Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[CH2:13][C:14](O)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].Cl>C1(C)C=CC=CC=1>[C:1]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C[C@@H]1CCCC[C@@H]1c1ccccc1
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCC[C@@H]1CCCC[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A stirred suspension of (cis-2-phenylcyclohexyl)acetic acid (15 g.) in dry toluene (100 ml.),cooled at -10° C. under argon, was treated with a 3.46 M solution of sodium bis(2-methoxyethoxy)aluminium hydride in toluene (25 ml.). The mixture was stirred overnight, diluted with ice/water (50 ml.), acidified with concentrated hydrochloric acid to pH 2. and extracted with ethyl acetate (3×150 ml.). The extracts were combined, washed with water (3×100 ml.), dried (MgSO4) and the solvent removed by evaporation to give 2-(cis-2-phenylcyclohexyl)ethanol (10.3 g.), which solidified on standing to give material of m.p. 48°-50° C.; NMR (CDCl3): 1.08-2.0 (12H,m), 2.81 (lH, d of t, Jaa=11 Hz, Jae=4 Hz, Jae=4 Hz, indicating cis-relative stereochemistry about the cyclohexane ring), 3.21 (1H,m), 3.37 (1H, m), 7.09 (3H,m), and 7.22 (2H,m).
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>>[NH2:26][C:24]1[C:25]2=[C:17]([C:14]3[CH:15]=[CH:16][C:10]4[S:9][C:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[N:12][C:11]=4[CH:13]=3)[CH:18]=[C:19]([CH:27]3[CH2:32][CH2:31][N:30]([C:36]([NH:35][CH2:33][CH3:34])=[O:37])[CH2:29][CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CCN=C=O
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c12
Product: CCNC(=O)N1CCC(c2cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 12 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 331 and using 5-(2-benzyl-1,3-benzothiazol-5-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and ethylisocyanate as starting material, 7 mg (12%) of the desired product was isolated.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].CCN(CC)CC.[F:18][C:19]1([F:34])[O:23][C:22]2[CH:24]=[CH:25][C:26]([C:28]3([C:31](Cl)=[O:32])[CH2:30][CH2:29]3)=[CH:27][C:21]=2[O:20]1>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:31]([C:28]2([C:26]3[CH:25]=[CH:24][C:22]4[O:23][C:19]([F:34])([F:18])[O:20][C:21]=4[CH:27]=3)[CH2:30][CH2:29]2)=[O:32])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1ccc(N)nc1Br
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
To a solution of 6-bromo-5-methoxypyridin-2-amine (510 mg, 2.5 mmol) and Et3N (690 L, 4.9 mmol) in dichloromethane (10 mL) was added a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (650 mg, 2.5 mmol) in dichloromethane (5 mL). The resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was then washed with 1N HCl (1×20 mL) and saturated aqueous NaHCO3 (1×20 mL). The organics were dried over sodium sulfate and evaporated to yield the product (850 mg, 81%). ESI-MS m/z calc. 426.0. found 427.3 (M+1)+. Retention time 2.05 minutes.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21]1[O:23][CH:22]1[CH2:24][OH:25]>[OH-].[Na+].C1(C)C=CC=CC=1>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:20][CH2:21][CH:22]([OH:23])[CH2:24][OH:25])=[O:19]
Reactant: OCC1CO1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO
Reaction time: 5 h
Yield: 86.1 %

