Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:9][CH:8]([CH2:10][C:11]([O:13]CC)=O)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.[NH2:17][NH2:18]>C(O)C>[CH:1]1([C:4]([N:6]2[CH2:9][CH:8]([CH2:10][C:11]([NH:17][NH2:18])=[O:13])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: NN
Reactant: CCOC(=O)CC1CN(C(=O)C2CC2)C1
Solvent: CCO
Solvent: O
Product: NNC(=O)CC1CN(C(=O)C2CC2)C1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
In a round bottom flask equipped with reflux condenser under nitrogen, a solution of ethyl [1-(cyclopropylcarbonyl)-3-azetidinyl]acetate (0.433 g, 2.097 mmol) and hydrazine monohydrate (1.3 mL, 41.9 mmol) in ethanol (10 mL) was stirred at 80° C. for 16.5 h. The reaction was cooled to room temperature and concentrated in vacuo. The residue was then concentrated down from methanol and then toluene. The residue was dissolved in dichloromethane, filtered through sodium sulfate, and concentrated in vacuo to a colorless oil. The oil still looked wet and was too heavy, so it was dissolved again in dichloromethane and filtered through sodium sulfate, rinsing with additional dichloromethane. The combined organics were concentrated in vacuo and then concentrated under high vacuum pressure to yield the crude title product as a yellow oil (0.316 g, 86% pure, 66% yield). MS(ES)+ m/e 198.1 [M+H]+, 395.1 [2M+H]+.
Reaction SMILES: [H-].[Na+].CO.[CH3:5][CH:6]([CH3:19])[CH2:7][C:8]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[OH:18])=[O:9].Cl[CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24]>CCCCCC.CCOCC>[CH3:5][CH:6]([CH3:19])[CH2:7][C:8]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[CH:12][C:11]=1[OH:18])=[O:9]
Reactant: CC(C)=CCCl
Reactant: Cc1cc(O)cc(O)c1C(=O)CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOCC
Product: CC(C)=CCOc1cc(C)c(C(=O)CC(C)C)c(O)c1
Yield: 7.8 %

Procedure:
Under an atmosphere of nitrogen, 300 mg (7.50 mmol, 1.50 equivalents) of an oil dispersion of 60% sodium hydride was washed with petroleum ether to remove paraffin and then combined with 7.5 ml of dry methanol. Then, a methanol (5.0 ml) solution of 1.04 g (5.00 mmol) of (2,4-dihydroxy-6-methylphenyl) (2-methylpropyl) ketone (47) was added cooling with ice and stirred. Further, a methanol (5.0 ml) solution of 784 mg (7.50 mmol, 1.50 equivalents) of 1-chloro-3-methyl-2-butene was slowly added dropwise. The resultant mixture was stirred at room temperature for two hours. The mixture was combined with ether. The ether layer was washed with a saturated aqueous ammonium chloride solution and saturated brine, dried over sodium sulfate, and distilled to remove the solvent and obtain 1.296 g of a dark red oily substance. This oily substance was combined with a small amount of hexane and left standing in a refrigerator to recover 277 mg of the starting substance in the form of colorless needle crystals. The filtrate, 965 mg in weight, was subjected to silica gel column chromatography (49 g of Wako Gel C-300, eluted with hexane:ethyl acetate at varying ratios=29 1-7:3) to produce sequentially by fractionation in the order of elution 108 mg of {2-hydroxy-6-methyl-4-(3-methyl-2-butenyloxy)phenyl} (2-methylpropyl) ketone (48) in the form of a yellow oily substance, 78 mg of {2,4-dihydroxy-6-methyl-3-(3-methyl-2-butenyl) phenyl} (2-methylpropyl) ketone (49) in the form of colorless fine crystals, and 260 mg of a yellowish brown oily substance which was again purified by column chromatography (6.0 g of Wako Gel C-300, eluted with hexane:ethyl acetate=19:1) to obtain 162 mg of {4,6-dihydroxy-2-methyl-3-(3-methyl-2-butenyl)phenyl} (3-methylpropyl) ketone (50) in the form of a yellow viscous oily substance.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.O>[C:12]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]([N:29]2[CH2:28][CH2:27][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])[CH2:31][CH2:30]2)=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C(=O)CC(c2ccccc2)c2ccccc2)CC1
Yield: 100 %

