Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([N:42]([CH:46]([CH3:48])[CH3:47])[CH:43]([CH3:45])[CH3:44])=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].CN(C)CCN(C)C.CCCCCC.C([Li])CCC.CN([CH:71]=[O:72])C>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH:71]([C:36]1[C:37]2[C:32](=[CH:31][C:30]([C:2]([OH:1])([C:6]3[N:7]=[CH:8][N:9]([C:11]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:10]=3)[CH:3]([CH3:5])[CH3:4])=[CH:39][CH:38]=2)[CH:33]=[CH:34][C:35]=1[C:40]([N:42]([CH:43]([CH3:45])[CH3:44])[CH:46]([CH3:48])[CH3:47])=[O:41])=[O:72]
Reactant: CN(C)C=O
Reactant: CC(C)N(C(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1)C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)N(C(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1C=O)C(C)C
Reaction time: 2 h

Procedure:
To a solution (1000 mL) of 6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-N,N-diisopropyl-2-naphthamide (50.0 g) and N,N,N′,N′-tetramethylethylenediamine (94.9 mL) in toluene was added dropwise a butyllithium hexane solution (1.6 M: 196 mL) at −70° C. After stirring at the same temperature for 2 hrs., DMF (60.9 mL) was added dropwise and mixture was stirred for 20 min. Water was added to the reaction solution and the mixture was diluted with ethyl acetate. The organic layer was washed successively with water, 10% aqueous citric acid solution, water and saturated aqueous sodium hydrogen carbonate, and dried over magnesium sulfate. The solvent was evaporated and the obtained residue was recrystallized from hexane-ethyl acetate (3:1) to give the title compound (36.0 g) as a colorless powder.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[C@@H:42]([CH3:47])[CH2:41]3)=[CH:36][N:35]=2)[C:30](=[O:48])[N:29]([CH3:49])[CH:28]=1)(=O)C.[OH-].[Li+]>>[CH3:47][C@@H:42]1[N:43]([CH3:46])[CH2:44][CH2:45][N:40]([C:37]2[CH:38]=[CH:39][C:34]([NH:33][C:31]3[C:30](=[O:48])[N:29]([CH3:49])[CH:28]=[C:27]([C:7]4[C:6]([CH2:5][OH:4])=[C:11]([N:12]5[CH2:24][CH2:23][N:15]6[C:16]7[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=7[CH:22]=[C:14]6[C:13]5=[O:25])[CH:10]=[C:9]([F:26])[CH:8]=4)[CH:32]=3)=[N:35][CH:36]=2)[CH2:41]1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)[C@@H](C)C4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Product: C[C@H]1CN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)CCN1C
Yield: 35.6 %

