Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([C:14](=[O:16])[CH3:15])=[C:9]([CH3:17])[CH:8]=2)=[CH:4][CH:3]=1.[Br-:20].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:20][CH2:15][C:14]([C:10]1[C:11]([CH3:13])=[CH:12][C:7]([O:6][C:5]2[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][C:9]=1[CH3:17])=[O:16]
Reactant: CC(=O)c1c(C)cc(Oc2ccc(F)cc2)cc1C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(Oc2ccc(F)cc2)cc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
To a solution of 1-(4-(4-fluorophenoxy)-2,6-dimethylphenyl)ethanone (4.40 g, 17.0 mmol) in acetonitrile (34.1 mL) was added tetrabutylammoniumtribromide (TBABr3, 9.04 g, 18.8 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-(4-fluorophenoxy)-2,6-dimethylphenyl)ethanone (5.8 g), which was used directly for the next step without further purification.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[ClH:1].[C:2]1([N:8]([CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccc3)ccc21
Yield: 97 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)amide hydrochloride and sodium hydroxide solution. Yield: 97% of theory, C26H25N5O3 (455.5); EKA mass spectrum: (M+H)+=456; (M+Na)+=478; (M+2Na)++=250.6.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[C:8]([OH:21])=[C:7]([CH2:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]=O>C1COCC1>[C:24]([N:23]1[CH2:22][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=3)[C:8]=2[O:21][CH2:28]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: C=O
Reactant: CC(C)(C)NCc1cc(C(C)(C)C)cc(-c2ccc(C(F)(F)F)nc2)c1O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2c(c(-c3ccc(C(F)(F)F)nc3)c1)OCN(C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
4-(tert-Butyl)-2-((tert-butylamino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol (2.00 g, 5.26 mmol) was added to a 37% aqueous solution of formaldehyde (0.47 mL, 5.78 mmol) in THF (6 mL) and the reaction mixture stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the solid was recrystallized by heating 1.1 g of product in methanol (10 mL) then cooling to room temperature to yield a first crop of 3,6-di-tert-butyl-8-(6-(trifluoromethyl)pyridin-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (588 mg, 29%) as a white crystalline solid.
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13](I)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:17])(=[O:6])=[O:5])([CH3:3])[CH3:2].C1([Li])C=CC=CC=1.C([Li])(C)(C)C.[B:30](OC(C)C)([O:35]C(C)C)[O:31]C(C)C.Cl.[OH-].[Na+]>O.O1CCCC1>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([B:30]([OH:35])[OH:31])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:17])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(I)cc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(B(O)O)cc21
Temperature: -77 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
Charge a 5 L round bottom flask equipped with dry ice/acetone bath, nitrogen atmosphere, mechanical stirrer, thermocouple, and addition funnel with septum with 1-isopropylsulfonyl-2-amino-6-iodobenzimidazole (125 g, 342 mmol) and tetrahydrofuran (1.2 L) and cool to −77° C. (results in a slurry). To this slurry add phenyllithium (1.8 M in cyclohexane/diethyl ether, 599 mL, 1078 mmol) over 25 minutes keeping the temperature below −67° C. After stirring the resulting green slurry for 20 minutes while cooling to −77° C., add tert-butyllithium (1.7 M in pentane, 503 mL, 856 mmol) over 25 minutes keeping the temperature of the reaction below −67° C. Stir the mixture at −75° C. for 40 minutes then add triisopropyl borate (276 mL, 1198 mmol) over 15 minutes keeping the temperature below −65° C. Warm the resulting slurry slowly to 0° C. over 2 hours, then add a mixture of concentrated hydrochloric acid and water (400 mL) until pH 2 is reached. Stir the mixture for 1 hour then adjust to pH>12 with 5 N sodium hydroxide while keeping the temperature <10° C. Add water (1 L), and separate the layers. Wash the aqueous layer with ethyl acetate (300 mL) then adjust to pH 6 with concentrated hydrochloric acid. Extract the mixture with ethyl acetate (2×700 mL), dry the combined extracts over sodium sulfate, filter, and concentrate in vacuo to an orange paste (116 g). Dissolve the paste in warm (˜60° C.) 2-propanol (360 mL) then add water (1.4 L). Cool the solution to 0° C. for 3 hours. Collect the resulting solid by filtration, wash with water then air-dry to constant weight to afford the title compound (34.9 g, 36% yield) as light tan crystals. Obtain a second crop from the filtrate (4.95 g, 41% yield overall). MS (ES+): m/z=284 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][C:5]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][C:3]=1[C:20]#[C:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][CH:23]=1.[H][H]>CCOC(C)=O.CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[C:7]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][C:5]([C:16]([CH3:17])([CH3:18])[CH3:19])=[CH:4][C:3]=1[CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][CH:27]=1
Reactant: [H][H]
Reactant: COc1ncccc1-c1cc(C(C)(C)C)cc(C#Cc2ccc(NS(C)(=O)=O)cc2)c1N
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1cc(C(C)(C)C)cc(CCc2ccc(NS(C)(=O)=O)cc2)c1N
Yield: 70.7 %