Procedure:
To a solution of 1.13 g of 3,3-diphenylpropionic acid and 1.06 g of 1-(2-methoxyphenyl)piperazine in 25 mL of N,N-dimethylformamide at a temperature within the range of 0-5° C., were added, in succession, 0.9 mL of 93% diethyl cyanophosphonate and 0.77 mL of triethylamine under stirring. The resultant solution was then stirred at room temperature for 5 h, poured into 250 mL of water and extracted with ethyl acetate. The organic phase was then washed with water, dried on anhydrous sodium sulphate, and evaporated to dryness under vacuum. The obtained oily residue was then puirified by flash-chromatography (chloroform-ethyl acetate 9:1). This procedure afforded the title compound (100%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]2)[CH:15]=[N:16][CH:17]=1)[CH3:10]>>[Br:1][C:17]1[N:16]=[CH:15][C:14]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:20][CH2:19]2)=[CH:13][C:12]=1[O:11][CH2:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1cncc(N2CCCN(C(=O)OC(C)(C)C)CC2)c1
Product: CCOc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)cnc1Br
Reaction time: 0.03 h

Procedure:
N-Bromosuccinimide (2.7 g, 15.2 mmol) was added to 1-(5-Ethoxy-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (4.5 g, 14.0 mmol) at room temperature. The mixture was stirred for 2 min. The mixture was washed with saturated sodium sulfite (100 ml) was. Chromatography on silica gel with a mixture of petroleum:ethyl acetate (1:1) gave the title compound as an oil. Yield 3.3 g, 58%.
Reaction SMILES: [ClH:1].Cl.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=CN=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)=[O:28])[CH2:12][CH2:11]2)[N:6]=[CH:5]1.C([Sn](CCCC)(CCCC)C1[O:45]C=CC=1)CCC>>[ClH:1].[ClH:1].[O:45]1[CH:24]=[CH:25][CH:26]=[C:21]1[C:19]1[CH:18]=[CH:17][C:16]2[N:10]([CH2:9][C:7]3[N:6]=[CH:5][NH:4][CH:8]=3)[CH2:11][CH2:12][N:13]([C:27]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)=[O:28])[CH2:14][C:15]=2[CH:20]=1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3ccccn3)cc2C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3ccco3)cc2C1
Yield: 11 %

Procedure:
Example 38 was prepared as a green solid in 11% yield from Compound A of Example 37 and 2-(tributylstannyl)furan as described for Compound B of Example 37.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[BH4-].[Na+].C([O-])(O)=O.[Na+].[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH:9][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: N#Cc1nccc(Cl)c1COC1CCCCO1
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(=O)NCc1nccc(Cl)c1COC1CCCCO1

Procedure:
4-Chloro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine-2-carbonitrile (30 mg. 0.12 mmol) was dissolved in a mixture of MeOH (0.75 mL) and THF (1 mL). CoCl2 hexahydrate (56 mg. 0.24 mmol) and NaBH4 (45 mg. 1.19 mmol dissolved in 1 mL MeOH) were added. After stirring for 8 min at RT sat. NaHCO3 solution (1 mL) and isobutyryl chloride (125 μL. 1.19 mmol) were added. The solvents were removed in vacuo and the residue was partioned between sat. NH4Cl solution (10 mL) and DCM (10 mL) and extracted with DCM (3×10 ml). The combined organic layers were washed with brine and dried over Na2SO4 filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EtOAc 2:1→1:2) to give the title compound. MS (m/z): 326.8 [M+H+]
Reaction SMILES: [C:1]12([CH2:12][C:11](=[O:13])[O:10][C:8](=[O:9])[CH2:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.N1C=CC=CC=1.[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC=CC=1>>[CH2:20]([O:27][C:11]([CH2:12][C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCc1ccccc1
Reactant: O=C1CC2(CCCCC2)CC(=O)O1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(O)CC1(CC(=O)OCc2ccccc2)CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A mixture of 1,1-cyclohexanediacetic anhydride (5.0 g, 27 mmol), pyridine (2.2 mL, 27 mmol), and benzyl alcohol (2.8 mL, 27 mmol) and toluene (5.0 mL, 47 mmol) was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and 1 N HCl. The organic layer was washed three times with 1 N HCl and brine. The organic extract was dried over sodium sulfate, filtered, and concentrated to dryness to yield the title compound (7.06 g, 89% yield) as a clear oil. 1H NMR (DMSO-d6, 400 mHz) δ (ppm): 11.96 (s, 1H), 7.32 (m, 5H), 5.03 (s, 2H), 2.52 (s, 2H), 2.34 (s, 2H), 1.40 (m, 10H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:4][C:5]([CH3:18])=[C:6]([CH3:17])[C:7]=1[NH:8][CH2:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])([CH3:12])[CH3:11].C(N(CC)CC)C.[CH2:33]([O:35][CH2:36][C:37](Cl)=O)[CH3:34]>C(Cl)Cl>[CH2:33]([O:35][CH2:36][C:37]1[N:8]([CH2:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])([CH3:11])[CH3:12])[C:7]2[C:6]([CH3:17])=[C:5]([CH3:18])[N:4]=[C:3]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:2]=2[N:1]=1)[CH3:34]
Reactant: CC(=O)NC(C)(C)CNc1c(C)c(C)nc(Oc2ccccc2)c1N
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CC(C)(C)NC(C)=O
Reaction time: 8 h
Yield: 45.6 %

