Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=2[CH:14]([CH3:16])[CH3:15])[C:5](=[O:17])[CH2:4][S:3]1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.ClCCl>[CH:14]([C:8]1[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=1[N:6]1[C:5](=[O:17])[CH2:4][S:3]/[C:2]/1=[N:1]\[C:19](=[O:20])[O:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)([CH3:15])[CH3:16]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(C(C)C)c(N2C(=N)SCC2=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
A round-bottomed flask was charged with 2-imino-3-(2-isopropyl-5-methylphenyl)thiazolidin-4-one (CA49) (1.30 g, 5.23 mmol), 4-Nitrophenyl chloroformate (1.06 g, 5.23 mmol) and cesium carbonate (1.71 g, 5.23 mmol) were dissolved in acetonitrile (13 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction was diluted with dichloromethane and adsorbed onto silica gel. Purification by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent provided the title compound as a dark red solid (1.88 g, 86%): 1H NMR (400 MHz, CDCl3) δ 8.31-8.18 (m, 2H), 7.39-7.27 (m, 4H), 6.92-6.83 (m, 1H), 4.14-4.00 (m, 2H), 2.61 (p, J=6.9 Hz, 1H), 2.36 (d, J=0.7 Hz, 3H), 1.30-1.10 (m, 6H); ESIMS m/z 414 ([M+H]+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])=[O:7].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[O:7]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccccc1C(F)(F)F
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3C(F)(F)F)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-[2-(trifluoromethyl)phenyl]-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 461.2 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[C:23]1([C:34](O)=[O:35])[CH:24]=[CH:25][CH:26]=[C:27]2[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:34]([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=23)=[O:35])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: CC(C)(C)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CC(C)(C)c1ccc(CC(NC(=O)c2cccc3c2C=CCCC3)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butylphenyl)-1-(3-chlorophenyl)propan-1-ol (355 mg, 1.17 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (220 mg, 1.17 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (336 mg, 1.76 mmol) and 1-hydroxybenzotriazole hydrate (179 mg, 1.17 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (348 mg, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]2[CH2:22][NH+:10]3[CH2:11][CH2:12][C:13]4[C:18]([C:9]3=[C:8]([CH3:24])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH3:26])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4.[I-].[C:28]([Mg]Br)([CH3:30])=[CH2:29].O1CCCC1>C(OCC)C>[C:28]([CH:22]1[N:10]2[CH2:11][CH2:12][C:13]3[C:18]([C:9]2=[C:8]([CH3:24])[C:7]2[CH:6]=[CH:5][C:4]([O:25][CH3:26])=[C:3]([O:2][CH3:1])[C:23]1=2)=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=3)([CH3:30])=[CH2:29]
Reactant: COc1ccc2c(c1OC)C[NH+]1CCc3cc4c(cc3C1=C2C)OCO4
Reactant: C=C(C)[Mg]Br
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)C1c2c(ccc(OC)c2OC)C(C)=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a suspension of 9,10-dimethoxy-13-methyl-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (300 mg, 0.63 mmol) in anhydrous diethyl ether (100 mL) at 0° C. was added a solution of isopropenylmagnesium bromide in tetrahydrofuran (0.5 M, 18.8 mL, 9.4 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 8-isopropenyl-9,10-dimethoxy-13-methyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (90 mg, 36%). LC/MS m/e calcd for C24H23NO4 (M+H)+: 392.47, observed: 392.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (s, 3 H) 2.13 (s, 3 H) 2.62-2.71 (m, 1 H) 2.72-2.79 (m, 1 H) 3.00-3.08 (m, 1 H) 3.13-3.21 (m, 1 H) 3.71 (s, 3 H) 3.80 (s, 3 H) 4.59 (s, 1 H) 4.77 (s, 1 H) 5.12 (s, 1 H) 6.03 (s, 2 H) 6.83 (s, 1 H) 6.93 (s, 2 H) 7.02 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH:21](=[O:23])[CH3:22].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[C:11]([CH:21]([OH:23])[CH3:22])=[CH:10][C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC=O
Reactant: Fc1cccc2ccc(Cl)nc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)c1cc2cccc(F)c2nc1Cl
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
