Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[S:11][CH2:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1.N1[C:24]2C=CC=[CH:28][C:23]=2N=C1SCC1C(N)=NC=CC=1.BrCC(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:28][C:23]1[N:19]=[C:14]2[C:13]([CH2:12][S:11][C:3]3[NH:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:2]=3)=[CH:18][CH:17]=[CH:16][N:15]2[CH:24]=1
Reactant: Nc1ncccc1CSc1nc2ccccc2[nH]1
Agent: CC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cn2cccc(CSc3nc4ccccc4[nH]3)c2n1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
A mixture of 3.8 g (15 mmole) of 3-[(1H-benzimidazol-2-ylthio)methyl]-2-pyridinamine hemihydrate (see Example 1), 2.4 g (18 mmole) of bromoacetone, and 2.1 g (25 mmole) of sodium bicarbonate in 50 ml of ethanol was stirred at room temperature. After 18 hours the mixture was concentrated in vacuo to a residue that was partitioned between dilute hydrochloric acid and dichloromethane. The aqueous layer was made alkaline with potassium carbonate and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. Chromatography on basic alumina (using ethanol-toluene as eluent) yielded 1.6 g of the title compound. Structure assignment was supported by the nmr and infrared spectra.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15]C4(CCN(C)CC4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.Cl.Cl.[CH2:30]1[C:34]2(CNC[CH2:36][NH:35]2)[CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15][C:34]4([CH2:30][CH2:31][CH2:32][CH2:33]4)[NH:35][CH2:36][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CCC2(C1)CNCCN2
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Agent: Cl
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCNC4(CCCC4)C3)cc2n1

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using 6,9-diaza-spiro[4.5]decane dihydrochloride in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compound was obtained as a white solid (76 mg, 53%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22](=[S:24])[NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:26][C:27](=O)[CH3:28].C(O)C>ClCCl>[CH3:28][C:27]1[N:23]=[C:22]([C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:24][CH:26]=1
Reactant: NC(=S)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CC(=O)CCl
Solvent: CCO
Solvent: ClCCl
Product: Cc1csc(C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)n1
Yield: 60.7 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbothioamide (100 mg, 0.29 mmol), chloroacetone (46 μL, 0.57 mmol) and ethanol (5 mL) were combined and heated at reflux for 18 hours. The reaction mixture was concentrated in vacuo to give a cream coloured solid. This was dissolved in dichloromethane (100 mL) and washed with saturated NaHCO3 solution (50 mL). The organic extract was dried using Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography using 15 g of silica gel, eluting with dichloromethane:methanol:ammonia (97:3:0.3) to dichloromethane:methanol:ammonia (94:6:0.6) to give the title compound as a white solid (68 mg, 61%). 1H NMR (400 MHz, CDCl3) δ7.3 (d, 2H), 6.9 (d, 2H), 6.75 (s, 1H), 4.0 (t, 2H), 3.83 (m, 2H), 3.7 (m, 2H), 2.75-2.58 (m, 8H), 2.4 (s, 3H), 2.35 (m, 2H), 2.03 (m, 2H), 1.8 (m, 4H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].[C:30]1([C:36]2[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=2CBr)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:17][C:43]3[CH:42]=[CH:41][CH:40]=[CH:37][C:36]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: BrCc1ccccc1-c1ccccc1
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3-c3ccccc3)CC1)O2