Procedure:
Following the procedures in Example 108, hydrolysis of 107f (60 mg) with lithium hydroxide gave 107 as a white solid (20 mg, 36%). LCMS: [M+H]+ 626. 1H NMR (500 MHz, CDCl3) δ: 8.55 (s, 1H), 7.90 (d, J=2.5, 1H), 7.77 (s, 1H), 7.46 (d, J=2.5, 1H), 7.26 (dd, J=3.0, 9.5, 1H), 7.17 (dd, J=3.0, 9.5, 1H), 6.95 (dd, J=3.0, 9.0, 1H), 6.87 (s, 1H), 6.81 (d, J=9.0, 1H), 4.55 (d, J=10.5, 1H), 4.31-4.36 (m, 2H), 4.14-4.20 (m, 3H), 3.90-3.92 (m, 1H), 3.70 (s, 3H), 3.38 (d, J=11, 1H), 3.32 (d, J=11.5, 1H), 2.94 (s, 2H), 2.56-2.61 (m, 5H), 2.49 (s, 1H), 2.38 (s, 4H), 1.89-1.91 (m, 2H), 1.79-1.80 (m, 2H), 1.17 (d, J=5.0, 3H)
Reaction SMILES: B.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=O)[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[CH2:16][CH2:15]2)=O)=[CH:3]1>O1CCCC1>[Cl:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[O:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:12][CH2:11][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:2][CH:3]=2)[CH2:19][CH2:18]1
Reactant: O=C(C(=O)N1CCC(Oc2cccc(Cl)c2)CC1)c1c[nH]c2ccccc12
Agent: B
Solvent: C1CCOC1
Product: Clc1cccc(OC2CCN(CCc3c[nH]c4ccccc34)CC2)c1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
49 ml. of a 1M solution of boron trihydride in tetrahydrofuran are added dropwise to a stirred suspension of 5.3 g of 1-(indol-3-ylglyoxyloyl)-4-(m-chlorophenoxy)piperidine in 100 ml. of tetrahydrofuran under nitrogen. After an initial evolution of gas, the solution turns yellow and is stirred at ambient temperature for 13 hours. The tetrahydrofuran is removed under reduced pressure to give a solid white borane complex. The complex is destroyed by refluxing in 100 ml. of methanol with several drops of glacial acetic acid for one hour. After cooling, the methanol is removed under reduced pressure, leaving a yellow oil. The oil is evacuated at about 3 mm. for 72 hours and a gummy solid forms. The solid is recrystallized from acetonitrile and then from an ethanol and water mixture to give white microcrystals of 3{2-[4-(m-chlorophenoxy)piperidyl]ethyl}indole, m.p. 120°-123° C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[H-].[K+].[CH:12]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[C:27]([CH2:35][CH2:36][O:37][C:38]2[CH:48]=[CH:47][C:41]([C:42]([O:44]CC)=[O:43])=[CH:40][CH:39]=2)=[C:26]1[CH2:49][OH:50])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH:12]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[C:27]([CH2:35][CH2:36][O:37][C:38]2[CH:48]=[CH:47][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=2)=[C:26]1[CH2:49][O:50][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1ccc(OCCc2c(CO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCCc2c(COCc3ccccn3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.6 %

Procedure:
2-Picolyl chloride hydrochloride (164 mg, 1 mmol) was added to potassium hydride (228 mg of 40% KH, 2 mmol, in mineral oil, washed with hexanes) in 5 mL of dry N,N-dimethylformamide at room temperature. Ethyl 4-{2-[1-benzhydryl-5-chloro-2-(hydroxymethyl)-1H-indol-3-yl]ethoxy}benzoate (140 mg, 0.25 mmol) in 3 mL of N,N-dimethylformamide was added via syringe. After stirring at room temperature for 2 hours, the reaction was quenched with iced water, extracted with CH2Cl2, dried over magnesium sulfate and purified by preparative thin layer chromatography (20% methanol/CH2Cl2 as the developing solvents) to yield 16 mg (11%) of the desired product as a pale yellow solid. m/z (M−1) 600.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][C@@H:9]1[C@H:10]1[C@@H:12]2[CH:11]1[Si:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].[K+].C1C[O:26]CC1>>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:10]2[C@H:12]([CH:11]2[Si:17]([CH3:20])([CH3:19])[CH3:18])[C@@H:13]([C:14]([OH:15])=[O:26])[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@H]2C[C@@H]1[C@@H]1C([Si](C)(C)C)[C@@H]12
Reactant: C1CCOC1
Agent: [F-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)[C@H]2C([Si](C)(C)C)[C@H]21
Temperature: 60 °C
Yield: 100 %

Procedure:
A mixture of (1S,2R,4R,5R)-7-oxo-3-trimethylsilanyl-6-aza-tricyclo[3.2.1.0(2,4)]octane-6-carboxylic acid tert-butyl ester (1.7 g, 5.7 mmol) and potassium fluoride on alumina (2.10 g, 14.1 mmol) in THF (38 mL) was heated to about 60° C. for about 18 h. The mixture was cooled to ambient temperature and filtered through Celite®. The Celite® pad was rinsed with EtOAc (50 mL) and the filtrate was concentrated under reduced pressure to afford (1R,2S,4R,5R)-4-(tert -butoxycarbonylamino)-6-(trimethylsilyl)bicyclo[3.1.0]hexane-2-carboxylic acid (1.82 g, 100%): LC/MS (Table 2, Method a) Rt=2.62 min; MS m/z: 312 (M−H)−.
Reaction SMILES: C([Li])CCC.[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8].[O:16]([CH2:23][C:24](OCC)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[C:10]1([S:7]([CH2:6][C:24](=[O:25])[CH2:23][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:9])=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)COc1ccccc1
Reactant: CS(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)CS(=O)(=O)c1ccccc1
Temperature: -20 °C
Reaction time: 14 h

