Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1([OH:13])[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[H-].[Na+].I[CH3:19]>O1CCCC1>[CH3:19][O:13][C:3]1([C:2]([F:1])([F:14])[F:15])[CH2:4][CH2:5][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:11][CH2:12]1
Reactant: CI
Reactant: OC1(C(F)(F)F)CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(C(F)(F)F)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., 16.23 g (71.75 mmol) of 8-(trifluoromethyl)-1,4-dioxaspiro[4.5]decan-8-ol (Example 7A) were dissolved in 582 ml of tetrahydrofuran, 5.74 g (143.50 mmol) of sodium hydride (60% in paraffin oil) were added a little at a time and the mixture was stirred at room temperature for 1 hour. 50.92 g (358.76 mmol) of iodomethane were added dropwise to the resulting suspension, and the reaction mixture was stirred at room temperature overnight. For work-up, the mixture was poured into about 1 l of ice-water and the product was extracted with dichloromethane. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. Drying gave 17.34 g (100% of theory) of the title compound as a brownish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[C:34]1[NH:38][C:37](=[O:39])[O:36][N:35]=1)[O:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:23][CH2:24][CH2:25]OS(C)(=O)=O.[NH:40]1[CH2:43][CH2:42][CH2:41]1.C(N(C(C)C)CC)(C)C>C(#N)C>[N:40]1([CH2:25][CH2:24][CH2:23][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)[S:12][C:8]=2[CH2:7][O:6][C:5]2[CH:31]=[CH:32][C:33]([C:34]3[NH:38][C:37](=[O:39])[O:36][N:35]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:43][CH2:42][CH2:41]1
Reactant: C1CNC1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOS(C)(=O)=O)ccc1-c1noc(=O)[nH]1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCN2CCC2)ccc1-c1noc(=O)[nH]1
Temperature: 60 °C

Procedure:
To a suspension of 130 mg of methanesulfonic acid 3-[5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propyl ester in 7 mL of acetonitrile was added 25 μL of azetidine and 57 mg of diisopropylethyl amine. The resulting mixture was heated in a sealed tube to 60° C. under microwave irradiation for 30 minutes and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient from dichloromethane 100 to dichloromethane 90/methanol 10/water 1/acetic acid 1) followed by a 2 g SCX Waters column with gradient CH2Cl2/MeOH 30/70 to 7N NH3 in MeOH and another column chromatography on silica gel (eluting with dichloromethane 90/methanol 10) to give 3.5 mg of 3-{4-[4-(3-azetidin-1-yl-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]([O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)([CH3:11])[CH3:10]>>[Cl:1][C:2]1[N:7]=[C:6]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH:9]([CH3:11])[CH3:10])[CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)Oc1cccc(B(O)O)c1
Reactant: Clc1ccnc(Cl)n1
Product: CC(C)Oc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
2,4 dichlorpyrimidine was coupled with 3-isopropoxyphenylboronic acid following procedure A. LC-MS showed the product had the expected M+H+ of 249.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11]([O-])(=O)[CH3:12].[K+]>CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]2[N:6]([C:11]([CH3:12])=[N:9][N:8]=2)[N:7]=1
Reactant: NNc1nnc(Cl)cc1N
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1nnc2c(N)cc(Cl)nn12
Temperature: 170 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
A MW vial was charged with 6-chloro-3-hydrazinylpyridazin-4-amine (Step 112.2) (475 mg, 2.98 mmol) and potassium acetate (467 mg, 4.76 mmol) in AcOH (5 mL). The MW vial was sealed and the resulting mixture was heated up and stirred at 170° C. for 4 hr. The reaction was cooled down to RT and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (NH3 1%/CH2Cl2/MeOH 1-3%) to afford the title product (450 mg, 2.451 mmol, 82% yield). tR: 2.32 min (HPLC 1); tR: 0.55 min (LC-MS 2); ESI-MS: 184 [M+H]+ (LC-MS 2); ESI-MS: 182 [M−H]− (LC-MS 2); Rf=0.45 (CH2Cl2/MeOH 9:1).