Procedure:
step 4—A mixture of 84 (0.131 g, 0.29 mmol) and Pd(OH)2 (20% wt. on carbon, 0.100 g) in EtOAc (20 mL) and MeOH (20 mL) in a Parr bottle at RT was shaken under 40 psi hydrogen atmosphere for 45 min. The catalyst was filtered and the filtrate was concentrated to afford 0.093 g (66%) of N-(4-{2-[2-amino-5-tert-butyl-3-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-phenyl)-methanesulfonamide (86) as an off-white solid.
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[C:5]2[N:6]([C:10](I)=[C:11]([CH2:13][O:14][CH3:15])[N:12]=2)[CH:7]=[CH:8][CH:9]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]2=[C:23]([CH:39]=1)[O:24][CH2:25][C:26]1[CH:36]=[C:35]([CH:37]=[O:38])[CH:34]=[CH:33][C:27]=1/[C:28]/2=[C:29](/[CH3:32])\[C:30]#[N:31]>>[F:1][CH:2]([F:17])[O:3][C:4]1[C:5]2[N:6]([C:10]([CH:37]([OH:38])[C:35]3[CH:34]=[CH:33][C:27]4/[C:28](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:22]5[CH:21]=[CH:20][C:19]([F:18])=[CH:39][C:23]=5[O:24][CH2:25][C:26]=4[CH:36]=3)=[C:11]([CH2:13][O:14][CH3:15])[N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COCc1nc2c(OC(F)F)cccn2c1I
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: COCc1nc2c(OC(F)F)cccn2c1C(O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 77.6 %

Procedure:
[step 4] Using 8-(difluoromethoxy)-3-iodo-2-(methoxymethyl)imidazo[1,2-a]pyridine (700 mg, 1.98 mmol) obtained in step 3 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (290 mg, 0.988 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8F, step 4, (E)-2-(8-{[8-(difluoromethoxy)-2-(methoxymethyl)imidazo[1,2-a]pyridin-3-yl](hydroxy)methyl}-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (400 mg, 78%) was obtained.
Reaction SMILES: [C:1]([NH:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14](=O)[CH2:15][O:16][CH3:17])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH3:19][O-:20].[Na+]>CO>[C:1]([NH:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[O:16][CH2:17]2)=[C:9]([O:20][CH3:19])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: COCC(=O)Oc1ccc(C=CNC(C)=O)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C=CNC(C)=O)ccc1OCC1CO1
Temperature: 50 °C

Procedure:
7.5 g (0.03 mol) of 4-(2-acetylaminovinyl)-2-methoxyacetoxybenzene are suspended in 60 ml of absolute methanol a solution of 1.65 g (0.03 mol) of sodium methoxide in 15 ml of absolute methanol is added and thereafter the mixture is warmed to 50° C. for 15 minutes. It is then evaporated to dryness in vacuo. The resulting crude sodium salt of 4-(2-acetylaminovinyl)-2-methoxy-phenol is heated to the boil with 40 ml of epichlorohydrin for 18 hours whilst stirring and under a reflux condenser. Thereafter the excess epichlorohydrin is removed by distillation under reduced pressure. The residue is partitioned between water and methylene chloride and the organic phase is separated off, dried over sodium sulphate and evaporated. After crystallisation of the crude product, thus obtained, from ethyl acetate, 1-[4-(2-acetylaminovinyl)-2-methoxy-phenoxy]-2,3-epoxy-propane of melting point 173°-174° C. is obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH:19]4[CH2:24][O:23]C(C)(C)[O:21][CH2:20]4)[CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:27][C:28]([C:30]2[NH:31][CH:32]=[C:33]([C:35]#[N:36])[N:34]=2)=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C1COCC1.O>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH:19]([CH2:20][OH:21])[CH2:24][OH:23])[CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:27][C:28]([C:30]2[NH:31][CH:32]=[C:33]([C:35]#[N:36])[N:34]=2)=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC1(C)OCC(N2CCC(c3ccc(NC(=O)c4nc(C#N)c[nH]4)c(C4=CCCCC4)c3)CC2)CO1
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(CO)CO)CC3)cc2C2=CCCCC2)n1
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2,2-dimethyl-[1,3]dioxan-5-yl)-piperidin-4-yl]-phenyl}-amide (22 mg, 0.04 mmol, as prepared in the previous step) in THF—H2O (1 mL, 4:1 v/v) was added TFA (0.4 mL), and the reaction was allowed to stir for 1 h. Removal of the solvent under vacuum afforded 14 mg (60%) of the title compound as an amber foam. 1H-NMR (CD3OD, 400 MHz): δ 1.78-1.90 (m, 4H), 2.03-2.16 (m, 3H), 2.29 (br s, 4H), 2.88-2.96 (m, 1H), 3.37-3.40 (m, 1H), 3.46-3.53 (m, 2H), 3.74-3.78 (m, 3H), 5.83 (s, 1H), 7.13 (d, 1H, J=2.0 Hz), 7.22 (dd, 1H, J=2.0, 8.4 Hz), 8.03 (s, 1H), 8.17 (d, 1H, J=8.4 Hz); Mass spectrum (ESI, m/z): Calcd. for C25H31N5O3, 450.2 (M+H). found 450.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].I[C:21]1[CH:22]=[N:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:25]=1[CH3:26].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(NC(C)C)(C)C>[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].[Cu]I.C(#N)C>[CH3:19][O:18][C:8]1[C:7]2[N:6]([N:5]=[CH:4][C:3]=2[C:1]#[C:2][C:21]2[CH:22]=[N:23][N:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:25]=2[CH3:26])[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[CH:9]=1
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Reactant: Cc1c(I)cnn1-c1ccccc1
Agent: Cl[Pd+]
Agent: [Cu]I
Agent: C=C[CH2-]
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3cnn(-c4ccccc4)c3C)c12
Temperature: 45 °C

