Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([I:18])[CH:3]=1.[Cl:19][C:20]1[N:25]=[C:24](Cl)[C:23]([Cl:27])=[CH:22][N:21]=1>>[Cl:19][C:20]1[N:25]=[C:24]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[C:4]([I:18])[CH:3]=2)[C:23]([Cl:27])=[CH:22][N:21]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1I
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: CC(C)(C)OC(=O)NCCc1ccc(Nc2nc(Cl)ncc2Cl)cc1I
Yield: 57 %

Procedure:
The desired compound was prepared according to the procedure of Example B5, step G using tert-butyl (4-amino-2-iodobenzyl)methylcarbamate and 2,4,5-trichloropyrimidine as the starting materials in 57% yield. LCMS for C17H20Cl21N4O2 (M+H)+: m/z=509.1, 511.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)=[C:6]([C:7]#[N:8])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1cc(Br)ccc1F
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cc2C#N)CC1
Temperature: 110 °C

Procedure:
5-bromo-2-fluorobenzonitrile (2.00 g, 10.00 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (5.01 g, 25.0 mmol) were dissolved in a minimal amount of chloroform (3 ml) and heated at 110° C. for 20 h, during which all of the solvent evaporated. The resulting crude golden yellow oil was taken up in CH2Cl2 and washed with saturated aqueous NaHCO3 and brine, and dried (MgSO4). Flash chromatography with 25:10:65 and 35:10:55 EtOAc-CH2Cl2-Hexane of the concentrated organic layers gave the desired product, tert-butyl 4-(4-bromo-2-cyanophenylamino)piperidine-1-carboxylate as a light yellow glassy foam. MS m/e 379.1 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][C@H:16]3[O:21]C(=O)C(C)(C)C)([CH3:14])[C@@H:12]([O:28]C(=O)C(C)(C)C)[CH2:11][CH2:10]4)[CH2:7][C:6](=[O:35])[C:5]=2[CH:4]=1.[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][C@H:16]3[OH:21])([CH3:14])[C@@H:12]([OH:28])[CH2:11][CH2:10]4)[CH2:7][C:6](=[O:35])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)C[C@@H]1[C@@H]2[C@H](OC(=O)C(C)(C)C)C[C@]2(C)[C@@H](OC(=O)C(C)(C)C)CC[C@@H]12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)C(=O)C[C@@H]1[C@@H]2[C@H](O)C[C@]2(C)[C@@H](O)CC[C@@H]12
Reaction time: 3.5 h
Yield: 84.3 %

Procedure:
The keto-diester (16) (30 mg, 0.06 mmole) was added to a degassed 10% solution of potassium hydroxide in methanol-water (19:1) (4 ml), and the solution was boiled for 3.5 h under nitrogen. The solvent was removed by evaporation under reduced pressure, and the residue was dissolved in ether. The residue was washed in succession with dilute hydrochloric acid and water, dried, and evaporated to give a residue which was chromatographed on silica (1 g) eluted with ether to give the product (5) (16 mg, 82%), m.p. 113°-4° C. (from ether-light petroleum), νmax 3400 (OH) and 1675 cm-1 (CO), δ (400 MHz) 8.08 (1 H, dd, J 8.5 and 1 Hz, 1-proton), 7.54 (1 H, d, J 3 Hz, 4-proton), 7.12 (1 H, dd, H 8.5 and 3 Hz, 2-proton), 4.27 (1 H, dt, H 10 and 5 Hz, 11-proton), 3.85 (3 H, s, OCH3), 3.79 (1 H, t, J 8 Hz, 17-proton), 2.78 (1 H, dd, J 17 and 2,5 Hz, 12-proton), 2.45 (1 H, t, J 10 Hz, 9-proton), 2.35 (1 H, A portion of ABX system, J 12 and 5 Hz, 7-proton), 2.35 (1 H, B portion of ABX system, J 12 and 5 Hz, 7-proton), 2.18 (2 H, m), 1.96 (1 H, qt, J 14, 10, 5, and 3.5 Hz, 8-proton), 1.86 (2 H, br s, OH), 1.56-1.27 (5 H, m), 0.8 (3 H, s, 18-CH3);
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:15][C:16]2[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)=[O:14])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(N)cc1
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Product: COC(=O)COc1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1
Yield: 86 %

