Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][N:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])#[N:2].[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[CH3:22][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:5]=1[N:4]([CH2:3][C:1]#[N:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(N(CC#N)c2ccccc2)c(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(OC)ccc1N(CC#N)c1ccccc1
Yield: 68.8 %

Procedure:
A mixture of 7.1 g (0.025 mole) of 2-[(cyanomethyl)phenylamino]-5-methoxybenzoic acid [P. C. Unangst and M. E. Carethers, J. Heterocyclic Chem., 21, 709 (1974)], 4.0 g (0.029 mole) of anhydrous potassium carbonate, and 3.0 ml (4.0 g; 0.032 mole) of dimethyl sulfate in 200 ml of acetonitrile was stirred at reflux for 24 hours. The mixture was cooled and filtered, and the filter cake was washed several times with fresh acetonitrile. The combined filtrates were evaporated to an oil, which crystallized upon standing at room temperature. Recrystallization from aqueous methanol yielded 5.1 g (68% yield) of the ester product. A sample recrystallized again as above was analytically pure, mp 107°-109° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[CH:3]=1.O[C:14]1C=CN(CCC(C)C)C(=O)C=1.C(N1C=CC(O)=CC1=O)CCC.C(OC1C=CNC(=O)C=1)C1C=CC=CC=1.BrCCC(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH:10]([CH3:14])[CH3:11])[C:4](=[O:12])[CH:3]=1
Reactant: CCCCn1ccc(Br)cc1=O
Reactant: CC(C)CCn1ccc(O)cc1=O
Agent: CCCCn1ccc(O)cc1=O
Agent: O=c1cc(OCc2ccccc2)cc[nH]1
Solvent: CC(C)CCBr
Product: CC(C)CCn1ccc(Br)cc1=O

Procedure:
Intermediate D4 was prepared following the same procedure implemented for the synthesis of D3, using 4-hydroxy-1-(3-methylbutyl)-1H-pyridin-2-one as starting material, which was prepared by the same method used for the synthesis of intermediate D2, by reaction of 4-benzyloxy-1H-pyridin-2-one with 1-bromo-3-methylbutane.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.O.[Cl-].[Na+]>C(#N)C.C(OCC)(=O)C>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([C:4](=[O:5])[CH:3]=[CH2:2])=[CH:11][CH:10]=1
Reactant: O=C(CCCl)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
60 g (295.5 mmol) of 3-chloro-1-(4-chlorophenyl)propan-1-one were dissolved in 900 ml of acetonitrile. With ice bath cooling, 41.2 ml (295.5 mmol) of triethylamine were then slowly added dropwise to the solution (exothermal reaction). After the addition had ended, the reaction solution was stirred at room temperature for 4 h. About one liter of water, one liter of ethyl acetate and about 250 ml of saturated sodium chloride solution were then added to the reaction mixture. The phases were separated, the organic phase was then dried over magnesium sulphate and filtered and the filtrate was concentrated to dryness. The crude product obtained was purified by chromatography on silica gel (about 1.3 kg) (mobile phase cyclohexane/ethyl acetate 6:1). This gave 45 g of the target product (91% of theory).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.Br[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1
Reactant: COC(=O)c1c[nH]c2ncccc12
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cn(-c2nccs2)c2ncccc12
Temperature: 130 °C

Procedure:
A mixture of methyl 1H-pyrrolo[2,3-b]pyridine-3-carboxylate (200 mg, 1.135 mmol), 2-bromothiazole (205 μl, 2.271 mmol) and cesium carbonate (1110 mg, 3.41 mmol) in NMP (1135 μl) was heated at 130° C. for 2 h. The mixture was then purified by HPLC to afford the title compound as a brownish-white solid.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl>C1COCC1.[Cl-].[Na+].O>[O:17]=[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:1]([O:5][CH2:6][CH3:7])=[O:8]
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCCC1=O
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
A 1000 mL flashk was charged with diethyl carbonate (146 mL, 1.2 mol) and 150 mL of dry THF, and NaH (60%, 63 g, 1.6 mol) was added to the mixtrure under stirring. The mixture was heated to reflux for 1 h, and then, a solution of cyclohexanone (50 mL, 0.48 mol) in anhydrous THF (50 mL) was added dropwise to the mixture, and the addition of cyclohexanone was continued for ca. 0.5 h. The mixture was refluxed for an additional 1.5 h. After cooled, the mixture was hydrolyzed by 3N hydrochloric acid, then poured into brine, extracted by DCM (75 mL×3). The combined organic layer was dried and evaporated to give the title compound (66 g, 80% yield) as brown oil which was set to do next step without any purification. MS: m/z 171.3 [M+H]+.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH3:31][NH:32][CH3:33].[ClH:34]>O1CCCC1.ClCCl>[ClH:34].[CH3:31][N:32]([CH3:33])[CH2:3][C@H:2]([OH:1])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CNC
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@@H]2CO2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C[C@H](O)Cn1ncc2cc(-n3ccc(-c4ccc(C(F)(F)F)cc4)cc3=O)ccc21
Temperature: 45 °C
Yield: 71 %

