Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:17])C(OCC)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][NH:19][CH2:20][CH2:21][NH2:22]>CO>[CH3:18][N:19]1[CH2:20][CH2:21][N:22]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[C:11]1=[O:17]
Reactant: CNCCN
Reactant: CCOC(=O)C(=O)Cc1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: CN1CCN=C(c2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen, charged with ethyl 4-nitrophenylpyruvate (5.00 g, 22.4 mmol) and anhydrous methanol (112 mL). The resulting solution was cooled to 0° C. with an ice bath, and N-methylethylenediamine (1.66 g, 22.4 mmol) was added dropwise. After addition was complete, the bath was removed and the reaction was stirred at room temperature for 18 h. After this time the reaction was concentrated under reduced pressure. The residue was purified by column chromatography to afford 1-methyl-3-(4-nitrophenyl)-5,6-dihydropyrazin-2(1H)-one (102h) in 20% yield (1.02 g) as a yellow solid: mp 191-192° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.26 (d, 2H, J=6.9 Hz), 8.05 (d, 2H, J=7.2 Hz), 3.94 (t, 2H, J=6.3 Hz), 3.55 (t, 2H, J=6.3 Hz), 3.02 (s, 3H); MS (ESI+) m/z 234.1 (M+H).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:37])=[C:5]([C:28]([O:35]C)=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:32][O:31][C:30]1[C:3](=[O:2])[C:4]([CH3:37])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])[C:28](=[O:35])[C:29]=1[O:33][CH3:34]
Reactant: COc1c(C)c(Cc2ccc(Oc3cccnc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3cccnc3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 57.7 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyloxy)benzoyl]morpholine (0.022 g, 0.0435 mmol) was dissolved in a mixed solution of acetonitrile (6 ml) and water (2 ml) and after adding thereto CAN (0.060 g, 0.109 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.012 g, 0.0251 mmol, 58%).
Reaction SMILES: [H-].[Na+].COC1C=CC(CO)=CC=1.[H][H].[C:15]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([Br:37])[C:33](Br)([F:35])[F:34])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.C(OCC)C>[C:15]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([Br:37])=[C:33]([F:35])[F:34])(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(OCCCCCCCCC(Br)C(F)(F)Br)c1ccccc1
Reactant: [H][H]
Agent: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(OCCCCCCCCC(Br)=C(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.5 %

Procedure:
Under a nitrogen atmosphere a stirred mixture of 0.09 gram (0.0036 mole) of sodium hydride in 10 ml of tetrahydrofuran was cooled in an ice bath, and 0.5 gram (0.0036 mole) of 4-methoxyphenylmethanol was added dropwise. When the evolution of hydrogen ceased, a solution of 1.5 grams (0.0033 mole) of 9,10-dibromo-10,10-difluorodecyl benzoate in 5 ml of tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 18 hours. After this time the reaction mixture was taken up in 150 ml of diethyl ether and was washed with 50 ml of water and then with 50 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure yielding 0.44 gram of 9-bromo-10,10-difluoro-9-decenyl benzoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:22]3[C:21]4[CH:23]=[C:24]([NH:27][C:28](=[O:36])[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[Cl:35])[CH:25]=[CH:26][C:20]=4[CH2:19][CH2:18][C:17]=3[C:16]([C:37]([NH2:39])=[O:38])=[N:15]2)=[CH:10][CH:9]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2].I[CH3:41]>CN(C=O)C>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:20]2[CH2:19][CH2:18][C:17]3[C:16]([C:37]([NH2:39])=[O:38])=[N:15][N:14]([C:11]4[CH:10]=[CH:9][C:8]([S:5]([NH:4][CH3:1])(=[O:6])=[O:7])=[CH:13][CH:12]=4)[C:22]=3[C:21]=2[CH:23]=1)=[O:36].[C:1]([N:4]([CH3:41])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:22]3[C:21]4[CH:23]=[C:24]([NH:27][C:28](=[O:36])[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[Cl:35])[CH:25]=[CH:26][C:20]=4[CH2:19][CH2:18][C:17]=3[C:16]([C:37]([NH2:39])=[O:38])=[N:15]2)=[CH:12][CH:13]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)NS(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Reactant: CI
Solvent: CN(C)C=O
Product: CC(=O)N(C)S(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Product: CNS(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a stirring solution of 1-{4-[(acetylamino)sulfonyl]phenyl}-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (563 mg, 1 mmol) in DMF (20 mL) was added NaH2 (40 mg, 1 mmol). The mixture was stirred at room temperature for 1 h. To the mixture was added a solution of Iodomethane (170.3 mg, 1.2 mmol) in DMF (1 mL). The solution was stirred at room temperature for 4 h and concentrated. It was purified by HPLC to give a solid of the desired compound 1-(4-{[acetyl(methyl)amino]sulfonyl}phenyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (155 mg, 27%.)
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C:7]([O:15][CH3:16])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1.[Cl-].[NH4+].N>O1CCCC1.C(OCC)(=O)C>[CH2:5]([O:4][C:2]([N:10]1[CH:11]=[CH:12][CH:13]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[C:8]([C:7]([O:15][CH3:16])=[O:14])=[CH:9]1)=[O:3])[CH3:6]
Reactant: COC(=O)c1cccnc1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)Cl
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)N1C=CC(c2ccc(F)cc2)C(C(=O)OC)=C1
Reaction time: 0.33 h
Yield: 93 %

