Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[CH2:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:24])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(cc1OCc1ccccc1)N=CCC2=O
Product: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A mixture of 7-benzyloxy-6-methoxy-4-quinolone (9.72 g 34.5 mmol) and phosphorus oxychloride (130 ml) was stirred at 110° C. for 3 hours. The stirred mixture was concentrated at atmospheric pressure. The residue was dissolved in chloroform (150 ml), then ice and water was added to the solution. The mixture was rendered weakly alkaline by the addition of saturated sodium carbonate solution. The two phases were separated, the aqueous layer was extracted with chloroform. The extract was washed with water, dried over sodium sulfate, and the solvent was removed by evaporation under the reduced pressure. The residue was solidified under diisopropyl ether to give 9.82 g of product [E]. Yield: 94%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:17]=[C:16]([CH:18]([NH2:20])[CH3:19])[O:15][N:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:17]=[C:16]([CH:18]([NH:20][C:30](=[O:32])[CH3:31])[CH3:19])[O:15][N:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ncc(-c3cc(C(C)N)on3)s2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Oc2ncc(-c3cc(C(C)NC(C)=O)on3)s2)cc1
Reaction time: 0.33 h
Yield: 95.1 %

Procedure:
To a solution of Example 53A (740 mg, 2.33 mmol) and triethylamine (975 μL, 7 mmol) in dichloromethane (15 mL) was added acetic anhydride (282 μL, 2.8 mmol) at ambient temperature. The reaction was stirred for 20 minutes, concentrated, and purified by flash chromatography on silica gel eluting with a solvent gradient from 30% to 80% ethyl acetate in hexanes to provide 796 mg (95%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.42 (d, J=6.99 Hz, 3H) 1.87 (s, 3H) 3.80 (s, 3H) 5.09 (m, 1H) 6.89 (s, 1H) 6.99-7.12 (m, 2H) 7.27-7.46 (m, 2H) 7.95 (s, 1H) 8.51 (d, J=8.09 Hz, 1H); MS (ESI) m/z 360.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[C:8]=2[NH:12][C:13](=[O:22])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[N:3]=1.[N:24]1(C(OC(C)(C)C)=O)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C.FC(F)(F)C(O)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[NH3:3].[Cl:23][C:7]1[C:8]([NH:12][C:13](=[O:22])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH:11]=[CH:10]2
Reactant: O=C(CCC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N
Product: O=C(CCC1CCCCC1)Nc1c(Cl)ccc2nc(N3CCNCC3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 10 %
Yield: 32.9 %

Procedure:
N-(2,6-Dichloro-5-quinolinyl)-cyclohexanepropanamide (Example 90(a)) (0.16 g), 1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (0.34 g,), triethylamine (0.15 mL) and tetra-butylammonium bromide (80 mg) were heated at 140° C. for 1 hour in a microwave. The resulting precipitate was filtered and then washed with acetonitrile to give a solid. This solid was dissolved in dichloromethane and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hours, then concentrated under vacuum to dryness. Purification (HPLC, Symmetry—0.1% aqueous trifluoroacetic acid:acetonitrile followed by Varian SCX cartridge using methanol and then 10% ammonia in methanol as eluant) gave the title compound as a white solid (30 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.CO>O1CCCC1.[C].[Pd]>[NH2:1][C:4]1[CH:31]=[CH:30][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:19][CH2:20][CH:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:22][CH2:23]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCC(CN2CCCC2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCCC4)CC3)c2)cc1
Reaction time: 10 h
Yield: 85.2 %

