Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Reactant: C1CCNC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCCC5)c34)cc2Cl)cn1
Yield: 17 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and pyrrolidine to give the title compound in 17% yield; NMR Spectrum: 1.66-1.68 (m, 4H), 2.45 (s, 3H), 2.51-2.56 (m, 4H), 2.90 (t, 2H), 4.44 (t, 2H), 7.20 (d, 1H), 7.27 (br s, 2H), 7.71 (d, 1H), 8.11 (s, 1H), 8.20 (s, 1H), 8.36 (s, 1H), 8.68 (br s, 1H; Mass Spectrum: 466 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[CH:31]=[CH:32][CH:33]=2)O1.C(=O)([O-])O.[Na+].C(O)(C)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C.O>[N+:17]([C:4]1[C:5]2[C:9]([CH:10]=[C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[CH:29]=3)[CH:3]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2)([O-:19])=[O:18]
Reactant: CC1(C)OB(c2cccc(OC3CCCCO3)c2)OC1(C)C
Reactant: O=[N+]([O-])c1cc(Br)cc2nn(C3CCCCO3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(-c2cccc(OC3CCCCO3)c2)cc2nn(C3CCCCO3)cc12
Temperature: 150 °C

Procedure:
6-Bromo-4-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (500 mg, 1.53 mmol), Pd(dppf)Cl2 (125 mg, 0.153 mmol), 2-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxy}tetrahydro-2H-pyran (700 mg, 2.3 mmol), saturated sodium hydrogen carbonate (aq) (2 ml) and isopropyl alcohol (8 ml) were added to each of 5 microwave vessels. All 5 reactions were heated at 150° C. for 10 mins in a Biotage Initiator microwave. Reaction mixtures 1, 4, 5 were combined and water (250 ml) and ethyl acetate (250 ml) were added. The separated organic layer was washed with water followed by brine, then dried over sodium sulphate. The solvent was removed in vacuo and the residue was purified using silica gel chromatography, eluting with 10-35% ethyl acetate in cyclohexane. Appropriate fractions were combined and the solvent was removed in vacuo. This process was then repeated on combined reaction mixtures 2 and 3. Finally, the residues were combined to give the title compound, 1.06 g.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.NN>CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc2ncccc2c1
Agent: NN
Solvent: CO
Solvent: O
Product: NCc1ccc2ncccc2c1
Yield: 45.5 %

Procedure:
To a solution of 2-(quinolin-6-ylmethyl)isoindoline-1,3-dione (20 g, 69.4 mmol) in MeOH (100 mL) was added hydrazine monohydrate (3.47 g, 69.4 mmol). The solution was heated at reflux for 3 h, then cooled to it and filtered through celite. The filtrate was concentrated in vacuo. EtOAc then was added to the residue and the resulting solution was filtered and concentrated in vacuo to afford 5 g (41%) of the title compound. LCMS (method B): [MH]+=159, tR=0.93 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21](O)=[O:22])[C:17]=3[O:19][CH3:20])[NH:12][N:11]=2)=[CH:4][CH:3]=1.Cl.[C:25]([O:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[C:25]([O:29][C:30](=[O:33])[CH:31]([C:21]([C:16]1[C:17]([O:19][CH3:20])=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2/[CH:9]=[CH:8]/[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:22])[NH2:32])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CN
Reactant: COc1c(C(=O)O)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(C(=O)C(N)C(=O)OC(C)(C)C)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic acid obtained by Example 234 and 258 mg of glycine ter-butyl ester hydrochloride were dissolved in 20 mL of N,N-dimethylformamide, and 0.871 mL of diisopropylethylamine and 235 mg of 1-hydroxybenzotriazole were added, and stirred at room temperature for 10 minutes. After cooling to 0° C., 491 mg of WSC hydrochloride was added, and stirred overnight at room temperature. After adding ice water to stop the reaction, the solution was extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, to afford 547 mg of the title compound as pale green crystals.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][NH:6][S:7]([C:10]1[CH:11]=[C:12]([C:20]([OH:22])=O)[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1)(=[O:9])=[O:8]>C(Cl)(Cl)Cl>[CH3:5][NH:6][S:7]([C:10]1[CH:11]=[C:12]([C:20]([Cl:3])=[O:22])[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1)(=[O:9])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2

