Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:39])[CH:3]([C:5]1[CH:38]=[CH:37][CH:36]=[CH:35][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([Cl:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]2[CH:18]=[N:19][N:20]([CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH:21]=2)[N:10]=1)[CH3:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:14]1[C:9]([CH2:8][CH2:7][C:6]2[CH:35]=[CH:36][CH:37]=[CH:38][C:5]=2[CH:3]([CH3:4])[C:2]([NH2:1])=[O:39])=[N:10][C:11]([NH:16][C:17]2[CH:18]=[N:19][N:20]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:21]=2)=[N:12][CH:13]=1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCNCC3)c2)ncc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26 %

Procedure:
To a stirred solution of tert-butyl 4-(4-(4-(2-(1-amino-1-oxopropan-2-yl)phenethyl)-5-chloropyrimidin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate A32 (0.090 g, 0.162 mmol) in DCM (5 mL) was added TFA (2.0 mL) and the mixture was stirred at room temperature for 1.5 hours. The solvent was removed and the residue was suspended in EtOAc (5 mL) and washed with 1M HCl. The aqueous layer was basified with 1M NaOH and extracted with EtOAc (2×5 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a crude purple oil which was purified by flash chromatography (Combiflash Rf, 0-30% MeOH in DCM) to give the title compound 43 as a red oil (0.019 g, 26% yield). LCMS-C: rt 4.24 min; m/z 454 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:17](=[O:31])[NH:18][C:19]2=S)=[N:14]1.O.[NH2:37][NH2:38]>C1COCC1.O.C(OCC)(=O)C.[Hg]Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:17](=[O:31])[N:18]=[C:19]2[NH:37][NH2:38])=[N:14]1
Reactant: Cn1cc(C#N)cc1-c1c2c(=S)[nH]c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Reactant: NN
Agent: Cl[Hg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(C#N)cc1-c1c2c(NN)nc(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Reaction time: 4 h

Procedure:
To a solution of 5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-6-oxo-4-thioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile (0.24 g) in THF (5 mL) were added hydrazine hydrate (0.30 mL) and mercury chloride (0.30 g). After 4 h, a second addition of hydrazine hydrate (0.20 mL) and mercury chloride (0.30 g) was done. After stirring overnight, the mixture was diluted with water and ethyl acetate. The mixture was then filtered through a celite bed. The organic solution was collected, washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography using a FlashMaster™ yielding 0.18 g.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1.[Li+].[OH-].Cl>CO>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1
Reactant: COC(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
The compound from Example 34a (29.6 g, 96.2 mmol) in 200 mL of MeOH was treated with aqueous LiOH (1 M) and heated under reflux for 1 hour. Cooled to room temperature and acidified with aqueous HCl (1 M). Precipitate was filtered, washed with H2O and air-dried giving the title compound as a yellow solid (28.2 g, 100%).
Reaction SMILES: OS(O)(=O)=O.[C:6]([O:9]C(=O)C)(=O)[CH3:7].CO[CH2:15][N:16]([C:21]([CH:25]([CH3:27])[CH3:26])=[C:22]([CH3:24])[CH3:23])[C:17](=[O:20])[CH2:18][Cl:19].C(#[N:30])C>>[C:6]([NH:30][CH2:15][N:16]([C:21]([CH:25]([CH3:27])[CH3:26])=[C:22]([CH3:23])[CH3:24])[C:17](=[O:20])[CH2:18][Cl:19])(=[O:9])[CH3:7]