Procedure:
In the same manner as that of Example 2, 4,5-diisopropylfuran-2-carboxylic acid (60 mg, 0.306 mmol) was condensed with methyl 4-aminophenoxyacetate, and the resultant was purified by silica gel chromatography (0.5% methanol-chloroform) to obtain methyl 4-[(4,5-diisopropylfuran-2-carbonyl)amino]phenyloxyacetate (94 mg, 86%) as colorless needles.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([C:21]([O:23][CH3:24])=[O:22])[CH:5]=1.S(OC)(O[CH3:29])(=O)=O.O>CN(C=O)C>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([N:8]([CH3:29])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[C:6]([C:21]([O:23][CH3:24])=[O:22])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C)cc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1N(C)S(=O)(=O)c1ccc(C)cc1
Yield: 85.1 %

Procedure:
To a suspension of sodium hydride (60%, 0.43 g (10.8 mmol)) in DMF (10.0 ml), 4′-chloro-2′-methoxycarbonyl-p-toluenesulfonanilide (3.33 g (9.80 mmol)) was added under cooling with ice and with stirring. After 15 minutes' stirring under cooling with ice, dimethyl sulfate (1.02 g (10.8 mmol)) was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. Then, resulting reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 2.95 g (85%) of 4′-chloro-2′-methoxycarbonyl-N-methyl-p-toluenesulfonanilide as white crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][N:36]=2)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=[C:2]([C:38]2[CH:37]=[N:36][C:35]([N:32]3[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]3)=[CH:40][CH:39]=2)[CH:3]=1)=[O:16]
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C)CC4)nc3)nc3c2c(C)nn3C(C)C)c(=O)[nH]1

Procedure:
To a 10-mL microwave vial were added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.180 mmol), 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (71.1 mg, 0.235 mmol), DMSO (2.0 mL) and sodium carbonate (0.271 mL, 0.541 mmol) and the mixture was degassed for 10 min under nitrogen. Bis(triphenylphosphine)palladium(II) chloride (10.13 mg, 0.014 mmol) was added and the contents were sealed. The mixture was irradiated (microwave) at 140° C. for 8 h. The reaction mixture was then quenched with water (5 mL) and filtered. The crude product was washed with water, dried, and then purified via silica gel chromatography (eluent: gradient of 0 to 15% (9:1 MeOH/NH4OH)/DCM). The resulting product was treated with MeOH and 1N HCl. The mixture was concentrated in vacuo, dried under high vacuum and collected as the HCl salt, 42 mg (36%). LCMS E-S (M+H)=529.0 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (d, 6 H), 2.13 (s, 3 H), 2.25 (s, 3 H), 2.42 (s, 3 H), 2.81 (d, J=4.55 Hz, 3 H), 3.03-3.21 (m, 2 H), 3.41 (br. s., 2 H), 3.52 (d, J=11.37 Hz, 2 H), 4.39 (d, J=5.05 Hz, 2 H), 4.56 (d, J=14.40 Hz, 2 H), 5.23 (quin, J=6.63 Hz, 1 H), 5.91 (s, 1 H), 7.19 (d, J=9.09 Hz, 1 H), 7.68 (s, 1 H), 8.50 (dd, J=9.09, 2.27 Hz, 1 H), 8.73 (t, J=4.93 Hz, 3 H), 8.98 (d, J=2.02 Hz, 3 H), 10.97-11.21 (m, 2 H)
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C.[CH3:21][O:22][C:23](=[O:45])[CH:24]([O:43][CH3:44])[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33]CC2C=CC=CC=2)=[C:29]([O:41][CH3:42])[CH:28]=1)O>C(Cl)Cl>[CH3:21][O:22][C:23](=[O:45])[CH:24]([O:43][CH3:44])[CH2:25][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([O:41][CH3:42])[CH:28]=1
Reactant: COC(=O)C(OC)C(O)c1ccc(OCc2ccccc2)c(OC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)C(Cc1ccc(O)c(OC)c1)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.5 %