Procedure:
176.5 g of thionyl chloride were introduced into a balloon flask provided with a condenser. Then, in portions, 135 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were added under heating at 40°-45° C. The mixture was heated under reflux and then treated with 250 cm3 chloroform. The precipitate was dried off and washed with chloroform.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:27])[O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:19]([CH2:20][CH2:21][CH3:22])[C:18]([CH2:23][CH2:24][O:25][CH3:26])=[N:17][C:12]=3[CH:13]=[N:14][C:15]=2[CH:16]=1)([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:51]>C(Cl)(Cl)Cl>[CH:1]([NH:4][C:5](=[O:27])[O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:19]([CH2:20][CH2:21][CH3:22])[C:18]([CH2:23][CH2:24][O:25][CH3:26])=[N:17][C:12]=3[C:13]([NH2:51])=[N:14][C:15]=2[CH:16]=1)([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CCCn1c(CCOC)nc2cnc3cc(OC(=O)NC(C)C)ccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCn1c(CCOC)nc2c(N)nc3cc(OC(=O)NC(C)C)ccc3c21
Reaction time: 1.5 h

Procedure:
2-(2-Methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl isopropylcarbamate (1.89 g, 5.10 mmol) was dissolved in chloroform (41 mL). 3-Chloroperoxybenzoic acid (60% pure, 1.60 g, 5.56 mmol) was added in one portion. After 30 minutes the golden solution was diluted with ammonium hydroxide (41 mL), and p-toluenesulfonyl chloride (0.927 g, 4.86 mmol) was added. The reaction was stirred for 1.5 hours. The layers were separated and the aqueous fraction was extracted with dichloromethane. The organic fractions were combined, washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solid residue was recrystallized from acetonitrile to provide 0.986 g of 4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl isopropylcarbamate as a granular, peach-colored solid, mp 144.0-146.0° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][S:18][C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)[C:11]=2[CH3:28])[CH2:4][O:3]1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:29])[O:3][CH2:4][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][S:18]([C:19]3[NH:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[O:38])[C:11]=2[CH3:28])[CH2:6][O:7]1
Reactant: Cc1cnc(CSc2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cnc(CS(=O)c2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Reaction time: 0.75 h
Yield: 61.9 %

Procedure:
To a toluene (20 ml)-methanol (2 ml) solution of the 2-(((4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole (424 mg, 1.03 mmol) obtained in the step (11g), a toluene (1 ml)-methanol (1 ml) solution of 3-chloroperbenzoic acid (246 mg, 0.927 mmol as the content was regarded as 65%) was added dropwise at −65° C. for 5 minutes in a nitrogen atmosphere. The mixture was stirred for 45 minutes in the same conditions. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 20 g, elution solvent: dichloromethane, dichloromethane/methanol=10/1). The fractions containing the title compound were collected with ethyl acetate and concentrated. To the residue, diethyl ether was added. The resulting precipitate was collected by filtration and washed with diethyl ether to obtain the title compound (274 mg, yield: 61.9%) as a white solid.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:19][CH3:20])[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[S:12][N:11]=1)#[N:2].I([O-])(=O)(=O)=[O:22].[Na+].CO>O>[C:1]([N:3]=[C:4]([NH:19][CH3:20])[NH:5][CH2:6][CH2:7][S:8]([CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[S:12][N:11]=1)=[O:22])#[N:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CNC(=NC#N)NCCSCc1nsc(NC(=N)N)n1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNC(=NC#N)NCCS(=O)Cc1nsc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-[2-(2-cyano-3-methylguanidino)-ethylthiomethyl]-5-guanidino-1,2,4-thiadiazole (0.626 g.), sodium metaperiodate (0.428 g.), methanol (20 ml.) and water (70 ml.) was stirred overnight at room temperature. The reaction mixture was evaporated to dryness and the residue extracted with absolute ethanol (120 ml.). The extract was filtered and evaporated to dryness. The residue was crystallised from methanol (with charcoal treatment) to give 3-[2-(2-cyano-3-methylguanidino)-ethylsulphinylmethyl]-5-guanidino-1,2,4-thiadiazole as a white powder, m.p. 185°-186°.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH3:12])=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C([S-])C.[Na+].[CH2:26]([N:28](CC)CC)[CH3:27].CN(C)C=O>O>[CH2:26]([NH:28][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH3:12])=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:27]
Reactant: COc1ccc(C2=C(Br)c3ccc(OC)cc3C2=O)cc1
Reactant: CCN(CC)CC
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC1=C(c2ccc(OC)cc2)C(=O)c2cc(OC)ccc21
Temperature: 80 °C
Yield: 89 %

