Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[CH:22]=O.[BH4-].[Na+].C(O)(=O)C>C(O)C>[ClH:1].[ClH:18].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:22][C:21]3[CH:20]=[C:19]([Cl:18])[CH:26]=[C:25]([Cl:27])[CH:24]=3)[CH3:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(N)CNc1ccnc2cc(Cl)ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(CNc1ccnc2cc(Cl)ccc12)NCc1cc(Cl)cc(Cl)c1
Product: Cl

Procedure:
1.25 g of N1 -(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine and 0.88 g of 3,5-dichlorobenzaldehyde were heated under reflux in 10 ml of ethanol for 3 hours. The solvent was evaporated in a vacuum in order to complete the reaction. The resulting Schiff's base was again taken up in 10 ml of ethanol and reduced to the amine by the addition of 0.19 g of sodium borohydride. Excess reducing agent was decomposed after 3 hours by the addition of 10 ml of glacial acetic acid. The turbid solution was then evaporated on a rotary evaporator. The residue was taken up in 10 ml of methanol, which was again evaporated. Addition of methanol and evaporation were repeated twice. The evaporation residue was then dissolved in 15 ml of hot methanol. After the addition of 3.6 ml of 3N isopropanolic hydrochloric acid the hydrochloride of the product crystallized upon cooling. The crude salt (1.1 g) was purified by recrystallization from 30 ml of methanol. Yield: 0.63 g (26%), m.p. >250° C.; 1H-NMR in DMSO-d6, δ (ppm): 1.50 (s, 6H), 4.03 (br.s, 2H), 4.35 (m, 2H), 7.27 (d, J=7 Hz, 1H), 7.69 (m, 1H), 7.82 (dd, J=2 Hz and 9 Hz), 7.89 (m, 2H), 8.11 (d, J=2 Hz, 1H), 8.68 (d, J=7 Hz, 1H), 8.99 (d, J=9 Hz, 1H), 9.65 (br., 1H), 9.8 (m, 2H), 14.5 (br.s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH2:9][CH2:10][NH2:11])=[CH:7][O:8][C:4]=2[CH:3]=1.O=[C:15]([CH3:28])[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[I:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]3[CH2:9][CH2:10][NH:11][C:15]([CH2:16][N:17]4[C:25](=[O:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])([CH3:28])[C:7]=3[O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: NCCc1coc2cc(I)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(CN2C(=O)c3ccccc3C2=O)NCCc2c1oc1cc(I)ccc21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-(6-iodo-benzofuran-3-yl)-ethylamine (2.00 g, 6.97 mmol) and 2-(2-oxo-propyl)-isoindole-1,3-dione (4.25 g, 20.9 mmol) was added trifluoroacetic acid (8.00 mL, 104 mmol) and then heated at 80° C. After 16 h, additional ketone (3 eq) was added and heating continued. After a total of 3 days, the reaction mixture was basified (DCM-aq. NaHCO3) and the resulting precipitate was filtered, rinsed with DCM and dried to give an off-white solid. mp 302-304° C. dec.; MS m/z 473 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[CH3:19][S:20]([CH2:23][C:24](=O)[CH3:25])(=[O:22])=[O:21].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:34]1[CH:17]=[CH:16][CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[C:24]1[CH3:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Reactant: NCc1ccccc1
Reactant: CC(=O)CS(C)(=O)=O
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccccc3)C(C)=C1S(C)(=O)=O)C2=O

Procedure:
The title compound 81 is prepared according to the procedure reported in Example 27 with aldehyde 54 (60.9 mg, 0.25 mmol), commercial 1-methylsulfonylpropan-2-one (34.0 mg, 0.25 mmol) and benzylamine (26.8 mg, 0.25 mmol) as reactants. Purification by column chromatography on SiO2 (gradient of EtOAc in Petroleum Ether) afford the title compound 81 as a pale yellow solid. (Yield 32.8 mg, 29%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[CH3:20])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Mg]Cl)(C)C.[B:26](OC)([O:29]C)[O:27]C>O1CCCC1>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[CH3:20])=[CH:3][C:2]=1[B:26]([OH:29])[OH:27]
Reactant: COB(OC)OC
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(I)c2)c(C)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)c(B(O)O)c2)c(C)c1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
