Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:15][CH:14]([S:16][C:17]3[C@H:18]([CH3:48])[C@@H:19]4[C@@H:36]([C@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH3:38])[C:35](=[O:47])[N:20]4[C:21]=3[C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[CH2:13]2)[S:10][CH:11]=1)=[O:6])C=C.CC1(C)CC(=O)CC(=O)C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:13][CH:14]([S:16][C:17]3[C@H:18]([CH3:48])[C@@H:19]4[C@@H:36]([C@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[CH3:38])[C:35](=[O:47])[N:20]4[C:21]=3[C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)=[O:23])[CH2:15]2)[S:10][CH:11]=1)([OH:6])=[O:4]
Reactant: C=CCOC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]4[C@H]3C)C2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)O)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-[1-(4-allyloxycarbonyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (3.73 g, 5.2 mmol) (obtained Reference Example 41(6)) in methylene chloride (180 ml) were added dimedone (1.46 g, 10.4 mmol), tetrakis(triphenylphosphine)palladium(0) (603 mg, 0.522 mmol) and triphenylphosphine (205 mg, 0.783 mmol), and the mixture was stirred at room temperature under an atmosphere of nitrogen for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1)→methylene chloride:methanol (10:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-carboxy-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methyl-carbapen-2-em-3-carboxylate (1.91 g, yield 54%) as a pale brown solid.
Reaction SMILES: [CH:1]1[C:6]([I:7])=[C:5]([N+:8]([O-])=O)[CH:4]=[C:3]2[N:11]=[C:12]([Cl:14])[NH:13][C:2]=12>CCO.[Ni]>[CH:1]1[C:6]([I:7])=[C:5]([NH2:8])[CH:4]=[C:3]2[N:11]=[C:12]([Cl:14])[NH:13][C:2]=12
Reactant: O=[N+]([O-])c1cc2nc(Cl)[nH]c2cc1I
Agent: [Ni]
Solvent: CCO
Product: Nc1cc2nc(Cl)[nH]c2cc1I
Reaction time: 7 h
Yield: 61.8 %

Procedure:
A mixture of 0.339 g (1.048 mmol) of 26 and 0.090 g (wet) of Ra-Ni in 10 mL of EtOH was hydrogenated at room temperature, 50 psi of H2 for 7 h. The reaction mixture was filtered and the filtrate was evaporated. The residue was chromatographed on a silica column (2×6 cm, eluted successively with 1%, 2%, 3% MeOH/CHCl3). Evaporation of fractions 11-17 (20 mL per fraction) gave 0.190 g (62%) of 26a as a foam. An analytical sample (a yellowish crystalline compound) was obtained by recrystallization from MeOH. MP: >200° C. (dec). MS: (EI) m/e 292.9202 (100%, M+ =292.9217). 1H NMR (DMSO-d6): d 12.80 (br s, 1, 1-NH), 7.75 (s, 1, 4-H), 6.87 (s, 1, 7-H), 5.03 (s, 2, 6-NH2). Anal. Calcd. for C7H5ClIN3 : C, 28.65; H, 1.72; N, 14.32. Found: C, 28.84; H, 1.66; N, 14.17.
Reaction SMILES: Cl.[C:2]1([CH:8]([CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:15][C:16]#[N:17].[K+].Cl.C([O-])(O)=O.[Na+]>O.CCOC(C)=O>[C:2]1([CH:8]([CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[NH:9][C:16]([NH2:17])=[O:15])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[O-]
Reactant: NC(c1ccccc1)C1CCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)NC(c1ccccc1)C1CCCO1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Phenyl(tetrahydrofuran-2-yl)methanamine HCl (640 mg, 2.99 mmol) was taken up in water (3 ml). Potassium cyanate (1215 mg, 14.97 mmol) and HCl (3 ml, 36.5 mmol) were then added. The reaction mixture was allowed to stir under microwave irradition at 80° C. for 1 hr. Saturated NaHCO3 and EtOAc were added. The products were extracted into EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give 1-(phenyl(tetrahydrofuran-2-yl)methyl)urea. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 7.23 (m, 4H), 7.18 (m, 1H), 6.43 (d, J=9.5, 1H), 5.57 (br s, 2H), 4.68-4.47 (dd, J=3.5, J=5.5, 1H), 3.97 (m, 1H), 3.76 (q, J=8.0 1H), 3.56 (q, J=7.0, 1H), 1.79-1.75 (m, 3H), 1.73 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[CH:7]([C:19]([O:21]CC)=[O:20])[C:8](=[O:18])[N:9]2[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][C:3]=1[NH:25][C:26]1[C:31]([F:32])=[CH:30][C:29]([F:33])=[CH:28][C:27]=1[Cl:34].Cl>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[CH:7]([C:19]([OH:21])=[O:20])[C:8](=[O:18])[N:9]2[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][C:3]=1[NH:25][C:26]1[C:31]([F:32])=[CH:30][C:29]([F:33])=[CH:28][C:27]=1[Cl:34]
Reactant: CCOC(=O)C1C(=O)c2cc(Nc3c(F)cc(F)cc3Cl)c(Cl)cc2N(c2cccnc2)C1=O
Agent: Cl
Solvent: CCO
Product: O=C(O)C1C(=O)c2cc(Nc3c(F)cc(F)cc3Cl)c(Cl)cc2N(c2cccnc2)C1=O
Temperature: 90 °C
Yield: 62.7 %