Procedure:
Trifluoroacetic anhydride (0.62 mL, 4.36 mmol) and triethylamine (0.62 mL, 4.36 mmol) were added to a solution of 3-(4-benzyloxy-3-methoxy-phenyl)-3-hydroxy-2-methoxy-propionic acid methyl ester (1.01 g, 2.91 mmol) in methylene chloride (30 mL) at 0° C. The resulting mixture was stirred for 4 hours at room temperature and was concentrated under vacuum. The residue was dissolved in ethyl acetate (30 mL), and 10% palladium on carbon (0.3 g) was added to the solution. The mixture was stirred under hydrogen pressure (4 atm) for 16 hours. The mixture was filtered through Celite and concentrated under vacuum. The residue was purified by silica gel column chromatography (silica gel, hexanes/ethyl acetate 7:3) to produce 3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid methyl ester as an oil (598 mg, 86%). 1H-NMR (200.15 MHz, CDCl3): δ 6.80 (d, 1H, J=7.8), 6.7 (s, 1H), 6.62 (d, 1H, J=7.8), 3.96 (dd, 1H, J=7.8, 4.0), 3.80 (s, 3H), 3.68 (s, 3H), 3.30 (s, 3H), 3.09 (dd, 1H, J=14.2, 4.0), 2.91 (dd, 1H, J=14.2, 7.8).
Reaction SMILES: O.[CH2:2]([N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([O:21]C)=[O:20])[CH:15]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1COCC1.Cl>CC(=O)OCC.CO>[CH2:2]([N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([OH:21])=[O:20])[CH:15]=2)[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc2c(c1)C(=O)N(Cc1ccccc1)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)C(=O)N(Cc1ccccc1)C2

Procedure:
H2O (0.30 g, 7.11 mmol) was added to a solution of methyl 2-benzyl-3-oxoisoindoline-5-carboxylate (Chemical Formula 7) (0.5 g, 1.78 mmol) in a mixture of 3:1:1(v/v/v) THF:methanol:H20 which was then stirred for 1 hour. The reaction progress was monitored using TLC [Hex:EA=1:1]. When the reaction was completed, the pH of the reaction mixture was adjusted to 4 with 1N HCl, followed by extraction with ethyl acetate. The organic layer thus obtained was dried over anhydrous MgSO4, filtered and concentrated in a vacuum to afford 2-benzyl-3-oxoisoindoline-5-carboxylic acid (Chemical Formula 8) at a yield of 85%.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([F:11])=[CH:7][CH:8]=2)/[C:3]/1=[CH:12]/[C:13]([NH2:15])=[O:14].[CH3:16][OH:17]>[N+]([O-])([O-])=O.[Ag+]>[F:11][C:6]1[CH:5]=[C:4]2[C:9]([CH2:10][CH:2]([O:17][CH3:16])/[C:3]/2=[CH:12]\[C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1
Reactant: CO
Reactant: NC(=O)/C=C1/c2cc(F)ccc2CC1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: COC1Cc2ccc(F)cc2/C1=C/C(N)=O
Yield: 32 %