Into a 10000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of methyl 4-(3-iodo-4-methoxyphenyl)-3-methylbenzoate (600 g, 1.57 mol, 1.00 equiv) in tetrahydrofuran (5000 mL). This was followed by the addition of isopropyl magnesium chloride (960 mL, 1.20 equiv) dropwise with stirring at <−25° C. over 60 min. The reaction was maintained for 1 h at −15° C., followed by addition of trimethyl borate (329.2 g, 3.17 mol, 2.00 equiv) dropwise with stirring at <−20° C. over 30 min. The resulting solution was stirred for 60 min at <0° C., then quenched by the addition of 5000 mL of H3PO4 (aq. 1M). The bulk of THF was removed under vacuum. The solid was collected by filtration and washed with 2×200 ml of toluene. This resulted in 300 g (crude) of [2-methoxy-5-[4-(methoxycarbonyl)-2-methylphenyl]phenyl]boronic acid as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CN1CCCC1=O.ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(-c2c[nH]cn2)c1
Reactant: Brc1ccccn1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: N#Cc1cccc(-c2cn(-c3ccccn3)cn2)c1
Temperature: 160 °C
Yield: 9.2 %

Procedure:
A solution of 4-(3-cyanophenyl)imidazole (0.02 g, 0.11 mmol) in N-methylpyrrolidinone (0.5 mL) was treated with 2-bromopyridine (1.05 mL, 11.1 mmol) and the reaction mixture heated overnight at 160° C. After cooling the reaction mixture was diluted with dichloromethane (40 mL) and the organic phase was successively washed with water (10×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography using 30% ethyl acetate in hexanes afforded 2.5mg (9%) of 4-(3-cyanophenyl)-1-(2-pyridyl)-1H-imidazole, as an off-white solid.
Reaction SMILES: C([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[O:10][C:9]=1[CH:20]([NH:24][CH2:25][CH2:26][NH:27][C:28](=O)[C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[CH:21]([CH3:23])[CH3:22])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[C:42]1([CH3:48])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:48]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[O:10][C:9]=1[CH:20]([N:24]1[CH2:25][CH2:26][N:27]=[C:28]1[C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[CH:21]([CH3:23])[CH3:22])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Cc1ccccc1
Reactant: Cc1ccc(C(=O)NCCNC(c2oc3cc(Cl)ccc3c(=O)c2Cc2ccccc2)C(C)C)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C2=NCCN2C(c2oc3cc(Cl)ccc3c(=O)c2Cc2ccccc2)C(C)C)cc1
Temperature: 85 °C
Yield: 50 %

Procedure:
A mixture of N-{2-[1-(3-benzyl-7-chloro-4-oxo-4H-chromen-2-yl)-2-methyl-propylamino]-ethyl}-4-methyl-benzamide (2.8 g, 5.5 mmol) and phosphorus oxychloride (9.4 mL, 100 mmol) in toluene (60 mL) was heated at 85° C. for 7 hours, then heated at reflux for 1 hour. The reaction was concentrated and the residual phosphorus oxychloride removed by toluene azeotrope. The residue was diluted with ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (100 mL) and brine (100 mL), dried over magnesium sulfate, and concentrated. The resultant residue was purified by flash chromatography (0→8% methanol/methylene chloride) to give 1.4 g (50%) of the title compound. MS (ES+) m/e 485 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:11]3[C:12]4[C:19]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[CH:18][N:17](COCC[Si](C)(C)C)[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:7]=[CH:8]2)=[N:3]1.C(O)(C(F)(F)F)=O.C(#N)C.[OH-].[NH4+]>C(Cl)Cl>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:11]3[C:12]4[C:19]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: C=CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3ccc4cn(C)nc4c3)c12
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCOC(=O)c1c[nH]c2ncnc(-c3ccc4cn(C)nc4c3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Prop-2-en-1-yl 4-(2-methyl-2H-indazol-6-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate was dissolved in DCM (1.0 mL) and then TFA (0.91 mL, 12 mmol) was added. The resulting solution was stirred for 2 hours at room temperature before being concentrated in vacuo. Acetonitrile (0.50 mL) and ammonium hydroxide (0.50 mL, 3.6 mmol) were added to the residue and the solution was heated to 50° C. for 3 hours. The reaction was concentrated in vacuo and purified by reverse phase chromatography using a 5-35% acetonitrile gradient in water with 0.1% TFA modifier. Pure fractions were free-based by extracting from a saturated sodium bicarbonate solution using 3:1 CHCl3:IPA (×3). The combined organic layers were then washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford prop-2-en-1-yl 4-(2-methyl-2H-indazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a white solid. LRMS (ESI) calcd for C18H16N5O2 [M+H]+: 334, found 334. 1H NMR (600 MHz, DMSO-D6) δ 13.04 (s, 1H), 8.96 (s, 1H), 8.43 (s, 1H), 8.39 (s, 1H), 7.81 (m, 1H), 7.79 (dd, 1H, J=8.4, 0.8 Hz), 7.39 (dd, 1H, J=8.4, 1.4 Hz), 5.5 (m, 1H), 4.97-5.04 (m, 2H), 4.30 (dm, 2H, J=5.7 Hz), 4.25 (s, 3H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:12]([CH3:30])[C:13](=[O:29])[C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Br:31]Br>CN(C)C=O.ClCCl>[Br:31][C:16]1[CH:15]=[C:14]2[C:19]([C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=3[CH3:28])=[C:11]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([OH:9])=[O:8])[N:12]([CH3:30])[C:13]2=[O:29])=[CH:18][CH:17]=1