Procedure:
To (R)-1-(1-(oxiran-2-ylmethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)-phenyl)pyridin-2(1H)-one (230 mg, 0.56 mmol) in tetrahydrofuran (5 mL) was added LiClO4 (892 mg, 8.38 mmol) followed by dimethylamine (2.8 ml of a 2 M solution in tetrahydrofuran, 5.6 mmol). The reaction mixture was heated in a 45° C. oil bath for 3.75 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml), washed with water (25 mL) and brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The material was purified by column chromatography (silica gel, 9:1 CH2Cl2/MeOH to 90:9:1 CH2Cl2/MeOH/conc. NH4OH). The dried residue (198 mg, 0.43 mmol) was dissolved in dichloromethane (2 mL), and HCl (1.25 M solution in methanol, 0.38 mL, 0.47 mmol) was added. The mixture was concentrated under reduced pressure and dried to afford the title compound (198 mg, 71%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 9.42 (br s, 1H), 8.20 (s, 1H), 8.02-8.00 (m, 2H), 7.88-7.80 (m, 5H), 7.46 (dd, J=8.5, 1.5 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.74 (dd, J=7.0, 2.0 Hz, 1H), 5.60 (br s, 1H), 4.56-4.52 (m, 1H), 4.48-4.44 (m, 1H), 4.27 (br s, 1H), 2.92-2.88 (br m, 2H), 2.58 (br s, 6H); ESI MS m/z 457 [M+H]+; HPLC (Method B)>99% (AUC), tR=14.5 min; [α]23D −9.5° (c 0.14, Methanol).
Reaction SMILES: [H-].[Na+].[Na+].[I-].C[C:6]1([CH3:13])[O:10][CH:9]([CH2:11][OH:12])[CH2:8][O:7]1.S(C1C=CC(C)=CC=1)(O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]CC)(=O)=O>CN(C=O)C.O>[CH2:6]([O:7][CH2:8][CH:9]([CH2:11][OH:12])[OH:10])[CH2:13][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CC1(C)OCC(CO)O1
Reactant: CCCCCCCC/C=C\CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCOCC(O)CO
Reaction time: 72 h

Procedure:
To a mixture of NaH (4.8 g, 120 mmol) and NaI (0.2 g) in dry DMF (20 mL) was added solketal (5.0 mL, 40 mmol) dropwise over a 30 min period. Once the effervescence had stopped, oleyl tosylate (Compound 13) (16.9 g, 40 mmol) was added and the reaction mixture was left for 3 days at 50° C. Then, H2O (10 mL) was added and the mixture was extracted with diethyl ether (2×100 mL), the combined organic phases were dried (MgSO4) and evaporated to dryness. The residue was taken up in THF (150 mL), 2M HCl was added until the solution turned turbid and the reaction was left to stir for 16 hours. The mixture was concentrated and subjected to silica-gel column chromatography [eluent: ethyl acetate/hexane, 50/50, v/v] to give 1-O-oleyl-rac-glycerol (Compound 20) as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:11]=[CH:12][NH:13][C:14]=1[CH3:15])=[S:4].[IH:16].[CH3:17]I>CO>[IH:16].[IH:16].[CH3:1][NH:2][C:3](=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:11]=[CH:12][NH:13][C:14]=1[CH3:15])[S:4][CH3:17]
Reactant: CNC(=S)NCCSCc1nc[nH]c1C
Reactant: CI
Agent: I
Solvent: CO
Product: CNC(=NCCSCc1nc[nH]c1C)SC