Procedure:
A solution of N-{2-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]-1,1-dimethylethyl}acetamide (1.80 g, 5.23 mmol) in 50 mL of CH2Cl2 was cooled to 0° C., under N2, and treated with triethylamine (728 μL, 5.23 mmol) and ethoxyacetyl chloride (574 μL, 5.23 mmol). After stirring overnight, the reaction mixture was concentrated under reduced pressure. The resulting syrup was taken up in 50 mL of EtOH and treated with 3 mL of triethylamine. The solution was heated to reflux for 4 d. The reaction mixture was then concentrated and redissolved in 50 mL of xylenes and treated with pyridinium hydrochloride (0.5 g) and the mixture was heated to reflux for 4 d. The reaction mixture was concentrated and taken up in 100 mL of EtOAc and washed with saturated NaHCO3 solution, H2O (2×) and brine. The organic portion was dried over Na2SO4 and concentrated. The resulting syrup was purified by column chromatography (SiO2, 80% EtOAc/hexanes) to give N-{2-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]-1,1-dimethylethyl}acetamide (980 mg) as a mustard colored foam.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:16]([O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: FC(F)(F)c1nc2ncc(Cl)cc2n1OCc1ccccc1

Procedure:
1-Hydroxy-6-chloro-2-(trifluoromethyl)-1H-imidazo-(4,5-b)pyridine (5 grams), 10 milliliters of benzyl bromide, 20 grams of anhydrous potassium carbonate, and 100 milliliters of ethanol were mixed, heated to reflux, and refluxed for one hour. The reaction mixture was then filtered, evaporated under vacuum, and extracted with diethyl ether. The extract was filtered and evaporated under vacuum yielding a dark oil which on standing crystallized as the desired 1-benzyloxy-6-chloro-2-(trifluoromethyl)- 1H-imidazo(4,5-b)pyridine. It was recrystallized from a mixture of acetone and petroleum ether boiling at 60°-80° C., m.p., 107°-09° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[C:17]([CH3:18])=[N:16][C:15]2[N:11]([N:12]=[C:13]3[CH2:21][N:20]([C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[O:23])[CH2:19][C:14]3=2)[C:10]=1[CH3:37]>C(Cl)Cl>[Cl:8][C:9]1[C:17]([CH3:18])=[N:16][C:15]2[N:11]([N:12]=[C:13]3[CH2:21][N:20]([C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH:31]4[CH2:36][CH2:35][N:34]([C:1](=[O:3])[CH3:2])[CH2:33][CH2:32]4)=[O:23])[CH2:19][C:14]3=2)[C:10]=1[CH3:37]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCNCC1)C3
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCC(Oc2ccccc2C(=O)N2Cc3nn4c(C)c(Cl)c(C)nc4c3C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
Acetic anhydride (27 μL; 0.28 mmol; 1.2 eq.) was added to a suspension of Example 3 (100 mg; 0.23 mmol; 1 eq.) and TEA (82 μL; 0.59 mmol; 2.5 eq.) in DCM (3 mLl) and the resulting mixture was stirred at room temperature for 2 hours. The solution was diluted with DCM, washed with 0.1M HCl and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (72 mg, 66%) as a white solid. 1H NMR (CDCl3) δ 7.42-7.35 (m, 2H), 7.11-7.04 (m, 1H), 7.02-6.97 (m, 1H), 5.01-4.99 (m, 2H), 4.71-4.58 (m, 3H), 3.75-3.68 (m, 1H), 3.60-3.46 (m, 2H), 3.40-3.32 (m, 1H), 2.91 (s, 2H), 2.85 (s, 1H), 2.69 (s, 1H), 2.62 (s, 2H), 2.04 (s, 3H), 1.90-1.74 (m, 4H). HPLC (max plot) 99.4%, Rt 3.16 min. UPLC/MS: (MS+) 468.4 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].Cl.[CH2:20]([O:22][C:23](=[O:30])[CH2:24][CH:25]([NH2:29])[CH2:26][CH2:27][CH3:28])[CH3:21]>CO>[CH2:20]([O:22][C:23](=[O:30])[CH2:24][CH:25]([NH:29][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:26][CH2:27][CH3:28])[CH3:21]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCCC(N)CC(=O)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCCC(CC(=O)OCC)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
4-Fluorobenzaldehyde (0.287 mL, 2.68 mmol), sodium acetate (0.439 g, 5.35 mmol), powdered/activated 4 Å molecular sieves (0.72 g) and sodium cyanoborohydride (0.336 g, 5.35 mmol) were added sequentially to a solution of racemic 3-amino-hexanoic acid ethyl ester hydrochloride (0.524 g, 2.68 mmol) in methanol (10 mL) at 25° C. The mixture was stirred at 25° C. for 2 h, and then was filtered through Celite. The Celite was washed with ethyl acetate (2×30 mL) and the combined filtrate and washings were partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-80% ethyl acetate in hexanes) to afford rac-3-(4-fluoro-benzylamino)-hexanoic acid ethyl ester (0.43 g, 1.61 mmol, 60%) as a colorless oil.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](O)=[O:33])[CH:27]=[C:28]([CH3:30])[CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:15](=[N:16][CH:17]=[N:18][C:19]=5[NH2:21])[N:14]([CH3:22])[N:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:33])[CH:27]=[C:28]([CH3:30])[CH:29]=1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: Cc1cc(C)cc(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(C)cc(CC(=O)N2CCc3cc(-c4nn(C)c5ncnc(N)c45)ccc32)c1
Temperature: 25 °C