Reactant: BrBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3cc(Br)ccc23)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An ice cold mixture of methyl 2-(tert-butoxy)-2-(4-(2,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (383 mg, 0.940 mmol) in N,N-dimethylformamide (DMF) (5.0 mL) was treated slowly with a solution of bromine (0.053 mL, 1.034 mmol) in dichloromethane (dichloromethane) (280 μl) to give an orange solution. The ice bath was removed and the mixture, which was excluded from light by wrapping the reaction vessel with aluminum foil, was stirred at ambient temperature overnight. The mixture was cooled to 0° C., quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-50% ethyl acetate/hexanes gradient) to give the impure desired product as a white solid. The solid was re-purified by reverse phase chromatography to afford the desired product as a white solid (128 mg, 28%). LC/MS (m/z) ES+=486 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([N:11]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:12]2[CH:13]=[CH:14][C:15]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[C:16]([CH:23]=2)[CH2:17]OS(C)(=O)=O)=[N:4][CH:3]=1.[CH3:37][NH:38][CH3:39].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[NH3:4].[C:33]([O:32][C:30](=[O:31])[N:11]([C:5]1[C:6]2[N:7]([CH:8]=[CH:9][N:10]=2)[C:2]([Br:1])=[CH:3][N:4]=1)[C:12]1[CH:13]=[CH:14][C:15]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[C:16]([CH2:17][N:38]([CH3:39])[CH3:37])[CH:23]=1)([CH3:35])([CH3:34])[CH3:36]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)c(COS(C)(=O)=O)c1)c1ncc(Br)n2ccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)Cc1cc(N(C(=O)OC(C)(C)C)c2ncc(Br)n3ccnc23)ccc1N1CCOCC1
Product: N
Temperature: 75 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of methanesulfonic acid 5-[(5-bromo-imidazo[1,2-a]pyrazin-8-yl)-tert-butoxycarbonyl-amino]-2-morpholin-4-yl-benzyl ester (0.098 g, 0.169 mmol) in THF (0.5 mL) is added 2M N,N-dimethylamine solution in THF (0.50 mL, 1.1 mmol) followed by K2CO3 (0.028 g, 0.202 mmol). The reaction mixture is stirred at room temperature for 1.5 hours and at 75° C. for an additional 3 hours. The solvent is removed under vacuum and the residue is partitioned between ethyl acetate and water. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to give the crude compound which is purified by silica gel column chromatography. Elution using 97:3 DCM:NH3 (7M in MeOH) affords the title compound (0.0543 g, 61%). LCMS: Rt 2.37 min (95%), m/z (ES+) 531/533 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)=[O:7])=[CH:4][CH:3]=1.C(C1OC1)Cl.C(N)(C)C>>[NH2:23][C:19]1[CH:18]=[C:17]([C:9]2[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:8]=2[C:6](=[O:7])[C:5]2[CH:26]=[CH:27][C:2]([OH:1])=[CH:3][CH:4]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(c1ccc(O)cc1)c1c(-c2cccc([N+](=O)[O-])c2)oc2ccccc12
Solvent: CC(C)N
Solvent: ClCC1CO1
Product: Nc1cccc(-c2oc3ccccc3c2C(=O)c2ccc(O)cc2)c1

Procedure:
2-(3'-Aminophenyl)-3-(4'-hydroxybenzoyl)benzofuran is prepared by reduction of 3-(4'-hydroxybenzoyl)-2-(3'-nitrophenyl)benzofuran according to the procedure of Example 40. Reaction of this compound with epichlorohydrin followed by ring opening of the resultant epoxy compound with isopropylamine as previously described gives the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][CH2:17][CH3:18]
Reactant: Oc1ccccc1Br
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In DMF (120 ml) was dissolved 2-bromophenol (12 g). To the mixture was added potassium carbonate (12.5 g) and then was added bromopropane (7.2 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 1-bromo-2-propoxybenzene (10.5 g).