Reactant: COCN(C(=O)CCl)C(=C(C)C)C(C)C
Reactant: CC(=O)OC(C)=O
Reactant: CC#N
Agent: O=S(=O)(O)O
Product: CC(=O)NCN(C(=O)CCl)C(=C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a stirred solution of 36 gm of concentrated H2SO4 at 5° C. was added 8.7 ml of acetic anhydride, and the mixture was stirred in the cold for about 0.5 hours. Acetonitrile (5.35 gm) was added, the solution was stirred for 5 minutes, and then 6.81 gm of N-methoxymethyl-2-chloro-N-[2-methyl-1-(1-methyl-ethyl)-1-propenyl]-acetamide was added. The reaction mixture was allowed to warm to room temperature over 4 hours and then partitioned between 100 ml of methylene chloride and 100 ml of H2O. The organic layer was washed with 75 ml of H2O, then 75 ml of saturated NaCl, and dried over MgSO4. Filtration and concentration gave an off-white solid which was washed through a 5 cm plug of silicagel with 50% ethyl acetate in hexane to afford 3.6 gm of product as a white solid (m.p. 113°-114° C.). (48% yield) Analysis for C12H21ClN2O2 :
Reaction SMILES: [CH3:1]C(=CC=CC=C(C)C=O)C=O.[CH2:13]([O:15][CH:16]([O:18][CH2:19][CH3:20])[CH3:17])[CH3:14].[CH2:21]([O:23][CH:24]=[CH:25]C)[CH3:22]>>[CH2:13]([O:15][CH:16]([O:18][CH2:19][CH3:20])[CH:17]([CH3:1])[CH:21]([O:23][CH2:24][CH3:25])[CH3:22])[CH3:14]
Reactant: CC=COCC
Reactant: CC(C=O)=CC=CC=C(C)C=O
Reactant: CCOC(C)OCC
Product: CCOC(C)C(C)C(OCC)OCC

Procedure:
According to the present invention, a method for synthesizing 2,7-dimethyl-2,4,6-octatriene-1,8-dialdehyde comprises the following steps: (1) adding acetaldehyde diethyl acetal (abbreviation: acetal) and ethyl-(1-propenyl)-ether under effects of a catalyst at a temperature of −10° C.˜0° C. to produce 1,1,3-triethoxy-2-methyl-butane; wherein the catalyst is ferric chloride or aluminum chloride; acetaldehyde diethyl acetal is prepared by the Chinese Patent No. ZL97115390.6 of Hoffmann-La Roche Ltd; (2) pyrolysis synthesizing 1,1,3-triethoxy-2-methyl-butane under catalytic effects of isoquinoline and p-Toluenesulfonic acid at a temperature of 180-200° C. to produce 1-methoxy-2-methyl-1,3-butadiene; but the catalyst used in the Chinese Patent ZL97115390.6 of Hoffmann-La Roche Ltd. is silicon-aluminum ball, to pyrolysis produce 1-methoxy-2-methyl-1,3-butadiene at high temperature, its conversion rate is only 41%, and its selectivity is 90%; (3) dissolving 1-methoxy-2-methyl-1,3-butadiene in anhydrous ethanol solvent for synthesis with a phase transfer catalyst and a chlorinating agent at a temperature of −5˜0° C. to generate 4,4-diethoxy-3-methyl-1-chloro-butene; wherein the phase transfer catalyst is cetyl-trimethyl ammonium bromide, the chlorinating agent is trichloroisocyanuric acid; (4) combining 4,4-diethoxy-3-methyl-1-chloro-butene with a triphenylphosphine salt at a temperature of 60˜65° C. to produce a phosphonic salt; and (5) condensing the phosphonic salt under effects of hydrogen peroxide at a temperature of 0˜5° C. in conjunction with sodium carbonate solution to generate 1,1,8,8-tetramethyl-2,7-dimethyl-2,4,6-octatriene at pH=8˜10; and then hydrolyzing under acidic conditions to synthesize 2,7-dimethyl-2,4,6-octatriene-1,8-dialdehyde.