Yield: 69.7 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (169 mg, 0.500 mmol, Intermediate 1, hydrochloride salt) was alkylated using 2-phenylbenzyl bromide (0.18 ml, 1.0 mmol) following the procedure described in Example 2, Step A, giving (E)-3-{1′-(biphenyl-2yl-methyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (163 mg) as a white solid. The intermediate was hydrolyzed as described in Example 55, Step B, giving (E)-3-{1′-(Biphenyl-2yl-methyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (162 mg) as a white solid (hydrochloride salt). The acid was suspended in DCM (5 ml), TEA (0.07 ml, 0.47 mmol) was added, and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-(biphenyl-2yl-methyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (163 mg) as a light yellow solid. The compound was dissolved in DCM (5 ml) and treated with 4 M HCl in dioxane (0.4 ml, 1.6 mmol) as described in Example 55, Step D, giving a light yellow solid (114 mg, hydrochloride salt).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CC(C)([O-])C.[Na+]>O1CCOCC1.C(OCC)(=O)C.[Pd].C1(=O)C2C(=CC=CC=2)C(=O)C=C1>[CH3:10][O:9][N:7]([CH3:8])[C:5](=[O:6])[C:4]1[CH:11]=[CH:12][N:13]=[C:2]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1
Reactant: C1COCCN1
Reactant: CON(C)C(=O)c1ccnc(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C1C=CC(=O)c2ccccc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccnc(N2CCOCC2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-N-methoxy-N-methyl-isonicotinamide (800 mg, 4 mmol), morpholine (452 mg, 5.2 mmol), sodium tert-butoxide (500 mg, 5.2 mmol), 1,3-bis(2,6-di-isopropylphenyl)imidazol-2-ylidene(1,4-naphthoquinone palladium(0) dimer in dioxane (4 mL) was stirred at 80° C. overnight. The mixture was diluted with ethyl acetate, washed with water and purified by flash column to give N-methoxy-N-methyl-2-morpholin-4-yl-isonicotinamide.
Reaction SMILES: [C:1]([C:5]1[N:19]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][Si](C)(C)C)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1I.CCN(CC)CC.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:5]1[N:19]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:25]3[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=3[F:27])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(F)c(I)c1
Reactant: CC(C)(C)c1nc2ncc(C#C[Si](C)(C)C)cn2n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2ncc(C#Cc3cc(F)ccc3F)cn2n1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 63.2 %

Procedure:
2-tert-Butyl-6-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 43, step 1) (100 mg, 0.37 mmol) was dissolved in DMF (1 ml). 1,4-Difluoro-2-iodobenzene (176 mg, 0.73 mmol, 2 equiv.), Et3N (150 μl, 1.1 mmol, 3 equiv.), Bis-(triphenylphosphine)-palladium(II)dichloride (13 mg, 0.02 mmol, 0.05 equiv.), triphenylphosphine (3 mg, 0.011 mmol, 0.03 equiv.) and copper(I)iodide (2 mg, 0.011, 0.03 equiv.) were added under nitrogen and the mixture was heated to 80° C. TBAF 1M in THF (440 μl, 0.44 mmol, 1.2 equiv.) was added dropwise in 20 minutes at 80° C. The reaction mixture was stirred for 5 minutes at 80° C. The reaction mixture was evaporated and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a 20 g silica gel column and eluting with heptane:ethyl acetate 100:0→50:50. The desired 2-tert-butyl-6-(2,5-difluoro-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine (73 mg, 64% yield) was obtained as a light yellow solid, MS: m/e=313.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>CCOCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reaction time: 24 h
Yield: 52.6 %

Procedure:
A mixture of 100.0 g of methyl 2-methyl-3-nitrobenzoate, 100.0 g of N-bromosuccinimide, 3.0 g of dibenzoyl peroxide and 1000 ml of carbon tetrachloride was refluxed for 24 hours. The reaction mixture was cooled, 3.0 g of dibenzoyl peroxide added, and refluxing continued an additional 24 hours. The reaction mixture was cooled, filtered and the filtrate concentrated in vacuo. The crude reaction product was dissolved in ether and the organic solution washed sequentially with saturated sodium sulfite (500 ml), water (2×500 ml), 2.5% sodium hydroxide (500 ml), water (2×500 ml) and saturated brine (500 ml). The organic solution was dried over magnesium sulfate, filtered and the solvent evaporated in vacuo giving a pale yellow oily solid. Recrystallization from 350 ml of 1-chlorobutane/cyclohexane (2:1) gave 73.9 g of methyl 2-bromomethyl-3-nitrobenzoate, m.p. 67°-70°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH2:22])[C:12]2[N:13]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C.O>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([NH:22][C@H:11]([C:12]2[N:13]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:15][CH:16]=2)[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: NC(Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc(Cl)c1)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of 2-(4-nitrophenyl)-1-(2-thiophene2-ylthiazol-4-yl)ethylamine, 22, (0.41 g, 1 mmol) 3-chlorophenylacetic acid (0.170 g, 1 mmol) and 1-hydroxybenzotriazole (HOBt) (0.070 g, 0.50 mmol) in DMF (5 mL) at 0°, is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.190 g, 1 mmol) followed by triethylamine (0.42 mL, 3 mmol). The mixture is stirred at 0° C. for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5% aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.290 g (60% yield) of the desired product which is used without further purification. ESI− MS 482 (M−1).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[OH:12][CH:13]1[CH2:16][NH:15][CH2:14]1.CCN(CC)CC>C1COCC1>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([N:15]2[CH2:16][CH:13]([OH:12])[CH2:14]2)=[N:6][CH:7]=1
Reactant: COc1nc(Cl)ncc1Br
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1nc(N2CC(O)C2)ncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (3.3 g, 14.8 mmol), 3-hydroxyazetidine hydrochloride (3.2 g, 29.5 mmol), and Et3N (4.3 mL, 31.0 mmol) in THF (50 mL) was stirred for 18 h at rt. 3-Hydroxyazetidine hydrochloride (1 g) was added. The reaction mixture was stirred for 24 h at rt and concentrated. The residue was diluted in CH2Cl2/water and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude material was purified by flash chromatography (hexane/EtOAc, 1:1) to afford 3 g of the title compound. tR: 0.73 min (LC-MS 2); ESI-MS: 260.1/262.1 [M+H]+ (LC-MS 2); Rf=0.18 (hexane/EtOAc 1:1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)[CH2:4][CH2:3]1>FC(F)(F)C(O)=O.ClCCl>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)[CH2:4][CH2:3]1
Reactant: CC1CCN(CC[C@H]2CCCN2C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CCN(CC[C@H]2CCCN2)CC1
Yield: 101.9 %

Procedure:
A solution of the protected amine, (R)-2-[2-(4-methyl-piperidin-1-yl)ethyl ]pyrrolidine-1-carboxylic acid, tert-butyl ester (D5) (3.0 g, 10 mmol) in trifluoroacetic acid (15 ml) and dichloromethane (50 ml) was heated to reflux for 18 hours. The reaction mixture was concentrated and the residue partitioned between CH2Cl2 and sat. aqueous K2CO3. The organic phase was dried and concentrated to afford the title compound (2.0 g, q) MH+ 197.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1)[CH:11]=O.[CH2:22]([O:24][C:25](=[O:42])[CH:26](P(OCC)(OCC)=O)[CH2:27][CH2:28][CH:29]1[O:33][CH2:32][CH2:31][O:30]1)[CH3:23].O.[OH-].[Li+]>C(OCC)(=O)C.O>[CH2:22]([O:24][C:25](=[O:42])/[C:26](=[CH:11]/[C:10]1[CH:13]=[CH:14][C:15]([N:16]2[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]2)=[C:8]([O:7][CH3:6])[CH:9]=1)/[CH2:27][CH2:28][CH:29]1[O:33][CH2:32][CH2:31][O:30]1)[CH3:23]