Procedure:
12 mg (0.02 mmol) of ethyl 7-chloro-6-(2-chloro-4,6-difluorophenylamino)-4-oxo-1-pyridin-3-yl-1,4-dihydroquinolone-3-carboxylate were suspended in 6 ml of an ethanol/2 N sodium hydroxide solution mixture (1:1) and heated at 90° C. for 3 hours. After cooling to room temperature, the pH was adjusted to 2 with 2 N hydrochloric acid and the precipitate was filtered off with suction. 6 mg (53%) of the product were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:11]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:12]2[C:17]([N:18]=1)=[CH:16][N:15]=[C:14]([NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[N:13]=2.[C:32]1(=[O:38])[O:37][C:35](=[O:36])[CH2:34][CH2:33]1>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:11]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:12]2[C:17]([N:18]=1)=[CH:16][N:15]=[C:14]([NH:19][C@H:20]1[CH2:21][CH2:22][C@H:23]([O:26][C:32]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:38])[CH2:24][CH2:25]1)[N:13]=2
Reactant: O[C@H]1CC[C@H](Nc2ncc3nc(Nc4c(F)cccc4F)n(C4CCCC4)c3n2)CC1
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)O[C@H]1CC[C@H](Nc2ncc3nc(Nc4c(F)cccc4F)n(C4CCCC4)c3n2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
trans-4-(8-(2,6-Difluorophenylamino)-9-cyclopentyl-9H-purin-2-ylamino)cyclohexanol (1 mmol, 1 eq.) and succinic anhydride (10 mmol, 10 eq.) were mixed in 25 mL pyridine and stirred at room temperature for 3 days. The mixture was heated at 50° C. for about 10 hours and the solvent was subsequently evaporated. The residue was recrystallized from acetone/MeOH to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10](S(C)(=O)=O)[N:11]=[CH:12][C:7]=2[CH:6]=1.[NH2:29][C@H:30]([CH3:33])[CH2:31][OH:32]>O1CCCC1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10]([NH:29][C@H:30]([CH3:33])[CH2:31][OH:32])[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: C[C@@H](N)CO
Reactant: C[C@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(S(C)(=O)=O)nc21
Solvent: C1CCOC1
Product: C[C@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(N[C@H](C)CO)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a tetrahydrofuran (5 mL) solution of 6-(2,4-difluorophenoxy)-8-((S)-2-hydroxypropyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (400 mg, 1 mmol) was added (R)-2-amino-1-propanol (0.38 mL, 5 mmol) and stirred overnight at room temperature. Concentrated under vacuum and chromatographed on silica gel eluding with 2% methanol in dichloromethane and converted to the hydrochloride salt to give 370 mg 6-(2,4-difluoro-phenoxy)-2-((R)-2-hydroxy-1-methyl-ethylamino)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one (mass spec. M+1=407, MP=174.9-178.1° C.).
Reaction SMILES: [CH2:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][C:15]=2[O:28]CC2C=CC=CC=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([NH:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[OH:28])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCCCNC(=O)N1CCC(c2ccc(O)cc2O)CC1
Reaction time: 4 h

Procedure:
In a 25 ml round-bottomed flask, 0.25 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid butylamide is dissolved in 9 ml of methanol in the presence of 0.1 g of palladium-on-charcoal at 10%. The reaction mixture is stirred for 4 hours under a hydrogen atmosphere. The reaction mixture is filtered.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][O:7][C:8]1[C:9]([F:18])=[C:10]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[C:11]#[N:12]>O>[CH3:6][O:7][C:8]1[C:9]([F:18])=[C:10]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[C:11]([NH2:12])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: COc1c(F)c(F)cc(C#N)c1F
Solvent: O
Product: COc1c(F)c(F)cc(C(N)=O)c1F
Temperature: 0 °C