Procedure:
0.4 mole of stearic acid were heated to boiling (about 113° C.) under reflux with 280 grams of toluene and 0.29 gram of NaOH (water free) and, in the course of 20 minutes, 31.2 grams of glycidol dropped in. After a further 5 hours at this temperature, the glycidol was 99% reacted and the reaction ended. After working as in Example 1, there were obtained 123.5 grams (86%) of monostearin having the following properties:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][N:16]=1>C1COCC1>[N+:25]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[N:18]=[CH:17][N:16]=[C:15]2[O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)([O-:27])=[O:26]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
To a solution of 3-(trifluoromethyl)phenol (726 mg, 4.48 mmol) in THF (2 mL) was added NaH (179 mg, 4.48 mmol, 60% in mineral oil) at 0° C. and the reaction mixture was stirred for 15 min. Then a solution of 4-chloro-8-nitroquinazoline (Intermediate-7, step 2, 470 mg, 2.24 mmol) in THF (3 mL) was added to the reaction mixture at the same temperature and the reaction mixture was stirred at rt for 4 h. Then the reaction mixture was quenched with 1N HCl at 0° C. and the precipitate obtained was filtered and purified by column chromatography using 5-10% EtOAc in petroleum ether to afford 430 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.88 (s, 1H), 8.68 (d, J=7.8 Hz, 1H), 8.60 (d, J=7.2 Hz, 1H), 7.99-7.94 (t, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.77 (s, 3H); MS (m/z): 336.12 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH:7]1[CH2:12][CH:11]([C:13]([O:15]C)=[O:14])[CH2:10][CH2:9][N:8]1[C:17]([O:19][CH3:20])=[O:18].[Li+].[Br-].C(N(CC)CC)C.Cl>C(#N)C.O.C(OCC)(=O)C>[CH3:20][O:19][C:17]([N:8]1[CH2:9][CH2:10][CH:11]([C:13]([OH:15])=[O:14])[CH2:12][CH:7]1[CH2:6][C:5]1[CH:21]=[CH:22][CH:23]=[C:3]([C:2]([F:25])([F:24])[F:1])[CH:4]=1)=[O:18]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2cccc(C(F)(F)F)c2)C1
Agent: Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
Dimethyl 2-(3-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (6.1 g, 16.98 mmol) and LiBr (11.79 g, 135.8 mmol) were dissolved in acetonitrile (60 mL) and water (1.2 mL). Triethylamine (9.41 mL, 67.90 mmol) was added and the resulting suspension was heated at reflux for 1 h, then cooled to room temperature and stirred overnight. Dissolved between ethyl acetate and 3 M HCl. The water layer was extracted once with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered through celite and the solvent was evaporated to yield 1-(methoxycarbonyl)-2-(3-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid (5.8 g, 99%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)C#N.[OH-].[Na+]>OS(O)(=O)=O.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: N#CC(c1ccc2ccccc2n1)c1ccc2ccccc2n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc2nc(Cc3ccc4ccccc4n3)ccc2c1
Yield: 89.4 %

Procedure:
Bis(2-quinolinyl)acetonitrile (14.3 g, 48.4 mmol) was dissolved in 70% H2SO4 in H2O (85 mL), and the resulting solution was heated at reflux for 1.5 h. The reaction mixture was poured into a 2-L beaker full of ice and was neutralized very carefully with a NaOH solution. The aqueous solution was extracted with a mixture of ether and THF, and the organic layer was isolated and dried over MgSO4. The volatile components were removed, and the resulting solid was washed with a solution of heptane and ether to afford 11.7 g (89.5%) of bis(2-quinolinyl)methane as a reddish powder. Results of 1H NMR spectroscopy and electrospray mass spectroscopy are consistent with the product. 1H NMR (300 MHz, CDCl3): δ 4.74 (s, 2H), 7.42 (d, J=8.5 Hz, 2H), m, 2H), 7.51 (m, 2H), 7.72 (m, 2H), 7.77 (d, J=8.2 Hz, 2H), 8.04 (d, J=8.5 Hz, 2H), 8.11 (d, J=8.5 Hz, 2H).
Reaction SMILES: B1C2CCCC1CCC2.[CH2:10]=[CH:11][CH2:12][CH2:13][CH3:14].[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)=[O:17]>O1CCOCC1.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>[CH3:10][CH2:11][CH2:12][CH:13]([CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17])[CH3:14]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: C=CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Solvent: C1COCCO1
Product: CCCC(C)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.6 %

Procedure:
To a solution of 9-BBN (0.5 M in THF) (90.0 ml, 45.0 mmol) at 23° C., 1-pentene (4.93 ml, 45.0 mmol) was added. After 12 h, the solution was diluted with anhydrous dioxane (150 ml) and then 4-bromoacetophenone (5.97 g, 30.0 mmol) K3PO4 (9.55 g, 45.0 mmol), Pd(PPh3)4 (0.867 g, 0.750 mmol) were added. After deoxygenating the solution with N2 for 20 min, the solution was refluxed for 12 h. After cooling to ambient temperature, 3N NaOH (40 ml) and 30% H2O2 (40 ml) were added dropwise followed by dilution with hexanes (200 ml). After separation of layers, the organic layer was washed with brine (200 ml), dried, and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with 10% EtOAc/hexanes, to afford 4.09 g of 11 as an oil (72%). 1H NMR (CDCl3) δ 0.88 (t, J=6.9 Hz, 3H), 1.23-1.36 (m, 4H), 1.55-1.69 (m, 2H), 2.58 (s, 3 H), 2.66 (t, J=7.7 Hz, 2H), 7.25 (d, J=1.9 Hz, 2H), 7.86 (d, J=1.9 Hz, 2H); 13C NMR (CDCl3) δ 14.09, 22.58, 26.65, 30.89, 31.51, 36.04, 128.55, 128.68, 134.97, 148.92, 197.98.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:21])([C:17]([F:20])([F:19])[F:18])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH:6]=[C:5]([CH3:22])[C:4]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[C:26]=1F)[CH3:2].[C:36](=O)([O-])[O-:37].[K+].[K+]>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:21])([C:17]([F:20])([F:19])[F:18])[C:10]([F:16])([F:15])[C:11]([F:12])([F:13])[F:14])[CH:6]=[C:5]([CH3:22])[C:4]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[C:26]=1[O:37][CH3:36])[CH3:2]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1cccc([N+](=O)[O-])c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1cccc([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a suspension of N-[2-ethyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methylphenyl]-2-fluoro-3-nitrobenzamide (Example 12) (5 g, 9.6 mmol) in methanol (195 ml) was added potassium carbonate (2.6 g, 16.2 mmol) at ambient temperature. The reaction mixture was stirred for 16 hours at ambient temperature. The reaction mixture was concentrated and the residue was dissolved in dichloromethane. The organic phase was washed with water, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1) to give N-[2-ethyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methylphenyl]-2-methoxy-3-nitrobenzamide (5.1 g, 99% yield). 1H NMR (400 MHz, CDCl3): 8.90 (bs, 1H), 8.32 (d, 1H), 7.97 (d, 1H), 7.38 (m, 3H), 4.19 (s, 3H), 2.70 (q, 2H), 2.24 (s, 3H), 1.20 (t, 3H) ppm.
Reaction SMILES: [CH2:1]([N:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:19]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N(Cc1ccccc1)c1cccc(Br)c1
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)N(Cc1ccccc1)c1cccc(N2CCOCC2)c1
Yield: 73.4 %

