Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].C(N(CC)CC)C.[CH2:18]([O:20][C:21]([C:23]1[S:24][C:25]([C:28](Cl)=[O:29])=[CH:26][CH:27]=1)=[O:22])[CH3:19]>C(#N)C>[CH2:18]([O:20][C:21]([C:23]1[S:24][C:25]([C:28](=[O:29])[NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)=[CH:26][CH:27]=1)=[O:22])[CH3:19]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1ccc(C(=O)Cl)s1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 22 h
Yield: 90 %

Procedure:
Starting material (12(e)) was prepared as follows. To a stirring solution of 3,4-dichlorobenzylamine (0.53 mL; 4.0 mmole) in acetonitrile (10 mL) was added triethylamine (1.67 mL; 12.0 mmole) and a solution of (11(a)) (0.87 g; 4.0 mmole, see Example 11) in acetonitrile (20 mL). The solution was stirred at ambient temperature. under argon, for 22 hours. The solvent and excess triethylamine were removed in vacuo and the residue partitioned between chloroform and water. The organic phase was washed with water and brine, dried over magnesium sulphate and vacuumed to dryness to give 5-(3,4-dichlorobenzyl-carbamoyl)-thiophene-2-carboxylic acid ethyl ester (12(a)) as a cream solid ( 90%).
Reaction SMILES: [OH:1][C@H:2]([CH2:8][C@H:9]([OH:33])/[CH:10]=[CH:11]/[C:12]1[N:13]([CH:30]([CH3:32])[CH3:31])[C:14](=[O:29])[C:15]2[C:20]([C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:3][C:4]([O:6][CH3:7])=[O:5]>ClCCl.[O-2].[O-2].[Mn+4]>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:29])[N:13]([CH:30]([CH3:32])[CH3:31])[C:12]=2/[CH:11]=[CH:10]/[C:9](=[O:33])[CH2:8][C@@H:2]([OH:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5])=[CH:27][CH:26]=1
Reactant: COC(=O)C[C@H](O)C[C@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2c(=O)n1C(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)C[C@H](O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2c(=O)n1C(C)C
Reaction time: 17 h

Procedure:
A solution of methyl (3R,5S)-(E)-3,5-dihydroxy-7-[4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl]hept-6-enoate (as prepared in Example 10; 1.6 g) in dichloromethane (160 ml) was stirred at room temperature under argon with the exclusion of light. Manganese dioxide was added portionwise (4×4 g) over 3 hours and the mixture stirred for a further 17 hours. The mixture was filtered through diatomaceous earth and the filter pad washed with dichloromethane (3×50 ml). The combined filtrate and washings were evaporated to give a viscous orange gum which was purified by flash chromatography on silica gel using diethyl ether as eluant to give methyl (3R)-(E)-7-[4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl]-3-hydroxy-5-oxohept-6-enoate as a yellow foam (NMR (in CDCl3): 1.70 (6H, d, J=8 Hz), 2.47 (2H, d, J=6 Hz), 2.58 (2H, m), 3.30 (1H, d, J=4 Hz), 3.76 (3H, s), 4.28-4.58 (2H, m plus sept), 5.99 (1H, d, J=16 Hz), 6.97-7.59 (8H, m), 8.43 (1H, m)].
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:4](=[O:9])[CH2:5][C:6](=O)[CH3:7])[CH3:3].[CH3:11][N:12]([CH3:19])[CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH2:18].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[CH3:1][C:2]([CH3:10])([C:4](=[O:9])[CH2:5][C:6](=[N:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][N:12]([CH3:19])[CH3:11])[CH3:7])[CH3:3]
Reactant: CC(=O)CC(=O)C(C)(C)C
Reactant: CN(C)CCOCCN
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(CC(=O)C(C)(C)C)=NCCOCCN(C)C
Reaction time: 72 h