Procedure:
N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea (10.0 g) was dissolved in methanol (400 ml) and 55% aqueous hydriodic acid (12.2 ml) was added, followed by methyl iodide (5.3 ml). The solution was heated under reflux for 4 hours and concentrated. The residue was dissolved in methanol (100 ml) and ether was added to afford the title product as the dihydriodide (5.48 g) m.p. 185°-186° (from isopropyl alcohol).
Reaction SMILES: [NH2:1][C:2]1[C:17]([F:18])=[CH:16][C:5]2[O:6][C:7]([F:15])([F:14])[C:8](=[O:13])[N:9]([CH2:10][C:11]#[CH:12])[C:4]=2[CH:3]=1.Cl.[N:20]([O-])=O.[Na+].[Sn](Cl)Cl.[OH-].[Na+]>O>[F:15][C:7]1([F:14])[C:8](=[O:13])[N:9]([CH2:10][C:11]#[CH:12])[C:4]2[CH:3]=[C:2]([NH:1][NH2:20])[C:17]([F:18])=[CH:16][C:5]=2[O:6]1
Reactant: O=N[O-]
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N)cc21
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(NN)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a mechanically stirred suspension of 6-amino-2,2,7-trifluoro-4-(prop-2-ynyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (20 g, 78 mmol) in conc. hydrochloric acid (100 ml, 1218 mmol) at −5° C. was added dropwise, over a period of 30 minutes, a solution of sodium nitrite (5.82 g, 84 mmol) in water (40 ml), maintaining the temperature below −5° C. The resulting mixture was stirred at ˜0° C. for 1 hour. Subsequently the stirred reaction mixture was cooled to −35° C. with a dry-ice/2-propanol cooling bath. A cooled solution (−10° C.) of tin(II) chloride (37.0 g, 195 mmol) in conc. hydrochloric acid (40 ml, 487 mmol) was added over the course of ca. 1 minute, during which time the temperature increased from −35 to −10° C. The resulting mixture was stirred at 0° C. for 1 hour. Then 80 g kieselguhr was added to the reaction mixture and the resulting mixture was neutralised to pH˜7 by slow addition of 10% aqueous NaOH solution under stirring. The whole was filtered and the filter cake and filtrate were extracted twice with diethyl ether. The extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo to yield 17 g of product, having a purity of ca. 85%. Trituration with diisopropyl ether gave 11.87 g of product. A further quantity of 3.6 g of product was obtained by concentration of the mother liquor.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[N:14]2)C(OCC)=O)C.[OH-].[Na+]>CO>[N:17]1[C:18]2[C:13](=[CH:12][C:11]([CH2:5][C:4]([OH:21])=[O:3])=[CH:20][CH:19]=2)[N:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc2nccnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccc2nccnc2c1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A solution of 6-iodo-quinoxaline (0.323 g, 1.26 mmol), malonic acid diethyl ester (0.404 g, 2.52 mmol), copper iodide (0.012 g, 0.063 mmol), biphenyl-2-ol (0.021 g, 0.126 mmol) and cesium carbonate (0.616 g, 1.89 mmol) in THF (5 mL) was heated to 70° C. in a sealed tube for 24 hours. The solution was then cooled to room temperature, water was added and the crude product was extracted from ethyl acetate. The product was purified via silica gel column chromatography in hexane:ethyl acetate (1:1) to give 2-quinoxalin-6-yl-malonic acid diethyl ester. 2-quinoxalin-6-yl -malonic acid diethyl ester (0.066 g, 0.229 mmol) was added to a solution of sodium hydroxide [2N] (0.229 mL) in methanol (2 mL) and stirred for several hours at room temperature. The reaction was then evaporated in vacuo, 1N HCl was added and the product was extracted with ethyl acetate to give 0.030 g (70%) of quinoxalin-6-yl-acetic acid. 1H NMR (400 MHz, DMSO-d6) δ 12.6 (bs, 1H), 8.93 (dd, 2H, J=2.0, 6.0 Hz), 8.05 (d, 1H, 8.8 Hz), 7.99 (m, 1H), 7.79 (dd, 1H, J=2.0, 8.8 Hz), 3.89 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([CH:18]=1)[CH2:7][CH:8]1[CH2:11][N:10]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:27][C:28]1[O:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:27][C:28]2[O:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=2)=[C:6]([CH:18]=1)[CH2:7][CH:8]1[CH2:11][N:10]([C:12](=[O:17])[C:13]([F:15])([F:16])[F:14])[CH2:9]1
Reactant: O=C(N1CC(Cc2cc(Br)ccc2O)C1)C(F)(F)F
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N1CC(Cc2cc(Br)ccc2OCc2ccc(C(F)(F)F)o2)C1)C(F)(F)F
Reaction time: 16 h
Yield: 91.9 %