2-Chloro-8-fluoroquinoline (5.00 g, 27.5 mmol) was dissolved in THF (60 mL) and cooled to −78° C. To this solution was added freshly prepared and titrated lithium diisopropylamide (1M solution in THF, 30 mL, 30 mmol, 1.1 eq) over 5 min. The reaction was allowed to stir at −78° C. for 20 min, after which time acetaldehyde (2.3 mL, 41.3 mmol, 1.5 eq.) was added via syringe over 30 seconds (exothermic). After 30 min at −78° C., the reaction was quenched with 50% saturated NH4Cl solution and diluted with EtOAc. The layers were separated and washed with brine, dried over MgSO4, and filtered. The crude reaction mixture was deposited on 30 g of silica gel and passed through a plug of 60 g of silica gel, eluted with 8:2 hexanes:EtOAc. Fractions containing product and a closely (second) eluting regioisomer were collected. The fractions were concentrated and the crude solid was slurried in 140 mL of 9:1 hexanes:EtOAc at reflux for 30 min. After cooling to rt, the solid was filtered and washed with a small amount of cold 9:1 hexanes:EtOAc to afford pure 1-(2-chloro-8-fluoroquinolin-3-yl)ethanol (3.1 g, 13.7 mmol, 50% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (br s, 1H), 7.64 (td, J=7.8, 5.1 Hz, 1H), 7.41 (ddd, J=10.2, 7.4, 1.2 Hz, 1H), 5.39 (qdd, J=6.3, 3.9, 0.8 Hz, 1H), 2.22 (d, J=3.9 Hz, 1H), 1.62 (d, J=6.3 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)=[O:9])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([O:19][CH3:20])[CH:3]=1.C(Cl)(=O)C([Cl:24])=O>C1C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([Cl:24])=[O:9])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(Br)nc(C(=O)O)c1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COc1cc(Br)nc(C(=O)Cl)c1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 16 (2.54 g., 7.5 mmol) in benzene (30 mL) containing DMF (3 drops) was added oxalyl chloride (1.90 g, 15 mmol) in one portion. After gas evolution had ceased (about 45 min.), the now homogeneous solution was stirred an additional 15 min., then the solvent was evaporated. 1,2-dichloroethane (30 mL) was added and again the solvent was evaporated to give a quantitative yield of 3 as a nearly colorless oil. This material was dissolved in CH2Cl2 (10 mL) or THF (10 mL) and used directly in subsequent coupling reactions. 6-Bromo-3-Hydroxypicolinic Acid (17).
Reaction SMILES: [C@@H:1]12[N:8]([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]=[C:2]2[C:10]([O:12]CC)=O.[Si](Cl)(C)(C)[CH3:16].[Li]C>C1COCC1>[C:10]([C:2]1[C@@H:1]2[N:8]([CH3:9])[C@H:5]([CH2:4][CH:3]=1)[CH2:6][CH2:7]2)(=[O:12])[CH3:16]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)C1=CC[C@@H]2CC[C@H]1N2C
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)C1=CC[C@@H]2CC[C@H]1N2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a mixture, of ethyl trop-2-ene-2-carboxylate (3.43 g, 0.019 mol) and Me3SiCl (10.32 g, 0.095 mol) in THF (70 mL) cooled to -100° C., MeLi (1.4 M, 7.07 mL, 0.0239 mol) was added dropwise. After warming up to room temperature, the reaction mixture was stirred for 16 hours. Excess Me3SiCl and THF was evaporated off and the resulting residue was stirred with EtOH (6 mL) followed by water (6 mL). The mixture was then made acidic (6N HCl) and extracted with ether. The aqueous layer was made basic (solid K2CO3) and extracted with chloroform, dried (K2CO3) and concentrated to give 3.14 g (81%) of 2-acetyltrop-2-ene as an oil: IR (neat) 1670 (COCH3);
Reaction SMILES: [C:1]([O:18][CH2:19][CH:20]([CH2:22][OH:23])[OH:21])(=[O:17])[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][CH3:16].N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>ClCCl>[C:1]([O:18][CH2:19][CH:20]([CH2:22][O:23][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[OH:21])(=[O:17])[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][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)OCC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