Procedure:
In a 100 mL round bottom flask equipped with a magnetic stirrer, 8 g 2,2-dimethylhexane-3,5-dione was combined with 1.1 equivalents of 2-(2-(dimethylamino)ethoxy)ethylamine, anhydrous sodium sulfate and anhydrous diethyl ether and stirred over three days under nitrogen. The ether was removed on a rotary evaporator and the residue was vacuum distilled through a Vigreux column to yield 9.7 g of product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Mg].C(O[CH2:21][C:22]([F:34])=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)(=O)C>O1CCCC1>[F:34][C:22]([CH2:21][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1)=[CH:23][C:24]1([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH2:25][CH2:26]1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(F)cc2)CC1
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc(F)cc2)CC1)Cc1ccc(F)c(Oc2ccccc2)c1
Yield: 34.4 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.3 g), tetrahydrofuran (2 ml) and magnesium (21 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-fluorophenyl)-cyclopropane (Example 20) (88 mg). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C18; solvent: methanol; flow rate: 2 ml/min) to afford 1-(2-fluoro-3-(4-fluoro-3-phenoxy-phenyl)prop-1-enyl)-1-(4-fluorophenyl)cyclopropane (45.6 mg, 37%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]2C(=O)C3=CC=CC=C3C2=O)=[CH:6][CH:5]=[C:4]([Cl:20])[N:3]=1>CCO.CN(C=O)C>[Cl:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=[C:4]([Cl:20])[N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: NCc1ccc(Cl)nc1Cl
Yield: 81.9 %

Procedure:
In a mixture of 50 ml EtOH and 20 ml DMF was dissolved 3.1 g (0.01 mole) of N-(2,6-dichloro-3-pyridylmethyl)phthalimide under heating, followed by addition of 0.75 g (0.015 mole) of H2NNH2 ·H2O under reflux. After 1 hour of refluxing, EtOH and DMF were distilled off. To the residue were added 10 ml of concentrated hydrochloric acid and 5 ml of water, and the mixture was refluxed for 30 minutes. The resulting crystals were filtered off and the filtrate was neutralized with NaHCO3 and extracted with CH2Cl2 (30 ml×3). The extract was dried over MGSO4 and the solvent was distilled off to give 1.45 g of the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:17]=[C:18](O)[C:19](=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:20]([O:22][CH3:23])=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][C:25]([N+:26]([O-:28])=[O:27])=[C:16]([CH3:15])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])c(C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 93.7 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (5.4 g), methyl 4-methyl-5-nitrosalicylate (2.8 g) and triphenylphosphine (9.0 g) in dichloromethane (100 ml) was added diethyl azodicarboxylate (5.4 ml) and the mixture was stirred at room temperature for 9 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=4/1 as an eluant to give the desired compound (4.9 g, yield 93%) as a yellow oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[Br:37]Br.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([Br:37])=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3cccs3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 55.9 %

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-methyl-3-(2-thienylmethyl)benzene (11.08 g) obtained in Example 158-(1) was dissolved in chloroform (100 ml), and added dropwise thereto at 0° C. was a solution of bromine (3.71 g) in chloroform (13 ml). The mixture was stirred at 0° C. for 1.5 hours, and then, at room temperature for 1 hour, and the mixture was poured into a 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted twice with chloroform, washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20-67:33) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene (7.13 g) as a colorless solid. APCI-Mass m/Z 614/616 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene was treated in a manner similar to Example 106-(3) to give the desired 1-(β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene as colorless powder. APCI-Mass m/Z 446/448 (m+NH4).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])=[O:2].[CH3:12][S:13]([NH2:16])(=[O:15])=[O:14].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.ClCCl>[CH3:12][S:13]([NH:16][C:6]([C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH:1]=[O:2])=[O:7])(=[O:15])=[O:14]
Reactant: CS(N)(=O)=O
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1cccc(C=O)c1
Temperature: 25 °C
Yield: 26 %

Procedure:
A mixture of 10.18 g of 3-formylbenzoic acid, 6.99 g of methanesulfonamide, 200 ml of dichloromethane, 8.95 g of dimethylaminopyridine, 15.22 g of dicyclohexylcarbodiimide and 100 ml of tetrahydrofuran was stirred at room temperature. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, a 1 N aqueous sodium hydroxide solution was added, and the layers were separated. To the aqueous layer was added 2 N hydrochloric acid to adjust to pH 1, this was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then concentrated to obtain 4.01 g of 3-[(methanesulfonyl)aminocarbonyl]benzaldehyde [Compound No. (j)] as a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([O:11][C:12]2[CH:17]=[C:16](I)[C:15]([O:19][CH3:20])=[CH:14][C:13]=2[CH:21]([CH3:23])[CH3:22])=[CH:6][N:5]=1)[CH3:2].[C:24]([Cu])#[N:25].O>CN(C=O)C>[NH2:10][C:8]1[C:7]([O:11][C:12]2[C:13]([CH:21]([CH3:23])[CH3:22])=[CH:14][C:15]([O:19][CH3:20])=[C:16]([CH:17]=2)[C:24]#[N:25])=[CH:6][N:5]=[C:4]([NH:3][CH2:1][CH3:2])[N:9]=1
Reactant: CCNc1ncc(Oc2cc(I)c(OC)cc2C(C)C)c(N)n1
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: CCNc1ncc(Oc2cc(C#N)c(OC)cc2C(C)C)c(N)n1
Temperature: 120 °C
Yield: 71 %