Procedure:
A mixture of 3-Bromo-6-methoxy-2-(4-methoxyphenyl)-1H-inden-1-one (150 mg, 0.4345 mmol), sodium ethanethiolate (91.4 mg, 1.09 mmol), and triethyl amine (0.5 ml) in N,N, dimethyl formamide (3 mL) was heated at 80° C. for 24 h. The reaction was cooled to room temperature was poured into water and extracted with ethyl acetate. The organic extracts were washed with brine and were dried over MgSO4. Evaporation and flash chromatography (10% ethyl acetate/petroleum ether) gave (126 mg, 89% yield) of the product as a dark red solid: mp 88-90° C.; MS m/e 327 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[Br:9][C:10]1[CH:40]=[C:39](F)[C:13]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24]3[N:29]=[C:28]([NH:30][C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[C:27]([O:37][CH3:38])=[CH:26][N:25]=3)=[N:16]2)=[C:12]([F:42])[CH:11]=1.O>CN(C=O)C>[Br:9][C:10]1[CH:40]=[C:39]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[C:13]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24]3[N:29]=[C:28]([NH:30][C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[C:27]([O:37][CH3:38])=[CH:26][N:25]=3)=[N:16]2)=[C:12]([F:42])[CH:11]=1
Reactant: COc1cnc(-c2nn(Cc3c(F)cc(Br)cc3F)c3ccccc23)nc1Nc1ccncc1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc(-c2nn(Cc3c(F)cc(Br)cc3OCC(F)(F)F)c3ccccc23)nc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
38.2 mg of 2,2,2-trifluoroethanol (0.382 mmol, 2 eq.) were dissolved in 1.5 ml of dry DMF under nitrogen atmosphere. 16.8 mg of 60% sodium hydrid in paraffin oil (0.42 mmol, 2.2 eq.) were added. The suspension was stirred at room temperature for 15 minutes. 100 mg of 2-[1-(4-bromo-2,6-difluorobenzyl)-1H-indazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (2-12-1, 0.191 mmol, 1 eq.) were added. The reaction mixture was stirred at room temperature for 18 hours. Water was added dropwise. The suspension was filtered off. The precipitate was dried at 50° C. under vacuo. The precipitate was purified by preparative HPLC to yield 34 mg (0.05 mmol, 28%) of the analytically pure target compound.
Reaction SMILES: [CH:1](/[P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])=[CH:2]\[CH3:3].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:3]/[CH:2]=[CH:1]/[P:4](=[O:11])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10]
Reactant: C/C=C/P(=O)(OCC)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(/C=C/CBr)OCC
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a solution of diethyl trans-1-propenylphosphonate (32.04 g.) in carbon tetrachloride (320 ml.) were added N-bromosuccinimide (41.65 g.) and dibenzoylperoxide (2.8 g.). The reaction mixture was heated to reflux for 1.5 hours and stirred for 30 minutes under ice-cooling. Insoluble materials were removed off by filtration and the filtrate was concentrated under reduced pressure to give an oily residue (63.09 g.), which was subjected to a column chromatography on silicagel and eluted with chloroform. The eluates were evaporated to dryness under reduced pressure to give an oily diethyl 3-bromo-trans-1-propenylphosphonate (27.04 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:17]=1.BrN1C(=O)CCC1=O.C(N(CC)CC)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:17]=1
Reactant: Cc1nc2c(s1)CCc1cc(Cl)ccc1C2=O
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1nc2c(=O)c3ccc(Cl)cc3ccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the product from step (i) (6.05 g) in 1,2-dichloroethane (85 ml) with N-bromosuccinimide (4.1 g) was irradiated with a 500 Watt halogen lamp for 1 h. After cooling to room temperature, triethylamine (7 ml) was added with further stirring for 0.5 hours. The solvents were evaporated under reduced pressure and the residue triturated with acetone, filtered and then further washed with water and then dried under vacuum to leave the subtitle compound as a cream solid.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[C:4]([CH2:17][OH:18])[CH:3]=1.O[C:20]1C=CC(C)=CC=1C=O>>[CH:17]([C:4]1[CH:3]=[C:2]([CH3:20])[CH:16]=[CH:15][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9])=[O:18]
Reactant: Cc1ccc(O)c(C=O)c1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1CO
Product: Cc1ccc(OCC(=O)O)c(C=O)c1

