Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)([CH2:8][C:9]([Cl:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[Na+].[H][H]>C(O)C.[Pt]>[Cl:12][C:9]([F:10])([F:11])[CH2:8][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [H][H]
Reactant: CCOC(=O)C(Cl)(Cl)CC(F)(F)Cl
Agent: [Pt]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCC(F)(F)Cl
Yield: 75.2 %

Procedure:
25.5 g of ethyl 2,2,4-trichloro-4,4-difluorobutyrate are dissolved in 200 ml of absolute ethanol. 16.4 g of anhydrous sodium acetate and 2.0 g of 5% platinum/carbon catalyst are added and then gaseous hydrogen is passed in under atmospheric pressure until the hydrogen uptake is 2 equivalents. The catalyst is removed by filtration and the ethanol is removed by distillation and then the remaining oil is poured onto water, and the organic phase is separated off, dried with sodium sulfate, filtered and distilled under atmospheric pressure. 14.0 g of ethyl 4-chloro-4,4-difluorobutyrate are obtained in the form of a colourless oil of boiling point 154°-156° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.CC(C)([O-])C.[Na+]>>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][N:12]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:11]2)[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CC3CNCC3C2)cc1
Reactant: Fc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Fc1ccc(N2CC3CN(Cc4ccccc4)CC3C2)cc1
Yield: 71 %

Procedure:
2-Benzyloctahydropyrrolo[3,4-c]pyrrole (50.0 mg, 0.247 mmol), 1-bromo-4-fluorobenzene (33.0 μL, 0.303 mmol), and sodium tert-butoxide (144 mg, 1.50 mmol) were used to obtain the title compound (52.0 mg, yield 70%) by synthesis in a similar manner to Reference Synthesis Example 23.
Reaction SMILES: [CH2:1]([C:3]([C:8]1[C:9]([CH3:14])=[N:10][CH:11]=[CH:12][CH:13]=1)([O:6][CH3:7])[CH2:4][CH3:5])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:16].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[CH2:1]([C:3]([C:8]1[C:9]([CH2:14][OH:16])=[N:10][CH:11]=[CH:12][CH:13]=1)([O:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(OC)c1cccnc1C
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCC(CC)(OC)c1cccnc1CO
Reaction time: 24 h
Yield: 60 %

Procedure:
To a solution of 3-(1-ethyl-1-methoxy-propyl)-2-methyl-pyridine (0.185 g, 0.884 mmol) in CH2Cl2 (3 mL) was added TFAA (1 mL). The mixture was stirred for 24 h. K2CO3 (0.60 g, 4.3 mmol) in water (10 mL) was added. The aqueous mixture was extracted with CH2Cl2 (4×25 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (3:1 Et2O/CH2Cl2), affording [3-(1-ethyl-1-methoxy-propyl)-pyridin-2-yl]-methanol as a yellow oil (0.111 g, 60%). 1H NMR (CDCl3) δ 0.70 (t, 6H, J=7.5 Hz), 1.76-1.88 (m, 2H), 1.89-2.01 (m, 2H), 3.06 (s, 3H), 4.93 (s, 2H), 7.21 (dd, 1H, J=7.8, 4.8 Hz), 7.56 (dd, 1H, J=7.8, 1.5 Hz), 8.47 (dd, 1H, J=4.8, 1.5 Hz).
