Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Cl:12])[CH:6]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])=[C:7]([Cl:12])[CH:6]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)OC)cc1Cl
Yield: 86.2 %

Procedure:
A mixture of 45 g of product from Example 62, 62.2 g Of 1-bromotetradecane, 58.9 g of powdered potassium carbonate and 500 ml of acetone is heated at reflux temperature for 51 hours. The cooled solution is filtered and concentrated in vacuo. The residue is dissolved in methylene chloride, washed with 2% sodium bicarbonate and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:5% ethyl acetate) and recrystallized from hexane to give 76.8 g of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][CH3:27])=[O:25].FC(F)(F)C(O)=O>CC(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:10]2[CH2:11][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([NH:26][CH3:27])=[O:25])[N:7]=3)[CH2:9]2)=[CH:14][CH:15]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: Fc1ccc(OC2CN(c3ccnc(Cl)n3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2nccc(N3CC(Oc4ccc(F)cc4)C3)n2)c1
Temperature: 84 °C
Yield: 97.8 %

Procedure:
To 2-chloro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidine (90.0 mg, 0.322 mmol) and 3-amino-N-methylbenzamide (53.2 mg, 0.354 mmol) in a disposable sealed tube in 2-propanol (2.50 mL) was added trifluoroacetic acid (0.074 mL, 0.965 mmol). The resulting reaction mixture was heated at 84° C. for 18 h, cooled to RT, concentrated, taken up in MeOH-DCM, filtered through an SCX-2 column with MeOH. The product was eluted with 2.0 M NH3 in MeOH. Fractions containing the product were concentrated to afford 3-(4-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidin-2-ylamino)-N-methylbenzamide (123.9 mg).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.ClCCl.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>>[C:1]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH2:8])=[CH:12][CH:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[F:21][C:22]([F:27])([F:26])[C:23]([O-:25])=[O:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCCc1ccc(O)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc(CCN)cc1
Product: O=C([O-])C(F)(F)F
Reaction time: 4 h

Procedure:
A solution of pivaloyl-chloride (10.0 ml) was added dropwise to a stirred solution of tyramine (10.2 g) in a dichloromethane/trifluoroacetic acid mixture (1:1 v/v). The reaction mixture was stirred for 4 hours and the solvents then removed in vacuo. The syrupy residue was triturated with an ethyl acetate/diethyl ether mixture (3:1 v/v) to give 2-(4-pivaloyloxyphenyl)ethylamine as a colourless trifluoroacetate salt, m.p. 255°-257° C.; NMR: 1.3(s, 9H, pivaloyl-H), 2.85(m, 2H, CH2Ph), 3.05(m, 2H, CH2N), 7.05(d, 2H, phenyl-H), 7.3(d, 2H, phenyl-H), 8.0(broad s, 3H, NH3); m/e 222 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[C:1]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
Methoxyaryl 1 h can be coupled with benzoyl chloride 2h, either commercially available or prepared in situ from the corresponding benzoic acid, using a Lewis acid, typically AlCl3 or the like, to give benzophenone product 3h. Reduction of 3h can be accomplished by triethylsilane and an appropriate protic or Lewis acid, typically trifluoroacetic acid or borontrifluoroetherate, to give arylbenzyl 4h.
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[CH:16]=[CH:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:23][C:24](=[O:26])[CH3:25])[CH:6]=1)(=[O:3])[CH3:2].CC[O:29]CC.C1C=C(C(O)=O)C(C(OO)=O)=CC=1>CCOCC>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]3[O:29][C@@H:15]3[CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:23][C:24](=[O:26])[CH3:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOCC
Reactant: CC(=O)Oc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C=CC[C@H]3[C@H]1CC2
Agent: O=C(O)c1ccccc1C(=O)OO
Product: CC(=O)Oc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)[C@@H]4O[C@@H]4C[C@H]3[C@H]1CC2
Reaction time: 7.5 h