Procedure:
3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (20.0 mg, 0.079 mmol), 4-iodo-5-methyl-1-phenyl-1H-pyrazole (33.8 mg, 0.119 mmol), allylpalladium chloride dimer (2.9 mg, 7.93 mmol), tri(2-furyl)phosphine (3.7 mg, 0.016 mmol) and copper (I) iodide (0.8 mg, 4 mmol) were combined into one vial fitted with a Teflon septum. The vial was and flushed with nitrogen and acetonitrile (0.8 mL) and diisopropylamine (0.034 mL, 0.238 mmol) were added. After sparging with nitrogen for 5 minutes, the reaction was heated to 45° C. for one hour. The mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was separated, and the aqueous layer was back extracted with ethyl acetate two times. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 4-methoxy-3-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethynyl]-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[Br:31])[CH2:19][CH2:20][CH2:21]O)=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C.C1(P(=[CH:60][C:61]([O:63][CH3:64])=[O:62])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]([CH2:19][CH2:20]/[CH:21]=[CH:60]/[C:61]([O:63][CH3:64])=[O:62])[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[Br:31])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N(CCCO)Cc1cc(F)ccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)/C=C/CCN(Cc1cc(F)ccc1Br)C(=O)OC(C)(C)C
Temperature: -65 °C
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (1.8 eq) was added to a stirred solution of dimethylsulfoxide (3.8 eq) in methylene chloride (0.25 M) at −78° C. maintaining the temperature<−65° C. After 20 min, a solution of N-(tert-butoxycarbonyl)-N-((2-bromo-5-fluorophenyl)methyl)-N-(3-hydroxypropyl)amine (1 eq) was added and the resulting mixture stirred 30 minutes. Hunig's base (4 eq) was added and the reaction allowed to warm to RT. The mixture was then cooled to 15° C. and methyl (triphenylphosphoranylidene)acetate was added. The resulting mixture was stirred 12 h and purified by flash chromatography on silica gel (10-20% ethyl acetate/hexane) to give methyl (2E)-5-(N-(tert-butoxycarbonyl)-N-((2-bromo-5-fluorophenyl)methyl) amino)pent-2-enoate as a clear oil. EI-MS m/z 474, 476 (M−H+HOAc)−
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1)=[CH2:2].[BH4-].[Na+]>CO>[CH:1]([C:3]1[S:7][C:6]([CH2:8][OH:9])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C=O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=Cc1ccc(CO)s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 89.2 %

Procedure:
A solution of 5-vinyl-thiophene-2-carbaldehyde (900 mg, 6.4 mmol) in anhydrous methanol (20 mL) was cooled to 0° C. under an atmosphere of nitrogen and treated with sodium borohydride (268 mg, 7.1 mmol). The reaction was stirred at 0° C. for 5 minutes and then at room temperature for 5 minutes, before being quenched with water and concentrated in vacuo. The aqueous layer was extracted twice with dichloromethane, the combined organics dried through a hydrophobic frit and concentrated in vacuo. The product was purified by silica gel chromatography using iso-hexanes/ethyl acetate 7:1 then 2:1 to afford the title compound (800 mg, 88%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ1.76 (t, J=6.0 Hz, 1H), 4.80 (d, J=6.3 Hz, 2H), 5.15 (d, J=10.7 Hz, 1H), 5.55 (d, J=17.4 Hz, 1H), 6.78 (dd, J=17.4, 10.7 Hz, 1H), 6.85 (d, J=3.6 Hz, 1H), 6.88 (d, J=3.6 Hz, 1H).
Reaction SMILES: [CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:19]=[CH:18][C:17]([CH:20]=[CH:21][CH3:22])=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[N:5]1)([CH3:3])[CH3:2].Cl.C([BH3-])#N.[Na+]>CO>[CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][CH:6]([C:10]2[N:19]=[CH:18][C:17]([CH:20]=[CH:21][CH3:22])=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[NH:5]1)([CH3:3])[CH3:2]
Reactant: CC=Cc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)OC)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC=Cc1cnc(C2NC(=O)C(C)(C(C)C)N2)c(C(=O)OC)c1