Procedure:
n-Butyllithium (8.5 ml, 1.6M in hexane) was added at -72° C. to a solution of methylphenyl sulfone (2.14 g, 13.7 mmol) in 80 ml of tetrahydrofuran. The reaction mixture was then allowed to warm slowly to -20° C. and maintained at this temperature for 25 minutes. It was then recooled to -72° C. and ethyl phenoxyacetate (1.48 g, 8.22 mmol) was added dropwise. The cooling bath was removed, the mixture was stirred at 20° C. for 14 hrs. and then poured into 100 ml of saturated NH4Cl and extracted with diethyl ether. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The crude residue was purified by column chromatography (silica gel, methylene chloride) giving 1-phenylsulfonyl-2-oxo-3-phenoxypropane, the compound of formula (2a), 800 mg.
Reaction SMILES: [NH2:1][CH:2]([CH:20]([CH3:22])[CH3:21])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1)=O>C1COCC1>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][CH:8]1[CH2:7][CH2:6][N:5]([CH2:3][CH:2]([NH2:1])[CH:20]([CH3:21])[CH3:22])[CH2:10][CH2:9]1
Reactant: CC(C)C(N)C(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Solvent: C1CCOC1
Product: CC(C)C(N)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 70 °C
Yield: 91.2 %

Procedure:
The product of step (ii) (1.12 g) was dissolved in THF (10 ml) and Borane/THF complex (22.7 ml) added. The mixture was heated under reflux for 2 hours and cooled. The solvent was evaporated, the product dissolved in methanol (5 ml) and 50% aqueous HCl solution added. The mixture was heated to 70° C. for 1 hour and cooled to room temperature. The solvent was removed, ethyl acetate and 2N aqueous NaOH solution were added to give pH 9.0. The organic phase was separated and the solvent evaporated to give the sub-titled compound as an oil (0.98 g) which used without further purification.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(O)C>[CH2:5]([N:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH:2]=[CH2:1])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CCBr
Reactant: C(=Cc1ccccc1)CNCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=CCN(CC=Cc1ccccc1)Cc1ccccc1
Yield: 78 %

Procedure:
11.0 g (90 mmol) of allyl bromide were added to 10.0 g (44.8 mmol) of N-cinnamylbenzylamine in 60 ml of ethanol, and then 5.0 g (50.0 mmol) of triethylamine were added while stirring. The mixture was refluxed for 4 h. Concentration under water pump vacuum was followed by partition of the contents of the flask between methylene chloride and water, rendition alkaline with dilute sodium hydroxide solution and extraction twice more with methylene chloride. The combined organic phases were washed with dilute sodium hydroxide solution, dried and concentrated. The crude product (12.5 g) was purified by column chromatography (silica gel, mobile phase methylene chloride/methanol 98/2). 9.2 g (80%) of product (oil) were obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:22]2[CH2:23][CH2:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Reactant: c1ccc2c(c1)CCNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: c1ccc(CN2CC(CN3CCc4ccccc4C3)C(c3ccccc3)C2)cc1

Procedure:
The title compound was prepared from 20 mg of 1-Benzyl-3-(SR)-formyl-4-(SR)-phenylpyrrolidine, 0.010 mL of 1, 2, 3, 4-tetrahydro-isoquinoline and 25 mg of sodium triacetoxyborohydride using a procedure analogous to that described in Example 9, Step B to provide 25 mg of the title compound. RF : 0.51 (50% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3): δ2.51-2.78 (m, 9H), 2.94-3.00 (m, 3H), 3.40-3.69 (m, 4H), 6.91-6.94 (m, 1H ), 7.02-7.38 (m, 13H). Mass spec. (ESI): 383.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.I[CH:31]([CH3:33])[CH3:32].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:32][CH:31]([O:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=2)[CH:7]=1)[CH3:33]
Reactant: CC(C)I
Reactant: O=c1c(O)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cn(-c2cccc(C(F)(F)F)c2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 72.2 %