Procedure:
A solution of 350 mg. of 1,3-diacetoxy-8α-estra-1,3,5(10),16-tetraene in 15 ml. of ether is combined with 7 ml. of a 12% strength ether - monoperphthalic acid solution. After allowing the mixture to stand at room temperature for 7.5 hours, the mixture is worked up, yielding 1,3-diacetoxy-16α,17α-epoxy-8α-estra-1,3,5(10)-triene which, in the form of the crude product, is heated to the boiling point with 30 ml. of glacial acetic acid for 2-3 hours. After concentration under vacuum, the residue is heated, for purposes of esterification, with 2 ml. of pyridine and 2 ml. of acetic anhydride for 1.5 hours on a steam bath under N2. After the mixture has been introduced into ice water, it is taken up in methylene chloride and worked up, thus producing, after purification by chromatography on SiO2, 1,3,16β,17α-tetraacetoxy-8α-estra-1,3,5(10)-triene.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH:13]C(OC)=O)[N+:10]([O-:18])=[C:9]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:8]=2)[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O.CO>[NH2:13][C:11]1[N+:10]([O-:18])=[C:9]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:8]=[C:7]([N:1]2[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]2)[N:12]=1
Reactant: COC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OC)[n+]1[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Reaction time: 0.5 h

Procedure:
10 G. of dimethyl 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidinedicarbamate-3-oxide are dissolved in 350 ml. of chloroform and 100 ml. of methanol. The solution obtained is treated with 5 g. of sodium carbonate in 100 ml. of water and the resulting mixture is stirred at room temperature for 80 hours. The mixture is then diluted with 250 ml. of water and adjusted to pH 12.5 with concentrated sodium hydroxide. The mixture is then stirred for 30 minutes and then the two phases are separated. The aqueous phase is extracted twice with methylene chloride. The combined organic extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is chromatographed over silica gel using a mixture of chloroform and ethanol (90:10) for the elution, there being obtained pure methyl 2-amino-6-[3,6-dihydro-1(2H)-pyridyl]-4-pyrimidinecarbamate-3-oxide having a melting point of 174°-176° C.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)#[CH:2].Br[C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1.CCN(C(C)C)C(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:17]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[C:3]([C:1]#[C:2][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: Brc1ccc2ccccc2n1
Reactant: C#Cc1nc2c(N3CCOCC3)ccnn2c1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of compound 41d (1.4 g, 3.4 mmol) in DMF (5 mL) was treated with 2-bromoquinoline (2.0 g, 9.6 mol), Pd(PPh3)2Cl2 (240 mg, 0.34 mmol), Cut (30 mg, 0.16 mmol) and DIPEA (4.4 g, 34.11 mmol) under N2. The reaction mixture was stirred at rt overnight, and concentrated in vacuo. The residue obtained was purified by flash column chromatography on silica gel (EtOAc:petroleum ether (1:2)) to obtain compound 41e as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C31H34N6O3: 539.3 (M+H). found: 539.4.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:17](Br)[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Br.N1(O)CCCCC1>CC(C)=O>[CH2:17]([N:5]1[CH2:6][CH2:7][C:2]([OH:1])([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH2:3][CH2:4]1)[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCC=Cc1ccccc1
Reactant: OC1(c2ccc3c(c2)OCO3)CCNCC1
Agent: Br
Agent: ON1CCCCC1
Solvent: CC(C)=O
Product: OC1(c2ccc3c(c2)OCO3)CCN(CC=Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
4.4 g. 4-hydroxy-4-(3.4-methylene dioxy phenyl) -piperidine are dissolved hot in 75 ml. acetone, the solution obtained is mixed with 2.5 g. cinnamyl bromide and the reaction mixture is heated at reflux to boiling over the course of 4 hours. After boiling for 1 hour, part of the hydrobromide of the piperidinol used as the starting compound forms a precipitate and this is filtered off on completion of the reaction. The filtrate is then evaporated to dryness and extracted 3 times with 70 ml. ether each time. The ether solutions are combined, concentrated and mixed with petroleum ether during which time 1-cinnamyl-4-hydroxy-4-(3.4-methylene dioxy phenyl)-piperidine with a melting point of 114° - 115°C precipitates.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:12](C#N)=[CH:13][CH2:14][NH:15]C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:30][C:31]([NH2:33])=[NH:32].[CH3:34][O-].[Na+]>C(O)C>[NH2:32][C:31]1[N:33]=[C:14]([NH2:15])[C:13]([CH2:12][C:11]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)=[CH:34][N:30]=1
Reactant: C[O-]
Reactant: N=C(N)N
Reactant: COc1ccc(C(C#N)=CCNc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Cc2cnc(N)nc2N)cc1OCc1ccccc1
Yield: 38.9 %