Procedure:
5 ml of concentrated sulfuric acid and 1.2 ml of water were added to 1.24 g (0.007 mole) of 3-methoxy-2,4,5-trifluorobenzonitrile (XXIV) [prepared as described in Step (E4) above], and the mixture was heated at 100°-140° C. for 30 minutes, poured into ice-water, and extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was removed by evaporation under reduced pressure to afford 1.10 g of 3-methoxy-2,4,5-trifluorobenzamide (XXV) as a pale brown powder melting at 131°-133° C.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][O:9][CH:10]([P:19](=[O:26])([O:23]CC)[O:20]CC)[P:11](=[O:18])([O:15]CC)[O:12]CC)C(=O)C2=CC=CC=C12.Cl>O>[NH2:5][CH2:6][CH2:7][CH2:8][O:9][CH:10]([P:19](=[O:20])([OH:23])[OH:26])[P:11](=[O:12])([OH:15])[OH:18]
Reactant: CCOP(=O)(OCC)C(OCCCN1C(=O)c2ccccc2C1=O)P(=O)(OCC)OCC
Agent: Cl
Solvent: O
Product: NCCCOC(P(=O)(O)O)P(=O)(O)O

Procedure:
A mixture of tetraethyl (3-(phthalimido)-propoxymethylene)-bisphosphonate (4.4 g) and 6N hydrochloric acid (25 ml) was refluxed overnight. After cooling, the mixture was diluted with water and extracted twice with ether. The aqueous phase was evaporated to dryness, and the residue was stirred with absolute ethanol. The title compound was isolated by filtration and dried in vacuo.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[CH2:12][OH:13].[CH3:14][N:15](CCN(C)C)C>CN(C=O)C.[C-]#N.[C-]#N.[Zn+2]>[OH:13][CH2:12][CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([C:14]#[N:15])[C:3]=2[CH2:4][CH2:5][O:6]1
Reactant: OCC1OCCc2c(Br)cccc21
Reactant: CN(C)CCN(C)C
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: N#Cc1cccc2c1CCOC2CO

Procedure:
A mixture of (5-bromo-3,4-dihydro-1H-isochromen-1-yl)methanol (390 mg, 1.6 mmol), Zn(CN)2 (113 mg, 0.960 mmol), TMEDA (0.37 mg), xantphose (4.6 mg) and Pd(dba)3 (2.6 mg) in anhydrous DMF was microwaved 10 min at 100° C. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was purified with prep-HPLC to give 1-(hydroxymethyl)-3,4-dihydro-1H-isochromene-5-carbonitrile. 1H-NMR (400 MHz, CDCl3) δ: 7.49˜7.50 (m, 1H), 7.24˜7.48 (m, 2H), 4.76˜14.78 (m, 1H), 4.17˜4.22 (m, 1H), 3.76˜3.95 (m, 3H), 3.01˜3.09 (m, 1H), 2.89˜2.95 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20]>COCCOC>[C:11]1(=[O:20])[N:10]([CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]12
Reactant: O=C1c2ccccc2C(=O)N1CCl
Reactant: Oc1ccncc1
Solvent: COCCOC
Product: O=C1c2ccccc2C(=O)N1COc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 10.76 g (55 mmol) of N-chloromethylphthalimide in 80 ml of DME, 8.23 ml (55 mmol) of 1,8-diazabicyclo[5,4,0]-2-undecene was added. The mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, the reaction mixture was poured into water and extracted with ethyl acetate. The precipitate was filtered off. The aqueous layer was further extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.67 g of the desired compound (yield: 21%, colorless crystals).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]=C)[C:9]=1[CH3:17].FC(F)(F)C(C)=O.OO>O.ClCCl.C(#N)C.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+]>[CH3:17][C:9]1[C:8]([CH3:7])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:14][CH:15]1[CH2:1][O:4]1
Reactant: O=C([O-])[O-]
Reactant: C=CCc1cccc(C)c1C
Agent: CC(=O)C(F)(F)F
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: OO
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: Cc1cccc(CC2CO2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A buffer was prepared by dissolving K2CO3 (20.7 g) and EDTA-Na2 (11.5 mg) in water (100 mL). 1,2-Dimethyl-3-(2-propenyl)benzene, compound of formula (XXIII), prepared according to example 3 (0.90 g, 6.16 mmol), was dissolved in a mixture of dichloromethane and acetonitrile (v/v 1:1, 60 mL), and the buffer prepared as described above (9.3 mL) was added. To the resulting mixture, first 1,1,1-trifluoroacetone (60 μL) and then hydrogen peroxide (30% in water, 6.2 mL, 60.7 mmol) were added and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (100 mL), the organic phase was separated, and the aqueous phase was extracted with dichloromethane (2 times with 50 mL each). The combined organic phases were dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by via silica gel column chromatography using hexane:ethyl acetate as eluent (v/v 32:1) to give 851 mg (85%) of the title compound.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH2:5]([N:8]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[N:10]([C:16]2[C:17]([Cl:34])=[CH:18][C:19]([F:33])=[C:20]([N:22]3[C:31](=[O:32])[C:26]4[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=4[C:23]3=[O:24])[CH:21]=2)[C:9]1=[O:35])[CH:6]=[CH2:7].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([N:12]1[C:13](=[O:14])[N:8]([CH2:5][C:6]#[CH:7])[C:9](=[O:35])[N:10]([C:16]2[C:17]([Cl:34])=[CH:18][C:19]([F:33])=[C:20]([N:22]3[C:31](=[O:32])[C:26]4[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=4[C:23]3=[O:24])[CH:21]=2)[C:11]1=[O:15])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)[nH]c(=O)n(-c2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCn1c(=O)n(CC=C)c(=O)n(-c2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)c1=O
Reaction time: 7 h
Yield: 55.2 %