Procedure:
4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (295 mg) was dissolved in tetrahydrofuran (7 ml) and methanol (7 ml) under a nitrogen atmosphere, and then 10% palladium carbon (147 mg) was added, followed by stirring under a hydrogen atmosphere for 10 hrs. The reaction mixture was filtered to remove the catalyst, and the catalyst was washed with methanol. The filtrate was concentrated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing a target compound were concentrated to provide 4-(pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (233.7 mg) as white foam.
Reaction SMILES: ClC(Cl)C.[CH3:5][O:6][C:7]1[CH:44]=[CH:43][C:10]([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:13]2[N:18]=[CH:17][C:16]([C:19]3[C:20]4[CH2:33][CH2:32][NH:31][C:21]=4[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=3)=[CH:15][N:14]=2)=[CH:9][CH:8]=1.N1C=CC=CC=1.[C:51](OC(=O)C)(=[O:53])[CH3:52].[Cl-].[NH4+]>>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:44][CH:43]=2)[C:13]2[N:14]=[CH:15][C:16]([C:19]3[C:20]4[CH2:33][CH2:32][N:31]([C:51](=[O:53])[CH3:52])[C:21]=4[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=3)=[CH:17][N:18]=2)=[CH:40][CH:39]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(C)=O)cn2)cc1
Temperature: 25 °C

Procedure:
To dichloroethane solution (2 ml) of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg, 0.185 mmol), pyridine (45 μl, 0.556 mmol) and N,N-dimethylaminopyridine (2.3 mg, 0.0185 mmol) were added, and further acetic anhydride (52 μl, 0.556 mmol) was added, followed by refluxing for 3 hours. This was cooled to room temperature, followed by addition of saturated aqueous ammonium chloride solution, and passed through Whatman tube. The resulting organic phase was concentrated under reduced pressure, to obtain 1-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-ethanone as a crude product. To this, TFA (2 ml) and concentrated sulfuric acid (2 drops) were added, followed by stirring at 40° C. for 4 hours. After concentration of TFA under reduced pressure, water was added, followed by neutralization with 1M aqueous sodium hydroxide solution. After filtering the solid, dichloromethane (5 ml) was added, followed by stirring at room temperature for 30 minutes, and the solid was filtered off, to obtain the desired compound as a colorless solid (29.3 mg, yield 46%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[Cl:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[CH:45]=[C:44]([S:49]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)(=[O:51])=[O:50])[CH:43]=[CH:42]2>O1CCCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH2:17][CH2:18][C:19]([N:55]3[CH2:54][CH2:53][N:52]([S:49]([C:44]4[CH:43]=[CH:42][C:41]5[C:46](=[CH:47][CH:48]=[C:39]([Cl:38])[CH:40]=5)[CH:45]=4)(=[O:51])=[O:50])[CH2:57][CH2:56]3)=[O:21])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(CCC(=O)O)cc2C1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCc2sc(CCC(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
In tetrahydrofuran (10 ml), 3-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin -2-yl)propionic acid (445 mg) was dissolved, followed by the dropwise addition of N-methylmorpholine (170 μl) and isobutyl chloroformate (210 μl) successively at −20° C. After stirring at −20° C. for 10 minutes, 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride (607 mg) dissolved in advance in dichloromethane (10 ml) was added to the reaction mixture. The reaction mixture was stirred at −20° C. for 10 minutes and then heated to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloroethane. The resulting solution was washed with 1N hydrochloric acid, saturated sodium bicarbonate and saturate saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=4:1˜2:1), whereby the title compound (625 mg, 72%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][C:10]=2[F:32])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].[CH3:37]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH3:37])[CH:20]=[C:21]([CH2:25][C:26]4[CH:31]=[N:30][CH:29]=[N:28][CH:27]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][C:10]=2[F:32])=[CH:4][C:3]=1[C:33]([F:35])([F:36])[F:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)[nH]cc1Cc1cncnc1
Solvent: ClCCl
Solvent: CI
Product: Cn1cc(Cc2cncnc2)c(=O)nc1OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.2 %