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S(Cl)([Cl:14])=O>C(Cl)Cl>[ClH:14].[Cl:14][CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:9]=1
Reactant: CC(C)c1cccc(CO)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1cccc(CCl)n1
Product: Cl
Reaction time: 1 h
Yield: 98 %

Procedure:
To (6-isopropylpyridin-2-yl)methanol (3.13 g, 20.7 mmol) in DCM (20 mL) at 0° C. was added sulfurous dichloride (12.3 g, 104 mmol). The cold bath was removed and the reaction mixture was stirred for one hour. Solvent was removed under reduced pressure to give the desired product (98%).
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[CH3:11])([CH3:5])[C:3]#[N:4].[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>C1COCC1.C(OCCCC)CCC.O>[CH3:5][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[CH3:11])([CH3:1])[CH:3]([NH2:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [Li]c1ccccc1
Reactant: CC1CCCN1C(C)(C)C#N
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCOCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1CCCN1C(C)(C)C(N)c1ccccc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 2-methyl-2-(2-methyl-1-pyrrolidinyl)propanenitrile D25 (2.82 g; 18.56 mmol) in THF (100 ml) at −70° C. under argon was added over 15 minutes a solution of phenyllithium in dibutylether (20.6 ml of a 1.8M solution; 37.11 mmol). The reaction mixture was stirred at −70° C. for 2 hours then allowed to warm to room temperature and stirred overnight. Saturated aqueous sodium hydrogen carbonate (100 ml) was added and stirring continued for a further 10 minutes. The mixture was extracted with diethyl ether (2×150 ml). Combined organics were dried (Na2SO4) and evaporated in vacuo. The residual yellow oil was dissolved in methanol (100 ml) and sodium borohydride (2.12 g; 0.056 mol) added portionwise over 5 minutes. The reaction mixture was stirred at room temperature for 4 hours, further sodium borohydride (1 g; 0.026 mol) added and the mixture heated at 60° C. for 1.5 hours. The mixture was cooled and excess sodium borohydride decomposed by dropwise addition of water. The reaction mixture was evaporated in vacuo and the residue partitioned between saturated sodium hydrogen carbonate (150 ml) and DCM (150 ml). Solid potassium carbonate was added and the aqueous layer extracted with DCM (150 ml) Combined organic extracts were dried (Na2SO4) and evaporated to give a green oil. This was divided into 8 portions and each portion passed down a 10 g SCX column. After washing each column with DCM, 50% DCM in methanol and methanol the product was eluted with 1 M ammonia in methanol to yield the title compound as a pale yellow oil (3.46 g: 80%). Mass spectrum (Electrospray LC/MS), ES+: Found 233 (MH+). C15H24N2 requires 232. Ret. times 0.96 and 1.07 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:10]=1)[C:5]([OH:7])=O.[CH3:18][C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:10]=1)[C:5]([NH:24][C:21]1[S:22][CH:23]=[C:19]([CH3:18])[N:20]=1)=[O:7]
Reactant: O=C(O)c1cc(F)cc(Oc2cncnc2)c1
Reactant: Cc1csc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1csc(NC(=O)c2cc(F)cc(Oc3cncnc3)c2)n1
Yield: 50.8 %

Procedure:
