br:12][CH:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[C:7](=[O:11])[O:6]1
Reactant: BrBr
Reactant: O=C1OCc2cc(Br)ccc21
Solvent: Brc1ccccc1
Product: O=C1OC(Br)c2cc(Br)ccc21
Temperature: 158 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
The mixture of 5-bromo-3H-isobenzofuran-1-one (A3) (51.5 g, 242 mmol) in bromobenzene (100 mL) is heated to 158° C. Bromine (18.8 mL, 363 mmol) is added dropwise to the mixture over 2 h. The mixture is stirred for another 30 min. at 158° C. The bromobenzene is removed by distillation under vacuum. The residue is vacuum dried 1 hour at 120° C. to yield a black crystalline residue. Recrystallization: The residue is dissolved in hot isopropyl ether (300 mL). Activated charcoal (1 g) is added, stirred and filtered while hot. The filtrate is cooled in ice-water bath (0° C.) over night. The solid is filtered and is rinsed with cold isopropyl ether (2×10 mL) and vacuum dry over KOH (KOH) to yield 3,5-dibromo-3H-isobenzofuran-1-one (B3) (38 g, 54%, mp: 100° C.).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[F:16][C:17]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>C(Cl)Cl.O>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:3]=1[NH:4][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:24]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:25][C:17]=1[F:16]
Reactant: Nc1cc(Br)ccc1Br
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(F)c1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)Nc2cc(Br)ccc2Br)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
2-Fluoro-4-(methylsulfonyl)benzoic acid (1 g, 4.6 mmol) dissolved in DCM (15 ml), cooled to 0° C. and added oxalyl chloride (0.6 ml, 6.9 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 2-fluoro-4-(methylsulfonyl)benzoyl chloride quantitatively. 2,5-Dibromoaniline (0.9 g, 3.59 mmol) dissolved in DCM (10 ml) and added Pyridine (0.34 g, 4.30 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 2-fluoro-4-(methylsulfonyl)benzoyl chloride (1.01 g, 3.59 mmol). After continuing stirring at rt for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (1.6 g) as a brown solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.34 (s, 1H), 8.34-7.99 (m, 1H), 7.98-7.93 (m, 2H), 7.92-7.89 (m, 1H), 7.68 (d, J 8.6, 1H), 7.43 (dd, J 2.4, 8.6, 1H), 3.33 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])[C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[K+]>C(O)C>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(Br)ncn1-c1ccc(C)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-n2cnc(Br)c2C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To 1.88 g (5.8 mmol) of ethyl 4-bromo-1-(2,4-dimethylphenyl)-1H-imidazole-5-carboxylate in 30 mL of ethanol was added 3.0 mL (18 mmol) of 6N KOH and the resulting mixture was stirred for 3 h at room temperature. Volatiles were removed in vacuo, the residue was diluted with water, washed with ether and acidified with 1N HCl. The resulting precipitate was collected by filtration and dried to give 1.54 g (90%) of the title compound as a white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:17][CH2:18][CH3:19])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])C.[OH-].[K+]>C(O)C>[CH2:18]([O:17][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:8]=12)[CH3:19]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c(C(=O)O)cnc2c1cnn2CC

Procedure:
263 g. of 4-Ethoxy-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (1 mol.) are heated with a solution of 114 g. of potassium hydroxide (2 mol.) in 1 liter of ethanol at 60° for 12 hours. After this time, the solvent is removed in vacuo and the residue is dissolved in 1.5 liters of water. After acidifying with acetic acid, 4-ethoxy-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid precipitates. Recrystallization from alcohol yields 215 g. (91%), m.p. 198°-199°.
Reaction SMILES: [CH2:1]([CH:8]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1>[CH2:1]([CH:8]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CNC(=O)OC(C)(C)C)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(Cc1ccccc1)C(=O)O
Temperature: 60 °C
Reaction time: 5 h
Yield: 80.9 %

Procedure:
To a solution of ethyl 2-benzyl-3-[(tert-butoxycarbonyl)amino]propanoate (310 mg) in tetrahydrofuran (15 mL) were added 1N sodium hydroxide aqueous solution (6.0 mL) and the mixture was stirred at 60° C. for 5 hours. The mixture was cooled and adjusted to pH=2 by addition of 1N HCl. The mixture was extracted with ethyl acetate and the separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to afford 2-benzyl-3-[(tert-butoxycarbonyl)amino]propanoic acid (228 mg) as an crude oil.
Reaction SMILES: [CH:1]1([CH:4]([N:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]#[N:15])[C:7]2=[O:16])[CH3:5])[CH2:3][CH2:2]1.[Br:17]N1C(=O)CCC1=O>CN(C)C=O>[Br:17][C:10]1[C:9]([O:12][CH3:13])=[C:8]([C:14]#[N:15])[C:7](=[O:16])[N:6]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[CH3:5])[CH:11]=1
Reactant: COc1ccn(C(C)C2CC2)c(=O)c1C#N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COc1c(Br)cn(C(C)C2CC2)c(=O)c1C#N
Temperature: 60 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
A mixture of 1-(1-cyclopropylethyl)-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step A of Example 163 (2.45 g), N-bromosuccinimide (3.00 g) and N,N-dimethylformamide (50 mL) was stirred at 60° C. for 16 hr. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.73 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[CH:17]2)=[O:13].Cl.Cl.[CH3:26][N:27]([CH3:35])[C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([N:27]([CH3:35])[CH3:26])[CH:29]=2)=[O:7])=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[CH:17]2)=[O:13]
Reactant: CN(C)c1cccc(N)c1
Reactant: O=C(Cl)c1ccc(Cl)c(NC(=O)c2ccc3ncccc3c2)c1
Agent: Cl
Product: CN(C)c1cccc(NC(=O)c2ccc(Cl)c(NC(=O)c3ccc4ncccc4c3)c2)c1