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[O:15])=[CH:9][CH:8]=1.C(N(CC)CC)C.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[Cl:33])N>C(#N)C>[Cl:33][C:32]1[CH:31]=[CH:30][C:28]([NH:16][C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][CH:9]=2)=[O:15])=[CH:27][C:26]=1[C:25]([F:24])([F:34])[F:35]
Reactant: NC(=O)Nc1ccc(O)cc1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1ccc(O)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 11 h
Yield: 76.8 %

Procedure:
To the dry N,N-dimethylformamide (45 ml) and 1-(4-hydroxyphenyl)urea (15 g, 0.0985 mol) solution were added triethylamine (34 ml, 0.24646 mol) and 3-trifluoromethyl-4-chloroaniline (19.28 g, 0.0985 mol) in one lot. This reaction mass was then agitated at 100° C. for 10-12 hours, quenched in water and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was back washed with water and dried over sodium sulfate. It was evaporated under vacuum to obtain solid. The obtained solid was slurried in acetonitrile (100 ml) at ambient temperature, filtered and washed repeatedly with acetonitrile till the clear filtrate was obtained. The obtained cake was then suck dried for 10 minutes and vacuum dried at 50° C. to give 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (25 g).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:19]1[CH2:20][O:21][C:22](=[O:24])[CH:23]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[O:24]=[C:22]1[O:21][CH2:20][C:19]([N:3]2[CH2:4][CH2:5][C:6]3([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]3)[C:2]2=[O:1])=[CH:23]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=CC(=O)OC1)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C=C(N2CCC3(CCNCC3)C2=O)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (5.70 g, 16.9 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (26.1 mL, 339 mmol) and the resulting solution was stirred at rt for 1 h. After concentration the residue was basified on ion exchange column followed by washing with 1N ammonia in methanol solution to give 2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one. LC/MS: (M+1)+: 237.06.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:9]([O:12][CH3:13])([O:10][CH3:11])[CH2:8][CH2:7][N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5]1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>CN(C=O)C>[CH2:21]([O:3][CH:4]1[C:9]([O:10][CH3:11])([O:12][CH3:13])[CH2:8][CH2:7][N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
Sodium hydride (55% content, 0.79 g, 18 mmol) was added to a solution of tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (described in Tetrahedron Lett.; [[EN;]] 46; 3; 2005; 447-450, 3.9 g, 15 mmol) in DMF (50 mL). Following stirring at room temperature for 30 minutes, benzyl bromide (2.82 g, 16.5 mmol) was added, and the mixture was stirred at room temperature for two hours. A 0.5 N aqueous hydrochloric acid solution was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with water (three times) and brine, and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 4.99 g of the title compound as a colorless solid (95%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([O:19][CH2:20][C:21]2[CH:25]=[CH:24][O:23][CH:22]=2)[CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.[C@H:26]1([CH2:36]O)[C@@H:35]2[N:30]([CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:29][CH2:28][CH2:27]1>>[C@H:26]1([CH2:36][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]3[NH:11][C:12]4[C:17]([CH:18]=3)=[C:16]([O:19][CH2:20][C:21]3[CH:25]=[CH:24][O:23][CH:22]=3)[CH:15]=[CH:14][CH:13]=4)=[O:9])[CH2:3][CH2:2]2)[C@@H:35]2[N:30]([CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:29][CH2:28][CH2:27]1
Reactant: OC[C@@H]1CCCN2CCCC[C@H]12
Reactant: O=C(NC1CCNCC1)c1cc2c(OCc3ccoc3)cccc2[nH]1
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3ccoc3)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid piperidin-4-ylamide, 165 (preparation see below) and (1R,9aR)-1-(octahydro-quinolizin-1-yl)-methanol analogously to the method described in example 127.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9]C)[CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]>Br>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: COc1ccc(C(C)=O)c(N)c1Cl
Agent: Br
Product: CC(=O)c1ccc(O)c(Cl)c1N
Temperature: 0 °C
Yield: 60.9 %

Procedure:
1-(2-Amino-3-chloro-4-methoxyphenyl)ethanone (prepared according to Raboisson, P. J.-M. B., et al., WO2007014926, p 78; 70.7 g, 354 mmol) was stirred in 48% aq. HBr (500 mL) at 110° C. for 72 h. After the mixture was cooled to 0° C. with stirring, the solids were filtered and washed with water. The resulting solids were triturated with a saturated NaHCO3 solution (˜350 mL), filtered, washed with water, and dried under vacuum to give 40 g (61% yield) of 1-(2-amino-3-chloro-4-hydroxyphenyl)ethanone as a dark brown solid.
