Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[C:2]1=[N:11][OH:12].[H-].[Na+].Br[CH2:16][CH2:17][OH:18].O>CN(C)C=O>[OH:18][CH2:17][CH2:16][O:12][N:11]=[C:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1
Reactant: O=C1C(=NO)Oc2ccccc21
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C(=NOCCO)Oc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
11.8 g (0.0725 mol) of benzofuran-2,3-dione 2-oxime (XI-1) (Stoermer, Kahlert, B. 35, 1644) are dissolved in 75 ml of dimethylformamide. With cooling, 3 g (0.075 mol) of 60% strength sodium hydride (mineral oil suspension) are added a little at a time and stirring is continued at a temperature of 25° C. for about one hour until the formation of gas has ceased. The mixture is then cooled to 0° C., and at this temperature 9.3 g (0.0744 mol) of 2-bromoethanol are added dropwise and stirring is continued at 25° C. for a further 24 hours. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is recrystallized from a mixture of 150 ml of toluene and 100 ml of cyclohexane. 11.5 g (64% of theory) of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] (VII-1) are obtained (content according to HPLC analysis: 83.5%). A sample recrystallized from toluenes has a melting point of 110-111° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[C:9]=1[CH2:10][C:11]#[N:12])=O.[Li+].[BH4-].CO.[NH4+].[Cl-]>C1COCC1.CC(C)=O>[OH:2][CH2:3][C:5]1[S:6][C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[C:9]=1[CH2:10][C:11]#[N:12]
Reactant: COC(=O)c1sc(-c2ccccc2)c(-c2ccc(SC)cc2)c1CC#N
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CSc1ccc(-c2c(-c3ccccc3)sc(CO)c2CC#N)cc1
Temperature: 50 °C

Procedure:
To a solution of 3-cyanomethyl-4-(4-(methylthio)phenyl)-5-phenylthiophene-2-carboxylic acid methyl ester (480 mg) (Step 1) in THF (13 mL) was added 55 mg of LiBH4 followed by 50 μL of MeOH; then the mixture was heated at 50° C. for 90 min. After cooling to r.t. a few drops of acetone were slowly added, then a saturated solution of NH4Cl. The mixture was then extracted twice with EtOAc, the organic layers combined, washed with brine, dried over MgSO4, filtered and the solvent evaporated under vacuum. Purification by silica gel chromatography using 30% of EtOAc in hexane afforded the title compound.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+].[CH2:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][C:19]1=O>CO>[ClH:1].[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][CH:19]1[CH2:18][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)[CH3:3]
Reactant: O=C1Cc2ccccc2C1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Product: CCOC(=O)CNC1Cc2ccccc2C1
Temperature: 0 °C
Yield: 56.8 %

Procedure:
Glycine ethyl ester hydrochloride (20 g) is dissolved in a solution of 10 g of 2-indanone in 200 ml of methanol, and then 5.0 g of sodium cyanoborohydride is added portionwise to the solution with ice cooling and stirring. After stirring at room temperature for 2 hours, the reaction mixture is poured into 500 ml of ice water, and the whole mixture is made alkaline with sodium hydrogen carbonate and extracted with 300 ml of ethyl acetate. The extract is washed with water and dried, the ethyl acetate is distilled off under reduced pressure, 10 ml of 20% ethanolic hydrochloric acid and 200 ml of ethyl ether are added to the residue, and the mixture is allowed to stand at room temperature. The resulting crystalline precipitate is collected by filtration and dried to give 11 g of N-(indan-2-yl)glycine ethyl ester hydrochloride as colorless needles melting at 164°-167° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Cl:13])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(I)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCCc1ccc(I)cc1
Yield: 98.6 %