Procedure:
A mixture of (Z)-2-(2-bromo-6-fluoro-1-indanylidene)acetamide (2.60 g, 9.60 mmoles) and silver nitrate (5.10 g, 27.43 mmoles, Aldrich) in methanol (200 mL) was refluxed for 8 hours. Additional silver nitrate (5.10 g, 27.43 mmoles) was added and the mixture was refluxed for 18 hours. The mixture was filtered, and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel, eluting with hexane:ethyl acetate (1:4), gradually increasing the polarity to 100% ethyl acetate. The fractions containing the compound with Rf=0.15 with hexane:ethyl acetate (1:1) as the eluant were combined and evaporated in vacuo and dried in a vacuum at 50° C. for 18 hours to give 0.68 g (32%) of crude (Z)-2-(6-fluoro-2-methoxy-1-indanylidene)acetamide as a tan solid. Recrystallization from ethyl acetate:hexane mixtures gave 0.49 g (23%) of (Z)-2-(6-fluoro-2-methoxy-1-indanylidene)acetamide as an off-white solid, mp 128°-130° C.; 1H-NMR (DMSO-d6): d 7.13-7.48 (m, 5H), 6.54 (s, 1H), 5.34 (d, 1H), 3.25 (s, 3H), 3.05 (dd, 1H, J=5.7 Hz, 17.3 Hz), and 2.87 (d, 1H, J=17.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4](=[CH:9][N:10]([CH2:12][CH2:13][O:14]C3CCCCO3)[N:11]=2)[N:5]=[CH:6][C:7]=1[F:8].ClC1C(F)=CN=C2C=NN(CCOC3CCCCO3)C=12.[F:41][C:42]1[C:43]([C:49]2[CH:54]=[C:53]([NH2:55])[C:52]([CH3:56])=[CH:51][N:50]=2)=[N:44][C:45]([CH3:48])=[CH:46][CH:47]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(O)(C)C>[F:8][C:7]1[CH:6]=[N:5][C:4]2=[CH:9][N:10]([CH2:12][CH2:13][OH:14])[N:11]=[C:3]2[C:2]=1[NH:55][C:53]1[C:52]([CH3:56])=[CH:51][N:50]=[C:49]([C:43]2[C:42]([F:41])=[CH:47][CH:46]=[C:45]([CH3:48])[N:44]=2)[CH:54]=1.[ClH:1]
Reactant: Cc1ccc(F)c(-c2cc(N)c(C)cn2)n1
Reactant: Fc1cnc2cn(CCOC3CCCCO3)nc2c1Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Agent: Fc1cnc2cnn(CCOC3CCCCO3)c2c1Cl
Solvent: CC(C)(C)O
Product: Cc1ccc(F)c(-c2cc(Nc3c(F)cnc4cn(CCO)nc34)c(C)cn2)n1
Temperature: 100 °C

Procedure:
To 7-chloro-6-fluoro-2-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-2H-pyrazolo[4,3-b]pyridine (85 mg, 0.284 mmol) and 7-chloro-6-fluoro-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazolo[4,3-b]pyridine (85 mg, 0.284 mmol) in t-BuOH (4 mL) was added 3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-amine (185 mg, 0.851 mmol), tri(dibenzylidene acetone)dipalladium(0) (26.0 mg, 0.028 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (27.0 mg, 0.057 mmol) and potassium carbonate (157 mg, 1.134 mmol) and the mixture was heated at 100° C. over night. The mixture was cooled and evaporated to give a residue which was partitioned between EtOAc (75 mL) and water. The layers were separated and the aqueous layer was extracted with EtOAc (75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a residue which was purified on HPLC using a gradient of 20-50% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column to give a residue. The residue was combined with 1N HCl (3 mL) and the solution was stirred for an hour, evaporated and lyophilized to give the title compound as a HCl salt. 1HNMR (400 MHz, DMSO-d6) δ ppm 2.52 (s, 3H) 2.58 (s, 3H) 3.80 (t, J=5.43 Hz, 2H) 4.47 (t, J=5.43 Hz, 2H) 7.28 (d, J=1.77 Hz, 1H) 7.57 (dd, J=8.59, 3.54 Hz, 1H) 7.82 (dd, J=11.37, 8.59 Hz, 1H) 8.52 (s, 1H) 8.74 (d, J=2.78 Hz, 1H) 8.87 (s, 1H) 10.16 (br. s., 1H). MS [M+H] found 397.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].C([Mg]Cl)(C)C.[CH:13]1([C:16]2[CH:20]=[C:19]([NH:21][C:22]3[C:23]4[CH2:39][CH2:38][CH2:37][C:24]=4[N:25]=[C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH:29]4[C:33](OC)=[O:34])[N:27]=3)[NH:18][N:17]=2)[CH2:15][CH2:14]1>C1COCC1>[CH:13]1([C:16]2[CH:20]=[C:19]([NH:21][C:22]3[C:23]4[CH2:39][CH2:38][CH2:37][C:24]=4[N:25]=[C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH:29]4[C:33]([NH:7][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:34])[N:27]=3)[NH:18][N:17]=2)[CH2:15][CH2:14]1
Reactant: Nc1cnccn1
Reactant: COC(=O)C1CCCN1c1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCC2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(Nc1cnccn1)C1CCCN1c1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.3 %