Reaction SMILES: ClC(Cl)(Cl)C(O)O.CC1C=CC=[CH:13][C:14]=1[N:15]1[C:24](=O)[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=[C:16]1C.CN1C(=O)CN=C(C2C=CC=CC=2)C2C=C(Cl)C=CC1=2.CCN(CCN1C(=O)CN=C(C2C=CC=CC=2F)C2C=C(Cl)C=CC1=2)CC.C1C=CC(C2(N3CCCCC3)CCCCC2)=CC=1.CNCCC(OC1C=CC(C(F)(F)F)=CC=1)C1C=CC=CC=1>>[N:15]1[CH:24]=[C:23]([CH:18]2[CH2:19][CH2:20][CH2:21][N:17]2[CH3:16])[CH:22]=[CH:13][CH:14]=1
Reactant: Cc1ccccc1-n1c(C)nc2ccccc2c1=O
Agent: CCN(CC)CCN1C(=O)CN=C(c2ccccc2F)c2cc(Cl)ccc21
Agent: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Agent: CNCCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Product: CN1CCCC1c1cccnc1

Procedure:
Depressants, for example, nonbarbiturates (e.g. bromides, chloral hydrate etc.), methaqualone, barbiturates, diazepam, flurazepam, phencyclidine, and fluoxetine;
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:4]([O:28][CH3:29])[CH:3]=1.[H-].[Na+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C)C=O>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([N:9]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:5]3[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=3[O:28][CH3:29])=[O:11])[CH2:13][CH2:14]2)[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=1
Reactant: CCOC(=O)CBr
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C)c(C)cc3OC)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C(=O)N1CCN(c2cc(OC)cc(OC)c2)CC1)c1cc(C)c(C)cc1OC
Temperature: 25 °C
Yield: 79 %

Procedure:
1-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(0.2 g, 0.5 mmol) was dissolved in dimethylformamide(15 ml), sodium hydride(18.5 mg, 0.5 mmol) was added thereto, and the resulting mixture was stirred at room temperature. Then, ethyl bromoacetate(83.5 mg, 0.5 mmol) was added thereto and the resulting mixture was stirred for 3 hours, concentrated under the reduced pressure to remove the used solvent and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[CH2:8]=[CH:9][CH2:10][CH2:11]CC.ClC(Cl)C1C=CC=CC=1.C(OCC)=C.C(OCCCCC=CCCCC)(=O)C>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C=CCCCCCl
Reactant: C=CCCCC
Agent: C=COCC
Agent: CCCCC=CCCCCOC(C)=O
Solvent: ClC(Cl)c1ccccc1
Product: CCCCC=CCCCCCl
Reaction time: 3 h

Procedure:
1-Chloro-5-decene was synthesized as follows: 200.1 g (1.61 mol 95% pure) of 1-chloro-5-hexene, 282 g (416 mL, 3.35 mol) of 1-hexene and 2.0 mL of α,α-dichlorotoluene (metal hydride inhibitor) were added to a dry 1-L 2-necked round-bottomed flask containing a reflux condenser and a stir bar. This mixture was sparged sub-surface with Argon. After 10 minutes 5.5 g (6.67 mol) of the metathesis catalyst of Example 1 was added. The mixture was placed in a 62° C. oil bath and stirred. Samples were taken periodically and analyzed by gas chromatography (GC) to determine the extent of conversion. After 3 hours, the reaction stopped and the catalyst was inactivated by the addition of 3 mL of ethyl vinyl ether. The catalyst was removed by filtering the mixture through 200 g of silica gel. The silica gel was rinsed with 500 mL of hexane and combined with the post-filtered reaction solution. 1-chloro-5-decene was purified by vacuum distillation to yield 105.9 g. This was converted to 5-decenyl acetate as follows.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[CH:8][CH:7]=1)[OH:5]>ClCCl.[O-2].[Mn+4].[O-2]>[CH3:1][O:2][C:3](=[O:22])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[CH:10][CH:11]=1)=[O:5]
Reactant: COC(=O)C(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Reaction time: 12 h

Procedure:
[4-(3,4-Dichlorobenzyloxy)phenyl]-hydroxy-acetic acid methyl ester (85.25 g) was dissolved in dry dichloromethane (500 mL). To the resulting solution, activated manganese (IV) oxide (<5 μm, 175 g) was added. The mixture was stirred vigorously for about 12 hours (until TLC showed no presence of unreacted starting material). The reaction mixture (slurry) was diluted with dichloromethane (500 mL) and was passed through a pad of celite. The filtrate was concentrated to yield the title compound. Proton NMR (400 MHz, CDCl3) was recorded. The following chemical shifts (in ppm) were recorded relative to TMS reference of 0.0 ppm, and include the following: 3.97 (s, 3H); 5.11 (s, 2H); 7.03 (m, 2H); 7.26 (m, 1H); 7.47 (d, 1H); 7.54 (d, 1H); 8.02 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[C:6]12([OH:18])[CH2:15][C:10]3([OH:16])[CH2:11][CH:12]([CH2:14][C:8]([OH:17])([CH2:9]3)[CH2:7]1)[CH2:13]2>CN(C=O)C>[CH3:1][O:2][C:3]([O:18][C:6]12[CH2:15][C:10]3([O:16][C:3]([O:2][CH3:1])=[O:4])[CH2:11][CH:12]([CH2:14][C:8]([O:17][C:3]([O:2][CH3:1])=[O:4])([CH2:9]3)[CH2:7]1)[CH2:13]2)=[O:4]
Reactant: COC(=O)Cl
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Solvent: CN(C)C=O
Product: COC(=O)OC12CC3CC(OC(=O)OC)(C1)CC(OC(=O)OC)(C3)C2
Temperature: 25 °C
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3,5-adamantanetriol obtained by the method of Example 32 and 36 mmole of pyridine were dissolved in 10 mL of DMF. To the mixture, 33 mmole of methoxycarbonyl chloride was added dropwise with stirring at room temperature. Cooling of the resultant mixture with ice was started at about the time exothermic reaction began. When the exothermic reaction is completed, the mixture was heated to 60° C. and then stirred for one hour. As a result, the conversion of 1,3,5-adamantanetriol was 99% and 1,3,5-tris(methoxycarbonyloxy)adamantane (yield 95%) was formed.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[CH3:12][C:13]1[C:18]([OH:19])=[C:17]([C:20](OC)=[O:21])[C:16]([C:24](OC)=[O:25])=[C:15]([CH:28]=[CH2:29])[N:14]=1.C(=O)=O>O>[CH3:12][C:13]1[C:18]([OH:19])=[C:17]([CH2:20][OH:21])[C:16]([CH2:24][OH:25])=[C:15]([CH:28]=[CH2:29])[N:14]=1
Reactant: C=Cc1nc(C)c(O)c(C(=O)OC)c1C(=O)OC
Agent: O=C=O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: C=Cc1nc(C)c(O)c(CO)c1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 0.15 moles of lithium aluminum hydride in 250 ml. of ether is added dropwise with stirring a solution of 0.05 moles of dimethyl 2-methyl-3-hydroxy-6-vinylpyridine 4,5-dicarboxylate in 150 ml. of ether. The mixture is refluxed for 6 hours and stirred overnight at room temperature. The reaction mixture is cooled and 100 ml. of water added dropwise with stirring. The resulting mixture is saturated with carbon dioxide for 30 minutes and then filtered. The precipitate is stirred with 250 ml. of ethanol-water (1:1) and saturated again with carbon dioxide and filtered. The solid is then extracted twice with 100 ml. of boiling ethanol. The combined filtrates are evaporated to dryness in vacuo. The residue is extracted 5 times with 100 ml. of boiling ethanol. The combined extracts are filtered and evaporated to dryness to give 2-methyl-3-hydroxy-4,5-di(hydroxymethyl)-6-vinylpyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:26]=1[C:32]([F:35])([F:34])[F:33]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:31][C:28]4[CH:29]=[CH:30][C:25]([Cl:24])=[C:26]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(Cl)c(C(F)(F)F)c4)ncnc32)CC1

Procedure:
4-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 2-chloro-5-hydroxybenzotrifluoride (available from Alfa Aesar, Ward Hill, Mass., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.96-2.05 (m, 4H), 2.96-3.04 (m, 2H), 4.08-4.11 (m, 2H), 4.99-5.04 (m, 1H), 7.73-7.76 (m, 1H), 7.86-7.89 (m, 1H), 7.96-7.98 (m, 1H), 8.41 (s, 1H), 8.58 (s, 1H). Mass spectrum MH+=498.