1-palmitoyl-glycerol (33.0 g), dichloromethane (330 ml) and imidazole (13.6 g) were added into 1 L reactor, and the reaction mixture was cooled to 0° C. Then, t-butyl-dimethylsilylchloride (18.0 g) was added, and the reaction mixture was stirred for 2 hours. After filtering the reaction mixture, the solvent was removed by distillation under reduced pressure, and purified water (165 ml) and heptane (150 ml) were added for an extraction. The separated organic layer was extracted with purified water (80 ml) again, and then the organic layer was dehydrated with anhydrous MgSO4, and filtered. Then, the solvent was removed by distillation under reduced pressure to obtain 1-palmitoyl-3-t-butyldimethylsilyl-glycerol (yield: 100%) {1H NMR (400 MHz, CDCl3): δ 0.78-0.83 (m, 18H), 1.18-1.31 (m, 24H), 1.50-1.56 (m, 2H), 2.24 (t, 2H), 3.51-3.60 (m, 2H), 3.76-3.79 (p, 1H), 4.01-4.10 (m, 2H)}.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:11])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([Li])CCC.CN(C)[C:19](=[O:21])[CH3:20].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[C:4]([CH2:11][C:19](=[O:21])[CH3:20])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccnc(C)c1OC
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccnc(CC(C)=O)c1OC
Temperature: 0 °C

Procedure:
To a stirred solution of 3,4-dimethoxy-2-methylpyridine (1.53 g) in tetrahydrofuran (15 ml) was added a solution of n-butyllithium in n-hexane (1.63M, 7.36 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (1.21 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×2). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, 25% ethyl acetate in n-hexane) to give 1-(3,4-dimethoxypyridin-2-yl)propan-2-one (1.85 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[N:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1.[BH4-].[Na+].CC(O)(C)C>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[NH2:8])=[CH:12][CH:11]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: N#Cc1cnccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: NC(c1ccc(Cl)cc1)c1cnccn1
Temperature: 60 °C
Reaction time: 6 h
Yield: 34 %

Procedure:
Pyrazine-2-carbonitrile (10.5 g, 100 mmol) was dissolved in PhMe (100 mL) at 0° C. and 4-chlorophenyl magnesium bromide (100 ml, 1.0 M in Et2O, 100 mmol) was added portion-wise over 5 min. The reaction mixture was stirred for 6 h and NaBH4 (7.58 g, 201 mmol) and tBuOH (100 mL) were added. The reaction mixture was warmed to 60° C. for 18 h and quenched with 1 M aq NaOH solution. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (DCM:EtOH:NH3 200:8:1 to 50:8:1) to give the title compound as a brown oil (7.46 g, 34%). MS (ESI+) m/z=220.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.CI.[H-].[Na+].[CH2:14]1[CH2:18][O:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH2:16][O:17][CH2:18][CH2:14][C:15]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: OCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Brc1ccc(CCOCCc2ccc(Br)cc2)cc1
Temperature: 25 °C

Procedure:
4-Bromobenzylalcohol (5.0 g, 26.7 mmol) was dissolved in THF (130 ml) and methyl iodide added (6.7 ml, 107.0 mmol). Sodium hydride (1.20 g of 80% dispersion in oil, 40.1 mmol) was added in two portions while stirring at room temperature under nitrogen. After stirring for 2 hours, the solvents were removed in vacuo and the residue partitioned between water and ether. The water was reextracted with ether and the combined organic fractions were then washed with water and brine before drying (Na2SO4) and evaporating in vacuo to give 4-bromobenzylmethyl ether as an orange liquid (5.3 g, 26.4 mmol). δH (250 MHz, CDCl3) 3.39 (3H, s, CH3), 4.40 (2H, s, CH2), 7.21 (2H, d, J 7.5 Hz, Ar-H), 7.48 (2H, d, J 7.5 Hz, Ar-H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH:16]([NH2:18])[CH3:17].[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24](Cl)[N:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24]([NH:18][CH:16]([C:8]2[N:9]=[C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]3[C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH3:17])[N:23]=[CH:22][N:21]=1
Reactant: CC(N)c1nc2cnccn2c1-c1ccccn1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc(N)c1C#N)c1nc2cnccn2c1-c1ccccn1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(3-pyridin-2-yl-imidazo[1,2-a]pyrazin-2-yl)-ethylamine (250 mg, 1.04 mmol) and 4-amino-6-chloro-pyrimidine-5-carbonitrile (160 mg 1.04 mmol) in n-butanol (3 mL) was added DIEA (1.7 mL, 10.04 mmol) at rt. The reaction mixture was stirred at 110° C. overnight. The mixture was concentrated in vacuo. The residue was purified by column chromatography using silica gel (100-200 mesh) and 0-40% acetone in hexane to provide 4-amino-6-[1-(3-pyridin-2-yl-imidazo[1,2-a]pyrazin-2-yl)-ethylamino]-pyrimidine-5-carbonitrile: 1H NMR: (400 MHz, DMSO-d6) δ 1.537 (d, J=6.8 Hz, 3H), 5.837-5.906 (m, 1H), 7.269 (br s, 2H), 7.471-7.502 (m, 1H), 7.572-7.594 (m, 1H), 7.887-7.907 (m, 1H), 7.983-8.043 (m, 3H), 8.814-8.826 (m, 1H), 8.928-8.944 (m, 1H), 9.180 (d, J=1.2 Hz, 1H); LC-MS (ESI) m/z 358.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:8]([O:10][CH2:11]Cl)[CH3:9]>CS(C)=O>[CH2:8]([O:10][CH2:11][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:9]