Procedure:
To a solution of pyrazin-2-amine (284 mg, 2.99 mmol) in dry THF (12 mL) was added 2M solution of isopropylmagnesium chloride (1.5 mL, 2.99 mmol) in THF dropwise under nitrogen at 0° C. The resultant mixture was stirred at 0° C. for 20 min. To this solution was added a solution of methyl 1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (200 mg, 0.746 mmol) in THF (2 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 1.5 h. The reaction was quenched with saturated ammonium chloride solution (20 mL). The product was extracted with EtOAc (2×40 mL) and the organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure afforded an oily residue that was purified by reverse phase HPLC to afford 1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrazin-2-yl)pyrrolidine-2-carboxamide (120 mg). 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.57-0.67 (m, 2H), 0.78-0.95 (m, 2H), 1.70-1.81 (m, 1H), 2.02-2.18 (m, 4H), 2.25-2.39 (m, 2H), 2.63-2.78 (m, 2H), 2.79-2.85 (m, 2H), 3.60-3.77 (m, 1H), 3.78-3.94 (m, 1H), 4.73-4.81 (m, 1H), 6.25 (s, 1H), 8.26 (d, 1H), 8.30 (s, 1H), 9.31 (s, 1H). Separation by chiral HPLC provided enantiomers 6a and 6b.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([C:8]1([OH:23])[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)#[CH:7].IC>CCCCCC.C1COCC1.CS(C)=O>[C:6]([C:8]1([O:23][CH3:1])[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)#[CH:7]
Reactant: C#CC1(O)CCC(C2CCC(CCC)CC2)CC1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCCCCC
Product: C#CC1(OC)CCC(C2CCC(CCC)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
28.85 ml of a 15% solution of butyllithium in hexane are added dropwise to a solution, cooled to −30° C., of 13.0 g of 4-ethynyl-4′-propylbicyclohexyl-4-ol in 24 ml of THF. A solution of 4.67 ml of iodomethane in 36 ml of dimethyl sulfoxide is subsequently added dropwise to the reaction mixture at −5° C. The mixture is stirred at RT overnight and subjected to conventional work-up, giving 4-ethynyl-4-methoxy-4′-propylbicyclohexyl (C 45 I, Δε−3.72, Δn−0.022).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:3]=1
Reactant: C1COCCN1
Reactant: O=Cc1nccc(Cl)n1
Product: Clc1ccnc(CN2CCOCC2)n1

Procedure:
The title compound was prepared according to the general procedure in Example 45 Step 1 using 4-chloropyrimidine-2-carbaldehyde (2 g, 14.03 mmol) and morpholine (1.467 mL, 16.84 mmol) as the starting materials.
Reaction SMILES: O1[CH:3]([C:4]([CH:6]2[O:8][CH:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[C:11](C(F)(F)F)[CH:10]=2)=O)[CH:2]1[C:19]1C=C[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1.O1C(C2C=CC=C(C(F)(F)F)C=2)C1C(C1C=CC=CC=1)=O>>[C:9]1([CH2:7][C:6](=[O:8])[CH2:4][C:3]2[CH:2]=[CH:19][CH:20]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:22]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(C1OC1c1cccc(C(F)(F)F)c1)C1OC1c1cccc(C(F)(F)F)c1
Agent: O=C(c1ccccc1)C1OC1c1cccc(C(F)(F)F)c1
Product: O=C(Cc1ccccc1)Cc1cccc(C(F)(F)F)c1