Reaction SMILES: CN(C=O)C.[CH2:6]([Cl:8])Cl.C(Cl)(=O)C(Cl)=O.[N:15]1[C:20]2[S:21][CH:22]=[CH:23][C:19]=2C(=O)[NH:17][CH:16]=1>O>[Cl:8][C:6]1[C:19]2[CH:23]=[CH:22][S:21][C:20]=2[N:15]=[CH:16][N:17]=1
Reactant: ClCCl
Reactant: O=c1[nH]cnc2sccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncnc2sccc12
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a solution of DMF (90 μL) and CH2Cl2 (2 mL) at 0° C. under N2, oxalyl chloride (148 mg, 1.2 mmol) is added slowly and stirred for 10 min. 3H-Thieno[2,3-d]pyrimid-4-one (81 mg, 0.52 mmol) is added as a solid to the solution and warmed with a heat gun until the solid dissolves. The reaction is stirred at 25° C. for 12 h under N2. The reaction mixture is poured into water and extracted with CH2Cl2. The phases are separated and the organic layer is dried (Na2SO4) and stripped under reduced pressure to yield 4-chlorothieno[2,3-d]pyrimidine (87.6 mg, 97%) as a solid. 1H NMR (DMSO) δ 8.96 (1H, s), 8.17 (1H, d, J=6.0 Hz), 7.62 (1H, d, J=6.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]=[C:10]=[O:11])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N=C=O)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C=Nc1ccc(CBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred solution of 100.0 grams (0.597 mole) of 3-chloro-4-methylphenylisocyanate in 1000 ml of carbon tetrachloride, under an argon atmosphere were added 116.8 grams (0.656 mole) of N-bromosuccinimide and 5.0 grams (0.021 mole) of benzoyl peroxide. The reaction mixture was warmed to reflux where it stirred for 4 hours; then it was allowed to cool to ambient temperature as it stood for 16 hours. The mixture was filtered and the filtrate concentrated under reduced pressure to give 147.1 grams of 4-bromomethyl-3-chlorophenylisocyanate as a residual oil. The oil was used without further purification.
Reaction SMILES: [C:1]([O:20]C)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+:23]>CO>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[K+:23]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
44.8 grams of methyl stearate (0.75 moles/mole of sucrose to be used in Step B) is saponified by stirring at reflux in 200 ml methanol containing an equivalent amount of KOH (9.4 grams of 90% purity). The reaction is stirred at 60° C. for about an hour with heating until all methyl ester has been converted to soap as indicated by infrared analysis. The soap solution is used, as is, in the next reaction step.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[C:10]1([CH3:25])[CH:15]=[CH:14][C:13]([S:16]([O:19][CH2:20][C:21]2([CH3:24])[CH2:23][O:22]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(#N)C>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]([CH2:24][C:21]([OH:22])([CH3:23])[CH2:20][O:19][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:25])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)CO2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCC(C)(O)Cn2cc([N+](=O)[O-])nc2Cl)cc1
Yield: 70.4 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (1 g, 6.78 mmol), 2-methyloxiran-2-ylmethyl paratoluenesulfonate (2.46 g, 10.15 mmol), benzyl(triethyl) ammonium chloride (1.50 mg, 0.66 mmol) and acetonitrile (10 ml) were stirred under reflux for 8 hours. The reaction mixture was allowed to return to room temperature, diluted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution twice, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=6/1) to afford 2-chloro-1-[2-hydroxy-2-methyl-3-(4-methylbenzenesulfonyloxy)propyl]-4-nitroimidazole (1.86 g, yield 70%) as a light yellow oil.