Procedure:
A solution of N-benzyl-N-(3-bromo-phenyl)-benzene sulfonamide (25 mg, 0.06 mmol), morpholine (6.5 μl, 0.07 mmol), palladium acetate (1 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2 mg) and sodium tert-butoxide (21 mg, 0.22 mmol) in dioxane (1 ml) were heated to 100° C. in the microwave for 30 minutes. The reaction was filtered, diluted with water (5 ml) and extracted with dichloromethane (3×6 ml). The combined organics were filtered, concentrated in vacuo and the residues purified by preparative TLC (eluent dichloromethane) to afford the title compound as a yellow solid (18 mg, 71%) HPLC retention time 8.3 min. Mass spectrum (ES+) m/z 409 (M+H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([CH:14]=O)[CH:5]=1>>[CH2:1]([NH:3][CH2:14][C:6]1[CH:5]=[N:4][C:13]2[C:8]([CH:7]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:2]
Reactant: O=Cc1cnc2ccccc2c1
Reactant: CCN
Product: CCNCc1cnc2ccccc2c1

Procedure:
prepared by reaction of ethylamine with quinoline-3-carbaldehyde
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([CH:35]=[O:36])C.O.CC(=O)OCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([CH:35]=[O:36])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nc(C=O)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A cooled (−30° C.) solution of 3-ethyl-1-iodo-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.000 g; 1.820 mmol) in anhydrous THF (10 ml) was treated dropwise with 1-Methylmagnesium bromide in THF (4.0 ml; 4.0 mmol), and the resulting suspension was then allowed to warm-up to rt in 10 min. After cooling to −35° C., a mixture of anhydrous DMF (2.0 ml; 25.831 mmol) and anhydrous THF (2 ml) was added dropwise, and the resulting mixture was then allowed to warm-up to rt (in 30 min.), and was further stirred at rt for 16 h. Water (2 ml) and EA were then successively added, and this mixture was washed with aq. sat. NH4Cl. The organic extract was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure (yellow oil; 950 mg). Purification by FC (EA/heptane=1/9 to 1/1) gave the pure product 3-ethyl-1-formyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a colorless oil (640 mg; 78%). LC-MS: tR=1.01 min.; [M+H]+=452.12 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10](#[N:14])[CH2:11][C:12]#[N:13].C([O-])(=O)C.[NH4+].C(O)(=O)C>C(O)(C)C.O>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:11]([C:10]#[N:14])[C:12]#[N:13]
Reactant: N#CCC#N
Reactant: Cc1ccccc1C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1C=C(C#N)C#N
Yield: 91 %

Procedure:
A solution of 2-methylbenzaldehyde (9.6 mL, 83 mmol), malononitrile (5.5 g, 83 mmol) and 3.5 M ammonium acetate in acetic acid (2.4 mL, 8.4 mmol) in isopropanol (83 mL) was stirred overnight at room temperature. A precipitate formed. Water (100 mL) was added and the precipitate was collected. The precipitate was washed with water (50 mL) and vacuum dried to afford of 2-(2-methylbenzylidene)malononitrile (12.7 g) as a white solid (mp 105-106°). 1H-NMR (CDCl3) δ: 8.10 (s 1H); 8.08 (d, 1H); 7.50 (dd, 1H); 7.30-7.40 (m, 2H); 2,45 (s, 3H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[C:19]#[CH:20].C(N(CC)CC)C.O>C1COCC1.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.[Cu]I>[C:7]1([C:5]2[S:6][C:2]([C:20]#[C:19][CH2:18][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#CCOC1CCCCO1
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(-c2ccccc2)sc1C#CCOC1CCCCO1
Temperature: 100 °C
Yield: 89 %