Procedure:
To a 500 mL round-bottomed flask equipped with dropping funnel, condenser and N2 inlet were added 307 g (124 mmol) 2-(4-iodophenyl)ethanol, 200 mL chloroform, and 10.0 mL (124 mmol) pyrdine. A solution of 13.5 mL (186 mmol) thionyl chloride in 50 mL chloroform was added dropwise over 15 min, and the reaction then heated at reflux for 2 hr. The reaction was cooled, the solvent evaporated, and the residue taken up in ethyl acetate, washed with 1 N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and brine, dried, and evaporated. The resulting oil was chromatographed on silica gel using 20% ethyl acetate in hexane as eluant to afford 32.6 g (99%) of the product as an oil.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:23](=[O:25])[CH3:24])[CH:10]=[CH:11][C:12]=2[CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]([CH3:22])([CH3:21])[CH2:14]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:26](=O)[CH2:27][CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)C.O1CCCC1>[CH2:26]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]([C:23](=[O:25])[CH3:24])[CH:10]=[CH:11][C:12]=2[CH:13]2[CH2:14][C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:19])([CH3:20])[CH2:18]2)[CH2:2][CH2:3]1)[CH2:27][CH3:28]
Reactant: CC(=O)c1ccc(C2CC(C)(C)CC(C)(C)C2)c(N2CCNCC2)c1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCN1CCN(c2cc(C(C)=O)ccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-[3-piperazin-1-yl-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanone (19 mg, 0.0555 mmol) produced in Example (82b), propionaldehyde (0.0119 mL, 0.166 mmol) and tetrahydrofuran (0.3 mL) was added sodium triacetoxyborohydride (35 mg, 0.166 mmol), followed by stirring for 1 hour at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with diethyl ether. The solvent was distilled off by nitrogen stream to the separated organic layer. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-[3-(4-propylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanone.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2].[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17].C1N2CCN(CC2)C1>O1CCOCC1.O>[N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]([OH:7])[C:16](=[CH2:17])[C:15]([O:19][CH3:20])=[O:18])([O-:3])=[O:2]
Reactant: C=CC(=O)OC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: C1CN2CCN1CC2
Solvent: C1COCCO1
Solvent: O
Product: C=C(C(=O)OC)C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
2,4-Dinitrobenzaldehyde was dissolved in dioxane and water, methyl acrylate and triethylenediamine were added thereto at room temperature, and the whole was stirred to obtain methyl 2-[(2,4-dinitrophenyl)(hydroxy)methyl]acrylate.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8])[C:2]#[CH:3].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>O>[CH2:1]([N:4]([CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8])[C:25](=[O:26])[CH2:24][Cl:23])[C:2]#[CH:3]
Reactant: C#CCNCC(OC)OC
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: C#CCN(CC(OC)OC)C(=O)CCl

Procedure:
N-Propargyl-N-(2,2-dimethoxyethyl)amine (9 grams), benzene (100 ml), water (100 ml) and sodium carbonate (8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture was cooled to a temperature of 5° to 10° C. and chloroacetyl chloride (5 ml) was added dropwise with stirring. Stirring was then continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase, was washed with water and was dried. The dried solution was then filtered and the filtrate stripped of solvent to yield the desired product N-propargyl-N-(2,2-dimethoxyethyl)-α-chloroacetamide as the residue.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[C:5]([NH2:13])[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:56]([O:60][C:61]([NH:63][C:64]1[S:68][C:67]([C:69]2[C:74]([F:75])=[CH:73][CH:72]=[CH:71][C:70]=2[F:76])=[N:66][C:65]=1[C:77](O)=[O:78])=[O:62])([CH3:59])([CH3:58])[CH3:57]>C(Cl)Cl>[F:76][C:70]1[CH:71]=[CH:72][CH:73]=[C:74]([F:75])[C:69]=1[C:67]1[S:68][C:64]([NH:63][C:61](=[O:62])[O:60][C:56]([CH3:58])([CH3:57])[CH3:59])=[C:65]([C:77](=[O:78])[NH:13][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:66]=1
Reactant: Cn1ncc(N)c1C1CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
A solution of 5-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-4-nitro-1H-pyrazole (80 mg, 0.38 mmol) in MeOH (20 mL) was passed through the H-Cube® (30 bar, 25° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude 1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine as a light yellow oil (64 mg, 0.35 mmol). To a solution of this amine (60 mg, 0.33 mmol) in DCM (20 mL) was added DIPEA (0.5 mL, 2.87 mmol), PyBOP (0.34 g, 0.66 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (124 mg, 0.35 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM and washed with water. The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-80% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (102 mg, 59%). This solid (100 mg, 0.19 mmol) was stirred in HCl in 1,4-dioxane (4.0 M, 1.9 mL) at room temperature for 18 hr. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and 7 N ammonia in MeOH to yield 301 as a peach solid (59 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.69 (s, 1H), 7.34-7.29 (m, 1H), 7.02 (t, J=8.7 Hz, 2H), 6.11 (s, 2H), 4.09 (dd, J=11.6, 4.2 Hz, 2H), 3.88 (s, 3H), 3.50 (t, J=11.6 Hz, 2H), 3.02-2.95 (m, 1H), 2.17-2.08 (m, 2H), 1.78 (d, J=13.4 Hz, 2H). LCMS (ES+) m/z 420 (M+1)
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5[CH:36]=[C:35]([C:37](N)=[O:38])[CH2:34][CH:33]=[CH:32]5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[C:45]([C:53](OC)=O)(=O)[C:46]1C=CC=C[CH:47]=1.P([O-])([O-])([O-])=O.[OH-].[Na+]>C(OCC)C.CCCCCC.CC(O)C>[C:33]1([C@H:34]2[CH2:36][C@@H:35]2[CH2:37][OH:38])[CH:32]=[CH:47][CH:46]=[CH:45][CH:53]=1
Reactant: COC(=O)C(=O)c1ccccc1
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CC(C)O
Product: OC[C@H]1C[C@@H]1c1ccccc1
Temperature: 25 °C