Procedure:
Examples 1 and 2 illustrate the production of phenyl alpha, beta-epoxy-beta-(3-trifluoromethylphenyl)ethyl ketone. Examples 3, 4 and 5 illustrate the use of phenyl alpha,beta-epoxy-beta-(3-trifluoromethylphenyl)ethyl ketone to produce 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10]([C:20](=[O:22])[CH3:21])[C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[Br:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10]([C:20](=[O:22])[CH3:21])[C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][Br:23])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1C)c1ccccc1n2C(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc2c(c1CBr)c1ccccc1n2C(C)=O

Procedure:
10 g (33.8 mmol) of 9-acetyl-4-methyl-β-carboline-3carboxylic acid ethyl ester is combined in 500 ml of carbon tetrachloride with 12 g (67.4 mmol) of N-bromosuccinimide and one spatula tip of azobisisobutyronitril and heated to reflux for 1.5 hours while simultaneously exposing the reaction mixture to light. After cooling, the mixture is suctioned off from the succinimide, concentrated, and the residue is extracted by stirring with hot water and suctioned off. Yield: 10.64 g (84%) of 9-acetyl-4-bromomethyl-β-carboline-β-carboxylic acid ethyl ester, mp 188°-189° C.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([C:18]2[N:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[N:20]=[C:21]3[C:26]=2[CH:25]=[CH:24][CH:23]=[CH:22]3)[CH2:14][CH2:15][O:16][CH3:17])=[O:12])=[C:6]([Cl:34])[CH:5]=1.[OH-].[Li+]>C(Cl)Cl.CCCCCCC>[Cl:34][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11]([N:13]([C:18]1[N:19]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[N:20]=[C:21]2[C:26]=1[CH:25]=[CH:24][CH:23]=[CH:22]2)[CH2:14][CH2:15][O:16][CH3:17])=[O:12])[C:3]([OH:35])=[O:2]
Reactant: COCCN(C(=O)Nc1ccc(C(=O)OC)cc1Cl)c1c2ccccc2nn1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: ClCCl
Product: COCCN(C(=O)Nc1ccc(C(=O)O)cc1Cl)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 2.2, 3-chloro-4-[3-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-3-(2-methoxy-ethyl)-ureido]-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 14 h at ambient temperature to give the title compound as yellow foam. MS: m/e=497.1 [M−H−].
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:27][CH2:28][C:29]#[N:30])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:23][CH2:24][C:25]#[N:26])[CH2:19][CH2:20][C:21]#[N:22])#[N:2].[H][H]>O1CCOCC1>[NH2:26][CH2:25][CH2:24][CH2:23][N:18]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:1][NH2:2])[CH2:27][CH2:28][CH2:29][NH2:30]
Reactant: [H][H]
Reactant: N#CCCN(CCC#N)CCCCCCCCCCCCN(CCC#N)CCC#N
Solvent: C1COCCO1
Product: NCCCN(CCCN)CCCCCCCCCCCCN(CCCN)CCCN
Yield: 97.8 %

Procedure:
5.00 g of N,N,N′,N′-tetrakis(2-cyanoethyl)dodecamethylenediamine, 0.50 g of Raney Co and 50 mL of 1,4-dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 8.0 MPa at 170° C. for 2 hours. After the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness to give 5.08 g of the title compound as a pale red oil.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([Sn](CCCC)(CCCC)CCCC)=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1.Br[C:40]1[C:41]2[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=2[S:43][C:44]=1[CH3:45]>>[CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([C:40]4[C:41]5[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=5[S:43][C:44]=4[CH3:45])=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1
Reactant: Cc1sc2ccccc2c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Product: Cc1sc2ccccc2c1-c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1

Procedure:
Following General Procedure G for Stille coupling, N,N-dimethyl-1-((4-morpholino-2-(tributylstannyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-amine and 3-bromo-2-methylbenzo[b]thiophene were reacted to give 229. LCMS m/z: 508.7 (MH+)