Procedure:
Ethyl chloroformate (3.5 ml) was added to a stirred suspension of cuprous chloride (0.33 g) in dry tetrahydrofuran (100 ml) under nitrogen. After cooling to 0°, a solution of methyl nicotinate (5.0 g) in tetrahydrofuran (10 ml) was added slowly followed by the addition of 4-fluorophenyl magnesium bromide solution [from 4-bromo-fluorobenzene (4.4 ml) and magnesium (0.93 g) in tetrahydrofuran (25 ml)]. After stirring for 20 minutes, the mixture was diluted with ethyl acetate and decomposed by the addition of a saturated ammonium chloride/ammonia solution (1:1, 100 ml). The organic phase was washed with dilute acid and brine and dried over anhydrous sodium sulphate. Evaporation of the solvent gave 1,4-dihydro-1-ethoxycarbonyl-4-(4'-fluorophenyl)-3-methoxycarbonylpyridine as an off-white solid (10.37 g, 93%). A sample crystallised from ethyl acetate had m.p. 83-85°.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH2:11]([N:13]([CH2:28][CH3:29])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH2:21])=[CH:16][CH:15]=1)[CH3:12].C([O-])(=O)C.[Na+]>ClCCCl.O>[CH2:28]([N:13]([CH2:11][CH3:12])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:21][CH:8]=[O:9])=[CH:16][CH:15]=1)[CH3:29]
Reactant: C=C(c1ccccc1)c1ccc(N(CC)CC)cc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCCl
Product: CCN(CC)c1ccc(C(=CC=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 57 %

Procedure:
After adding dropwise 3.9 g of phosphorus oxychloride to a solution of 2.2 g of dimethylformamide (DMF) and 50 ml of 1,2-dichloroethane at from 0° to 5° C., the mixture was stirred at that temperature for 30 minutes. Then, a solution of 5.2 g of 1-(p-diethylaminophenyl)-1-phenylethylene in 50 ml of 1,2-dichloroethane solution was added dropwise thereto at that temperature over 30 minutes, and the mixture was reacted from 5 hours at room temperature. Hydrolysis was conducted with an addition of 100 cc of water containing 10 g of sodium acetate. After separating and water-washing an organic layer, the solvent was distilled off to obtain 4.8 g of an oily substance which was subsequently separated and purified on silica gel column chromatography to obtain 3.3 g (yield: 57% (theory)) of an oily product.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=O)=[CH:3][CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.[OH-].[Na+]>C1(C)C(C)=CC=CC=1.P(Cl)(Cl)(Cl)=O>[CH3:19][C:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:17]3[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)NCCc2ccccc2Cl)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1ccc(C2=NCCc3c(Cl)cccc32)cc1
Yield: 44.3 %