Procedure:
A reaction mixture was formed by admixing (i) 50 mg NAD, (ii) 4 ml of 2-propanol and (iii) 5 mmoles of 1-carboxyaldehyde-2-phenylcyclopropane (Example 5), Compound 5, in a liquid medium containing 1 gm of lyophilized PED alcohol dehydrogenase preparation, 75 ml of 50 mM phosphate buffer, pH 7.1, and 25 ml of hexane. The pH of the reaction was maintained constant by addition of 1N NaOH. The reaction mixture was maintained at room temperature until product formation stopped. When product formation stopped, (S,S)-2-phenylcyclo-propylmethanol, Compound 5a, was isolated by removal of the hexane layer and extraction of the aqueous layer with ethyl ether (3×75 ml).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12].C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.C(O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: COc1cccc([N+](=O)[O-])c1Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cccc(N)c1Cl
Yield: 103.5 %

Procedure:
2-Chloro-3-nitroanisole 2c2 (1.38 g; 7.36 mmol) was dissolved in a mixture of glacial acetic acid (19 ml_)/ethanol (19 ml_). To this solution was added iron powder (1.64 g; 29.4 mmol). The mixture was stirred at reflux for 3.5 hr and worked up. The reaction mixture was diluted with water (70 ml_), neutralized with solid Na2CO3 and the product extracted with CH2Cl(3×150 mL). The extracts were combined and washed with sat. brine and then dried over (Na2SO4), filtered and concentrated in vacuo to afford the crude product, 2-chloro-3-methoxyaniline 2c3 (100%; 1.2 g) as a yellow oil. This material was used as such in the following steps. MS 157.9 (MH)+; Homogeneity by HPLC (TFA) @ 220 nm: 86%.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10](=O)[C:11]#[C:12][CH3:13])=[CH:6][C:5]=12.Cl.[NH2:16][OH:17].C(N(CC)CC)C>CN(C=O)C>[CH3:13][C:12]1[O:17][N:16]=[C:10]([C:7]2[CH:8]=[CH:9][N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=2)[CH:11]=1
Reactant: NO
Reactant: CC#CC(=O)c1ccn2ccnc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccn3ccnc3c2)no1
Temperature: 80 °C
Yield: 25.4 %