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.O1CCCC1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:36]([CH:37]([OH:49])[C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)=[C:35]([CH:50]([CH3:52])[CH3:51])[CH:34]=[C:33]3[C:25]=2[C:26](=[O:53])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:20][CH:19]=1>CO>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:36]([C@H:37]([OH:49])[C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:47])([F:48])[F:46])=[CH:40][CH:39]=3)=[C:35]([CH:50]([CH3:51])[CH3:52])[CH:34]=[C:33]3[C:25]=2[C@@H:26]([OH:53])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:22][CH:23]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(OC(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@H](O)c1ccc(OC(F)(F)F)cc1)[C@@H](O)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 1.5 mg (0.01 mmol) of (1R,2S)-1-aminoindan-2-ol are dissolved in 1.5 ml of abs. tetrahydrofuran, 69 μl (0.39 mmol) of borane/N,N-diethylaniline complex are added and the mixture is stirred at room temperature for 30 min. After this time, 50 mg (0.10 mmol) of 5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethoxy)phenyl]methyl}-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 58A), dissolved in 2 ml of abs. tetrahydrofuran, are added at room temperature over a period of 10 min, and the mixture is then stirred at room temperature overnight. 2 ml of methanol are added, and the mixture is stirred for 15 min and then concentrated to dryness. The residue is taken up in ethyl acetate and washed twice with 1 N hydrochloric acid, twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The crude product is purified by preparative thick-layer chromatography (mobile phase: cyclohexane/ethyl acetate 5:1). This gives 13.5 mg (27% of theory, 78% ee) of Example 38 and 16.5 mg (33% of theory) of Example 39.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH3:24])=[C:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]#[N:35]>CC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:33][C:34]#[N:35])=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[C:10]([CH3:24])=[C:9]1[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: Cc1c(C)n(Cc2ccccc2)c2ccc(-c3ccc(O)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(C)n(Cc2ccccc2)c2ccc(-c3ccc(OCC#N)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(1-benzyl-2,3-dimethyl-1H-indol-5-yl)-phenol (0.300 g, 0.916 mmol) was reacted with K2CO3 (0.152 g, 1.099 mmol) and bromoacetonitrile (0.132 g, 1.099 mmol) in acetone (10 ml) to give the product (0.207 g, 0.565 mmol, 62%) as a pale-blue solid, mp 167-169° C. 1H NMR (DMSO-d6) δ 2.25 (s, 3H), 2.28 (s, 3H), 5.19 (s, 2H), 5.39 (s, 2H), 6.98 (d, J=7.5 Hz, 2H), 7.12 (d, J=8.6 Hz, 2H), 7.21 (t, J=7.2 Hz, 1H), 7.26-7.30 (m, 3H), 7.39 (d, J=8.4 Hz, 1H), 7.65-7.67 (m, 3H); [ESI(+)], m/z 367 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:28][C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)[CH2:12][C:11](=[O:29])[C:10]=2[CH:30]=1)(=[O:4])=[O:3].N1C=CC=CC=1.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:28][C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([NH:27][C:37](=[O:39])[CH3:38])=[CH:25][CH:26]=4)[CH2:15][CH2:14]3)[CH2:12][C:11](=[O:29])[C:10]=2[CH:30]=1)(=[O:3])=[O:4]
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(N)cc3)CC1)O2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CCN2CCC3(CC2)CC(=O)c2cc(NS(C)(=O)=O)ccc2O3)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
A suspension of 6-methanesulfonamido-3,4-dihydro-1'-(2-(4-aminophenyl)ethyl)-spiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one (0.50 g, 1.2 mmol), and pyridine (0.09 mL, 1.2 mmol) in 25 mL of methylene chloride was cooled in an ice bath and treated dropwise with acetyl chloride (0.09 mL, 1.2 mmol). The mixture was stirred at 0° C. for 2 hours, and then filtered. The tan solid was washed with methylene chloride and dried in the air. The solid was found to be a mixture by thin layer analysis, and was chromatographed on silica gel using 10% methanol in methylene chloride eluant. The pure oil was dissolved in 20 mL of absolute ethanol and was treated with excess 4.8N ethanolic HCl. The solution was then concentrated to 10 mL. The resulting ivory colored solid was collected, washed with diethyl ether, and dried 3 hours at 100° C. under vacuum to give 0.10 g (18%) of product, mp 294° C. (dec).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:6]=12.C(N(CC)CC)C.[CH:32]1([C:35]#[CH:36])[CH2:34][CH2:33]1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[CH:32]1([C:35]#[C:36][C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[C:9]([C:11]4[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=4)[CH:8]=[C:7]([O:17][CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[C:6]=23)[CH2:34][CH2:33]1