Procedure:
Prepared by the method of example 1 part (d) using 2-hydroxy-5-methyl-benzaldehyde to give the title compound.
Reaction SMILES: C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:15][S:16]([O:19][C@H:20]1[CH2:24][N:23]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[C@H:22]([C:38]([OH:40])=O)[CH2:21]1)(=[O:18])=[O:17].[OH:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>O1CCCC1>[OH:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][N:47]([C:38]([C@@H:22]2[CH2:21][C@@H:20]([O:19][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:24][N:23]2[C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)=[O:26])=[O:40])[CH2:46][CH2:45]1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: OCCN1CCNCC1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
0.21 ml of triethylamine, followed by 0.19 ml of pivaloyl chloride, were added dropwise at -20° C. to a solution of 0.5 g of trans-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-L-proline in 5 ml of dry tetrahydrofuran, and the resulting mixture was stirred at the same temperature for 5 minutes. A solution of 0.25 g of N-(2-hydroxyethyl)piperazine in 3 ml of dry tetrahydrofuran was then added, and the reaction mixture was stirred at the same temperature for 30 minutes, after which the solvent was removed by distillation under reduced pressure. The resulting residue was worked up and purified in a similar manner to that described in step 54(a)(ii), to give 0.42 g of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the product were identical with those of the compound obtained as described in step 54(a)(ii) above.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23](S(C)(=O)=O)[N:22]=1.C1[C:40]2(C[NH:42][CH2:41]2)CO1.C(N(CC)CC)C>C1COCC1>[CH2:41]([NH:42][C:23]1[N:22]=[C:21]([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=1)[CH3:40]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(S(C)(=O)=O)n1
Reactant: C1NCC12COC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNc1nc(-c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)cc(N2CCOCC2)n1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a solution of N-(4-methyl-3-(2-(methylsulfonyl)-6-morpholinopyrimidin-4-yl)phenyl)-3-(trifluoromethyl)benzamide (1.0 equiv.) and 2-oxa-6-azaspiro[3.3]heptane (1.0 equiv.) in THF (0.20M) was added triethylamine (3.5 equiv.) and the allowed to stir at 75° C. for 48 hours. LCMS analysis indicated formation of the desired product. The volatiles were removed in vacuo. The crude material was purified via preparative reverse phase HPLC. Upon lyophilization of the pure fractions, N-(3-(2-(ethylamino)-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide was isolated as the TFA salt in 21% yield. 1H NMR (400 MHz, <cd3od>) δ ppm 1.28 (t, J=7.24 Hz, 3H) 2.38 (s, 3H) 3.52 (q, J=6.65 Hz, 2H) 3.80 (br. s., 6H) 4.05 (br. s., 2H) 6.50 (s, 1H) 7.41 (d, J=8.61 Hz, 1H) 7.66 (dd, J=8.22, 2.35 Hz, 1H) 7.72-7.78 (m, 1H) 7.91 (d, J=7.83 Hz, 1H) 7.96 (d, J=2.35 Hz, 1H) 8.21 (d, J=7.83 Hz, 1H) 8.26 (s, 1H). LCMS (m/z) (M+H)=486.3, Rt=0.86 min.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[C:6]([OH:9])(=[O:8])[CH3:7].C(O)(=[O:12])C.[CH2:14](O)[CH2:15][CH2:16]C>O>[CH:15]1[CH:16]=[C:2]2[C:1]([C:6]([OH:9])([OH:8])[C:7](=[O:12])[C:3]2=[CH:4][CH:14]=1)=[O:5]
Reactant: CC(=O)O
Reactant: CCCCO
Solvent: O
Product: O=C1c2ccccc2C(=O)C1(O)O

