Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:33][C@H:34]([C:39]([OH:41])=[O:40])[CH2:35][CH2:36][S:37][CH3:38]>C1COCC1.O>[C:14]([O:13][C:11]([NH:1][C@H:2]([C:8]([NH:33][C@H:34]([C:39]([OH:41])=[O:40])[CH2:35][CH2:36][S:37][CH3:38])=[O:10])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CSCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
A solution of Boc-L-Gln (Bachem, 4.92 g, 20 mmole) in THF (45 ml) was cooled to -15°, neutralized with N-methylmorpholine (2.2 ml, 20 mmole) and treated with isobutylchlorocarbonate 2.74 g (20 mmole). After 5 min a solution of L-methionine (4.48 g, 30 mmole) and N-methylmorpholine (3.3 ml. 30 mmole) in H2O (45 ml) was added. (Some warming was necessary to obtain a clear solution of the methionine salt). The mixture was stirred and allowed to warm up to room temperature; gradually a clear solution formed. After 1.5 hr the solution was concentrated in vacuo to remove most of the THF and then acidified with a 20% solution of citric acid in H2O. Saturation with NaCl and extraction with EtOAc (3×50 ml), was necessary to isolate the desired material. The organic layer was washed with H2O and evaporated with a stream of N2. The solid residue was suspended in warm EtOAc (100 ml), stirred for 1 hr, filtered, washed with EtOAc and dried. The product (4.75 g, 63%) melted at 149°-150°; [α]D20 -11.8° (c 2, DMF); RfB, 0.60; RfE, 0.73, Glu, 1.0; Met, 1.0. The proton nmr spectrum, in CD3COOD, showed the expected resonances.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2].Cl[C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[C:1]([C:3]1([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Reactant: Fc1cccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C#N)(c2ncccc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a stirred suspension of tert-butyl 3-cyanoazetidine-1-carboxylate (5 g; 27.43 mmol) and 2-chloro-3-fluoropyridine (5.05 g; 38.41 mmol) in toluene (100 ml) cooled in an acetone/ice bath under an atmosphere of N2, was added a solution of potassium bis(trimethylsilyl)amide (0.5M solution in toluene; 71.34 ml; 35.67 mmol) over 30 minutes keeping the internal temperature below −10° C. The reaction mixture was allowed to warm to ambient temperature, then stirred an additional 2 hours. The reaction was poured into brine (150 ml) and extracted with EtOAc (3×100 ml). The combined organic phase was washed with brine (100 ml), dried (MgSO4), filtered and evaporated to give a brown oil. The crude product was chromatographed on silica gel eluted with 5% EtOAc in DCM to give the desired product as colourless oil (2.67 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:9]([CH3:24])([CH3:23])[CH2:8]2)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([CH:10]2[C:9]([CH3:24])([CH3:23])[CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)[NH:11]2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(OC)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 83.8 %

Procedure:
To a stirred mixture solution of 2-(3-methoxy-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.5, 4.6 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-(3-methoxy-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.2 g, 90%) as a white foam: LC/MS m/e calcd for C19H21NO3 (M+H)+: 312.38, observed: 312.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:11]3[CH:12]=[C:13]([CH2:16]O)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]1(=[O:54])[NH:48][C:47](=[O:49])[C:46]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:45]12.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:18]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[C:11]3[CH:12]=[C:13]([CH2:16][N:48]4[C:44](=[O:54])[C:45]5[C:46](=[CH:50][CH:51]=[CH:52][CH:53]=5)[C:47]4=[O:49])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
