Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH:5]1[CH3:19])([CH3:3])[CH3:2].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:36][C:37]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[C:42]([O:48][CH3:49])[C:38]=1[C:39]([NH2:41])=[O:40]>CC(N(C)C)=O.O>[CH:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:18]=[CH:17][C:14]([C:15]3[NH:41][C:39](=[O:40])[C:38]4[C:37](=[CH:45][C:44]([O:46][CH3:47])=[CH:43][C:42]=4[O:48][CH3:49])[N:36]=3)=[CH:13][CH:12]=2)[CH2:6][C@H:5]1[CH3:19])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(C)CN(c2ccc(C=O)cc2)CC1C
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4C[C@@H](C)N(C(C)C)[C@@H](C)C4)cc3)nc2c1
Temperature: 140 °C
Reaction time: 4 h
Yield: 17.4 %

Procedure:
A mixture of 4-(4-isopropyl-3,5-dimethylpiperazin-1-yl)benzaldehyde (0.400 g, 1.50 mmol), NaHSO3 (0.195 g, 1.80 mmol), and p-TsOH (0.030 g, 0.15 mmol) was added to a solution of 2-amino-4,6-dimethoxybenzamide (0.400 g, 2.40 mmol) in DMA (10 mL). The reaction was stirred at 140° C. for 4 hours, then at room temperature overnight. The mixture was diluted with H2O and extracted with CH2Cl2. The organics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 1% to 10% MeOH/CH2Cl2, followed by reverse-phase chromatography, eluting with 10% to 90% CH3CN in H2O, afforded the title compound (0.114 g, 17%). 1H NMR (300 MHz, DMSO-d6): δ 11.68 (s, 1H), 8.09 (d, J=8.9 Hz, 2H), 6.78 (d, J=9.0 Hz, 2H), 6.66 (s, 1H), 6.44 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.41-3.44 (m, 2H), 3.11-3.23 (m, 5H), 1.00-1.03 (m, 12H). ESI MS m/z 437 [M+H]+.
Reaction SMILES: Cl.C([O:4][C:5](=[O:29])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]2[C:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[N:19][CH2:20][CH2:21][C:8]=12)C.[OH-].[K+]>O.CO>[ClH:28].[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]1[C:18]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)=[N:19][CH2:20][CH2:21][C:8]1=[C:7]2[CH2:6][C:5]([OH:29])=[O:4]
Reactant: CCOC(=O)Cc1c2n(c3ccc(OC)cc13)C(c1ccc(Cl)cc1)=NCC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)c(CC(=O)O)c1n2C(c2ccc(Cl)cc2)=NCC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
117.2 g (0.27 mol) of 7-methoxy-1-(p-chlorophenyl)-3,4-dihydro-pyrimido[1,6-a]indole-5-acetic acid ethyl ester hydrochloride are introduced, while stirring, into a solution of 550 g of potassium hydroxide in 200 ml of water and 1500 ml of methanol. The mixture is stirred for 10 hours at room temperature, the methanol is distilled off in vacuo, the residue is dissolved in 1500 ml of ice-water, and 700 ml of concentrated hydrochloric acid are added to the solution while cooling with ice. The separated hydrochloride is filtered with suction and recrystallised from 2300 ml of 50% ethanol to yield 7-methoxy-1-(p-chlorophenyl)-3,4-dihydro-pyrimido[1,6-a]indole-5-acetic acid hydrochloride in the form of yellowish crystals having a melting point of 225°-228° (with decomposition).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([OH:32])=[C:27](B(O)O)[CH:28]=1>>[OH:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:25]3[CH:24]=[C:23]([CH3:22])[CH:28]=[CH:27][C:26]=3[OH:32])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(-c2cccc(-c3cccc(Br)n3)n2)c(O)c1
Reactant: Cc1ccc(O)c(B(O)O)c1
Product: Cc1ccc(-c2cccc(-c3cccc(-c4cc(C)ccc4O)n3)n2)c(O)c1
Yield: 44 %

Procedure:
6-(2-Hydroxy-4-methylphenyl)-6′-(2-hydroxy-5-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine and 5-methyl-2-hydroxyphenylboronic acid in 44% yield using method F; δH [2H6]-DMSO 13.60,(1H, b), 13.10,(1H, b), 8.32,(2H, t), 8.23,(2H, m), 8.13,(2H, d), 8.03,(1H, d), 7.95,(1H, s), 7.18,(1H, d), 6.92,(1H, d), 6.83,(2H, m), 2.33,(3H, s), 2.34,(3H, s), MS 369 (MH)+; HPLC retention time (system 1) 4.46 minutes.