Procedure:
To a solution of 1-Imidazo[1,2-a]pyridin-7-yl-but-2-yn-1-one (168 mg, 0.91 mmol) and hydroxylamine hydrochloride (94 mg, 1.37 mmol) in DMF (10 ml) was added triethylamine (0.21 ml, 1.83 mmol). The reaction mixture was heated at 80° C. for 18 h, then partitioned between EtOAc and H2O. The organic fraction was separated, dried (MgSO4), filtered and the solvent removed in vacuo. The crude residue was purified by silica column chromatography (0-50% MeOH in Et2O) to afford the product (46 mg). MS: [M+H]+=200.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:29][CH2:30]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 87 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 87%). 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 2.42-2.48 (m, 3H), 3.20-3.28 (m, 4H), 3.75-3.80 (m, 3H), 4.10-4.13 (m, 4H), 6.59 (s, 3H), 7.00-7.12 (m, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.48-7.65 (m, 2H).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[N:5]1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.[CH3:17]O>>[CH:1]([N:4]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:17])=[O:10])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)n1ccc(C(=O)O)n1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccn(C(C)C)n1
Reaction time: 5 h
Yield: 76 %

Procedure:
To a solution of 1-isopropyl-1h-pyrazole-3-carboxylic acid (0.9757 g, 6.33 mmol, Matrix Scientific) in MeOH (31.6 ml) in a glass pressure vessel was added sulfuric acid (0.355 ml, 6.33 mmol Sigma Aldrich). The vessel was sealed and the r×n was brought to reflux to stir. (NOTE: A portable blast shield was used.) R×n was allowed to stir for 5 hours. The r×n was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The organic extract was washed with water, dried over MgSO4, filtered and concentrated in vacuo to give methyl 1-isopropyl-1H-pyrazole-3-carboxylate (0.8073 g, 4.80 mmol, 76% yield) as a clear oil. MS m/z=168.9 [M+H]+. Calculated for C8H12N2O2: 168.09. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.55 (d, J=6.85 Hz, 6 H) 3.93 (s, 3 H) 4.63 (dt, J=13.50, 6.75 Hz, 1 H) 6.83 (d, J=2.35 Hz, 1 H) 7.46 (d, J=2.35 Hz, 1 H)
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl[C:29]1[N:34]=[CH:33][C:32](/[CH:35]=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C>[C:1]12([C:11]3[CH:12]=[C:13]([C:29]4[N:30]=[CH:31][C:32](/[CH:35]=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:33][N:34]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OB(O)c1ccc(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)c1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)/C=C/c1cnc(-c2ccc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)c2)nc1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
To a solution of 3-(1-adamantyl)-4-benzyloxyphenylboronic acid (Zhang Y. et al., Blood, 2002; 100:2917-2925, Dawson M. I. et al., J. Med. Chem., 2004; 47:3518-3536) (3.62 g, 10.0 mmol) and ethyl (2E)-3-(2-chloro-5-pyrimidinyl)-2-propenoate (1.76 g, 8.30 mmol) in dimethoxyethane (50 mL) was added under argon tetrakis(triphenylphosphine)-palladium (1.15 g, 1.00 mmol) and 2 M aqueous Na2CO3 (10 mL). The reaction mixture was heated at reflux for 18 h, cooled to room temperature, diluted with ethyl acetate, washed (water and brine) and dried. After solvent removal at reduced pressure, the residue was chromatographed (9% to 14% ethyl acetate/hexane) to give 3.98 g (96%) of ethyl(E)-3-[2-(3-(1-adamantyl)-4-benzyloxyphenyl)-5-pyrimidinyl]-2-propenoate as a yellow solid, mp 164-167° C. IR 2903, 1710, 1432, 1225 cm−1; 1H NMR δ (CDCl3) 1.40 (t, J=7.2 Hz, 3H, OCH2CH3), 1.77 (bs, 6H, AdCH2), 2.11 (bs, 3H, AdCH), 2.26 (bs, 6H, AdCH2), 4.33 (q, J=7.2 Hz, 2H, OCH2CH3), 5.24 (s, 2H, CH2), 6.59 (d, J=16.2 Hz, 1H, CH═CHCO), 7.08 (d, J=8.7 Hz, 1H, 5-ArH), 7.35-7.58 (m, 5H, C6H5), 7.65 (d, J=16.2 Hz, 1H, CH═CHCO), 8.33 (dd, J=8.7 Hz, 2.1 Hz, 1H, 6-ArH), 8.47 (d, J=2.1 Hz, 1H, 2-ArH), 8.91 ppm (s, 2H, 4-PyrH, 6-PyrH). HRMS calcd C32H34N2O3 [M+H]+ 495.2642. found 495.2636.
Reaction SMILES: [CH2:1]([C@H:9]([C@H:12]([OH:14])[CH3:13])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)#[N:16].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CCCCCC.C(Cl)Cl.O.C1(C)C=CC=CC=1>[CH2:1]([C@H:9]1[CH2:10][O:11][C@H:29]([C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[CH:18][CH:19]=3)=[CH:28][CH:27]=2)[O:14][C@@H:12]1[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: N#Cc1ccc(-c2ccc(C=O)cc2)cc1
Reactant: CCCCCCCC[C@@H](CO)[C@@H](C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCC[C@H]1CO[C@H](c2ccc(-c3ccc(C#N)cc3)cc2)O[C@@H]1C
Yield: 85.7 %