Reactant: C#CC1CC1
Reactant: Cn1cc(-c2cc(OCc3cccnc3)c3c(I)cnn3c2)cn1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cc(OCc3cccnc3)c3c(C#CC4CC4)cnn3c2)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-iodo-6-(1-methyl-1H-pyrazol-4-yl)-4-(pyridin-3-ylmethoxy)pyrazolo[1,5-a]pyridine from Step 2 (11.0 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium (0) (3.0 mg, 2.6 μmol), and CuI (2.9 mg, 0.02 mmol) were suspended in DMF (1 ml). Triethylamine (11 μl, 0.08 mmol) and cyclopropyl acetylene (5.1 mg, 0.08 mmol) were added and the mixture was sparged with argon for 10 minutes. After stirring at ambient temperature for 1.5 h, the reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated to afford 3-(cyclopropylethynyl)-6-(1-methyl-1H-pyrazol-4-yl)-4-(pyridin-3-ylmethoxy)pyrazolo[1,5-a]pyridine. 1H NMR (500 MHz, DMSO-d6) δ 8.79 (s, 1H); 8.65 (s, 1H); 8.57-8.60 (m, 1H); 8.30 (s, 1H); 8.00-8.05 (m, 2H); 7.98 (s, 1H); 7.49 (dd, 1H); 7.12 (s, 1H); 5.37 (s, 2H); 3.87 (s, 3H), 1.39-1.45 (m, 1H); 0.71-0.76 (m, 2H); 0.42-0.46 (m, 2H). LRMS (ESI) calculated for C22H20N5O [M+H]+, 370.2; found 370.0.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[S:7]1[CH2:10][CH:9]([OH:11])[CH2:8]1.CN(C)C1C=CC=CC=1.S(=O)(=O)(O)O>>[C:1]([O:11][CH:9]1[CH2:10][S:7][CH2:8]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: OC1CSC1
Agent: O=S(=O)(O)O
Solvent: CN(C)c1ccccc1
Product: C=C(C)C(=O)OC1CSC1
Temperature: 0 °C
Reaction time: 192 h
Yield: 26.9 %

Procedure:
22.99 g of methacryloyl chloride (0.22 mole) are slowly poured (20 mins), with stirring, into a solution of 18 g of 3-thietanol (0.2 mole) in dimethylaniline (80 g, i.e. 0.66 mole). Stirring is then continued at ambient temperature for 8 days. After this time, the reaction mixture is poured on to the following mixture: 270 g of ice-27 cm3 (47.5 g) of concentrated sulphuric acid. The solution is stirred for 2 hours, then theorganic phase is extracted with ether. It is then washed with demineralisedwater until neutral and dried over sodium sulphate. The ether is eliminatedand then the remaining product is distilled in the presence of hydroquinone. The distillation temperature is 44° C. under a pressure of 0.1 mm of Hg. 8.5 g of 3-thietanyl methacrylate are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[NH:10][CH:11]([CH3:40])[CH:12]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24])[C:13]12[O:20][CH2:19][C:16]([CH3:21])([CH2:17][O:18]1)[CH2:15][O:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:49][C:50]([O:52][CH3:53])=[O:51]>CN(C)C=O.C(OCC)(=O)C>[CH3:53][O:52][C:50](=[O:51])[CH2:49][N:22]([S:23]([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:30][CH:31]=1)(=[O:25])=[O:24])[CH:12]([C:13]12[O:20][CH2:19][C:16]([CH3:21])([CH2:17][O:18]1)[CH2:15][O:14]2)[CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:41])[CH3:40]
Reactant: CC(NC(=O)OCc1ccccc1)C(NS(=O)(=O)c1ccc(OCc2ccccc2)cc1)C12OCC(C)(CO1)CO2
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN(C(C(C)NC(=O)OCc1ccccc1)C12OCC(C)(CO1)CO2)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A solution of [2-(4-benzyloxy-benzenesulfonylamino)-1-methyl-2-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-ethyl]-carbamic acid benzyl ester (compound of formula LII, 1.2 g, 2.0 mmol) in 2 ml of dimethylformamide was treated with cesium carbonate (1.12 g, 3.4 mmol) and methyl bromoacetate (0.2 ml, 0.32 g, 2.1 mmol). After stirring for about 2 hours, the mixture was diluted with ethyl acetate, washed 5 times with water, and the organic phase was dried over sodium sulfate, filtered and concentrated, affording 1.3 g of {(4-benzyloxy-benzenesulfonyl)-[2-benzyloxycarbonylamino-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-propyl]-amino}-acetic acid methyl ester (compound of formula LIII) as a colorless syrup.