Reactant: c1c[nH]cn1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOCn1ccnc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 9.1 %

Procedure:
To a solution of imidazole (10.0 g, 146.9 mmole) in 100 ml dimethyl sulfoxide at room temperature under nitrogen is added sodium hydride (6.46 g, 161.6 mmole). The solution is stirred at 80° C. for 2 hours. Chloromethyl ethyl ether (16.35 ml, 176.3 mmole) is added dropwise. The reaction mixture is stirred for another 2 hour at 80° C., cooled to room temperature, poured into 5% aqueous solution and extracted with dichloromethane (4×200 ml). The combined organic extracts are dried over sodium sulfate, filtered, concentrated in vacuo. The residue is fresh chromatographed in hexane/ethyl acetate from 5:1 to 2:1 to give 1-ethoxymethyl-1H-imidazole as a brown oil 1.68 g (90%) MS(ES+): (M+H)=127.0 To the solution of 1-ethoxymethyl-1H-imidazole (1.24 g, 0.98 mmole) in 3.92 ml anhydrous tetrahydrofuran at −78° C. is added n-butyllithium (1.6 M in hexane) over 5 minutes. Reaction mixture is stirred at −78° C. for 1.5 hour, then (1S,2E)-1-isopropyl-4-[methoxy(methyl)amino]-3-methyl-4-oxobut-2-enyl(methyl)carbamate (427 mg, 1.36 mmole) in 2 ml anhydrous tetrahydrofuran is added over 10 minutes. The reaction mixture is stirred at −78° C. for 1 hour. Then, it is warmed to room temperature, stirred for 1 hour at room temperature. The reaction mixture is diluted with dichloromethane/water. The organic layer is washed with 5% sodium bicarbonate, dried over sodium sulfate, filtered, concentrated in vacuo. The residue is fresh chromatographed in hexane/ethyl acetate from 3:1 to 1:1 to give light yellow oil: [4-(1-Ethoxymethyl-1H-imidazol-2-yl)-1-isopropyl-3-methyl-4-oxo-but-2-enyl]-methyl-carbamic acid tert-butyl ester (120 mg, 23%) MS(ES+): (M+H)=380.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.[C:23]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[CH:28][C:27]=1[O:37][CH3:38])(=[O:25])[CH3:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:33][CH2:32][CH2:31][O:30][C:29]3[CH:35]=[CH:36][C:26]([C:23](=[O:25])[CH3:24])=[C:27]([O:37][CH3:38])[CH:28]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: COc1cc(OCCCCl)ccc1C(C)=O
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Product: COc1cc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)ccc1C(C)=O

Procedure:
Following the procedure of Examples 1 and 66, [α,α-bis (p-fluorophenyl)]-4-piperidinemethanol and 3-(p-acetyl-m-methoxyphenoxy)propyl chloride are reacted to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](C(O)=O)=[C:5]2[CH3:14].[H-].[Na+].[CH3:17][C@@H:18]1[CH2:20][O:19]1>C1(OC2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C@H:18]([OH:19])[CH3:20])[CH:6]=[C:5]2[CH3:14]
Reactant: C[C@@H]1CO1
Reactant: Cc1c(C(=O)O)[nH]c2ccc(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cn(C[C@@H](C)O)c2ccc(F)cc12
Reaction time: 5 h
Yield: 70 %

Procedure:
A suspension of 1.16 g of 5-fluoro-3-methyl-indole-2-carboxylic acid in 16 ml of diphenyl ether was stirred at 260° for 5 hours and, after cooling to 0°, diluted with 30 ml of tetrahydrofuran. 225 mg of sodium hydride dispersion were added and the mixture was stirred for one hour. Subsequently, 0.63 ml of (R)-methyloxirane was added and the reaction mixture was stirred at room temperature for 90 hours. The mixture was extracted with diethyl ether, water and saturated sodium chloride solution and the organic phase was dried over sodium surfate. The solvent was removed and the residue was chromatographed over 120 g of silica gel with hexane-toluene (1:1) and subsequently with toluene-ethyl acetate (19:1). 0.87 g (70%) of (R)-1-(5-fluoro-3-methylindol-1-yl)-propan-2-ol was obtained as a pale brown oil.