Reaction SMILES: [OH:1][C:2]1([CH:14]([CH3:18])C(O)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([N:21]([CH2:24]C)CC)C.ClC(OCC)=[O:28].[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[CH3:18][CH:14]1[C:2]2([CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:1][C:24](=[O:28])[NH:21]1
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CC(C(=O)O)C1(O)CCCCC1c1ccccc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1NC(=O)OC12CCCCC2c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-(1-Hydroxy-2-phenylcyclohexyl) propionic acid (Example II, Compound I) (33 g) in 110 ml acetone is teated with 20.5 ml triethylamine. The solution is cooled to -5° and 14 ml ethyl chloroformate in 35 ml acetone added at a temperature below 0°. The mixture is stirred 10 minutes and 17.2 g of sodium azide in 50 ml water is added at or below 0°. The mixture is stitted 11/2 hours, added to 500 ml ice water and extracted with toluene. The extract is dried and heated at 100° until the evolution of nitrogen is above over, then refluxed 2 hours, concentrated to a slurry on the rotovap and the solid filtered and washed with benzene and cyclohexane to give 28.8 g of 4-methyl-6-phenyl-1-oxa-3-azaspiro [4.5] decan-2-one, m. 171°-3°.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[CH2:7][CH2:6]1)=[N+]=[N-].Cl.[H][H]>[Pd].C(O)C.O>[NH2:1][CH2:4][C@@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: CCCCOC(=O)[C@H]1CC[C@@H](CN=[N+]=[N-])CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCOC(=O)[C@H]1CC[C@@H](CN)CC1

Procedure:
A mixture of butyl cis-4-(azidomethyl)cyclohexanecarboxylate (27.85 g, 116 mmol), 6N hydrochloric acid (39 ml, 234 mmol) and 10% palladium on carbon (3.78 g) in ethanol (500 ml) was hydrogenated (hydrogen balloon) for 2.5 days. The catalyst was removed by filtration through Celite. The filter cake was washed with ethanol (3×50 ml) and the filtrate was concentrated under reduced pressure to give a gum. The gum was taken up in water (250 ml) and washed with ether (250 ml). The aqueous layer was basified to pH 10 with 10N sodium hydroxide solution and extracted with ethyl acetate (3×250 ml). The ethyl acetate layer was washed with water (100 ml) and brine (100 ml), dried (sodium sulfate), filtered, and the solvent was evaporated under reduced pressure to give butyl cis-4-(aminomethyl)cyclohexanecarboxylate (15.25 g, 62%) as a gum: 1H NMR (CDCl3) 4.08 (2H, t, J 7 Hz), 2.57 (2H, d, J 8 Hz), 2.02 (2H, m), 1.66-1.51 (6H, m), 1.45-1.23 (5H, m), 0.94 (3H, t, J 7 Hz). MS: 214.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([CH2:9][OH:10])[NH:6][N:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][C:18]1([CH3:21])[CH2:20][O:19]1>>[OH:10][CH2:9][C:7]1[N:6]([CH2:17][C:18]([CH3:21])([OH:19])[CH3:20])[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(CO)[nH]n1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(O)Cn1nc([N+](=O)[O-])cc1CO
Temperature: 70 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
A sealed tube was charged with 330d (2.145 g, 15 mmol), Cs2CO3 (978 mg, 3.0 mmol), and 2,2-dimethyloxirane (15 mL). The mixture was stirred at 70° C. for 3 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (5:1 to 1:1) to afford 330e (1.2 g, 38%) as a white solid. MS-ESI: [M+H]+ 216.2
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH3:22])=[C:17]([N+:23]([O-])=O)[CH:16]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:43])([F:42])[CH2:30][N:31]1[C:35]2=[N:36][CH:37]=[CH:38][CH:39]=[C:34]2[CH:33]=[C:32]1[CH:40]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:15]2[CH:20]=[CH:19][C:18]3[N:21]([CH3:22])[C:40]([C:32]4[N:31]([CH2:30][C:29]([F:43])([F:42])[F:28])[C:35]5=[N:36][CH:37]=[CH:38][CH:39]=[C:34]5[CH:33]=4)=[N:23][C:17]=3[CH:16]=2)=[O:26])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNc1ccc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Reactant: O=Cc1cc2cccnc2n1CC(F)(F)F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1c(-c2cc3cccnc3n2CC(F)(F)F)nc2cc(C(=O)N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccc21
Temperature: 90 °C
Yield: 62.6 %

Procedure:
To a mixture of (R)-tert-butyl(1-(4-(methylamino)-3-nitrobenzoyl)piperidin-3-yl)carbamate (2.1 g, 5.55 mmol) and 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (1.3 g, 5.70 mmol) in ethanol (55 ml) was added portionwise a solution of sodium hydrosulfite (3.41 g, 16.65 mmol) in water (25 ml). The mixture was flushed with nitrogen and heated at 90° C. overnight for 17 hours. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. DCM was added to the residue and the heterogeneous solution was dried over sodium sulfate. The solid was filtered off and the filtrate was concentrated under vacuo. The residue was loaded in dichloromethane and purified by SP4 SNAP on 2 silica (Si) 100 g columns using an initial gradient of 25-80% (15 CVs), followed by 80-100% (10 CVs) ethyl acetate/cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a pale yellow solid (1.934 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.C1C(=O)N([Br:23])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClC(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][Br:23])=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccccc1-c1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccccc1-c1ccc(CBr)cc1