Reaction SMILES: CN1CCN(C([O:10][CH:11]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][N:26]=3)[C:18](=[O:19])[C:13]3[N:14]=[CH:15][CH:16]=[N:17][C:12]2=3)=O)CC1.NC1C=CC(Cl)=CN=1.N1C=CN=C2C(OC(=O)C=12)=[O:43]>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:18]([C:13]2[C:12]([C:11]([OH:43])=[O:10])=[N:17][CH:16]=[CH:15][N:14]=2)=[O:19])=[N:26][CH:25]=1
Reactant: O=C1OC(=O)c2nccnc21
Reactant: CN1CCN(C(=O)OC2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1
Agent: Nc1ccc(Cl)cn1
Product: O=C(O)c1nccnc1C(=O)Nc1ccc(Cl)cn1

Procedure:
U.S. Pat. No. 3,862,149 describes a process for preparing zopiclone. The process comprises reacting 2-amino-5-chloropyridine with pyrazine 2,3-dicarboxylic acid anhydride to obtain 3-(5-chloropyrid-2-yl)carbamoyl-pyrazine-2-carboxylic acid, which is further treated with thionyl chloride to obtain 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydro-5H-pyrrolo[3,4-b]pyrazine 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydro-5H-pyrrolo[3,4-b]pyrazine is reduced using potassium borohydride in a mixture of dioxane and water followed by neutralization with acetic acid to obtain 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydro-5H-pyrrolo[3,4-b]-pyra-zine. The reaction of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydro-5H-pyrrolo[3,4-b]pyra-zine with 1-chlorocarbonyl-4-methyl piperazine in anhydrous dimethyl formamide and sodium hydride (50% dispersion in mineral oil) yields the final product, Zopiclone.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:13]=[C:14]([N+:18]([O-])=[O:19])[CH:15]=[CH:16][CH:17]=1.O.NN>O1CCCC1.[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:13]=[C:14]([NH:18][OH:19])[CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccc(OCc2nc3ccccc3s2)c1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: ONc1cccc(OCc2nc3ccccc3s2)c1
Yield: 85.4 %

Procedure:
To a solution of 3-[(2-benzthiazolyl)methoxy]nitrobenzene (1.6 g), prepared as in Example 1B, in tetrahydrofuran with 10% palladium on carbon is slowly added hydrazine hydrate (0.4 ml). Fresh catalyst is added twice over 4 hours. The mixture is filtered through celite and the solvent is removed in vacuo to give 1.3 g (81% yield) of product, m.p. 112°-114° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:13]=[N:12][NH:11][C:10]=2[NH2:14])[CH:4]=1.[CH3:15][O-].[Na+].IC>>[CH3:15][N:12]1[CH:13]=[C:9]([C:5]2[CH:4]=[C:3]([S:2][CH3:1])[N:8]=[CH:7][N:6]=2)[C:10]([NH2:14])=[N:11]1
Reactant: CSc1cc(-c2cn[nH]c2N)ncn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Product: CSc1cc(-c2cn(C)nc2N)ncn1
Reaction time: 0.5 h

Procedure:
To the solution of 4-(6-Methylsulfanyl-pyrimidin-4-yl)-2H-pyrazol-3-ylamine (245 mg, 1.18 mmol) is added with NaOMe solution (25 wt % in MeOH, 425 μL, 1.53 mmol) dropwise. The reaction mixture is kept stirring for 30 minutes. Then Iodomethane (110 uL, 1.76 mmol) is added into the reaction mixture drop wise. After stirring overnight at room temperature, the reaction mixture is concentrated, treated with 75 mL ethyl acetate, and washed with water. Filtration removes the undissolved solid. The obtained filtrate is separated, and the collected organic layer is dried over sodium sulfate, and concentrated. The crude product is purified by ISCO chromatography eluting with ethyl acetate in hexanes from 25% to 100% to afford 1-Methyl-4-(6-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazol-3-ylamine: 1H NMR 400 MHz (d6-DMSO) δ 8.73 (s, 1H), 8.27 (s, 1H), 7.44 (s, 1H), 5.81 (s, 1H), 3.65 (s, 3H), 2.53 (s, 3H); MS m/z 222.07 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][CH2:23][OH:24].CN(C=O)C>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:22][CH2:23][OH:24])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To a flask charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.000 g, 5.154 mmol), Cs2CO3 (2.687 g, 8.246 mmol), and 2-bromoethanol (0.5479 mL, 7.730 mmol) was added 10 mL of DMF and the flask was sealed under nitrogen and heated to 100° C. for 48 hours. The reaction was diluted with ethyl acetate (100 mL) and stirred for 30 minutes before it was passed through a glass microfiber filter and the cake was washed with ethyl acetate. The organic was concentrated under reduced pressure. The crude was then purified by silica gel chromatography eluting with a gradient of 75-100% ethyl acetate in Hexanes to afford 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol (0.4290 g, 1.622 mmol, 31.47% yield). MS (apci) m/z=239.2 (M+H).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=[O:26])[C:5]1=[O:29])[CH:2]=[CH2:3].[CH2:31]([Mg]Br)[CH:32]([CH3:34])[CH3:33]>C1COCC1>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH:25]([OH:26])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:27][CH3:28])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CC(C)C[Mg]Br