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C(CCC1OCCO1)P(=O)(OCC)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCC1OCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a THF (20 mL) solution of (1.75 g) of the 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde obtained in Example 1, 2-(diethoxyphosphoryl)-4-[1,3]dioxolan-2-yl-butyric acid ethyl ester (2.50 g) and lithium hydroxide monohydrate (388 mg) were added one by one, and the reaction solution was agitated at room temperature overnight. Water and ethyl acetate were added to the reaction solution after confirming disappearance of the starting materials, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; heptane-ethyl acetate=1:2→ethyl acetate), and 1.05 g of the title compound as an isomer mixture (E:Z=4:1) was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][C@H:2]1[C:7](=[O:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1.[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@:7]2([OH:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C@H:2]2[CH3:1])=[CH:14][CH:13]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: C[C@@H]1NC(C)(C)COC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H]1NC(C)(C)CO[C@@]1(O)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
A solution of 15 (166 mg, 1.16 mmol) in dry THF (1.2 mL, 1M) under an N2 atmosphere was cooled to −78° C. and treated with 4-fluorophenylmagnesium bromide (1.3 equiv., 1.5 mmol, 1.9 mL, 0.8 M solution in THF). The reaction mixture was stirred at −78° C. for 3 h. A saturated aqueous solution of NH4Cl was added to the reaction vessel, and the mixture was allowed to warm to room temperature. EtOAc (5 mL) was added to the reaction vessel and the organic layer was separated. The aqueous phase was extracted with EtOAc (three times). The combined organic extracts were washed (water, brine), dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2 to CH2Cl2-MeOH (90:10) as the eluent to afford 80 mg of 4h as a white solid: [α]22D +31.2° (c 0.5, CHCl3); 1H NMR (CDCl3) δ 7.60-7.55 (m, 2H), δ 7.08-7.00 (m, 2H), 3.83 (d, 1H, J=11.3 Hz), 3.40 (d, 1H, J=11.3 Hz), 3.17 (q, 1H, J=6.4 Hz), 1.38 (s, 3H), 1.08 (s, 3H), 0.78 (d, 3H, J=6.4 Hz); 13C NMR (CDCl3) δ 128.0, 127.9, 114.87, 114.58, 103.2, 98.4, 96.8, 69.5, 53.5, 27.3, 22.8, 16.4; LCMS (ESI) m/z 240.0 [(M+H)+, M=C13C18FNO2].
Reaction SMILES: C(OC1C(F)=CC=C2C=1C([C:19](=[O:25])[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])=CN2)C1C=CC=CC=1.[Br:26][C:27]1[CH:35]=[C:34]2[C:30]([CH:31]=[CH:32][N:33]2[CH2:36][CH3:37])=[C:29]([O:38][CH3:39])[CH:28]=1>>[Br:26][C:27]1[CH:35]=[C:34]2[C:30]([C:31]([C:19](=[O:25])[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])=[CH:32][N:33]2[CH2:36][CH3:37])=[C:29]([O:38][CH3:39])[CH:28]=1
Reactant: CN(C)C(=O)C(=O)c1c[nH]c2ccc(F)c(OCc3ccccc3)c12
Reactant: CCn1ccc2c(OC)cc(Br)cc21
Product: CCn1cc(C(=O)C(=O)N(C)C)c2c(OC)cc(Br)cc21
Yield: 88 %

Procedure:
Following the procedure (step 5, scheme 1) used to prepare compound 1-6a, compound 36-2 gave compound 36-3 (669 mg, 88%) as a pale pink solid. LCMS: calc 352.0 and found: 353.0 [MH]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1.[I:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([OH:25])=[C:20]([CH3:26])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.CCCCCC>[I:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=3)[N:3]=2)=[C:20]([CH3:26])[CH:19]=1
Reactant: Cc1cc(I)cc(C)c1O