Procedure:
1-(p-Toluoylamino)-2-(2-chlorophenyl)ethane (70 g) was dissolved in 700 ml of xylene and 320 ml of phosphorus oxychloride, and while the solution was heated with stirring, 240 g of phosphorus pentoxide was added. The mixture was heated under reflux for 4 hours. Water was added to the reaction mixture. The aqueous layer was made weakly alkaline with an aqueous solution of sodium hydroxide, extracted with benzene, washed in water, and dried. The solvent was distilled off, and the residue was recrystallized from benzene to afford 29 g of 1-(4-methylphenyl)-5-chloro-3,4-dihydroisoquinoline as colorless needles.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[C:9]([Cl:16])[C:7]=2[N:8]=1.[CH2:17]([O:24][CH2:25][CH2:26][O:27][CH2:28]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[Cl:3][C:4]1[N:5]([CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:6]2[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[C:9]([Cl:16])[C:7]=2[N:8]=1
Reactant: ClCOCCOCc1ccccc1
Reactant: Clc1nc2c(Cl)c(Cl)c(Cl)c(Cl)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1c(Cl)c(Cl)c2c(nc(Cl)n2COCCOCc2ccccc2)c1Cl
Yield: 38.4 %

Procedure:
NaH (0.033 g, 1.52 mmole, 90% oil disperson) was added to a stirred suspension of 2,4,5,6,7-pentachlorobernzimidazole (14) (0.3 g, 1.03 mmole) in dry CH3CN (35 mL) under a N2 atmosphere. The solution was stirred until H2 evolution had ceased and a clear solution was obtained (20 min.). (2-Benzyloxyethoxy)methylchloride (0.31 g, 1.54 mmole) in CH3CN (10 mL) was then added dropwise. The reaction mixture was stirred for an additional 15 hr. The resulting mixture was concentrated under reduced pressure, diluted with H2O (50 mL), extracted with EtOAc (100 mL), washed with H2O (100 mL), dried (anhyd. Na2SO4) and the solvent was removed under reduced pressure to yield an oil. The resulting oil was purified by flash column chromatography (2×24 cm) (230-400 mesh). Elution of the column with hexane:EtOAc (6:4, v/v) and evaporation of the appropriate fractions followed by crystallization from hexane:EtOAc afforded 0.18 g (38.4%) of blocked product: m.p. 95° C.; 1H NMR (CDCl3): d 7.22-7.34 (m, 5H, C6H5), 5.93 (s, 2H, C-1'), 4.47 (s, 2H, CH2C6H5), 3.70-3.73 (m, 2H, C-3'), 3.45-3.57 (m, 2H, C-4'), 1.83 (s, 3H, Ac). Anal. Calcd. for C17H13NCl5O2 : C, 44.88; H, 2.86; N, 6.16. Found: C, 44.95; H, 2.59; N, 6.05.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](I)[CH:21]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(OC(C1CCN(C2C=CC=CN=2)CC1)=O)C>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:21]=[C:22]([C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([C:30]([F:41])([F:40])[F:29])[CH:36]=4)[C:23]([CH3:26])=[CH:24][CH:25]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: CCOC(=O)C1CCN(c2ccccn2)CC1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(-c4cccc(C(F)(F)F)c4)c3)cn2)CC1

Procedure:
5′-(6-Methyl-3′-trifluoromethyl-biphenyl-3-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]-bipyridinyl-4-carboxylic acid ethyl ester was prepared from 5′-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester and 3-trifluoromethylphenyl boronic acid following a method similar to the one described in the synthesis of 5′42-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester above. The product was isolated after silica gel column purification with 20-40% EtOAc in hexanes gradient, HRMS m/z calcd for C28H28N3O3F3 [M+H]+: 512.2156. Found: 512.2155.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([NH:9][CH2:10][C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=2)=[O:8])=[CH:5][N:6]=1.[NH:29]1[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]1>>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([CH2:10][NH:9][C:7]([C:4]3[S:3][C:2]([N:29]4[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]4)=[N:6][CH:5]=3)=[O:8])=[CH:12][N:13]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: O=S1(=O)CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(Br)s1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(N2CCS(=O)(=O)CC2)s1

Procedure:
2-(1,1-Dioxo-thiomorpholin-4-yl)-thiazole-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate F and thiomorpholine-1,1-dioxide. MS calcd. for C24H21ClN4O4S2 [(M+H)+] 529.1, obsd. 529.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.[Br:8][C:9]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:10]=1[O:11][C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Br:8][C:9]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:10]=1[O:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:2]2[S:6][C:5]([NH2:7])=[N:4][N:3]=2)[CH2:13]1
Reactant: Nc1nnc(Br)s1
Reactant: Fc1ccc(Br)c(O[C@H]2CCNC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nnc(N2CC[C@H](Oc3cc(F)ccc3Br)C2)s1
Temperature: 90 °C