Procedure:
A mixture of 3.0 g of (2S,3R)-2-octyl-1,3-butanediol, 3.07 g of 4'-cyano-4-biphenylcarboxaldehyde, 0.1 ml of 1N sulfuric acid and 30 ml of toluene was placed under nitrogen in a round flask having a magnetic stirrer, water separator and condenser. The mixture was heated to reflux for 3 hours while separating water. The cooled reaction mixture was poured into aqueous sodium hydrogen carbonate solution and treated with methylene chloride. The aqueous phase was separated and extracted twice with methylene chloride. The combined organic phases were washed twice with water, dried over magnesium sulfate, filtered and evaporated. Recrystallization of the crude product obtained (5.84 g) from a mixture of 200 ml of hexane and 25 ml of ethyl acetate gave 4.97 g of 4'-[(2S,4R,5S)-5-octyl-4-methyl-1,3-dioxan-2-yl]-4-cyanobi-phenyl with m.p. (C-SA) 114.5° C., cl.p. (SA -I) 128.4° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][NH:15][C:16](OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[NH2:32][C:33]1[N:38]=[C:37](Cl)[C:36](C=O)=[C:35]([Cl:42])[N:34]=1.C1(C)C=CC=CC=1>O1CCCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:37]3=[N:38][C:33]([NH2:32])=[N:34][C:35]([Cl:42])=[C:36]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Reactant: CC(C)(C)OC(=O)NNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)nc(N)nc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
4-(tert-Butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 15; 315 mg, 1 mmol) and diisopropylethylamine (2 mmol) were added to a solution of 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 200 mg, 1 mmol) in tetrahydrofuran (3 mL). The mixture was warmed to room temperature, heated to reflux for 3 h, and then stirred overnight. The mixture was heated to reflux for a further 2 h and then cooled. Brine was added and the mixture was extracted three times with ethyl acetate. The combined organic extracts were dried (magnesium sulfate), filtered and evaporated to give a yellow foam. Toluene was added and the mixture was heated at 110° C. for 2 h. The mixture was cooled and purified by column chromatography (50% ethyl acetate/hexanes) to give 4-(6-amino-4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (315 mg, 69%) as a white powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([C:11]([F:14])([F:13])[F:12])=[N:5]1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>ClCCl.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:9][C:8]1[N:4]([CH2:3][CH2:2][O:1][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][O:15]2)[N:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:7]=1[OH:10]
Reactant: C1=COCCC1
Reactant: Cc1c(O)c(C(F)(F)F)nn1CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(O)c(C(F)(F)F)nn1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To a stirred solution of 1-(2-hydroxyethyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ol (600 mg, 2.86 mmol; Kenkyu Hokoku—Asahi Garasu Kogyo Gijutsu Shoreikai, 1988, 51, 139-49) in dichloromethane (10 ml) and ethyl acetate (4 ml) was added para-toluenesulphonic acid (27 mg, 0.14 mmol) followed by 3,4-dihydro-2H-pyran (340 μl, 3.7 mmol). The reaction mixture was stirred at room temperature for 3 hours before being concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (60:40, by volume) to provide the title compound (560 mg) as white solid.