Reaction SMILES: C(O)(=O)C.C(OC([NH:12][C@@:13]1([C:43]([O:45]C(C)(C)C)=[O:44])[C@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C@@H:17]([S:29][C:30]2[N:31]([CH3:35])[N:32]=[CH:33][N:34]=2)[C@@H:16]2[C@H:14]1[C@H:15]2[C:36]([O:38]C(C)(C)C)=[O:37])=O)(C)(C)C>O>[ClH:27].[NH2:12][C@@:13]1([C:43]([OH:45])=[O:44])[C@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C@@H:17]([S:29][C:30]2[N:31]([CH3:35])[N:32]=[CH:33][N:34]=2)[C@@H:16]2[C@H:14]1[C@H:15]2[C:36]([OH:38])=[O:37]
Reactant: Cn1ncnc1S[C@H]1[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@](NC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)[C@@H]1OCc1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Solvent: O
Product: Cl
Product: Cn1ncnc1S[C@H]1[C@H]2[C@H](C(=O)O)[C@H]2[C@](N)(C(=O)O)[C@@H]1OCc1ccc(Cl)c(Cl)c1
Temperature: 140 °C
Yield: 200 %

Procedure:
Add acetic acid (2.0 mL) and water (2.0 mL) to di-tert-butyl (1R,2R,3S,4S,5R,6R)-2-(tert-butoxycarbonylamino)-3-[(3,4-dichlorophenyl)methoxy]-4-[(2-methyl-1,2,4-triazol-3-yl)sulfanyl]bicyclo[3.1.0]hexane-2,6-dicarboxylate (0.305 g, 0.445 mmol) in a microwave vessel and seal and heat the mixture to 140° C. for 25 minutes. Cool and concentrate the mixture to dryness, and then add 5 N hydrochloric acid (2 mL), acetonitrile (2 mL), and transfer to a vial. Lyophilize overnight to yield the title compound as a white solid (0.227 g, 0.445 mmol; 95%): MS (m/z): 473/475/477 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][S:10][CH2:11][CH:12]=1)(=O)=O.[F:15][C:16]1[C:21](B(O)O)=[CH:20][CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[S:10]1[CH2:11][CH:12]=[C:7]([C:21]2[C:16]([F:15])=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:8][CH2:9]1
Reactant: O=S(=O)(OC1=CCSCC1)C(F)(F)F
Reactant: OB(O)c1cccnc1F
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ncccc1C1=CCSCC1
Temperature: 135 °C

Procedure:
A mixture of 3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate (4.0 g, 16.11 mmol), 2-fluoropyridin-3-ylboronic acid (2.498 g, 17.72 mmol), sodium carbonate (5.12 g, 48.3 mmol), and dichlorobis(tri-o-tolylphosphine)palladium(ii) (0.633 g, 0.806 mmol) in p-dioxane/H2O (10:1, 22 mL) was heated at 135° C. in 30 min. by microwave. The reaction mixture was cooled, diluted with H2O, extracted with EtOAc (3×), dried over MgSO4, concentrated and purified by ISCO (0-40% EtOAc/Hexanes) to give the expected product was a light brown oil. MS (M+1): 196.2.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[CH3:12][NH:13][O:14][CH3:15]>O1CCCC1.C(=O)(O)[O-]>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:13]([O:14][CH3:15])[CH3:12])=[O:5]
Reactant: CNOC
Reactant: O=C(Cl)c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