Procedure:
A suspension of 5-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 0.25 mmol), 2-iodopropane (0.050 mL, 0.50 mmol), and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 20 h at 60° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (1/1) and crystallized from hexane/AcOEt to give the title compound (79.5 mg, 72% yield) as colorless prisms: mp 137-139° C.; NMR (300 MHz, CDCl3): δ ppm 1.38 (6H, d, J=6.4 Hz), 4.96-5.09 (1H, m), 7.05 (1H, dd, J=1.9, 7.9 Hz), 7.18 (1H, s), 7.33-7.46 (7H, m), 7.55 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=1.9 Hz), 8.01 (1H, s). LC-MS (ESI) m/z 441 [M+H]+. Anal. Calcd for C23H19F3N4O2: C, 62.72; H, 4.35; N, 12.72. Found: C, 62.74; H, 4.40; N, 12.81.
Reaction SMILES: CC([O-])(C)C.[K+].C[O:8][C:9](=O)[CH:10]([NH:20][C:21](=[O:31])[CH2:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[CH3:30])[CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([O:18][CH3:19])[CH2:14][CH2:13]1.Cl>C1COCC1>[CH3:30][C:24]1[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=1[C:22]1[C:21](=[O:31])[NH:20][CH:10]([CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([O:18][CH3:19])[CH2:16][CH2:17]2)[C:9]=1[OH:8]
Reactant: COC(=O)C(CC1CCN(OC)CC1)NC(=O)Cc1cc(C)ccc1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CON1CCC(CC2NC(=O)C(c3cc(C)ccc3C)=C2O)CC1
Reaction time: 0.5 h

Procedure:
Under nitrogen, t-BuOK (1.8 g, 16.0 mmol) was added to a stirred solution of 2-[2-(2,5-dimethyl-phenyl)-acetylamino]-3-(1-methoxy-piperidin-4-yl)-propionic acid methyl ester (2.6 g, 8.0 mmol) in 15 ml of THF at 60° C. and the mixture was stirred at the same temperature for another 30 min. Then, the mixture was poured into diluted hydrochloric acid (50 ml) and extracted with ethyl acetate five times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel. Yield: 500 mg of 3-(2,5-dimethyl-phenyl)-4-hydroxy-5-(1-methoxy-piperidin-4-ylmethyl)-1,5-dihydro-pyrrol-2-one (compound P2.2) as a solid, mp 116-119° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9](O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Pd]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCC(O)c1cccc(F)c1F
Agent: [Pd]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCCCCCCCc1cccc(F)c1F

Procedure:
Quantities: compound from Example 19 (53.3 g, 0.22 mol), phosphorus pentoxide (95 g, 0.67 mol) and 5% palladium-on-charcoal (5.5 g). The experimental procedure was as described in Example 22.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>C1COCC1>[C:16]([O:15][C:13]([NH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:6]=1)=[O:12])([CH3:19])([CH3:18])[CH3:17]
Reactant: COCOc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COCOc1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 65 °C
Yield: 99.9 %