Procedure:
2-methoxy-4′-methylbiphenyl, 160 mg (0.81 mmol), NBS, 158 mg (0.91 mmol), and AIBN, 1 mg (0.006 mmol) were suspended in 7 mL tetrachloromethane, and refluxed for 24 hours. The product was filtered, and the solvent removed from the filtrate by rotary evaporation. Equal amounts of diethyl ether and water were added and the product extracted. The ether layer was separated and dried over MgSO4, filtered, and the solvent removed. 4-(2-Methoxyphenyl)benzyl bromide, 128 mg, was obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:11](O)[CH3:12].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(Cl)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
A flask equipped with a condenser was charged with 6-chloropicolinic acid (23.5 g, 149 mmol), 100 mL of ethanol and 400 mL of toluene. To this was added 4 mL of sulfuric acid and the mixture was warmed to reflux for three hours, and then allowed to cool to ambient temperature. The reaction mixture was concentrated under reduced pressure and the resulting oil was taken up in 200 mL of ethyl acetate, washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure to give 26 g of ethyl 6-chloropicolinate (94%).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([F:18])[CH:3]=1.[OH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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:18][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[OH:19])[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: OB(O)c1ccccc1O
Reactant: O=C(OCc1ccccc1)c1ccc(Br)cc1F
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
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(-c2ccccc2O)cc1F
Temperature: 0 °C
Yield: 89.5 %

Procedure:
To a mixed solvent solution of benzyl 4-bromo-2-fluorobenzoate (67.0 g) and 2-hydroxyphenylboronic acid (31.3 g) in 1,2-dimethoxyethane (750 ml) and water (250 ml) were added sodium carbonate (68.7 g) and tetrakis(triphenylphosphine)palladium (12.5 g), followed by stirring under heating at reflux for 5 hours. The reaction solution was brought back to room temperature, and then poured into ice water, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, and further washed with hexane to afford benzyl 3-fluoro-2′-hydroxybiphenyl-4-carboxylate (62.5 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@H:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@@H:5]([N:13]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:14]2=[O:29])[CH2:4][CH2:3]1.[CH3:30][C:31]([CH3:33])=O.[BH-](OC(C)=O)(OC(C)=O)O[C:36](C)=O.[Na+].C=O>C(Cl)Cl>[CH2:22]([O:21][C:19]([NH:18][C@H:15]1[CH2:16][CH2:17][N:13]([C@H:5]2[CH2:4][CH2:3][C@@H:2]([N:1]([CH:31]([CH3:33])[CH3:30])[CH3:36])[CH2:7][C@@H:6]2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:14]1=[O:29])=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)=O
Reactant: CCOC(=O)[C@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of (1S,2S,5R)-ethyl 5-amino-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)cyclohexanecarboxylate from Step 2 in CH2Cl2 (10 ml) was treated with acetone (1 ml) and NaBH(OAc)3 (1.7 g, 8 mmol) and stirred at room temperature overnight. A solution of 37% aq formaldehyde (2 ml) was added and stirred at room temperature for 1 h. The solution was diluted with CH2Cl2 (50 ml) and washed with 1 N NaOH, water, brine, concentrated in vacuo and the residue chromatographed (4% NH4OH:MeOH:CH2Cl2) to give 540 mg (73%) of (1S,2S,5R)-ethyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)-cyclohexanecarboxylate as a white foam. MS found: (M+H)+=460.51.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13].Cl.[Br:17][C:18]1[CH:19]=[C:20]([NH:24][NH2:25])[CH:21]=[CH:22][CH:23]=1>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[N:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Br:17])[CH:19]=2)[N:25]=1)=[O:15]
Reactant: COC(=O)C(=O)C=Cc1ccccc1Cl
Reactant: NNc1cccc(Br)c1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C1=NN(c2cccc(Br)c2)C(c2ccccc2Cl)C1
Temperature: 125 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
4-(2-Chloro-phenyl)-2-oxo-3-butenoic acid methyl ester (1.4 g, 6.0 mmol) prepared in Step 2 of Preparation 24 and 3-bromophenylhydrazine hydrochloride (1.4 g, 6.1 mmol) were added to acetic acid (20.0 mL). The reaction mixture was stirred at 125° C. for 3 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting yellow liquid residue was crystallized from methanol to give 1.2 g of the titled compound as a pale yellow solid.