2-Chloronicotinoyl chloride (36 g, 0.20 mol) was dissolved in tetrahydrofuran (290 mL) and separately N,O-dimethylhydroxylamine hydrochloride (48 g, 0.49 mol) was stirred in 290 mL saturated bicarbonate solution until the degassing subsided. Then the bicarbonate solution was added to the acid chloride solution and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate (2×), dried over sodium sulfate, filtered and evaporated to give the desired product (34 g, 83%). LCMS for C8H10ClN2O2 (M+H)+: m/z=201.0. Found: 200.9.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:15])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.[BH4-].[Na+]>CO.Cl[Ni]Cl>[NH2:29][C:27]1[CH:26]=[CH:25][C:3]([O:4][C:5]2[C:6]3[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:15])=[CH:11][C:7]=3[N:8]=[CH:9][N:10]=2)=[C:2]([F:1])[CH:28]=1
Reactant: O=C(NCCN1CCOCC1)c1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(Oc2ncnc3cc(C(=O)NCCN4CCOCC4)sc23)c(F)c1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 39.6 %

Procedure:
To a stirred solution of 24 (1.30 g, 2.72 mmol) in anhydrous MeOH (15 mL) at room temperature under nitrogen were added NiCl2×6H2O (605 mg, 2.54 mmol) and NaBH4 (192 mg, 5.08 mmol), respectively. The reaction mixture was stirred for 50 min, concentrated, cooled to 0° C., treated with HCl (10 mL, 1M) followed by addition of NH4OH (29%) (pH 9-10), and finally extracted with AcOEt. The organic extract was successively washed with water and brine, dried over Na2SO4, filtered, and concentrated to afford the title compound 25 (450 mg, 85% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ(ppm): 9.04 (t, J=5.6 Hz, 1H) 8.73 (s, 1H), 8.23 (s, 1H), 7.07 (t, J=8.8 Hz, 1H), 6.48 (dd, J=2.4 and 13.2 Hz, 1H), 6.40 (dd, J=2.4 and 8.8 Hz, 1H), 5.47 (s, 2H), 3.62-3.52 (m, 4H), 3.44 (q, J=6.8 Hz, 2H), 2.56-2.48 (m, 2H), 2.46-2.40 (m, 4H).
Reaction SMILES: Cl.[C:2]1([C:8]2[O:12][N:11]=[C:10]([CH:13]3[O:18][CH2:17][CH2:16][NH:15][CH2:14]3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[C:25](=[O:26])[CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)[N:22]=[C:21]1N1CCOC(C2ON=C(C3C=CC=CC=3)N=2)C1.C(N(CC)CC)C>O1CCCC1>[CH3:19][N:20]1[C:25](=[O:26])[CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)[N:22]=[C:21]1[N:15]1[CH2:16][CH2:17][O:18][CH:13]([C:10]2[N:9]=[C:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:12][N:11]=2)[CH2:14]1
Reactant: Cn1c(N2CCOC(c3nc(-c4ccccc4)no3)C2)nc(-c2ccncn2)cc1=O
Reactant: c1ccc(-c2nc(C3CNCCO3)no2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCOC(c3noc(-c4ccccc4)n3)C2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of the resulting 2-(5-phenyl-[1,2,4]oxadiazol-3-yl)-morpholine hydrochloride (intermediate 28) in tetrahydrofuran (6.0 ml) was added with 2-chloro-3-methyl-6-(pyrimidine-4-yl)pyrimidin-4-one (intermediate 1, 260 mg, 2.34 mmol) and triethylamine (1.81 ml, 13.0 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The solution was partitioned between water and chloroform, and the organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (eluent; 5% methanol in chloroform) to afford 1-methyl-2-[2-(5-phenyl-[1,2,4]oxadiazol-3-yl)-morpholin-4-yl]-1H-[4,4′]bipyrimidinyl-6-one (compound 2 in Table 1, 749 mg, 64%, 2 steps) as solid