Procedure:
To a solution of 1-[3-(5-bromo-2-hydroxy-benzyl)-azetidin-1-yl]-2,2,2-trifluoro-ethanone (59 mg, 0.17 mmol) in DMF (10 mL) was added KI (40 mg, 0.24 mmol), Cs2CO3 (170 mg, 0.51 mmol) and 2-bromomethyl-5-trifluoromethyl-furan (56 mg, 0.24 mmol). After 16 h, saturated sodium bicarbonate solution and EtOAc were added. The aqueous portion was extracted three times with EtOAc and the combined organic were dried (Na2SO4) and concentrated. The crude product was purified by RP HPLC (basic conditions) to provide the title compound (76 mg, 91%). MS (ESI): mass calcd. for C18H14BrF6NO3, 486.2; m/z found, 488.1 [M+H]+. 1H NMR (CDCl3): 7.34 (dd, J=8.7, 2.5 Hz, 1H), 7.21 (d, J=2.5 Hz, 1H), 6.89-6.76 (m, 2H), 6.48 (d, J=3.4 Hz, 1H), 5.02 (s, 2H), 4.40 (dd, J=9.6, 8.4 Hz, 1H), 4.22-4.11 (m, 1H), 4.08-4.02 (m, 1H), 3.84 (dd, J=10.7, 5.7 Hz, 1H), 3.11-2.97 (m, 1H), 2.97-2.82 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:14][C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[C:18]([CH3:29])[CH:17]=1)[C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:6]=2[N:5]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>O1CCCC1>[C:38]([NH:1][CH2:2][C@H:3]([NH:14][C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[C:18]([CH3:29])[CH:17]=1)[C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:6]=2[N:5]=1)(=[O:40])[CH3:39]
Reactant: Cc1cc(C(=O)N[C@@H](CN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
170 mg (0.4 mmol) of (1S)—N-[2-amino-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide is placed in 3.4 mL of tetrahydrofuran, while being cooled in the ice bath with 0.1 mL (0.6 mmol) of triethylamine and then combined with 0.05 g (0.45 mmol) of acetic anhydride. Then the mixture is heated to ambient temperature and stirred for 24 hours. Then the solvent is eliminated in vacuo and the residue purified by chromatography (gradient: dichloromethane/methanol=100:2). Yield: 23.5 mg (13%); Rf value: 0.28 (silica gel; dichloromethane/methanol=95:5); C24H26ClN5O3 (467.95); mass spectrum: (M+H)+=468/470 (chlorine isotope).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[CH:12]=[CH:11][CH:10]=2)=O)=[CH:3][CH:2]=1.[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])C=CC=CC=1>>[CH3:32][N:31]([CH3:33])[CH2:30]/[CH:29]=[C:7](/[C:9]1[N:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[CH:12]=[CH:11][CH:10]=1)\[C:4]1[CH:5]=[CH:6][C:1]([CH3:20])=[CH:2][CH:3]=1
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C(=O)c2cccc(/C=C/C(=O)O)n2)cc1
Agent: [Br-]
Product: Cc1ccc(/C(=C\CN(C)C)c2cccc(/C=C/C(=O)O)n2)cc1