Procedure:
To a solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3-fluorophenyl) ethyl]oxy}-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (80 mg, 0.154 mmol) and Hunig's base (0.040 mL, 0.230 mmol) in DCM (3.0 mL) was added MeI (0.019 mL, 0.307 mmol) dropwise. The mixture was stirred at room temperature for 2 h. Purification via reverse phase flash chromatography afforded the title compound (15 mg, 18.26% yield). LCMS: rt=3.32 min, [M+H+]=535
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([F:35])[C:33]=1[F:34])[C:28](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:17]([C:7]1[N:8]([CH2:12][C:13]2[N:16]=[C:28]([C:27]3[CH:26]=[C:25]([F:24])[C:33]([F:34])=[C:32]([F:35])[CH:31]=3)[O:15][N:14]=2)[C:9]2[C:5]([CH:6]=1)=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH2:18][CH3:19]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(F)c(F)c(F)c2)n1
Temperature: 150 °C
Yield: 45.4 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 3,4,5-trifluorobenzoyl chloride (0.241 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.065 g (45% yield) of pure product: MS (ES) m/z 464 (M+).
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1)([CH3:9])[CH3:8].C(O)(C)(C)C.F[C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34]([NH:36][C:37]3[CH:45]=[CH:44][CH:43]=[C:42]4[C:38]=3[C:39]([CH2:54][CH3:55])=[N:40][N:41]4[CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=3)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1>O>[CH2:54]([C:39]1[C:38]2[C:42](=[CH:43][CH:44]=[CH:45][C:37]=2[NH:36][C:34]([C:31]2[N:28]3[CH:29]=[CH:30][C:25]([O:18][CH2:17][CH2:16][N:13]4[CH2:12][CH2:11][N:10]([CH:7]([CH3:9])[CH3:8])[CH2:15][CH2:14]4)=[CH:26][C:27]3=[N:33][CH:32]=2)=[O:35])[N:41]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=2)[N:40]=1)[CH3:55]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Reactant: CC(C)N1CCN(CCO)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C(C)C)CC5)ccn34)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 50 mL round bottom flask was charged with solid potassium tert-butoxide (1.7 g, 14.8 mmol), 2-(4-isopropylpiperazin-1-yl)ethanol (2.88 g, 16.7 mmol), and tert-butanol (10 mL, 103 mmol). The mixture was stirred at ambient temperature for 1 hour before heating at 90° C. for 15 minutes to give a homogeneous mixture. 7-Fluoro-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (1.0 g, 2.3 mmol) was added in one portion. The mixture was heated at 90° C. with stirring for 16 hours. The mixture was cooled to ambient temperature before pouring into a 250 mL round bottom flask containing 150 mL of water. Vigorous stirring at ambient temperature for 2 hours resulted in a beige precipitate. The precipitate was collected by filtration and dried under high vacuum to give the product. MS (APCI), positive scan, m/z=581.1 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(O)[CH:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH3:10])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(c1nnnn1C)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C
Yield: 90.9 %

Procedure:
A slurry of 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)propanol (8.25 g, 0.025 mole) [prepared in Step B] and 100 mg of p-toluene sulfonic acid monohydrate in xylene (60 mL) was heated to reflux with a Dean & Stark water collecting apparatus for a period of 12 hours. The reaction mixture was washed with 1N NaOH (10 mL) while it was warm and with water (100 mL). Concentration of the organic layer gave off-white crystals of product. This was purified by recrystallization from ethanol-hexane to give 7.1 g (91%) of the title compound as white crystals; m.p.=146°-147° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[N:9]=[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2].[Se](=O)=[O:17]>O1CCOCC1>[CH:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)Cc1cccc(NC=O)n1
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)c1cccc(NC=O)n1
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To a solution of ethyl 2-(6-formamidopyridin-2-yl)acetate (26 g.) in dioxane (260 ml.) was added selenium dioxide (16.65 g.) in small portions at 85° to 90° C. over one hour and stirred at the same temperature for one hour. After cooling the resultant solution the dioxane layer was separated and concentrated under reduced pressure and then the residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate and treated with activated charcoal and then concentrated under reduced pressure. The residue was triturated with diethyl ether to give ethyl 2-(6-formamidopyridin-2-yl)glyoxylate (14.3 g.), mp. 124° to 126° C.
Reaction SMILES: [I-:1].Br[C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:7][N+:6]([CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26]([I:28])C>>[I-:28].[CH2:19]([N+:6]1[CH:7]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:3]([I:1])=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=1)[CH3:26]
Reactant: CCI
Reactant: C[n+]1cc(-c2ccccc2)c(Br)c(-c2cccc(C(F)(F)F)c2)c1
Agent: [I-]
Product: CC[n+]1cc(-c2ccccc2)c(I)c(-c2cccc(C(F)(F)F)c2)c1
Reaction time: 72 h