Procedure:
75 Grams (0.5 mole) of crude 3-benzyloxy-4-methoxy-β-cyano-N-phenylcinnamylamine is added to a suspension made by stirring 40 g (0.42 mole) of guanidine hydrochloride with 27.5 g (0.51 mole) of sodium methoxide in 320 ml of ethanol. The reaction mixture is stirred and heated at reflux for 1.5 hr., after which the mixture becomes quite thick. An additional 320 ml of ethanol is added, and the refluxing is continued for a total of 20 hr. Most of the ethanol is removed by vacuum distillation, the resulting residue is stirred with 1500 ml of water and washed well with water. The crude moist product is digested with 250 ml of hot ethanol, cooled, filtered, and washed with ethanol and with water to yield 55 g (81%) of 2,4-diamino-5-(3-benzyloxy-4-methoxybenzyl)pyrimidine, m.p. 210°-212°.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]=[CH2:12].[NH3:13].CO>O>[CH:11]([N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:13])=[CH2:12]
Reactant: N
Reactant: C=Cn1cnc2c(Cl)ncnc21
Solvent: CO
Solvent: O
Product: C=Cn1cnc2c(N)ncnc21
Temperature: 50 °C

Procedure:
6-Chloro-9-vinylpurine (0.48 g, 3 mmol) was added to saturated ammonia/methanol (20 mL) and the mixture was heated at 50° C. for 15 h. Water was added and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated on a rotavap then subjected to silica gel column chromatography (5% methanol/methylene chloride) yielding the desired product.
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=2)[N:8]=1.C(N(CC)CC)C.[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:37]([Cl:41])=[CH:36][C:32]=1[C:33](O)=[O:34]>C(#N)C.O>[Br:6][C:7]1[CH:11]=[C:10]([C:12]2[O:14][C:33](=[O:34])[C:32]3[CH:36]=[C:37]([Cl:41])[CH:38]=[C:39]([Cl:40])[C:31]=3[N:30]=2)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=2)[N:8]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncc(Cl)cc1Cl
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1oc(-c2cc(Br)nn2-c2ncc(Cl)cc2Cl)nc2c(Cl)cc(Cl)cc12
Reaction time: 1 h
Yield: 45 %

Procedure:
To a 150 mL flask, methanesulfonyl chloride (1.1 g, 9.8 mmol), acetonitrile (20 mL) was added. Then the mixture of 3-bromo-1-(3,5-dichloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (3.0 g, 8.9 mmol, the product of step (3), example 4) and triethylamine (0.89 g, 8.9 mmol) in acetonitrile (30 mL) were added dropwise in 10 minutes at room temperature. The mixture was stirred for 1 hour. 2-Amino-3,5-dichlorobenzoic acid (1.6 g, 17 mmol) was added, and the reaction mixture turned into reddish brown. After being stirred for 30 minutes, the solution of triethylamine (1.8 g, 17 mmol) in acetonitrile (10 mL) was added dropwise and yellow solid precipitated. The mixture was stirred for 1 hour, another solution of methanesulfonyl chloride (1.1 g, 9.8 mmol) in acetonitrile (10 mL) was added. The reaction mixture turned into yellow and solid was precipitated. After being stirred for 1 hour, another solution of triethylamine (0.89 g, 8.9 mmol) in acetonitrile (4 mL) was added. Then the reaction mixture was stirred for overnight at room temperature. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (2×100 mL), washed with saturated sodium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Fluent: ethyl acetate/petroleum ether=1/2) to give the product (2.0 g) as a yellow solid in 45% yield.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].Cl[C:7]1[CH:8]=[C:9]([Mg]Br)[CH:10]=C[CH:12]=1.[NH2:15]Cl>CCOCC.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[N:15]1[C:10]2[C:4](=[CH:12][CH:7]=[CH:8][CH:9]=2)[CH:3]=[CH:2][CH:1]=1
Reactant: [Li]CCCC
Reactant: NCl
Reactant: Clc1cccc([Mg]Br)c1
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Solvent: CCOCC
Product: c1ccc2ncccc2c1
Reaction time: 0.25 h
Yield: 59 %