Procedure:
Propargyl bromide (0.37 mL, 3.36 mmol) is added to a mixture of N-[5-(3-allylhexahydro-2,4,6-trioxo-s-triazin-1-yl)-4-chloro-2-fluorophenyl]-1-cyclohexene-1,2-dicarboximide (1.00 g, 2.24 mmol), and potassium carbonate (0.62 g, 4.48 mmol) in N,N-dimethylformamide. The reaction mixture is stirred for 7 hours, and poured into ethyl acetate. The organic solution is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a yellow oil. Flash column chromatography of the oil using silica gel and an ethyl acetate/hexanes (1:4) solution gives the title product as a white solid (0.60 g, mp 107°-114° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:23][C:12]2=[CH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1.[F:24][C:25]1[C:30]([F:31])=[CH:29][C:28]([F:32])=[C:27]([F:33])[C:26]=1[CH2:34][CH:35]([NH2:37])[CH3:36].C(N(CC)C(C)C)(C)C>C(O)CCC>[F:24][C:25]1[C:30]([F:31])=[CH:29][C:28]([F:32])=[C:27]([F:33])[C:26]=1[CH2:34][CH:35]([NH:37][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:23][C:12]2=[CH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1)[CH3:36]
Reactant: CN1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O
Reactant: CC(N)Cc1c(F)c(F)cc(F)c1F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cc1c(F)c(F)cc(F)c1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C)C3=O
Yield: 75.9 %

Procedure:
2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.58 g, 1.75 mmol), 1-(2,3,5,6-tetrafluorophenyl)propan-2-amine (0.36 g, 1.75 mmol), n-butanol (30 mL) and N,N-diisopropylethylamine (5 mL) were mixed together in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Solvents were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a yellow solid product, 0.66 g, 75.9% yield. MS: 497.8 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 13.44 (s, 1H), 10.90 (d, 1H, J=7.0 Hz), 8.12 (s, 1H), 7.93-7.90 (m, 2H), 7.73-7.71 (m, 1H), 7.40 (d, 1H, J=7.0 Hz), 6.16 (d, 1H, J=7.5 Hz), 4.23 (m, 1H), 3.38 (m, 2H), 3.05 (s, 3H), 1.38 (d, 3H, J=6.0 Hz).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17](O)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:56][C:57]1[CH:62]=[CH:61][C:60]([CH:63]2[CH2:68][CH2:67][N:66]([CH2:69][C:70]([NH2:72])=[O:71])[CH2:65][CH2:64]2)=[CH:59][CH:58]=1>>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([NH:56][C:57]4[CH:62]=[CH:61][C:60]([CH:63]5[CH2:64][CH2:65][N:66]([CH2:69][C:70]([NH2:72])=[O:71])[CH2:67][CH2:68]5)=[CH:59][CH:58]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: NC(=O)CN1CCC(c2ccc(N)cc2)CC1
Reactant: CC(C)Oc1cccc(-c2ccc3cnc(O)nn23)c1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cccc(-c2ccc3cnc(Nc4ccc(C5CCN(CC(N)=O)CC5)cc4)nn23)c1