Procedure:
A solution of 2.0 g of methyl 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2 -yl)-5-propenylnicotinate in 50 mL of absolute methanol is cooled in an ice bath to 2° and the pH is adjusted to 3 with dilute methanolic hydrogen chloride. Sodium cyanoborohydride is added in small portions, with maintenance of the pH at 3 by concurrent addition of dilute methanolic hydrogen chloride, until the disappearance of the starting material is indicated by TLC. The reaction mixture is concentrated in vacuo, and the residue is chromatographed on silica gel using hexane-ethyl acetate mixtures as eluant to give the cis and trans products as solids.
Reaction SMILES: C([O:3][C:4](=[O:19])/[C:5](/[C:13]1S[C:15]([Br:18])=[CH:16][CH:17]=1)=[CH:6]/[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Na+].[CH3:22]O>O1CCOCC1>[Br:18][C:15]1[CH2:22][C:13](/[C:5](=[CH:6]/[CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)/[C:4]([OH:3])=[O:19])=[CH:17][CH:16]=1
Reactant: CO
Reactant: CCOC(=O)/C(=C/C1CCCCC1)c1ccc(Br)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)/C(=C\C1CCCCC1)C1=CC=C(Br)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve (Z)-2-(5-bromo-thiophen-2-yl)-3-cyclohexyl-acrylic acid ethyl ester (116 g, 0.338 mol) in MeOH (600 mL) and dioxane (600 mL), add sodium hydroxide (730 mL, 1.0 M, 0.730 mol) and stir 16 h at ambient temperature. Concentrate the reaction mixture, acidify the aqueous residue with concentrated hydrochloric acid (75 mL) and extract with ethylacetate. Wash with saturated sodium chloride, dry over sodium sulfate and remove solvent under vacuum to get 124 g crude product. MS (m/e): 315.0/317.0 (M+H).
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[C:22]2[O:21][CH2:20][CH2:19][O:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)=[O:12].[CH3:23][C:24]1[S:25][C:26]([C:32]2[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=2)=[C:27]([C:29](O)=[O:30])[N:28]=1>>[CH3:23][C:24]1[S:25][C:26]([C:32]2[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=2)=[C:27]([C:29]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[C:22]3[O:21][CH2:20][CH2:19][O:18][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[O:12])=[O:30])[N:28]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: O=C(NC[C@H]1NC[C@@H]2CCC[C@@H]21)c1cccc2c1OCCO2
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCCO3)c1

Procedure:
prepared by reaction of 3,4-dihydro-benzo[1,4]dioxine-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@H:33]([CH3:36])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:35][CH2:34][C@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:22])[CH3:36]
Reactant: C[C@@H](N)CO
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.15 g, 0.33 mmol), (R)-2-aminopropan-1-ol (49 mg, 0.66 mmol), HBTU (155 mg, 0.41 mmol), and HOBT (58 mg, 0.49 mmol). Then added DMF (1.1 mL) followed by N,N-diisopropylethylamine (0.17 mL, 0.97 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0-60% EtOAc) to afford 110 mg (65%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)-amide as an off-white solid. MS: [M+H]+=515.
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[CH:8]=[N:9][C:10]([C:12](N(OC)C)=[O:13])=[CH:11][C:6]=2[N:5]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[CH:4]=1)[CH3:2].[CH3:23][Mg]Br>>[CH2:1]([C:3]1[C:7]2[CH:8]=[N:9][C:10]([C:12](=[O:13])[CH3:23])=[CH:11][C:6]=2[N:5]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[CH:4]=1)[CH3:2]
Reactant: CCc1cn(CCCOC)c2cc(C(=O)N(C)OC)ncc12
Reactant: C[Mg]Br
Product: CCc1cn(CCCOC)c2cc(C(C)=O)ncc12

Procedure:
3-Ethyl-N-methoxy-1-(3-methoxypropyl)-N-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxamide and methylmagnesium bromide were treated in the similar manner to Reference Example 6(5) to give 1-[3-ethyl-1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]ethanone [REx(106-4)] as a pale yellow oil