Procedure:
To a solution of N2-Ethyl-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (1.65 g, 4.12 mmol) in anhydrous DMF (10 ml) was added CuCN, and the reaction mixture was heated to 120° C. for 3 hrs. The reaction mixture was poured into water (200 ml) and the insoluble portion was collected by filtration. The solid was triturated with 10% MeOH/methylene chloride/0.1% NH4OH solution (100 ml) and filtered again. The filtrate was concentrated and flash chromatographed on silica (3% MeOH in methylene chloride with 0.1% NH4OH) to give 5-(4-Amino-2-ethylamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (0.87 g, 71%) as a white solid.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.Cl>O1CCCC1.C(OCC)C>[CH:5]1([CH2:4][CH:3]=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(CC1CCCCC1)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=CCC1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 131.7 %

Procedure:
To a solution of 60 gm (349 mMol) cyclohexylacetaldehyde dimethyl acetal in tetrahydrofuran (50 ml) and diethyl ether (100 ml) was added 1N hydrochloric acid (200 ml) and the resulting mixture was stirred for 2.5 hours at room temperature. The reaction mixture was then partitioned between diethyl ether and water. The ether layer was then separated, dried over magnesium sulfate and concentrated under reduced pressure to give 58 gm of crude cyclohexylacetaldehyde.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[C:27]([CH3:28])=[CH:26][S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:22]3[C:27]([CH3:28])=[CH:26][S:25][C:23]=3[N:24]=2)=[CH:17][CH:18]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)csc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCCc3ccccc3)c3c(C)csc3n2)cc1

Procedure:
The reaction procedure as above wherein phenethylamine is reacted with 4-(4-chloro-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-(4-phenethylamino-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:25][CH2:26][CH2:27]Br)[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][C:19]([Br:24])=[CH:18][CH:17]=3>COCCOC>[Br:24][C:19]1[CH:18]=[CH:17][C:16]2[N:15]([CH2:25][CH2:26][CH2:27][O:8][CH2:7][CH:5]3[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]3)[C:14]3[C:22]([C:21]=2[CH:20]=1)=[CH:23][C:11]([Br:10])=[CH:12][CH:13]=3
Reactant: BrCCCn1c2ccc(Br)cc2c2cc(Br)ccc21
Reactant: CC1(C)OCC(CO)O1
Solvent: COCCOC
Product: CC1(C)OCC(COCCCn2c3ccc(Br)cc3c3cc(Br)ccc32)O1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
Potassium terbutylate (0.8 g, 7.1 mmoles) are added, in an inert atmosphere, to a solution of solketal (0.9 g, 7.1 mmoles) in 10 ml of 1,2-dimethoxyethane. After 15 minutes, 3,6-dibromo-9-(3′-bromopropyl)carbazole (2.1 g, 4.7 mmoles) dissolved in 10 ml of 1,2-dimethoxyethane, are added dropwise. After hours, the 1,2-dimethoxyethane is removed by distillation at reduced pressure, the residue is recovered with water and extracted with ethyl acetate. After washing the organic phase with water until neutrality, said organic phase is anhydrified on sodium sulfate. The solvent is removed by distillation at reduced pressure. After purification by elution on an alumina column (heptane/ethyl acetate=9/1), 1.6 g of 3,6-dibromo-9-{(3-[(2,2-dimethyl-1,3-di-oxolan-4-yl)methoxy]propyl}-9H-carbazole are obtained (yield=70%).
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:24]=[C:25]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1cccc(C(F)(F)F)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3-(trifluoromethyl)phenyl isocyanate (0.37 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a beige solid (0.30 g, 41% yield), mp=60–62° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=−22.0° (c=1, EtOH).
Reaction SMILES: [F:1][C:2]1[C:3](/[N:9]=[CH:10]/[N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].C(=S)=S.I[CH2:20][CH3:21]>CN(C=O)C>[CH2:20]([N:6]1[CH:7]=[C:2]([F:1])[C:3](/[N:9]=[CH:10]/[N:11]([CH3:13])[CH3:12])=[N:4][C:5]1=[O:8])[CH3:21]
Reactant: CN(C)/C=N/c1nc(O)ncc1F
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: S=C=S
Solvent: CN(C)C=O
Product: CCn1cc(F)c(/N=C/N(C)C)nc1=O
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 91.6 %