Procedure:
A 2 g. portion of the 4-bromopyridine intermediate of Example 9 was combined with 10 ml. of ethyl iodide and allowed to stand at room temperature for 3 days. Volatile materials were then evaporated under vacuum, and the solids were crystallized from chloroform-hexane, yield 0.25 g., m.p. 235°-238°. Analysis by nuclear magnetic resonance and mass spectrometry techniques identified the product as consisting of approximately 60 percent of the compound of Example 12, and approximately 40 percent of the compound of Example 13.
Reaction SMILES: N1C=CC=CC=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11]N=1)=[O:8].[Br-].[C:16]([CH2:19][CH2:20][CH2:21]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=[O:17].CC([O-])(C)C.[K+].CO.[CH3:50][C:51]([OH:53])=[O:52].C(Cl)Cl>C1COCC1>[C:7]([OH:17])(=[O:8])/[CH:9]=[CH:14]/[CH2:13][CH2:12][CH3:11].[C:51]([OH:53])(=[O:52])/[CH:50]=[CH:16]\[CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)O
Reactant: O=C(c1ccccn1)c1ccccn1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CCC/C=C/C(=O)O
Product: CCC/C=C\C(=O)O
Yield: 19.8 %

Procedure:
Prepared as above from 150.0 mg (0.35 mmol) of the pyridyl ketone, 308.2 mg (0.70 mmol) of (4-carboxy-butyl)triphenylphosphonium bromide, and 1.4 mL (1.4 mmol) of 1.0 M t-BuOK in 1.5 mL of THF at 0° C. for :1.5 hr. Flash chromatography followed by preparative HPLC with MeOH-AcOH-CH2Cl2 (3.5:1.5:95) furnished 107.9 mg 60.2%) of (E)-hexenoic acid and 35.4 mg (19.8%) of (Z)-hexenoic acid (E/Z=3:1). The title (E)-isomer was characterized as follows: mp 86-90° C.; 1H NMR (CDCl3) δ8.55 (br s, 1H), 8.45 (d, J=4.7 Hz, 1H), 8.25 (s, 1H), 8.04 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.2 Hz, 2H), 7.21 (m, 1H), 7.12 (distorted t, J=~5.1 Hz, 1H), 6.19 (t, J=7.5 Hz, 1H), 3.44 (dt, J=7.0, 6.7, Hz, 2H), 2.34 (t J=7.1 Hz, 2H), 2.25 (dt, J=7.4, 7.3 Hz, 2H), 1.68-0.82 (m, 19H); FDMS 516 (M+1). Anal. (C31H37N3O4) C, H, N.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:11](=S)=[S:12].[OH-].[K+]>O.C(O)C>[SH:12][C:11]1[O:8][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[N:9][N:10]=1
Reactant: S=C=S
Reactant: NNC(=O)c1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Sc1nnc(-c2cccnc2)o1