Reaction SMILES: [OH:1][CH:2]([CH2:25][OH:26])[CH2:3][O:4][NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[C:8]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=1[F:23].C(N(CC)CC)C>O1CCCC1.[Ni]>[OH:1][CH:2]([CH2:25][OH:26])[CH2:3][O:4][NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[C:8]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:23]
Reactant: O=C(NOCC(O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NOCC(O)CO)c1ccc(F)c(F)c1Nc1ccccc1F
Yield: 31.8 %

Procedure:
A solution of N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4iodo-phenylamino)-benzamide (0.260 g, 0.539 mmol) and triethylamine (2.0 mL, 14.3 mmol) in tetrahydrofuran (14 mL) was hydrogenated over Raney Nickel (0.2 g wet) at 50 psig at room temperature for 20 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The afforded residue was partitioned between ethyl acetate and water. The organics were washed twice with saturated sodium bicarbonate solution, twice with water, collected, dried over sodium sulfate, filtered and concentrated in vacuo. HPLC purification was performed using a YMC 30×100 mm 5u (C18) column in 0-100% acetonitrile (3.0% n-propanol)/100-0% water (3.0% n-propanol) at 30 mL/min. The desired fractions were collected and concentrated. The afforded residue was extracted with ethyl acetate/water. Organic layers were washed with saturated NaCl solution, collected and dried in vacuo to afford N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-phenylamino)-benzamide as a white solid (0.061 g, 31%): m.p.=113-115° C.; 1NMR(400MHz; DMSO-d6) δ 11.90(s, 1H), 8.73 (s, 1H), 7.37 (m, 1H), 7.10-7.19 (m, 2H), 7.02 (t, 1H, J=7.4 Hz), 6.84-6.93 (m, 2H), 4.82 (m, 1H), 4.57-4.58 (m, 1H), 3.86-3.88 (m, 1H), 3.67-3.73 (m, 2H), 3.3 (2H, under HDO); MS(APCI+)=357.1; Anal.calcd/found for C16H15F3N2O4: C, 53.94/53.97; H, 4.24/4.37; N, 7.86/7.83.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[C:16]([C:17]#[N:18])=[C:15]([N:19]([CH3:21])C)[N:14](N=C)[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29]>CO>[C:4]([O:3][C:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[C:16]2[C:15](=[N:19][CH:21]=[N:18][C:17]=2[NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:26]([Cl:25])[CH:27]=2)[NH:14][N:13]=1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Nc1cccc(Cl)c1
Reactant: C=Nn1nc(NCCNC(=O)OC(C)(C)C)c(C#N)c1N(C)C
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 35 g (108.9 mmol) of 3-[2-(Boc-amino)-ethylamino]-4-cyano-5-dimethylamino-methyleneamino-pyrazole, 17.9 g (109.1 mmol) of 3-chloro-aniline hydrochloride and 350 ml of methanol is heated under reflux for 30 hours and then stirred at RT for 15 hours. Filtration and washing the filter residue with methanol yield 3-[2-(tert-butyloxy-carbonyl-amino)-ethylamino]-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine having a water content of 2.39%; m.p. 206-208° C.; ESI-MS: (M−H)−=402.