Procedure:
A mixture of 5-bromo-1,3,4-thiadiazol-2-amine (1 g, 5.6 mmol), (3S)-3-(2-bromo-5-fluorophenoxy)pyrrolidine (1.6 g, 6.1 mmol) and sodium carbonate (1.2 g, 11 mmol) in EtOH (11 mL) was degassed with nitrogen for 5 mins. The mixture was then heated at 90° C. for 3 h. The mixture was then cooled to room temperature and filtered. The solvent was evaporated and diluted with water (50 mL). The solid precipitate was filtered and washed with water followed by Et2O to afford the title product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([NH2:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(N(CC)CC)C.Cl>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][O:2][C:3](=[O:13])[CH:4]([NH:12][C:17]1[CH:16]=[C:15]([F:14])[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Reactant: C=CCCCCCC(N)C(=O)OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCCCCC(Nc1cc(F)cc(C(F)(F)F)c1)C(=O)OC
Reaction time: 0.08 h
Yield: 206.9 %

Procedure:
Reaction performed in parallel in 8×50 mL reaction flasks. Copper (II) acetate (270 mg, 1.48 mmol., 1.1 eq.) and 4 Å molecular sieves (700 mg) were charged in 50 mL round bottom flask. Dichloromethane (10 mL, previously saturated with air) was added a single portion. 2-amino-non-8-enoic acid methyl ester (250 mg, 1.35 mmol., 1.0 eq.) was added and the reaction mixture was stirred for a further 5 min by when the initial light blue solution had turned dark blue. 3-fluoro-5-trifluoromethylbenzene boronic acid (560 mg, 2.70 mmol., 2 eq.) was added followed by triethylamine (218 mg, 2.70 mmol., 2 eq.). The reaction mixture was stirred over night under an air atmosphere. The 8 reaction mixtures were combined together and 1M hydrochloric acid (150 mL) was added. The mixture was stirred for a further 5 min until the aqueous layer turned pale blue and the organic layer turned pale yellow. The organic layer was collected, dried over sodium sulfate and the solvent removed under vacuum. The residue was purified by flash column chromatography, using a dichloromethane:heptanes gradient (from neat heptane to 50% dichloromethane in heptanes). After combining the relevant fractions and solvent removal, 970 mg (26%) of the title compound was isolated as a yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 6.66 (d, J=8.54 Hz, 1 H), 6.61 (s, 1 H), 6.42 (d, J=10.83 Hz, 1 H), 5.72-5.87 (m, J=6.71, 6.71, 10.26, 17.05 Hz, 1 H), 5.00 (dd, J=1.83, 17.09 Hz, 1 H), 4.95 (dt, J=0.95, 10.15 Hz, 1 H), 4.48 (d, J=8.54 Hz, 1 H), 4.05 (dt, J=6.45, 8.32 Hz, 1 H), 3.76 (s, 3H), 2.05 (q, J=6.92 Hz, 2 H), 1.82-1.93 (m, 1 H), 1.71-1.82 (m, 1 H), 1.30-1.45 (m, 6 H). LC-MS: purity 94% (UV), tR 2.63 min, m/z [M+H]+ 348.00.
Reaction SMILES: C[O-].[Na+].CO[C:6](=[O:21])[CH:7]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:8]([O:10]C)=O.[F:22][C:23]([F:28])([F:27])[C:24]([NH2:26])=[NH:25]>CO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH:7]1[C:6](=[O:21])[NH:26][C:24]([C:23]([F:28])([F:27])[F:22])=[N:25][C:8]1=[O:10]
Reactant: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Reactant: N=C(N)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1OC1C(=O)N=C(C(F)(F)F)NC1=O
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a stirred solution of 22.9 g sodium methylate in 250 ml methanol was added 37.5 g dimethyl-2-(o-methoxyphenoxy)malonate in portions within 15 min. Stirring was continued for 30 min. Then 15.8 g trifluoro-acetamidine was added followed by stirring for 20 h at room temperature. Work up was done according to the procedure described in Example 1d) to give 29.77 g 5-(o-methoxyphenoxy)-2-trifluoromethyl-pyrimidine-4,6-dione (or its tautomeric form). LC-MS: tR=3.41 min, [M+1]+=303.32.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:9][C:10]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:11][CH:12]=1)(=O)=O.[C:30]([C@:32]1([OH:40])[CH:37]2[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]2)[CH2:33]1)#[CH:31].C(N(CC)CC)C>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.CN(C)C=O>[CH2:21]([C:8]1[C:7]([C:31]#[C:30][C@:32]2([OH:40])[CH:37]3[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]3)[CH2:33]2)=[CH:12][CH:11]=[C:10]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:9]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: O=S(=O)(Oc1ccc(OCC2CCCCO2)nc1Cc1ccccc1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O[C@]1(C#Cc2ccc(OCC3CCCCO3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 90 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A mixture of 428 mg of 2-benzyl-6-[(tetrahydro-4H-pyran-2-yl)methyloxy]-3-pyridyl trifluoromethanesulfonate, 180 mg of (3R)-3-ethynyl-3-quinuclidinol, 57.3 mg of tetrakis(triphenylphosphine)palladium(0), 1.9 mg of cuprous iodide, 415 μl of triethylamine and 5 ml of N,N-dimethylformamide was stirred at 90° C. for 3 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution, and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 3% methanol/ethyl acetate, to give 305 mg of the target compound.
Reaction SMILES: [N+](=[CH:3][C:4](=O)[CH2:5][CH2:6][CH:7]1[O:11][C:10](=[O:12])[C:9]([O:13][CH3:14])=[C:8]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N-].C([O:24][CH2:25]C)C.C[OH:28]>C(N(CC)CC)C.C([O-])(=O)C1C=CC=CC=1.[Ag+]>[CH3:14][O:13][C:9]1[C:10](=[O:12])[O:11][CH:7]([CH2:6][CH2:5][CH2:4][C:3]([O:24][CH3:25])=[O:28])[C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOCC
Reactant: COC1=C(c2ccccc2)C(CCC(=O)C=[N+]=[N-])OC1=O
Reactant: CO
Agent: [Ag+]
Agent: O=C([O-])c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCCC1OC(=O)C(OC)=C1c1ccccc1