Procedure:
Treatment of (E)-3-[6-(4-toluoyl)-2-pyridyl]acrylic acid, vide supra, with the Wittig reagent derived from triphenyldimethylaminoethylphosphonium bromide by the method of example 1 gave a mixture of isomeric acids which were separated by fractional crystallization from ethyl acetate. The less-soluble E-isomer, (E)-3-{6-[3-dimethylamino-1-(4-tolyl)prop-1E-enyl]-2-pyridyl}acrylic acid was purified by crystallization from isopropanol, m.p. 222°-225° (decomp.)
Reaction SMILES: [CH2:1]([N:3]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Br)[CH:15]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:2].[C-:22]#[N:23].[Na+].C(OCC)C.O>CN(C)C=O>[CH2:1]([N:3]([CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:22]#[N:23])[CH:17]=[CH:18][CH:19]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:2]
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
240 mg of (E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-bromomethylbenzylamine was dissolved in 4 ml of dimethylformamide, and 61 mg of sodium cyanide was added. The mixture was stirred overnight at room temperature, and then ethyl ether and water were added. The organic layer separated was worked up in a customary manner to give 195 mg of (E)-3-(N-ethyl-6,6-dimethyl-2-hepten-4-ynylaminomethyl)phenylacetonitrile as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[C:14]([OH:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+]>C1COCC1>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[C:14]([OH:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2ccc(C=O)c(O)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)OC(C)(C)C)oc2ccc(CO)c(O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To 5-formyl-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester (430 mg, 1.56 mmol) was added 8 mL of THF, followed by sodium cyanoborohydride (117 mg, 1.87 mmol) in one portion. The solution was stirred at room temperature for 1 h and then placed in a 65° C. oil bath overnight. The solvent was removed under vacuum and water was added. The mixture was extracted with ethyl acetate. Removal of the solvent gave the crude product, which was purified by column chromatography to give 200 mg of 4-hydroxy-5-hydroxymethyl-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was obtained as a yellow semi-solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42](Br)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[OH:52][CH2:53][C:54]1[CH:55]=[C:56](B(O)O)[CH:57]=[CH:58][C:59]=1[CH3:60].C([O-])([O-])=O.[Cs+].[Cs+]>C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:56]3[CH:57]=[CH:58][C:59]([CH3:60])=[C:54]([CH2:53][OH:52])[CH:55]=3)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Reactant: Cc1ccc(B(O)O)cc1CO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(C)c(CO)c5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (Step 2, Example 1u) (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added (3-(hydroxymethyl)-4-methylphenyl)boronic acid (CAS#1451391-54-0; 120 mg, 0.7 mmol), PdCl2(PPh3)2 (41 mg, 0.058 mmol), and Cs2CO3 (390 mg, 1.2 mmol). The reaction was heated to 60° C. for 16 h, then cooled to RT, filtered through celite and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate a white solid.
Reaction SMILES: [N:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[N+:18]([O-])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C1(C)C=CC=CC=1.[Pt]>[N:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[NH2:18])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NN1CCOCC1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Nc1cnc2ccccc2c1NN1CCOCC1
Reaction time: 15 h
Yield: 100.1 %

Procedure:
A solution of N-(morpholin-4-yl)(3-nitroquinolin4-yl)amine (4.54 g, 16.6 mmol) in 150 mL of toluene was treated with 5% platinum on carbon (0.65 g, 0.17 mmol) and the mixture was shaken under an atmosphere of hydrogen (3.8×105 Pa). After 15 h, the reaction mixture was filtered through a pad of CELITE filter agent and rinsed with 4:1 toluene:MeOH. The filtrate was concentrated under reduced pressure to yield N4-(morpholin-4-yl)quinoline-3,4-diamine (4.06 g) as a red foam.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10](Cl)[N:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=[C:8]2[N:7]=1)=[O:5])C.C(OC(C1C=CN2N=CC(C3C=CC=C(Cl)C=3)=C2N=1)=O)C>>[C:16]1([C:14]2[CH:15]=[C:8]3[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:11]=[CH:10][N:9]3[N:13]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1cc(Cl)n2nc(-c3ccccc3)cc2n1
Agent: CCOC(=O)c1ccn2ncc(-c3cccc(Cl)c3)c2n1
Product: O=C(O)c1ccn2nc(-c3ccccc3)cc2n1

Procedure:
This compound was synthesized from 2-phenyl-7-chloro-pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid ethyl ester, according to the process for synthesizing the foregoing 3-(3-chlorophenyl)-pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid ethyl ester.