Compound 5 (1.0 g, 4.3 mmol, 1.0 eq), 4-methylthiazol-2-amine (585 mg, 5.12 mmol, 1.20 eq), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (3.4 g, 8.9 mmol, 2.1 eq), and DIEA (1.56 mL, 8.94 mmol, 2.10 eq) were dissolved in CH2Cl2 (21 mL) and DMF (4.2 mL) and stirred rt for 48 h. The reaction was diluted with CH2Cl2 and washed with water (1×). The organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 721 mg (51%) of the title compound as a tan solid: 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.77 (s, 2H), 7.74-7.70 (m, 1H), 7.62 (t, J=1.6 Hz, 1H), 7.43 (dt, J=9.6, 2.3 Hz, 1H), 6.83 (d, J=1.0 Hz, 1H), 2.28 (s, 3H); [M+1]+: 331.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:8](=[O:13])[CH2:9][C@@H:10]([OH:12])[CH:11]=1)=[O:5])[CH3:2].N1C=CN=C1.[CH2:19]([Si:21]([CH2:25][CH3:26])([CH2:23][CH3:24])Cl)[CH3:20]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:8](=[O:13])[CH2:9][C@@H:10]([O:12][Si:21]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:19][CH3:20])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CCOC(=O)CC1=C[C@H](O)CC1=O
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1=C[C@H](O[Si](CC)(CC)CC)CC1=O
Temperature: 0 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
25 g of (R)-2-ethoxycarbonylmethyl-4-hydroxy-2-cyclopenten-1-one (5 g, 98% e.e.) was dissolved in ethyl acetate and the solution was placed in a nitrogen purged flask. Imidazole (13.87 g, 204 mmol) was added. The solution was cooled to 0° C. and triethylchlorosilane (26.6 g, 176 mmol) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for another 15 hours. After filtration, the filtrate was washed with a saturated sodium bicarbonate solution and a brine solution, respectively, dried over anhydrous magnesium sulfate, and concentrated to obtain the titled compound (38.5 g, 95%). [α]D: +27.8° (c 1.0, CH3CN).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:15]([Si:17]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:18]1[O:19][CH:20]=[C:21]([CH:23]=[O:24])[CH:22]=1)[CH3:16]>O1CCCC1>[OH:24][CH:23]([C:21]1[CH:22]=[C:18]([Si:17]([CH2:25][CH3:26])([CH2:15][CH3:16])[CH2:27][CH3:28])[O:19][CH:20]=1)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Reactant: CCCCCCCCCCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(O)c1coc([Si](CC)(CC)CC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dodecylmagnesium bromide (a 1M solution in tetrahydrofuran: 14.3 ml, 14.3 mmol) was added dropwise to a solution of 2-triethylsilyl-4-furaldehyde (2.0 g, 9.52 mmol) in THF (20 ml) at 0 degrees C. under argon. After stirring at room temperature for 2 hours, the mixture was quenched with dilute HCl and extracted with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by flash chromatography on silica using 30% ethyl ether/hexane to give the titled alcohol.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:43])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[CH:31][CH:30]=2)[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:43][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:30]=[CH:31][C:32]([CH2:35][N:36]3[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]3)=[CH:33][CH:34]=2)[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CN1CCN(Cc2ccc(-n3nc(C(C)(C)C)cc3N)cc2)CC1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Product: CN1CCN(Cc2ccc(-n3nc(C(C)(C)C)cc3NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)cc2)CC1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl)-2H-pyrazol-3-ylamine. Title compound: ES-MS: 563.10 [M+H]+; tR=2.66 min (System 3).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[CH3:16][N:17]=[C:18]=[O:19]>C1C=CC=CC=1>[CH3:16][NH:17][C:18]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[O:19]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 0.5 h

Procedure:
To 6.0 g. (0.024 mole) of 3-(3-trifluoromethylphenoxy) azetidine in 50 ml. of dry benzene was added dropwise 1.37 g. (0.024 mole) of methylisocyanate with stirring, and stirring was continued for 30 minutes. The solid which crystallized in the flask was recrystallized using 95% ethanol to give 5.0 g. (76%) of product (m.p. 145°-147° C.).