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-3-(6-quinolylcarbonylamino)benzoyl chloride was reacted with 3-dimethylaminoaniline dihydrochloride to give the title compound; NMR Spectrum: (DMSOd6) 3.04 (s, 6H), 6.5 (d, 1H), 7.08-7.20(m, 3H), 7.61-7.64 (m, 1H), 7.74 (d, 1H), 7.92 (d, 1H) 8.1-8.2 (m, 2H), 7.31 (d, 1H), 8.58 (d, 1H), 8.72 (s, 1H), 9.02 (s, 1H) 10.13 (s, 1H), 10.5 (s, 1H); Mass Spectrum: Mass Spectrum: M+H+ 445 and 447.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[CH:25]=[CH:26][C:27]([O:50][CH3:51])=[C:28]([C@H:30]2[CH2:34][CH:33]([OH:35])[CH2:32][N:31]2[C:36]2[CH:41]=[CH:40][N:39]3[N:42]=[CH:43][C:44]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:38]3[N:37]=2)[CH:29]=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[F:23][C:24]1[CH:25]=[CH:26][C:27]([O:50][CH3:51])=[C:28]([CH:30]2[CH2:34][C:33](=[O:35])[CH2:32][N:31]2[C:36]2[CH:41]=[CH:40][N:39]3[N:42]=[CH:43][C:44]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:38]3[N:37]=2)[CH:29]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CC(O)C[C@@H]3c3cc(F)ccc3OC)nc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cnn2ccc(N3CC(=O)CC3c3cc(F)ccc3OC)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.5 %

Procedure:
To a suspension of Dess-Martin periodinane (0.233 g, 0.549 mmol) in CH2Cl2 (2.2 mL) at 0° C. was added a solution of (R)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.200 g, 0.499 mmol) in CH2Cl2 (1.5 mL). The resulting mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was cooled to 0° C. and quenched with saturated aqueous NaHCO3 (5 mL) containing Na2S2O3 (0.608 g, 3.85 mmol). The resulting mixture was warmed to ambient temperature and stirred for 10 minutes. The organic layer was separated, washed with saturated aqueous NaHCO3 (10 mL) followed by brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-oxopyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.164 g, 82.4% yield). LC/MS (ES+APCI) m/z=399.1 (M+H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([F:35])([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](OCC4C=CC=CC=4)=O)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:41]([O:46][CH2:47][C@@H:48]1[O:50]C1)(=[O:45])CCC>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([F:35])([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][C@H:47]([CH2:48][OH:50])[O:46][C:41]4=[O:45])=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: O=C(Nc1ccc(C2(F)CCN(C(=O)OCc3ccccc3)CC2)c(F)c1)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(F)(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1
Temperature: -78 °C
Reaction time: 1.25 h

Procedure:
A solution of 4-fluoro-4-[4-[[(phenylmethoxy)carbonyl]amino]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 74, Step 2, 2.03 g, contaminated with the elimination side product) in dry tetrahydrofuran (21 mL) at -78° C. under N2 is treated with n-butyllithium (2.80 mL, 1.6 M in hexanes) dropwise over 5 mins. The resulting mixture is stirred at -78° C. for 1.25 hrs and is then treated with (R)-(-)-glycidyl butyrate (0.63 mL) dropwise. The resulting solution is stirred at -78° C. for 1 hr, warmed to ambient temperature and stirred for an additional 20 hrs, after which the reaction is quenched with saturated aqueous ammonium chloride (10 mL), diluted with water (10 mL), and the layers are separated. The organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 250 g), eluting with methanol/methylene chloride (3/97). Pooling and concentration of those fractions wl.th an Rf =0.51 by TLC (methanol/chloroform, 10/90) and repurification by silica gel chromatography (230-400 mesh, 100 g, methanol/methylene chloride (4/96) eluent) gives the title compound (contaminated with the elimination side product from the starting material). An analytical sample is prepared by radial chromatography (2000, silica gel rotor, ethyl acetate/hexane (60/40) eluent), NMR (400 MHz, CDCl3) 7.45, 7.34, 7.18, 5.16, 4.74, 4.17, 3.97, 3.72, 3.22, 2.25 and 1.90 δ and HRMS calculated for C23H24F2N2O5 : 446.1653. Found: 446.1660.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]([CH3:13])[N:5]=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[I:37]I>C(#N)C.O.C(OCC)(=O)C>[F:14][CH:2]([F:1])[O:3][C:4]1[C:8]([I:37])=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]([CH3:13])[N:5]=1
Reactant: COC(=O)c1cc(OC(F)F)nn1C
Reactant: II
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COC(=O)c1c(I)c(OC(F)F)nn1C
Temperature: 25 °C