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:18])([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[CH3:7])=[O:5])[CH3:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>CC#N>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([NH:50][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[C:9]([O:8][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])([CH3:7])[CH3:18])[CH:10]=2)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
1.30 g (5.0 mmol) of 3-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzoic acid [U.S. Pat. Appl. Publ. (2005), 89 pp. US 2005096337 A1] and 0.969 g (5.25 mmol) of 2-chloro-4,6-dimethoxy-1,3,5-triazine were dissolved under argon in 5 mL of MeCN and cooled down to 0° C.; then, 1.10 mL (1.064 g=2.0 eq.) of N-methylmorpholine was added and the mixture was stirred at 0° C. for 2 h. To this mixture was added 1.277 g (6.0 mmol) 4-amino-piperidine-carboxylic acid tert-butyl ester in small portions; afterwards the reaction was then warmed up to rt. After stirring for 16 h, it was poured into crashed ice and extracted twice with MeCl2; the organic phases were washed with water, dried over MgSO4, filtered and evaporated i.V. to yield 2.18 g of the crude title compound as off-white solid. MS: 435.2 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([C:15](=[N:20][C:21]#[N:22])OCCC)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][NH2:32]>CO>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([C:15](=[N:32][CH2:31][CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[Cl:23])[NH:20][C:21]#[N:22])[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1ccccc1Cl
Reactant: CCCOC(=NC#N)c1cncc(NCc2ccccc2)c1
Solvent: CO
Product: N#CNC(=NCCc1ccccc1Cl)c1cncc(NCc2ccccc2)c1
Reaction time: 1.75 h
Yield: 84.2 %

Procedure:
To a solution of propyl 5-benzylamino-N-cyano-3-pyridinecarboximidate (114 mg, 0.38 mmol) in methanol (2 ml) was added 2-(2-chlorophenyl)ethylamine (72 mg, 0.46 mmol), and the mixture was stirred for 105 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography (Wako Gel C-200, 20 g; eluted with chloroform:methanol=200:1) and further crystallized from diethyl ether to give the title compound (126 mg, 0.32 mmol) as colorless crystals in the yield of 85%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:14]=1>>[Cl:12][C:13]1[N:18]=[C:17]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:8]=2)[CH:16]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:14]=1
Reactant: Clc1cc(-c2ccccc2)nc(Cl)n1
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(-c2cc(-c3ccccc3)nc(Cl)n2)c1

Procedure:
2-chloro-4-(3-cyanophenyl)-6-phenylpyrimidine was synthesized by the same method as in syntheses of 2,4-dichloro-6-phenylpyrimidine in the above (3-1-1), except that 2,4-dichloro-6-phenylpyrimidine was used in place of 2,4,6-trichloropyrimidine and that 3-cyanophenylboronic acid was used in place of phenylboronic acid.