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]([O:11]C)=O)=[CH:7][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][N:4]=1)=[CH2:2].[NH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C.C(#N)C>CO>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:18]([N:17]2[CH2:2][CH2:1][C:3]3[N:4]=[CH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:8]=3[C:9]2=[O:11])[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: C=Cc1ncc(C(=O)OC)cc1C(=O)OC
Solvent: CC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc2c(c1)C(=O)N(C1CCN(C(=O)OC(C)(C)C)CC1)CC2
Temperature: 150 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
A mixture of dimethyl 2-vinylpyridine-3,5-dicarboxylate (1.8 g), tert-butyl 4-aminopiperidine-1-carboxylate (2.4 g), N,N′-diisopropylethylamine (2.13 mL), acetonitrile (10 mL), and methanol (10 mL) was stirred at 150° C. for 16 hours under microwave irradiation. The reaction mixture was allowed to cool to room temperature, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.8 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH2:21]([NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CON(C)[C:41](=O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1.CCCCCC>[CH2:21]([N:28]1[C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:36][C:31]2[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:29]1=[O:37])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1ccccc1C(=O)NCc1ccccc1
Reactant: CON(C)C(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=c1c2ccccc2cc(-c2ccccc2)n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 11 %

Procedure:
To a solution of diisopropylamine (0.2 mL, 1.43 mmol) in THF (3 mL) at 0° C. was added n-butyllithium (0.9 mL of a 1.6 M solution in hexane, 1.44 mmol). After stirring at 0° C. for 10 minutes, the resulting lithium diisopropylamide solution was treated with a solution of N-benzyl-2-methylbenzamide (145 mg, 0.64 mmol) in THF (2 mL). The resulting deep purple solution was stirred at 0° C. for 75 minutes at which time it was treated with a solution of N-methoxy-N-methyl-benzamide (117 mg, 0.71 mmol) in THF (2 mL). After slowly warming to ambient temperature over 100 minutes the reaction was quenched by the addition of 3N HCl (12 mL). The biphasic mixture was then heated to reflux with vigorous stirring. After 1 hour at reflux the reaction mixture was allowed to cool to ambient temperature. After cooling, the reaction was diluted with ether (50 mL), and basified by careful addition of solid Na2CO3. The basic aqueous was extracted with ether (3×20 mL), combined organics were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under educed pressure to afford a pale orange oil. The crude product was purified by silica gel column chromatography eluting with a gradient from 0% to 20% ethyl acetate/hexane on a 20 g silica column. The product peak was collected to afford 2-benzyl-3-phenyl-2H-isoquinolin-1-one (22 mg, 11% yield) as a clear oil that slowly solidified to a white waxy solid. 1H-NMR (400 MHz, CDCl3): δ 8.49 (1H, d J=8.3 Hz), 7.68-7.63 (1H, m), 7.53-7.48 (2H, m), 7.42-7.37 (1H, m), 7.35-7.30 (2H, m), 7.22-7.14 (5H, m), 6.92-6.88 (2H, m), 6.45 (1H, s), 5.25 (2H, s) ppm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[I:20][C:21]1[CH:29]=[C:28]2[C:24]([C:25]([CH3:31])([CH3:30])[CH2:26][NH:27]2)=[CH:23][CH:22]=1.Cl.O1CCOCC1>CN1C(=O)CCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:27]3[C:28]4[C:24](=[CH:23][CH:22]=[C:21]([I:20])[CH:29]=4)[C:25]([CH3:31])([CH3:30])[CH2:26]3)=[C:3]([CH3:19])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: CC1(C)CNc2cc(I)ccc21
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(I)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (250 mg, 0.92 mmol), 6-iodo-3,3-dimethylindoline (250 mg, 0.92 mmol) and 4.0M solution of HCl in 1,4-dioxane (0.22 mL, 0.92 mmol) in NMP (1.0 mL) and heating at 150° C. for 3 h in the microwave. After purification 7-fluoro-4-(6-iodo-3,3-dimethylindolin-1-yl)-3-methyl-2-(pyridin-2-yl)quinoline was obtained as a foam. Mass Spectrum (ESI) m/e=510 (M+1).