Procedure:
A solution of 500 mg (2.42 mmol) of methyl 3-(difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate in 20 ml of acetonitrile is admixed with 665 mg (1.21 mmol) of ammonium cerium(IV) nitrate and 369 mg (1.45 mmol) of iodine and heated under reflux for three hours and afterstirred at room temperature overnight. The reaction mixture is diluted with water and ethyl acetate, and the organic phase is washed with saturated sodium thiosulphate solution, dried over sodium sulphate, filtered and concentrated by evaporation in vacuo. This gives 750 mg of methyl 3-(difluoromethoxy)-4-iodo-1-methyl-1H-pyrazole-5-carboxylate (93%).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1)=O.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH:28]2[CH2:29][CH2:30][N:31]([CH2:1][C:3]3[O:7][C:6]([C:8]4[CH:12]=[CH:11][S:10][C:9]=4[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=3)[CH2:32][CH2:33]2)[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH:18]([CH3:34])[CH3:17]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COC(=O)c1sccc1-c1ccc(C=O)o1
Product: COC(=O)c1sccc1-c1ccc(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)o1

Procedure:
Prepared by Procedure F and Scheme R using methyl 3-(5-formyl-2-furyl)-2-thiophenecarboxylate and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 467.1 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH3:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CO.[C].[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[NH:2][CH3:1]
Reactant: CNc1cc(C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1cc(C)ccc1N
Yield: 101.3 %

Procedure:
3-(N-Methylamino)-4-nitrotoluene (7.95 g) was catalytically reduced in a solution in 200 ml of methanol using 1.0 g of 10% palladium carbon as a catalyst. After the catalyst was filtered off, the reaction solution was concentrated under reduced pressure to give 6.60 g (101%) of 1-amino-4-methyl-2-(N-methylamino)benzene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH3:19])[C:12]2=[N:11][C:10]=1[C:20](O)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:30][CH2:31][C:32]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:33]=1[C:34]([NH:36][CH3:37])=[O:35]>>[F:42][C:39]1[CH:40]=[CH:41][C:32]([CH2:31][NH:30][C:20]([C:10]2[N:11]=[C:12]3[N:18]([CH3:19])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:21])=[C:33]([C:34](=[O:35])[NH:36][CH3:37])[CH:38]=1
Reactant: CN1CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: CNC(=O)c1cc(F)ccc1CN
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCN2C
Yield: 54.4 %

Procedure:
Coupling of 6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 1.0 mmol) and 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetate salt (0.295 g, 1.0 mmol) as described for the synthesis of intermediate 3 gave 0.253 g (54% yield) of the title amide as white crystals; mp 184° C. (ethyl acetate-hexane). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.78 (3H, d, J=4.5 Hz, NCH3), 2.91 (3H, s, NCH3), 3.66 (2H, t, J=8.9 Hz, CH2), 4.02 (2H, t, J=8.9 Hz, CH2), 4.46 (2H, d, J=6.2 Hz, NCH2), 4.90 (2H, s, OCH2), 7.04 (1H, m, aromatic), 7.25 (1H, dd, J=2.6 Hz and J=9.1 Hz, aromatic), 7.29-7.46 (6H, m, aromatics), 8.49 (1H, broad q, NH), 8.78 (l H, broad t, NH). HRMS (ESI+) calculated for C24H25FN5O4 [M+H+]: 466.1891. found: 466.1899.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC(C)([O-])C.[K+].[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH2:25]Br)=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH2:25][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)c1ccc(OC)cc1)C(=O)OCC
Reaction time: 1 h
Yield: 72.5 %

Procedure:
3.50 g (21.8 mmol) of diethyl malonate were dissolved in 60 ml of anhydrous tetrahydrofuran, and 2.70 g (24.0 mmol) of potassium t-butoxide were added to the resulting solution, whilst ice-cooling. The mixture was then stirred for 1 hour. At the end of this time, a solution of 5.00 g (21.8 mmol) of 4-methoxyphenacyl bromide in 40 ml of anhydrous tetrahydrofuran was slowly added dropwise to the mixture, whilst ice-cooling. The mixture was stirred, whilst ice-cooling for 1 hour, and then a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue thus obtained was applied to a silica gel chromatography column and eluted with a 1:4 by volume mixture of ethyl acetate and hexane, to give 4.87 g of the title compound as a slightly yellow oily substance (yield 73%).