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (70 mg, 0.206 mmol), (3,5-dimethylphenyl)acetic acid (31.0 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at rt for over night. LCMS showed reaction was completed. The reaction was poured into water, white solid formed. The white solid was filtered to give the product. The final product has about 0.7 equivalent of DMF. LC/MS (ES) m/z=413.3 [M+H]+1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 6H), 3.23 (s, 2H), 3.79 (s, 2H), 3.93 (s, 3H), 4.21 (s, 2H), 6.88-6.95 (m, 3H), 7.45 (s, 1H), 7.49 (s, 1H), 8.20 (d, J=8.34 Hz, 1H), 8.24 (s, 1H).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]([NH2:41])=[O:40]>CN(C=O)C.C(OCC)(=O)C.CO>[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[C:17]4[CH:20]=[CH:21][C:22]([CH:24]5[CH2:29][CH2:28][N:27]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:26][CH2:25]5)=[CH:23][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Reactant: NC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(CC(N)=O)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.5 %

Procedure:
A mixture of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (120 mg, 0.28 mmol) in DMF (1.5 mL) was treated with potassium carbonate (97 mg, 0.7 mmol) followed by bromo acetamide (43 mg, 0.336 mmol) and stirred at RT for 18 h. The reaction mixture was diluted with ethyl acetate/methanol and washed with water, the organic layer dried (Na2SO4), filtered and concentrated in vacuo. The resultant solid residue was recrystallised from methanol to give 250 as a white solid (51 mg, 41%). 1H NMR δ (ppm) (DMSO-d6): 8.27 (1H, d, J=8.28 Hz), 7.81 (1H, s), 7.16 (1H, s), 7.07 (1H, s), 7.01 (1H, dd, J=8.36, 1.78 Hz), 6.87 (1H, d, J=1.72 Hz), 5.81-5.73 (1H, m), 4.45-4.41 (4H, m), 2.89-2.82 (2H, m), 2.83 (2H, s), 2.20 (3H, s), 2.16-2.07 (2H, m), 1.72-1.66 (4H, m), 1.40 (6H, d, J=6.61 Hz). 1 Proton obscured by solvent peak. LCMS: RT=2.97 [M+H]+=450
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([CH3:30])=[C:25]([CH:27]3[CH2:29][CH2:28]3)[N:26]=2)[N:23]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+].N>[Cu]I.CS(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([C:24]([CH3:30])=[C:25]([CH:27]5[CH2:29][CH2:28]5)[N:26]=4)[N:23]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Reactant: Cc1c(C2CC2)nc2ccc(Br)nn12
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: CS(C)=O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)nn12
Temperature: 150 °C
Yield: 28 %