Procedure:
Thin glass plated (20×20 cm) coated (0.4 mm to 0.5 mm thick) with silica gel G (Kieselgel G nach Stahl; E. Merck) were activated at 100° C. for half an hour. The solution containing the isolated substance was applied 1 cm above the edge of the plates were run in an organic solvent mixture of n-butanol and acetic acid and water. It should be n-butanol acetic acid and water (12:5:2). The developed plates were dried at room temperature and sprayed with 0.25% nin-hydrin in acetone. The nin-hydrin positive spots (R=0.19) of the isolate nearly corresponding to insulin were collected from about 200 unsprayed plates along with the silica gel G and extracted with 50% ethanol buffered with ammonium hydroxide/10% formic acid. The extract was filtered and dried in vacuo. Pure colorless crystals thus obtained were weighed (3 g/100 gram dry weight of seeds).
Reaction SMILES: CS(C)=O.[CH2:5]([O:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH-].[K+]>O.C1COCC1>[CH2:18]([O:17][CH2:16][CH:13]([CH2:14][O:15][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: OCC(CO)OCc1ccccc1
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCOCC(COCCCCCCCC)OCc1ccccc1
Yield: 76.5 %

Procedure:
In a mixed solution consisting of 50 ml of DMSO and 30 ml of THF were dissolved 3.64 g (20 mmole) of 2-benzylglycerin and 9.26 g (48 mmole) of octyl bromide, and 8.96 g (160 mmole) of powdered potassium hydroxide was added to the solution, followed by vigorous stirring. Two hours later, the reaction solution was poured in cold water, and the mixture was extracted with n-hexane. The extract was washed with water, dried and concentrated, followed by purification by silica-gel chromatography (eluent: n-hexane-ethyl acetate, 20:1) to give 6.22 g (77%) of the desired compound as colorless liquid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]([C:6]1[CH2:7][NH:8][CH2:9][CH2:10][CH:11]=1)=[O:5].[C:12]1([C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH2:20][CH2:21]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[ClH:1].[CH3:2][O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:21][CH2:20][CH:19]=[C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:9][CH2:10][CH:11]=1)=[O:5]
Reactant: BrCCC=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1=CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C1=CCCN(CCC=C(c2ccccc2)c2ccccc2)C1

Procedure:
A mixture of 5.0 g. (0.0282 mole) of 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester, hydrochloride, 8.08 g. (0.282 mole) of 4,4-diphenyl-3-butenyl bromide and 10 g. of crushed potassium carbonate was refluxed in 200 ml. of acetone for 15 hours. The reaction mixture was evaporated, extracted into ethyl acetate from water, dried, evaporated and chromatographed on silica (dry column) eluted with hexane/hexane:ethyl acetate to give 1,2,5,6-tetrahydro-1-(4,4-diphenyl-3-butenyl)-3-pyridinecarboxylic acid methyl ester hydrochloride.