Procedure:
13.7 g (0.1 mol) of nicotinic acid hydrazide and 8 g (0.105 mol) of carbon disulfide are added dropwise to a solution of 56 g (0.1 mol) of potassium hydroxide in 20 g of water and 350 ml of 95% ethanol. The reaction mixture is refluxed for 3 hours, then the solvent is evaporated off under vacuum and the residue is dried under a high vacuum. The dry residue is stirred in 75 ml of water, filtered, and the filtrate is neutralised with 1N hydrochloric acid. The precipitated product is isolated by filtration, washed in succession with acetone and hexane and vacuum dried, affording 9.9 g (55% of theory) of the title compound with a melting point of 237° C.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH:9][NH2:10])[CH:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:4]=1)[CH3:2].[CH3:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1)=O>C(O)C>[CH2:1]([C:3]1[N:8]=[C:7]([NH:9][N:10]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=2)[CH3:19])[CH:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:4]=1)[CH3:2]
Reactant: CCc1nc(NN)cc(-c2ccccc2OC)n1
Reactant: CC(=O)c1ccc(N(C)C)cc1
Solvent: CCO
Product: CCc1nc(NN=C(C)c2ccc(N(C)C)cc2)cc(-c2ccccc2OC)n1
Yield: 12.5 %

Procedure:
A solution of [2-Ethyl-6-(2-methoxy-phenyl)-pyrimidin-4-yl]-hydrazine (100 mg, 0.41 mmol) and 4-dimethylaminoacetophenone (67 mg, 0.41 mmol) in ethanol (1.0 mL) was heated in the microwave (CEM Discover, 150 C, QuickTest method) for 6 hours. An initial purification by Si gel chromatography (2:1 hexanes:ethyl acetate) was followed by a crystallization from ethyl acetate:hexanes to yield 20 mg (13%) of the title compound as a yellow solid. HPLC Purity: 97%.
Reaction SMILES: [Cl:1]C1C(F)=CC(C#N)=C(O[C@@H](C2C=CC=CC=2)CCI)C=1.CC(O[C:27](=O)[NH:28][CH2:29][CH2:30][CH:31]([OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(C)C.Cl[C:41]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:42]=1[C:48]([F:51])([F:50])[F:49]>>[ClH:1].[Cl:47][C:45]1[CH:46]=[CH:41][C:42]([C:48]([F:49])([F:50])[F:51])=[C:43]([CH:44]=1)[O:38][CH:31]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:30][CH2:29][NH:28][CH3:27]
Reactant: CC(C)(C)OC(=O)NCCC(O)c1ccccc1
Reactant: N#Cc1cc(F)c(Cl)cc1O[C@H](CCI)c1ccccc1
Reactant: FC(F)(F)c1ccc(Cl)cc1Cl
Product: CNCCC(Oc1cc(Cl)ccc1C(F)(F)F)c1ccccc1
Product: Cl

Procedure:
The title compound was prepared by the method of Example 3 (b) using racemic (3-hydroxy-3-phenylpropyl)carbamic acid 1,1-dimethylethyl ester and 2,4-dichloro-1-(trifluoromethyl)benzene to give 70 mg of the product as a colourless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2.[C-:13]#[N:14].[Na+].[Cl-].[NH4+]>CN1CCCC1=O.O>[C:13]([C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2)#[N:14]
Reactant: Oc1ccc2ncc(Br)cc2c1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cnc2ccc(O)cc2c1
Temperature: 150 °C
Reaction time: 7 h

Procedure:
3-Bromo-6-hydroxyquinoline (1.12 g) in dry N-methylpyrrolidin-2-one (10 ml) was treated with cuprous cyanide (0.55 g) and stirred at 150° C. for 7 hours under an atmosphere of nitrogen then stored at ambient temperature for 18 hours. The mixture was treated with sodium cyanide (1.5 g) in water (5 ml) and heated at 75° C. for 15 minutes. 10% Aqueous ammonium chloride solution (25 ml) was added and the mixture cooled to ambient temperature. The reaction mixture was extracted with ethyl acetate and the organic phase separated, washed with water, dried over magnesium sulphate and evaporated under reduced pressure to give a yellow brown solid. The solid was fractionated by chromatography to give the required product as a yellow solid.