Procedure:
7-(3-Isopropoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (100 mg, 0.4 mmol), N-Phenylbis(trifluoromethanesulphonimide) (146 mg, 0.408 mmol), N,N-Diisopropylethylamine (0.194 mL, 1.11 mmol), and N,N-Dimethylformamide (3 mL, 40 mmol) and stir at room temperature for half an hour. Add 2-[4-(4-Amino-phenyl)-piperidin-1-yl]-acetamide (139 mg, 0.594 mmol) and stir at 60° C. overnight. The reaction was concentrated, DMSO added, filtered and placed onto the Gilson for purification. The most pure fractions were basified with saturated sodium bicarbonate, extracted with ethyl acetate, dried, filtered and collected as a yellow solid (47 mg, 30%). MP 233-235° C. LCMS (E/I+) 485 (M+H). NMR 1H (DMSO-d6)-9.43 (s, 1H), 8.97 (s, 1H), 7.82 (s, 1H), 7.73 (d, 2H, J=8.04 Hz), 7.66 (d, 1H, J=7.72 Hz), 7.43 (t, 1H, J=7.80 Hz), 7.14-7.22 (m, 5H), 6.98 (d, 1H, J=8.17 Hz), 6.94 (d, 1H, J=4.50 Hz), 4.70-4.75 (m, 1H), 2.87-2.95 (m, 4H), 2.40-2.46 (m, 1H), 2.10-2.22 (m, 2H), 1.70-1.76 (m, 4H), 1.31 (d, 6H, J=5.79 Hz).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:41]>C1COCC1>[CH3:41][N:23]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)[C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][N:19]=2)[CH:14]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:12][CH:11]=2)[N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CC1CCCN(C(=O)OC(C)(C)C)C1)c1nc(-c2ccc(N3CCOCC3)cc2)cc2nccnc12
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of tert-butyl 3-((7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-ylamino) methyl)piperidine-1-carboxylate (100 mg, 0.2 mmol) in THF (20 mL) was added NaH (30 mg, 0.6 mmol). The mixture was stirred for 2-3 hours at 0° C., and iodomethane (142 mg, 1 mmol) was then added dropwise. The reaction mixture was stirred at room temperature overnight, quenched with water and concentrated under reduced pressure. The residue was purified by chromatography to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].N1C=CC=CC=1C1C=CC=CN=1.C([Li])CCC.[F:27][C:28]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([CH3:40])[C:29]=1C(Cl)=O.Cl>C1COCC1>[F:27][C:28]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([CH3:40])[C:29]=1[C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9]
Reactant: CCOC(=O)CC(=O)O
Reactant: Cc1c(F)c(F)c(F)c(F)c1C(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1c(C)c(F)c(F)c(F)c1F
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
A solution of 10.1 g (76.5 mmol) of malonic acid monoethylester, bipyridyl (catalytic), and 200 mL of dry THF was cooled to -35° C. under argon, treated with 52 mL of 1.5M n-butyllithium (78 mmol), and warmed to -5° C. To this mixture was added 52 mL of 1.5M n-butyllithium (78 mmol) until a pale pink color persisted for 10 minutes. The suspension was cooled to -78° C. and was treated with a solution of 8.8 g (38.8 mmol) of 2,3,4,5-tetrafluoro-6-methylbenzoyl chloride in 100 mL of dry THF. The reaction mixture was stirred at -78° C. for 45 minutes, then warmed to -35° C. and poured into a mixture of ice and 1N hydrochloric acid (77 mL). The organic layer was washed with 5% sodium bicarbonate solution, 3M hydrochloric acid, and water and dried over magnesium sulfate. Concentration gave an orange oil which was chromatographed on silica gel (E. Merck 230-400 Mesh), eluting with 80:20 chloroform:ethyl acetate, to give 8.2 g of the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([C:21]([O:23][CH3:24])=[O:22])[CH2:12][CH2:13]OC1CCCCO1.C(Br)(Br)(Br)[Br:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:26][CH2:13][CH2:12][CH:11]([C:21]([O:23][CH3:24])=[O:22])[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)C(CCOC1CCCCO1)c1ccc2ccccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(CCBr)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
The product of step (a) (2.0 g, 6.1 mmol) and carbon tetrabromide (2.83 g, 8.5 mmol) were dissolved in dichloromethane (30 ml) and cooled to 0° C. under nitrogen. Triphenylphosphine (4.48 g, 17.1 mmol) was added portionwise turning the reaction mixture deep yellow. After stirring at room temperature for 18 hours the reaction mixture was concentrated under reduced pressure. The oil was purified by flash chromatography on silica gel eluting with 1:1 dichloromethane:hexane to give 1-bromo-3-(methoxycarbonyl)-3-(2-naphthyl)propane as a white solid (0.56 g, 30%).