2-(4-Fluorophenyl)-5-hydroxymethyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine (Example 6. 68 mg, 0.213 mmol), triphenyl phosphine (168 mg, 0.64 mmol) and phthalimide (63 mg, 0.43 mmol) are dissolved in dry THF (3 mL). The stirred solution is cooled to 0° C. and diethyl azodicarboxylate (105 mg of 85% grade, 0.51 mmol) is added dropwise. The solution is stirred at 0° C. for 2 h during which time a white solid deposits and then stirred for 16 h at room temperature. The solution is then diluted with ether (20 mL) and the deposited solid filtered off. The solid is washed with ether and dried to give the first batch of product (20 mg). The ether solution is then washed with water and then extracted with dilute hydrochloric acid. A portion of the product deposits and is filtered off, washed twice with ether and dried to give the product as the hydrochloride salt (16 mg). The acidic phase is washed with ether and then made alkaline with sodium bicarbonate solution. Extraction with ethyl acetate (50 mL×3) followed by drying (MgSO4) and concentration gives the product as an off-white solid (32 mg). 1H NMR (d6-DMSO) δ 4.83 (s, 2H), 6.91 (dd, J=1.8, 7.2 Hz, 1H), 7.22 (t, J=8.9 Hz, 2H), 7.26 (d, J=5.9 Hz, 2H), 7.49 (dd, J=5.6, 8.6 Hz, 2H), 7.71 (s, 1H), 7.81–7.89 (m, 4H), 8.54 (d, J=4.7 Hz, 2H), 8.72 (d, J=7.1 Hz, 1H); APESI-MS m/z 449 (M+1)+
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:7]2[N:18]=[CH:19][C:20]([C:21]#[N:22])=[C:6]12)=[O:4].[CH2:23]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1(C)C=CC=CC=1.C(O)C.CCOCC>[ClH:1].[CH3:17][C:13]1[CH:12]=[C:11]([C:8]2[N:7]3[N:18]=[CH:19][C:20]([C:21]#[N:22])=[C:6]3[N:5]([C:3](=[O:4])[CH2:2][N:33]3[CH2:34][CH2:35][N:30]([CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:31][CH2:32]3)[CH2:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cc1cccc(C2=CCN(C(=O)CCl)c3c(C#N)cnn32)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cccc(C2=CCN(C(=O)CN3CCN(Cc4ccccc4)CC3)c3c(C#N)cnn32)c1

Procedure:
A mixture of 3.3 g of 4-(chloroacetyl)-4,5-dihydro-7-(3-methylphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile, 1.9 ml of 1-benzylpiperazine and 1.3 g of sodium carbonate in 130 ml of toluene was reacted as described in Example 146, giving 2.7 g of the neutral base form of the product. A 1.0 g portion of this base was warmed to solution in 20 ml of ethanol and then treated with 3 ml of 2.44N ethanolic hydrochloric acid and an excess of ether, giving 900 mg of the desired product, mp 205°-207° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH3:30][O:31][CH2:32][CH2:33]O.C([C@@H](O)C1C=CC=C(OC2C=CC=CC=2)C=1)#N>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:9])[O:8][CH2:33][CH2:32][O:31][CH3:30])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: COCCO
Agent: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: COCCOC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Step F of Example 9, the ester of Step A of Example 31 after reaction with 2-methoxyethanol and (S)α-cyano-3-phenoxy-benzyl alcohol was reacted to obtain (S)α-cyano-3-phenoxy-benzyl (IR,cis) 2,2-dimethyl -3-[(Z) 3-oxo-3-(2-methoxyethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+37.5°±2° (c=1% in CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[N:8][C:9](Br)=[CH:10][CH:11]=1.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:13])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[N:8][C:9]([C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:20][C:19]=2[F:21])=[CH:10][CH:11]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COC(=O)/C=C/c1ccc(Br)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)/C=C/c1ccc(-c2ccc(F)cc2F)nc1

Procedure:
1.0 g (4.13 mmol) of (E)-3-(6-bromopyridin-3-yl)acrylic acid methyl ester, 782.8 mg (4.95 mmol) of 2,4-difluorophenylboronic acid, 108.4 mg (0.413 mmol) of triphenylphosphane, 46.38 mg (0.2 mmol) of palladium(II)acetate and 1.75 g (5.37 mmol) of cesium carbonate were stirred in 40 ml of dioxane and 15 ml water under argon at 100° C. for 6 h. The mixture was filtered, evaporated and the residue dissolved in methanol. By treatment with thionyl chloride the partially saponified methyl ester was re-esterified. After evaporation, the crude product was purified by chromatography (RP18, acetonitrile/water containing 0.1% TFA). Yield: 434 mg (25%).