Procedure:
Nitrogen was bubbled through a solution of Ethyl 5-bromo-2-phenylthiazole-4-carboxylate (3.6 g, 11.5 mmol) and 2-(prop-2-ynyloxy)tetrahydro-2H-pyran (3.3 mL, 23.1 mmol) in THF (30 mL). Dichlorobis(triphenylphosphine)palladium (II) (405 mg, 0.6 mmol), copper (I) iodide (55 mg, 0.3 mmol), and triethylamine (TEA) (8 mL, 57.7 mmol) were added and the reaction mixture was heated at 100° C. for 30 min in a microwave reactor. The reaction mixture was poured into H2O and extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), and concentrated. The crude product was purified by MPLC eluting with pentane/EtOAc (0-50% gradient) to give ethyl 2-phenyl-5-(3-(tetrahydro-2H-pyran-2-yloxy)prop-1-ynyl)thiazole-4-carboxylate (3.8 g, 88% yield).
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH2:34])[CH3:24].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH:34][C:17]([C:14]([CH3:15])([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH3:21])[C:4]([OH:3])=[O:22])=[CH:12][CH:11]=1)[CH3:16])=[O:19])[CH3:24]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Reactant: CCOc1ccccc1CCN
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCOc1ccccc1CCNC(=O)C(C)(C)Oc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and 2-(2-ethoxy-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H31NO6 [M+H]+: 430.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH:29]=[N:28][C:27]([C:30](O)=[O:31])=[N:26]2)[CH:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH:29]=[N:28][C:27]([C:30]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=4)=[O:10])[CH2:12][C@H:13]3[CH3:17])=[O:31])=[N:26]2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(C(=O)N2CCN[C@H](C)C2)n1
Reactant: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)N2CCN(C(=O)c3ncn(-c4cccc(Cl)c4)n3)[C@H](C)C2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 71 mg (0.30 mmol) (6-methoxy-pyridin-2-yl)-((R)-3-methyl-piperazin-1-yl)-methanone, 67 mg (0.30 mmol) 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid, 0.11 g (0.33 mmol) TBTU and 77 μL (0.45 mmol) DIPEA in 1.5 mL DMF was stirred at RT for 12 h. The reaction mixture was purified by HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=1)=[N:6]2.[CH:33](B(O)O)=[CH2:34].C(=O)([O-])[O-].[K+].[K+].CN(C)C=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>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:4]1[N:5]2[C:10]([CH:9]=[N:8][C:7]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:6]2)=[C:2]([CH:33]=[CH2:34])[CH:3]=1
Reactant: COc1ccccc1-c1cc(Br)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nn12
Reactant: C=CB(O)O
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: [K+]
Solvent: CN(C)C=O
Product: C=Cc1cc(-c2ccccc2OC)n2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc12
Temperature: 140 °C

Procedure:
Into a 30 mL vial [5-Bromo-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (90.0 mg, 0.000182 mol), Vinyl boronic acid (100 mg, 0.002 mol), Potassium carbonate (1.12 g, 0.00814 mol), and Tetrakis(triphenylphosphine)palladium (0) (21.3 mg, 0.0000184 mol) were added and purged under an atmosphere of Nitrogen for 10 minutes. N,N-Dimethylformamide (5 mL, 0.06 mol) was added. The reaction mixture was heated at 140° C. for 4 hours. The reaction was partitioned with water and EtOAc. The organic was separated and washed with water. Subsequently the organic was washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with DCM and Methanol as eluant (0 to 10% methanol). The collected fractions afforded [7-(2-Methoxy-phenyl)-5-vinyl-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine a yellow solid (68 mg, 85%). MP 150-151° C. LCMS (E/I+) 441.24 (M+H). NMR 1H (DSMO-d6)-9.17 (s, 1H), 9.14 (s, 1H), 7.75 (dd, 1H, JJ=1.60, 6.04 Hz), 7.53 (d, 2H, J=8.96 Hz), 7.48 (dt, 1H, JJ=1.52, 6.92 Hz), 7.22 (d, 1H, J=8.36 Hz), 7.00-7.18 (m, 3H), 6.78 (d, 2H, J=9.04 Hz), 5.78 (d, 1H, J=17.56 Hz), 5.24 (d, 1H, J=11.81 Hz), 3.80 (s, 3H), 3.02 (t, 4H, J=4.56 Hz), 2.44 (t, 4H, J=4.68 Hz), 2.21 (s, 3H).