Reactant: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1cc(I)cc(C)c1Oc1ccnc(Nc2ccc(C#N)cc2)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A mixture of 4-(4-chloro-pyrimidin-2-ylamino)benzonitrile (Ludovici, et al. ibid) 2 (600.0 mg, 2.60 mmol), 4-iodo-2,6-dimethylphenol (Chabrier, et al., Ibid) (838.0 mg, 3.38 mmol) and cesium carbonate (2.20 g, 6.76 mmol) in dry DMF (12 mL) was heated to 90° C. (Zhang, et al., Tetrahedron Lett., 2002, 43, 8235-8239). After 3 hours, TLC (EtOAc/hexane=50:50) revealed a more polar product and consumption of compound 2. The mixture was poured into water (100 mL) and the product extracted into EtOAc (3×50 mL). The combined extracts were washed with brine (50 mL) followed by water (2×50 mL), and then dried over (Na2SO4) and the solvent evaporated in vacuo to furnish a residue that was subjected to silica-gel column chromatography using EtOAc/hexane (50:50) as eluent to produce 3 as a white solid (982.0 mg, 2.22 mmol, 85%).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:13]=[C:14]([O:16][CH3:17])[N:15]=2)[C:9]([NH:11][NH2:12])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:25][C:26]1[C:34]([CH3:35])=[CH:33][C:29]([C:30](O)=O)=[CH:28][C:27]=1[CH2:36][CH3:37])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C(Cl)Cl.CC(=O)OCC.O>[CH2:18]([O:25][C:26]1[C:34]([CH3:35])=[CH:33][C:29]([C:30]2[O:10][C:9]([C:8]3[CH:13]=[C:14]([O:16][CH3:17])[N:15]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:7]=3)=[N:11][N:12]=2)=[CH:28][C:27]=1[CH2:36][CH3:37])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Reactant: COc1cc(C(=O)NN)cc(C2CCCC2)n1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCc1cc(-c2nnc(-c3cc(OC)nc(C4CCCC4)c3)o2)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of 2-cyclopentyl-6-methoxy-isonicotinic acid hydrazide (870 mg, 3.70 mmol), 4-benzyloxy-3-ethyl-5-methyl-benzoic acid (1.00 g, 3.70 mmol) and DIPEA (1.44 g, 11.1 mmol) in DCM (30 mL), TBTU (1.43 g, 4.44 mmol) is added. The mixture is stirred at rt for 1 h before diluted with EA (150 mL) and water (50 mL). The org. phase is separated, washed with sat. aq. NaHCO3 solution (50 mL) followed by brine (50 mL), dried over MgSO4, filtered and concentrated. The remaining pale yellow oil is dissolved in THF (50 mL) and Burgess reagent (1.23 g, 5.18 mmol) is added. The mixture is stirred at 110° C. for 15 min under microwave irradiation before it is diluted with EA (200 mL) and washed twice with water (50 mL). The org. extract is dried over MgSO4, filtered and concentrated and the crude product is purified by CC on silica gel eluting with heptane:EA 1:9 to give 4-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-2-cyclopentyl-6-methoxy-pyridine (750 mg) as a pale yellow oil; LC-MS**: tR=1.06 min, [M+H]+=470.21.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.Cl[CH2:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:26]=1[CH2:35]Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:34][O:33][C:28]1[CH:27]=[C:26]2[C:25](=[CH:30][C:29]=1[O:31][CH3:32])[CH2:24][N:20]([C:15]1[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]3[O:3][C:2]([CH3:22])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=4)[C:5]=3[C:14]=1[CH3:21])[CH2:35]2
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Reactant: COc1cc(CCl)c(CCl)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)CN(c1c(C)c(C)c3c(c1C)C(c1ccc(C)cc1)C(C)(C)O3)C2
Temperature: 25 °C
Yield: 15.8 %

Procedure:
To a solution of 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine (806.1 mg, 2.76 mmol) in tetrahydrofuran (30 ml) were added 1,2-bis(chloromethyl)-4,5-dimethoxybenzene (686.6 mg, 2.92 mmol), sodium carbonate (878.5 g, 8.29 mmol), and tetrabutylammonium iodide (543.6 mg, 1.47 mmol) and the mixture was refluxed with heating for 11 hours. The reaction mixture was cooled down to room temperature and then poured into ice water. The product was extracted twice with ethyl acetate. The combined extracts were washed with an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 199.6 mg (16% yield) of the title compound. Melting point: 156-159° C.