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:17][C:18]1([CH3:32])[C:23](=O)[CH2:22][CH2:21][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19]1.C(OCC)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:17][C:18]1([CH3:32])[CH2:19][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:22]/[C:23]/1=[N:9]\[C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Reactant: C[C@@H](N)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](/N=C1\CCN(C(=O)OC(C)(C)C)CC1(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of (R)-1-phenylethanamine (2.56 g, 21.12 mmol) and triethylamine (14.7 mL, 106 mmol) in dichloromethane (40 mL) was cooled in an ice bath and titanium tetrachloride (8.80 mL, 8.80 mmol) was added dropwise giving a light brown mixture. The cold bath was removed and tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (4.00 g, 17.60 mmol) was added as solid in one portion and the resulting mixture was allowed to stir at rt overnight. To the resulting mixture was added 75 mL of diethyl ether and the mixture was stirred at rt for 15 min then filtered through a pad of CELITE® to remove the solids and the filter cake was rinsed with additional ether (30 mL×2). The resulting clear yellow filtrate was concentrated on a rotovap to afford a yellow liquid as the title compound (5.80 g, 17.6 mmol, quantitative). This material was used directly without any further purification.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:10]=[C:9]([F:11])[C:7]([NH2:8])=[C:6]([F:12])[CH:5]=1.[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[N:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([NH:8][C:7]3[C:9]([F:11])=[CH:10][C:4]([Br:3])=[CH:5][C:6]=3[F:12])=[N:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(F)cc(Br)cc3F)ncnc2cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
Sodium hydride (60%, 612 mg, 15.3 mmol) was added to a solution of 4-bromo-2,6-difluoroaniline (2.77 g, 6.65 mmol) in DMF (80 ml). After stiffing for 30 minutes at ambient temperature, 7-benzyloxy-4-chloro-6-methoxyquinazoline (2 g, 6.65 mmol), (prepared, for example, as described in WO 97/22596, Example 1, but the free base was generated prior to use), was added and stirring was maintained for 4 hours. The mixture was partitioned between ethyl acetate and water (200 ml). The organic layer was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with isopropanol, collected by filtration, washed with ether and dried under vacuum to give 7-benzyloxy-4-(4-bromo-2,6-difluoroanilino)-6-methoxyquinazoline (1.95 g, 62%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[N:12]([C:15]1[N:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:18]=[C:17]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:16]=1)=[C:13]=[O:14].CCOC(C)=O>C(Cl)Cl>[F:26][C:23]([F:24])([F:25])[CH2:22][O:21][C:19]1[CH:18]=[C:17]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:16]=[C:15]([NH:12][C:13](=[O:14])[N:2]([CH3:1])[C:3]2[S:4][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:6][CH:7]=2)[N:20]=1
Reactant: O=C=Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Reactant: CNc1ccc(C(F)(F)F)s1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C(=O)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)c1ccc(C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-methyl-5-(trifluoromethyl)thiophen-2-amine in CH2Cl2 (2 mL) was added 2-isocyanato-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine (1.6 mL, 1.0 M in THF) (prepared as described in U.S. Pat. No. 8,013,154, the contents of which were incorporated herein above by reference in their entirety). This reaction was stirred at ambient temperature overnight. TLC indicated the reaction was complete. The solvent was removed under reduced pressure and the residue was purified using normal phase chromatography which afforded product (471 mg, 56% over three steps) as an off-white solid, mp 99-101° C.: Rf=0.26 (30% EtOAc, hex); 1H NMR (DMSO-d6) 10.34 (s, 1H), 7.48 (d, 1H, J=3.3 Hz), 6.78 (d, 1H, J=4.3 Hz), 6.28 (s, 1H), 5.02 (q, 4H, J=17.8, 8.9 Hz), 3.49 (s, 3H); ESIMS m/z 497 [(M-1)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[C:13]([CH3:22])=[N:14][C:15]4[C:20]([N:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:11]=[C:4]2[N:3]=1.[CH3:23][NH:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:24]([CH3:23])[CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:5]2[N:9]=[C:10]([C:12]3[C:13]([CH3:22])=[N:14][C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:21]=3)[CH:11]=[C:6]2[CH:7]=1
Reactant: CNC1CCOCC1
Reactant: Cc1nc2ccccc2nc1-c1cc2nc(Cl)cc(Cl)n2n1
Product: Cc1nc2ccccc2nc1-c1cc2cc(Cl)nc(N(C)C3CCOCC3)n2n1

Procedure:
The preparation was performed in a similar manner as Example 1.001 (g) from 3-(5,7-dichloropyrazolo[1,5-a]pyrimidin-2-yl)-2-methylquinoxaline (200 mg, 0.606 mmol) and N-methyl-4-aminotetrahydropyran (84 mg, 0.729 mmol) to give 5-chloro-N-methyl-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]pyrimidin-7-amine. MS (APCI): m/z 409/411 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9](CCCCCCCCCCCCCCC)[C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:30]=1.C(N(CC)CC)C>ClCCl>[C:33]([C:32]1[CH:35]=[CH:36][C:29]([NH:28][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][CH2:1][CH3:2])=[CH:30][C:31]=1[C:37]([F:38])([F:39])[F:40])#[N:34]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccccc1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-ethoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-ethoxy-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: Br.[NH2:2][C:3]1[N:12]=[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][N:5]2[N:4]=1.[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1>CN(C)C(=O)C.O>[OH:11][C:9]1[CH:8]=[CH:7][C:6]2[N:5]([N:4]=[C:3]([NH:2][C:16]([CH:13]3[CH2:15][CH2:14]3)=[O:17])[N:12]=2)[CH:10]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2ccc(O)cn2n1
Agent: Br
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1nc2ccc(O)cn2n1)C1CC1
Yield: 172.7 %

Procedure:
To a solution of 2-amino[1,2,4]triazolo[1,5-a]pyridin-6-ol hydrobromide (1.50 g, 4.22 mmol) in N,N-dimethylacetamide (5 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (1.15 mL, 12.7 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (1.59 g, 89%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH:4]([OH:22])[CH:5]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:3].[H-].[Na+].[CH3:26]I.O>CN(C=O)C>[CH3:3][C:2]([CH3:23])([CH:4]([O:22][CH3:26])[CH:5]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:1]
Reactant: CI
Reactant: CC(C)(C)C(O)C(CCCCOc1ccccc1)n1cncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C(CCCCOc1ccccc1)n1cncn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 15.4 g of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-8-phenoxy-octan-3-ol in 50 ml of DMF is added dropwise to a suspension of 1.6 g of sodium hydride in 50 ml of DMF. The mixture is then stirred for 2 hours under reflux. When it has cooled to room temperature, 3.7 ml of methyl iodide are added. This mixture is stirred for five hours under reflux, 200 ml of water are then added, the reaction mixture is extracted three times with 100 ml of diethyl ether at a time and the combined extracts are washed three times with 50 ml of water at a time, dried over magnesium sulfate and concentrated under reduced pressure. The residue consists of 2.2 g of a yellowish resin. Infrared spectrum (film): 2,930, 2,862, 1,588, 1,576, 1,486, 1,460 1,264, 1,233, 1,126, 1,080, 1,005, 745, 682 and 670 cm-1.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23]([OH:25])[CH3:24]>>[CH2:23]([O:25][C:2]([C:4]1([OH:3])[CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]1)([CH3:11])[CH3:1])[CH3:24]
Reactant: CCO
Reactant: CC1=CCC2(CC1)OC2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(C)(C)C1(O)CC=C(C)CC1

Procedure:
By procedures similar to those described in Embodiments 57 and 58, 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene was treated with ethanol in the presence of p-toluenesulfonic acid to obtain 1-(1-ethoxy-1-methylethyl)-4-methyl-3-cyclohexen-1-ol. This alcohol was treated with vanadium(IV) bis(2,4-pentanedionate) oxide and tert-butyl hydroperoxide followed by p-toluenesulfonic acid to obtain (±)-2-exo-hydroxy-4-(1-ethoxy-1-methylethyl)-1 methyl-7-oxabicyclo[2.2.1]heptane. This intermediate was treated with benzyl chloride to yield the desired product, b.p. 120°-125° C. (0.2 mm).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.O.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C1=COCCC1
Reactant: COC(=O)c1ccc(O)c(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC2CCCCO2)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirred solution of 66.6E (38 g, 164 mmol) and 3,4-dihydro-2H-pyran (45 mL, 493 mmol) in DCM (355 mL,) was added 4-methylbenzenesulfonic acid hydrate (0.63 g, 3.30 mmol). The mixture was stirred at room temperature and monitored by TLC. After 2 hours, the solution was washed with a mixed aqueous solution of saturated aqueous sodium bicarbonate/brine/water (1:1:2). The aqueous layer was extracted three times with ether. After drying over anhydrous sodium sulfate and then filtering, the organic solvent was removed under reduced pressure. The crude material was purified on silica gel (0-10% EtOAc in hexanes) to yield a white solid. The product was recrystallized from MeOH to provide 66.6F (yield 90%). 1H NMR (400 MHz, CDCl3) δ ppm 8.24 (1H, d, J=2.0 Hz), 7.93 (1H, dd, J=8.6, 2.0 Hz), 7.17 (1H, d, J=8.6 Hz), 5.62 (1H, t, J=2.5 Hz), 3.90 (3H, s), 3.83 (1H, td, J=11.1, 2.9 Hz), 3.66 (1H, m), 2.18 (1H, m), 2.04 (1H, m), 1.94 (1H, m), 1.79 (2H, m), 1.67 (1H, m).)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][C:2]1[N:3]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCCc1nc(C)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), phenylboronic acid (1.00 g), triethylamine (1.95 mL), pyridine (1.13 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.02 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.83 g, 68%).