Procedure:
In a 25 mL 2-neck flask a solution of 18 (85 mg, 0.16 mmol) in Et2O (1.0 mL) was cooled to 0° C. and treated with a 2.5 M solution of n-butyllithium in hexanes (70 μL, 0.18 mmol, 1.0 equiv) and the reaction mixture was stirred for 15 min. A 1.0 M solution of chlorotitanium tri(isopropoxide) in hexanes (0.18 mL, 0.18 mmol, 1.0 equiv) was added and the reaction mixture was stirred at 0° C. for 15 min. A 1.0 M solution of m-chlorophenylmagnesium bromide in Et2O (0.65 mL, 0.65 mmol, 4.0 equiv) was added and the reaction mixture was stirred for 20 min. The reaction mixture was poured into saturated NH2Cl (5 mL), and extracted with EtOAc (3×4 mL). The extracts were washed with brine (1×5 mL), combined, dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (hexane/EtOAc, 10:1) afforded 39 mg (59%) of compound 19. Data for 19: 1H NMR (400 MHz, acetone-d6): 7.55 (d, J=8.4, 1H), 7.35 (dd, J=9.9, 2.9, 1H), 7.20 (m, 4H), 6.93 (s, 1H), 6.84 (d, J=8.4, 1H), 6.81 (dd, J=8.5, 5.0, 1H), 6.73 (td, J=8.5, 2.9, 1H), 5.67 (br s, 1H), 5.49 (s, 1 H), 1.99 (s, 3 H), 1.27 (s, 3 H, 1.24 (s, 3 H); 13C NMR (100 MHz, acetone-d6): 159.2 (d, JC-F =236), 147.8, 143.5, 134.8, 134.6, 130.7, 129.9, 129.1, 128.9, 127.8, 127.1 (d, JC-F =7.9), 125.0, 119.7, 119.6, 119.4 (d, JC-F =9.0), 116.1, 114.2 (d, JC-F =24), 109.1 (d, JC-F =25), 75.7, 51.2, 29.7, 29.4, 24.1.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:13]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:12][C@@H:11]1[O:44][C@H:45]1[C@H:50]([O:51][C:52](=[O:59])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C@@H:49]([CH2:60][O:61][C:62](=[O:69])[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:48][C@H:47]([O:70][C@H:71]2[C@H:84]([O:85][C:86](=[O:93])[C:87]3[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=3)[C@@H:83]([CH2:94][O:95][C:96](=[O:103])[C:97]3[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=3)[O:82][C@H:73]([O:74]CC3C=CC=CC=3)[C@H:72]2[O:104][C:105](=[O:112])[C:106]2[CH:111]=[CH:110][CH:109]=[CH:108][CH:107]=2)[C@H:46]1[O:113][C:114](=[O:121])[C:115]1[CH:120]=[CH:119][CH:118]=[CH:117][CH:116]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.C(Cl)(Cl)Cl.[Pd]>[C:1]([O:9][C@H:10]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:14]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:13]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:12][C@@H:11]1[O:44][C@H:45]1[C@H:50]([O:51][C:52](=[O:59])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C@@H:49]([CH2:60][O:61][C:62](=[O:69])[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:48][C@H:47]([O:70][C@H:71]2[C@H:84]([O:85][C:86](=[O:93])[C:87]3[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=3)[C@@H:83]([CH2:94][O:95][C:96](=[O:103])[C:97]3[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=3)[O:82][CH:73]([OH:74])[C@H:72]2[O:104][C:105](=[O:112])[C:106]2[CH:107]=[CH:108][CH:109]=[CH:110][CH:111]=2)[C@H:46]1[O:113][C:114](=[O:121])[C:115]1[CH:120]=[CH:119][CH:118]=[CH:117][CH:116]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC[C@H]1O[C@H](O[C@@H]2[C@H](OC(=O)c3ccccc3)[C@@H](O[C@@H]3[C@H](OC(=O)c4ccccc4)[C@@H](OCc4ccccc4)O[C@H](COC(=O)c4ccccc4)[C@H]3OC(=O)c3ccccc3)O[C@H](COC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(OC[C@H]1O[C@H](O[C@@H]2[C@H](OC(=O)c3ccccc3)[C@@H](O[C@H]3[C@H](OC(=O)c4ccccc4)[C@@H](COC(=O)c4ccccc4)OC(O)[C@H]3OC(=O)c3ccccc3)O[C@H](COC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 72 h
Yield: 93.1 %