Reaction SMILES: C([O:5][P:6]([C:13]([F:65])([F:64])[C:14]1[CH:63]=[CH:62][C:17]([CH2:18][C:19]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([P:50]([O:57]C(C)(C)C)([O:52]C(C)(C)C)=[O:51])([F:49])[F:48])=[CH:43][CH:42]=2)([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1)([O:8]C(C)(C)C)=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O.O>[F:65][C:13]([F:64])([P:6]([OH:8])([OH:7])=[O:5])[C:14]1[CH:15]=[CH:16][C:17]([CH2:18][C:19]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([C:47]([F:48])([F:49])[P:50]([OH:57])([OH:52])=[O:51])=[CH:45][CH:46]=2)([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:62][CH:63]=1
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CC(Cc2ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc2)(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)C(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)C(=O)OCc1ccccc1
Yield: 131 %

Procedure:
A solution of dibenzyl 2,2-di{4-[(di-tert-butoxyphosphoryl) (difluoro)methyl]benzyl}malonate (100 mg) in 2 mL of 10:1 TFA/water was stirred for 0.5 h and then concentrated. The residue was dissolved in 5 mL of water and lyopholized to give 100 mg of the title compound as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[C:11](N1C=CN=C1)(N1C=CN=C1)=S.[NH:23]([C:25](=[O:46])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C@H:35]2[CH2:40][CH2:39][C@H:38]([CH2:41][C:42]([O:44][CH3:45])=[O:43])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1)=[O:27])[NH2:24].C1N=CN(C(N2C=NC=C2)=O)C=1>CC#N.CN(C=O)C>[NH2:7][C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:11]2[O:46][C:25]([C:26]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([C@H:35]4[CH2:36][CH2:37][C@H:38]([CH2:41][C:42]([O:44][CH3:45])=[O:43])[CH2:39][CH2:40]4)=[CH:33][CH:34]=3)=[O:27])=[N:23][N:24]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)c1cccc(N)c1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cccc(C(N)=O)c4)o3)cc2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
3-Aminobenzamide (54 mg, 0.39 mmol) was added to a solution of thiocarbonyldiimidazole (71 mg, 0.39 mmol) in CH3CN (5 mL) and the mixture was stirred for 16 h. Methyl [trans-4-(4-{[hydrazino(oxo)acetyl]amino}phenyl)cyclohexyl]acetate (Intermediate 43) (110 mg, 0.33 mmol) and DMF (5 mL) was added and the mixture was stirred at 50° C. until a clear solution was obtained. PS-CDI (527 mg) was added and the temperature raised to 80° C. for 16 h. The mixture was filtered whilst hot and the polymer washed with DMF (2×5 mL). The filtrates were concentrated by evaporation to give the title compound as a solid; MS m/e (M+Na)+ 500; HPLC retention time=2.26 minutes.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:27])[C:10](=[O:26])[N:11]3[C@@H:21]([CH2:22][OH:23])[CH2:20][CH2:19][CH2:18][N:17]([CH3:24])[C:16](=[O:25])[C:12]3=2)[C:7]1=[O:28].C(N(C(C)C)CC)(C)C>CCO.[OH-].[OH-].[Pd+2]>[F:32][C:31]1[CH:2]=[CH:3][C:4]([CH2:5][N:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([OH:27])[C:10](=[O:26])[N:11]4[C@@H:21]([CH2:22][OH:23])[CH2:20][CH2:19][CH2:18][N:17]([CH3:24])[C:16](=[O:25])[C:12]4=3)[C:7]2=[O:28])=[CH:29][CH:30]=1
Reactant: CN1CCC[C@H](CO)n2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN1CCC[C@H](CO)n2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)cc2)CC3)C1=O
Reaction time: 20 h

Procedure:
A mixture of (6R)-11-(3-chloro-4-fluorobenzyl)-9-hydroxy-6-(hydroxymethyl)-2-methyl-3,4,5,6,12,13-hexahydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (109 mg, 0.24 mmol), 20% Pd(OH)2 on carbon (40 mg) and diisopropylethylamine (0.1 mL) in EtOH (2.4 mL) was stirred under hydrogen atmosphere for 20 hours. The reaction mixture was filtered through a Celite pad and the filtrate concentrated under vacuum to afford the title compound.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].[Li]CCCC.C=[O:15].Cl.C1C[O:20][CH2:19][CH2:18]1>CCOCC>[CH2:1]([OH:15])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:18][CH2:19][OH:20]
Reactant: C#CCCCCC#C