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)CC(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (1.755 mmol) (Example 91, Step C) in THF (5 mL) at 0° C. was added 2 M isobutylmagnesium bromide (878 μL, 1.742 mmol) under N2. The reaction was allowed to warm to rt. After being stirred for 2 h at rt, the reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed (sat. aq. NaCl solution), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by the flash chromatography on silica gel (eluent: 15 to 35% EtOAc/Hexane, gradient elution) to provide the title compound as a mixture of two diastereomers.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Li])CCC.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1.CCCCCC>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([OH:30])([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Brc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A solution of 2-bromoquinoline (2.0 g, 9.61 mmol) in tetrahydrofuran (10 mL) was added dropwise to a mixture of n-butyllithium in hexane (4.2 mL of a 2.5 M solution) and tetrahydrofuran (10 mL) at −65° C. under N2, and the mixture was stirred at this temperature for 1 hour. A solution of t-butyl-4-oxo-1-piperidine carboxylate (1.92 g, 9.61 mmol) in tetrahydrofuran (10 niL) was added dropwise over 3 minutes., after the addition, the reaction was slowly warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with sat. ammonium chloride (15 mL); the resulting mixture was stirred at ambient temperature for 10 minutes. The organic layer was separated, washed with water (20 mL), brine (20 mL), dried over magnesium sulfate. Concentration yielded 4-hydroxy-4-quinolin-2-yl-piperidine-1-carboxylic acid tert-butyl ester (3.16 g, 98%) as a yellow oil which was used without further purification. 1H NMR CDCl3 δ 8.20 (d, J=9 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.73 (t, J=8 Hz, 1H), 7.55 (t, J=7 Hz, 1H), 7.42 (d, J=9 Hz, 1H), 5.94 (brd s, 1H), 4.23-4.00 (m, 2H), 3.70 (t, J=6 Hz, 1H), 3.40-3.22 (m, 2H), 2.42 (t, J=6 Hz, 1H), 2.13-1.98(m, 2H), 1.49 (s, 9H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[NH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.O>S(=O)(=O)(O)O>[N+:1]([C:13]1[C:8]2[N:7]=[N:6][NH:5][C:9]=2[CH:10]=[CH:11][CH:12]=1)([O-:4])=[O:2]
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cccc2[nH]nnc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a cooled solution (20° C.) of 1,060 milliliters of 20% fuming sulfuric acid and 265 milliliters of 90% nitric acid is added in a dropwise fashion a solution of 537 grams of benzotriazole in 1000 milliliters of concentrated sulfuric acid. The temperature is not allowed to exceed 50° C. At the end of the addition, the reaction mixture is allowed to stand at room temperature overnight. The reaction mixture is then poured over 9 liters of ice and water and a heavy yellow precipitate forms. The solid is collected by filtration, washed with water and dried. The solid, which is a mixture of the 4-nitro (90%) and the 5-nitro (10%) isomers, is then slurried with 7.5 liters of refluxing acetonitrile, the mixture cooled and 537 grams (73%) of pure 4-nitrobenzotriazole is collected by filtration, m.p. 228°-231° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Cl:28])=[N:14][CH:15]=[N:16]2)=[C:11]([OH:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1(O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Cl:28])=[N:14][CH:15]=[N:16]2)=[C:11]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OCc4ccccc4)cc(O)c23)c1
Reactant: OC1CCCCC1
Product: COc1ccc(Cl)c(Nc2ncnc3cc(OCc4ccccc4)cc(OC4CCCCC4)c23)c1

Procedure:
Using an analogous procedure to that described in Example 1, 7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-hydroxyquinazoline (0.53 g) was reacted with cyclohexanol to give 7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-cyclohexyloxyquinazoline (0.25 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.3–1.4 (m, 1H), 1.4–1.55 (m, 2H), 1.55–1.65 (m, 1H), 1.7–1.85 (m, 4H), 2.15 (m, 2H), 3.82 (s, 3H), 4.95 (m, 1H), 5.4 (s, 2H), 7.0 (d, 1H), 7.05 (m, 1H), 7.2 (s, 1H), 7.4–7.65 (m, 7H), 8.9 (s, 1H); Mass Spectrum: M+H+ 490 and 492.