Procedure:
The benzyl glycoside 51 (385 mg, 0.235 mmol) was dissolved in MeOH (5 mL) and chloroform (5 mL). Palladium on charcoal (5%, 538 mg) was added. The mixture was stirred under hydrogen at 100 psi for 3 days. TLC indicated complete conversion. The mixture was filtered through a plug of Celite and rinsed with EtOAc (5×1 mL). The combined filtrate and washings were evaporated to dryness, co-evaporated with DCM (3 mL) to give the hemiacetal 52 as pale-yellow foam (338 mg, 93%), used without further purification or characterization in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2C(=[CH:10][CH:11]=1)NC(=O)[C:6]([OH:13])=[C:5]2[C:14]([O:16][CH2:17][CH3:18])=[O:15].O[C:20]1C(=O)N(C)C2C(C=1C(OCC)=O)=CC=CC=2.C([O-])([O-])=O.[Cs+].[Cs+].IC.[CH3:45][N:46]([CH:48]=[O:49])[CH3:47]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:45](=[CH:10][CH:11]=1)[N:46]([CH3:47])[C:48](=[O:49])[C:6]([O:13][CH3:20])=[C:5]2[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1c(O)c(=O)n(C)c2ccccc12
Reactant: CCOC(=O)c1c(O)c(=O)[nH]c2ccc(Cl)cc12
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CI
Product: CCOC(=O)c1c(OC)c(=O)n(C)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 101 %

Procedure:
A solution of ethyl 6-chloro-3-hydroxy-2-oxo-1,2-dihydroquinoline-4-carboxylate (470 mg, 1.76 mmol), prepared following procedure described for Intermediate 16, was stirred in DMF (2 mL) at rt. Cs2CO3 (1430 mg, 4.39 mmol) was added followed by iodomethane (0.220 mL, 3.51 mmol). The resulting mixture was stirred at rt for 72 h. CH2Cl2 was added. The mixture was washed with H2O, brine, dried over MgSO4, filtered and concentrated to give an off-white solid ethyl 6-chloro-3-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-4-carboxylate (527 mg, 1.78 mmol, 101% yield) as the major product. A small amount of the O-alkylated side product ethyl 6-chloro-2,3-dimethoxyquinoline-4-carboxylate was observed by LC-MS but not isolated (<5%). LC-MS (ESI) 295.9 (M+H), RT=1.97 min (Method B).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][C:29]=1[F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=1[F:26]>>[F:13][C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][C:29]=1[F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:2]2[CH:3]=[C:4]3[N:11]([CH3:12])[CH2:10][CH2:9][N:5]3[C:6](=[O:8])[N:7]=2)=[CH:20][C:19]=1[F:26]
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(F)c(F)c2)c(F)c1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(F)c(F)c3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to those described for E1 starting from 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (4-(3,4-difluorophenoxy)-3-fluorophenyl)methanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:24]Cl>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:24][C:23]2[CH:26]=[CH:27][C:28]([F:29])=[C:21]([F:20])[CH:22]=2)[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Reactant: Fc1ccc(CCl)cc1F
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(Cc3ccc(F)c(F)c3)n2)ccc1F
Yield: 66.7 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3,4-difluorobenzyl chloride were reacted. Without purification, the reaction product was reacted further following the procedure of Example 1(7) to yield the title compound as a pale yellow solid (yield: 66.7%).