Reactant: C=O
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: OCC#CCCCCC#CCO
Temperature: -78 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
2.12 g of commercially available 1,7 octadiyne (20.0 mmol) was first combined with 80 mL of Et2O and 30 mL of THF. The solution was cooled to -78° C. and treated with 15.6 mL (42 mmol, 2.7M) of BuLi. After 0.5 hr at this temperature, 4.8 g of paraformaldehyde (160 mmol) was added and stirred for a further 2.0 hr at 0° C. At 10% soln. of aqueous HCl was added and the crude product extracted into diethyl ether. Treatment of the ether extracts with sat. NaHCO3 and brine, followed by solvent removal and column chromatography (60:40 EtOAc: Hexane) gave pure deca-2,8-diyne-1,10-diol in 50% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[O:11][CH2:10][CH2:9][O:8]1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1
Reactant: BrCCCCCC1OCCO1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCCCCC2OCCO2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
To a stirred solution of 2-(5-bromopentyl)-1,3-dioxolane (4.38 g, 19.6 mmol) in dimethyl formamide (30 mL) was added 4-hydroxybenzaldehyde (3.00 g, 24.4 mmol) and potassium carbonate (4.52 g, 32.8 mmol). The reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to afford an oil. The crude material was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford the title compound (1.92 g, 36%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[NH:20][C:19]2[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH2:24][CH2:25]/[C:26](=[N:29]/[H])/[NH:27]O)[C:16](=[O:31])[N:15]([CH2:32][CH2:33][CH3:34])[C:14]=2[N:13]=1.ClC1NC2C(=O)N(CCCC/C(=N/[H])/NO)C(=O)N(CCCCC)C=2N=1>CS(C)=O>[Cl:11][C:12]1[NH:20][C:19]2[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[N:27]=[C:6]([C:5]4[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=4)[O:8][N:29]=3)[C:16](=[O:31])[N:15]([CH2:32][CH2:33][CH3:34])[C:14]=2[N:13]=1
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCC)c1=O)NO
Reactant: O=C(O)c1ccc(O)cc1
Agent: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCCC)c1=O)NO
Solvent: CS(C)=O
Product: CCCn1c(=O)n(CCCCc2noc(-c3ccc(O)cc3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
4-Hydroxybenzoic acid (18 mg, 0.13 mmol) and CDl (24 mg, 0.15 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(8-Chloro-2,6-dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (50 mg, 0.15 mmol; prepared in a manner similar to (1Z)-5-(8-Chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide as described in Example 128(b)) was added and the mixture was stirred at 90° C. for 2 h. The reaction mixture was purified by MDAP. The product fraction was combined and concentrated under high vacuum to give the title compound as a white solid (7 mg, 11%).
Reaction SMILES: [K].CC(C)([O-])C.[CH3:7][CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:19]([N:26]1[C:30]2[CH:31]=[CH:32][C:33]([C:35](=[O:40])[CH:36](Cl)[CH2:37][CH3:38])=[CH:34][C:29]=2[O:28][C:27]1=[O:41])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O.C(O)(=O)C>[CH2:19]([N:26]1[C:30]2[CH:31]=[CH:32][C:33]([C:35]([CH:36]([C:8]([CH3:7])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:37][CH3:38])=[O:40])=[CH:34][C:29]=2[O:28][C:27]1=[O:41])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCC(Cl)C(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C(=O)OCC)C(CC)C(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
23.00 g (204.96 mmol) potassium-tert.-butoxide are placed in 1200 mL DMSO and 36.00 g (206.67 mmol) diethyl 2-methyl-malonate are added. 64.00 g (194.07 mmol) 3-benzyl-6-(2-chloro-butyryl)-3H-benzoxazol-2-one are added batchwise while being cooled at 40° C. Then the mixture is stirred for 1 h, the reaction mixture is diluted with ice water and neutralised with 15 mL glacial acetic acid. The reaction mixture is extracted with DCM, the org. phase is concentrated by rotary evaporation i. V. and the residue is separated on silica gel (eluant cyclohexane/EA).