Procedure:
A mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (108 mg), 6-bromo-2-cyclopropyl-3-methylimidazo[1,2-b]pyridazine (150 mg), N,N′-dimethyl-1,2-ethanediamine (81 mg), CuI (87 mg), potassium carbonate (190 mg) and DMSO (3 ml) was heated at 150° C. for 1 h under microwave irradiation. The mixture was poured into 28% NH3 solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (hexane/EtOAc), followed by crystalization from EtOAc-hexane to give the title compound (52.3 mg) as pale yellow crystals.
Reaction SMILES: [I-].C[S+](C)(C)=O.[H-].[Na+].[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=1)[CH:10]=[CH2:11].[CH3:26]COCC>CS(C)=O.[Cl-].[Na+].O>[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:26][C@H:20]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=1)[CH:10]=[CH2:11]
Reactant: CCOCC
Reactant: C=CCOc1ccc(/C=C/C(=O)OCC)cc1
Agent: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Solvent: CS(C)=O
Solvent: O
Product: C=CCOc1ccc([C@@H]2C[C@H]2C(=O)OCC)cc1
Yield: 46 %

Procedure:
Trimethylsulfoxonium iodide (3.98 g, 18.08 mmol) was added in small portions to a suspension of NaH [0.72 g (60% in mineral oil), 18.08 mmol] in dry DMSO (20 mL). The mixture was stirred until gas evolution ceased and a clear solution was formed (1.5 h). Then, a solution of ethyl(E)-ethyl 3-(4-(allyloxy)phenyl)acrylate (Intermediate E, 4.00 g, 17.22 mmol) in DMSO (10 mL) was trasferred via cannula and the reaction was stirred for additional 1 h. The mixture was poured into brine (150 mL) and extrated with Et2O (100 mL); the organic layer was washed with brine (150 mL), dried over anhydrous Na2SO4 and filtered. Removal of the solvent afforded a yellowish solid, that was purified by column chromatography on silica gel (10% EtOAc/Hexanes), affording 1.96 g of (trans)-ethyl 2-(4-(allyloxy)phenyl)cyclopropanecarboxylate [Rf=0.4 (10% EtOAc/Hexanes), white solid, 46% yield].
Reaction SMILES: [NH2-].[Na+].N.[Na].[CH2:5]([O:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH2:21][CH2:22][C:23]#[N:24])=[C:15](Br)[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]2[C:16]([CH2:21][CH:22]2[C:23]#[N:24])=[CH:17][C:18]=1[O:19][CH3:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1cc(CCC#N)c(Br)cc1OCc1ccccc1
Agent: N
Agent: [NH2-]
Agent: [Na+]
Product: COc1cc2c(cc1OCc1ccccc1)C(C#N)C2
Temperature: -33 °C
Yield: 66.1 %

Procedure:
A suspension of sodium amide is prepared from 100 mL of liquid ammonia, sodium (0.52 g, 22.8 mmol) and a catalytic amount of ferric nitrate. To this is added 3-(4-benzyloxy-2-bromo-5-methoxyphenyl)-propionitrile (2 g, 5.7 mmol) in portions and the reaction stirred at −33° C. 45 minutes. The reaction then cooled down to −78° C. and quenched with ammonium chloride. The liquid ammonia is allowed to evaporate and the resulting solid residue is washed with water. The tan solid obtained is purified by flash chromatography, using 4:1 hexanes/ethyl acetate as an eluent. The clean fractions are combined and reduced in vacuo to yield 1 g of 4-benzyloxy-3-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile as a clear oil that solidified into a white solid upon standing, mp 85° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[CH2:3]1.[BH4-].[Na+].CO.O>C1COCC1>[CH3:1][C:2]1([CH3:10])[CH2:3][CH:4]([OH:5])[CH2:6][CH:7]([OH:8])[CH2:9]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC(O)CC(O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
14.0 g (0.1 mol) of dimedone were dissolved in 200 ml of THF. 3.8 g (0.1 mol) of NaBH4 and 5 mmol of CeCl3 dissolved in 50 ml of THF were then added at -30° C. The mixture was stirred at room temperature for another 2 hours and was hydrolyzed at 0° C. by means of methanol/water. The organic phase was separated off and the solvent was removed. The residue was extracted with ethanol and unreacted dimedone was removed by crystallization. This gave 11.5 g (80%) of 5,5-dimethylcyclohexane-1,3-diol.