Procedure:
To a solution of 5-(4-diazo-3-oxobutyl)-3-methoxy-4-phenyl-2(5H)-furanone (100 mg) in methanol (2 ml) was added dropwise a solution of silver benzoate (9.6 mg) in triethylamine (0.2 ml) over a period of 10 minutes at 0° C. with stirring and the mixture was stirred for 30 minutes at ambient temperature. The reaction mixture was filtered off and the filtrate was condensed and dituted with diethyl ether. The ethereal solution was washed with lN hydrochloric acid, water and brine successively and dried. Evaporation of the solvent gave methyl 4-(4-methoxy-5-oxo-3-phenyl-2,5-dihydro2-furyl)butyrate (100 mg) as an oil.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C[Si](N[Si](C)(C)C)(C)C>[C:12]([NH:3][C:2]1[NH:1][C:10](=[O:11])[C:9]2[N:8]=[CH:7][N:6]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:5]=2[N:4]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: O=c1[nH]c(NC(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 71.8 %

Procedure:
Freshly activated guanine (0.45 g, 3 mmol) and (NH4)2SO4 (60 mg) were stirred in HMDS (50 mL) under reflux for 24 h to give a clear solution. Volatiles were evaporated in vacuo, and the residue was dissolved in dried CH3CN (50 mL). Trityl chloride (3.5 g, 12.6 mmol) was added, and the solution was stirred under reflux for 48 h. Volatiles were evaporated in vacuo, and the residue was dissolved in CH2Cl2 (10 mL). NH3/H2O (28-30%, 30 mL) was added, and precipitation was observed immediately. The mixture was stirred at ambient temperature overnight. Volatiles were evaporated in vacuo, and the residue was washed (H2O, CH2Cl2) to give 2-N,9-bistritylguanine as a solid (1.37 g, 72%), which was further purified by dissolving in MeOH/CH2Cl2 (1:15) and filtering: 1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.35 (s, 1H), 7.08-7.19 (m, 19H), 6.87 (d, J=7.4 Hz, 6H), 6.81 (d, J=7.3 Hz, 6H); 13C NMR (125 MHz, DMSO-d6) δ 157.3, 151.8, 151.0, 145.3, 142.4, 139.6, 129.6, 128.8, 128.5, 128.3, 127.6, 126.9, 120.3, 75.4, 71.1; HRMS m/z 635.2675 (M+[C43H33N5O]=635.2685).