Procedure:
A solution of crude 12 (4.13 g, 27 mmol) in 135 mL anhydrous THF was treated with BOC2O (12.14 g, 54 mmol) and the reaction mixture was warmed at reflux (65° C.) for 18 h. The solvents were removed under reduced pressure, and flash chromatography (SiO2, 4×15 cm, 20% EtOAc/hexane) provided pure 13 (6.83 g, 100%) as a yellow oil: 1H NMR (CDCl3, 250 MHz) δ7.15 (m, 2H), 6.94 (m, 1H), 6.68 (m, 1H), 6.58 (br s, 1H), 5.13 (s, 2H), 3.44 (s, 3H), 1.50 (s, 9H); 13C NMR (CDCl3, 62.5 MHz) δ157.7, 152.5, 139.5, 129.6, 111.9, 110.7, 106.6, 94.2, 80.5, 55.9, 28.2; IR (film) νmax 3337, 2977, 1728, 1605, 1537, 1236, 1153, 1015 cm−1; FABHRMS (NBA/NaI) m/z 276.1203 (C13H19NO4+Na+ requires 276.1212)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:28][C:29]([F:45])([F:44])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH:40]=[CH:39][N:38]=[C:37]1[C:41]([OH:43])=O>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:41]([C:37]3[N:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[C:29]([F:28])([F:45])[F:44])[CH:40]=[CH:39][N:38]=3)=[O:43])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1nccn1-c1ccccc1C(F)(F)F
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3nccn3-c3ccccc3C(F)(F)F)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 78 and 1-[2-(trifluoromethyl)phenyl]-1H-imidazole-2-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7]CC)=O.[Cl:14][C:15]1[C:20](=O)[O:19][C:18](=O)[N:17](C)[C:16]=1[CH3:24]>O1CCCC1>[Cl:14][C:15]1[C:20]([OH:19])=[C:4]([C:3]([O:11][CH2:12][CH3:13])=[O:10])[C:5](=[O:7])[N:17]([CH3:18])[C:16]=1[CH3:24]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1c(Cl)c(=O)oc(=O)n1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)c(Cl)c(C)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To 0.43 g of sodium hydride (60%) was added 35 ml of tetrahydrofuran, 2.5 ml of a solution of 1.76 g diethyl malonate in tetrahydrofuran was further added under ice cooling, and the mixture was stirred at room temperature for 1 hour. To the mixture was added 1.74 g of 5-chloro-3,4-dimethyl-2H-1,3-oxazine-2,6(3H)-dione, and this was stirred for 3.5 hours under heat refluxing condition. The reaction mixture was concentrated under reduced pressure. To the residue, 20 ml of water and 15 ml of 1 mol/L hydrochloric acid were sequentially added, followed by extraction with 85 ml of chloroform twice. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The residue was washed with n-hexane to obtain 1.52 g of ethyl 5-chloro-1.6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate represented by the formula:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2.N1C=CC=CC=1.[CH3:24][C:25]1[S:26][CH:27]=[C:28]([C:30](Cl)=[O:31])[N:29]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:17][C:30]([C:28]2[N:29]=[C:25]([CH3:24])[S:26][CH:27]=2)=[O:31])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2
Reactant: Nc1cc(Br)cc2nn(C3CCCCO3)cc12
Reactant: Cc1nc(C(=O)Cl)cs1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(C(=O)Nc2cc(Br)cc3nn(C4CCCCO4)cc23)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a round bottom flask was introduced 6-bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (2.77 g) dissolved in DCM (120 ml) followed by the addition of pyridine (1.135 ml). The reaction mixture was left to stir for a few minutes before the addition of 2-methyl-1,3-thiazole-4-carbonyl chloride (2.267 g). The reaction mixture was left to stir at RT for 1 h. After this time the reaction mixture was extracted between DCM and saturated sodium bicarbonate aq. The extracted organic layer was dried down. The crude was dissolved in DCM and adsorbed onto fluorisil before purification by solid loading on companion using Si Column (40 g) eluting with 40-100% ethyl acetate in cyclohexane. The appropriate fractions were combined and evaporated to dryness to yield the title compound, 2.6 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[N:14]=[C:13]([C:28](=O)[CH2:29][NH:30][NH:31][C:32]([NH2:34])=[O:33])[C:12]=2[N:11]2[CH2:36][CH2:37][N:38]([CH3:41])[C:39](=[O:40])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>C(O)C>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[F:26])[CH2:19][N:15]1[C:16](=[O:18])[C:17]2[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]3[C:39](=[O:40])[N:38]([CH3:41])[CH2:37][CH2:36][N:11]3[C:12]=2[C:13]([C:28]2[CH2:29][NH:30][NH:31][C:32](=[O:33])[N:34]=2)=[N:14]1
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C(=O)CNNC(N)=O)c32)C1=O
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C4=NC(=O)NNC4)c32)C1=O

Procedure:
A solution of the above hydrazinecarboxamide (0.20 g, 0.34 mmol) and glacial acetic acid (0.1 mL) in absolute ethanol (5 mL) was heated in a sealed tube in an oil bath at 100° C. overnight. The reaction mixture was concentrated under vacuum. The residue was partitioned between chloroform and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the corresponding cyclized trazinyl intermediate. ES MS M+1=564