Procedure:
A 25 mL screw-top vial was charged with (E)-N′-(5-fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformimidamide (99.5 mg, 0.540 mmol), DMF (2 mL), and NaH (60% dispersion in mineral oil; 24.5 mg, 0.613 mmol) and was agitated on a rotary shaker at 50° C. for 40 min. After cooling to room temperature, carbon disulfide (0.036 mL, 0.599 mmol) was added, and the reaction mixture was agitated on a rotary shaker at room temperature for 90 min. At this point, iodoethane (0.052 mL, 0.650 mmol) was added, and the reaction mixture was further agitated at room temperature for 3.5 h, whereupon the crude mixture was concentrated in vacuo. The crude material was purified by normal phase chromatography (gradient, 0 to 30% MeOH/CH2Cl2) to afford (E)-N′-(1-ethyl-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)-N,N-dimethylformimidamide (105 mg, 67%) as a white solid: mp 157-160° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.09 (d, J=6.2 Hz, 1H), 3.70 (q, J=7.1 Hz, 2H), 3.20 (s, 3H), 3.07 (s, 3H), 1.18 (t, J=7.1 Hz, 3H); ESIMS m/z 213 ([M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C@H:9]2[C@@H:13]([CH2:14][OH:15])[O:12][C:11]([CH3:17])([CH3:16])[N:10]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=[CH:4][N:3]=1.[CH3:25][C:26]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])[CH3:27].N1C=CN=C1>>[Si:29]([O:15][CH2:14][C@H:13]1[O:12][C:11]([CH3:17])([CH3:16])[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:9]1[CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)([C:26]([CH3:28])([CH3:27])[CH3:25])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccnc(Cl)c2)[C@@H](CO)OC1(C)C
Agent: c1c[nH]cn1
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccnc(Cl)c2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C

Procedure:
The title compound was synthesized in a manner analogous to Example 475, step I via (4S,55)-tert-butyl 4-((2-chloropyridin-4-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate in the presence of TBSCl and imidazole and was used without further purification. Step 2: (4S,5S)-tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-4-((2-chloro-6-methylpyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:17][CH3:18])=[CH:11][C:12]([Br:16])=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I>O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:21])[C:12]([Br:16])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(Br)c(O)cc1OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cc(OCc2ccccc2)c(OC)cc1Br
Reaction time: 0.33 h
Yield: 28.7 %

Procedure:
5-Benzyloxy-2-bromo-4-methoxy-phenol 3 (2.76 g, 89.0 mmol) and NaH (0.89 g, 13.0 mmol, 60% dispersion in oil) were added to a flask and flushed with Ar. Dry THF (50 mL) was added and the suspension was stirred in an ice bath for 20 min. CH3I (1.7 mL, 27.0 mmol, filtered through basic alumina) was added and the mixture stirred at room temperature under Ar for 18 h. After cooling the reaction mixture in an ice bath, water was added slowly. The mixture was extracted with ethyl acetate, dried and concentrated to give yellow oil that solidified under vacuum. The oil was purified by silica gel chromatography using silica gel with (10% ethyl acetate/hexanes) to give 2.5 g (88%) of 4 as a white solid. 1H-NMR (400 MHz, CDCl3) dH 3.75 (3H, s, OCH3), 3.84 (3H, s, OCH3), 5.15 (2H, s, CH2Ph), 6.57 (1H, s, ArH), 7.07(1H,s,ArH), 7.32-7.42(5H,m,CH2Ph).
Reaction SMILES: [Br-].[CH3:2][NH:3]CC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:25]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:30]=[CH:29][C:28]([C:31]([C:33]2C=CC(C3C=CC=CC=3)=C[CH:34]=2)=O)=[CH:27][CH:26]=1>>[C:25]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:30]=[CH:29][C:28]([CH:31]=[C:33]=[CH:34][NH:3][CH3:2])=[CH:27][CH:26]=1
Reactant: O=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Reactant: CNCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CNC=C=Cc1ccc(-c2ccccc2)cc1

Procedure:
β-Methylaminoethyltriphenylphosphonium bromide was reacted with di-4-biphenylyl ketone by the method of Example 1 to give 1,1-di(4-biphenylyl-3-methylaminoprop-1-ene ene identical with that described in Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[Li][CH2:17][CH2:18]CC.C(I)C>C1COCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[CH:5]([CH2:17][CH3:18])[C:4]=2[CH:3]=1
Reactant: [Li]CCCC
Reactant: Clc1ccc2c(c1)Cc1cc(Cl)ccc1-2
Solvent: CCI
Solvent: C1CCOC1
Product: CCC1c2cc(Cl)ccc2-c2ccc(Cl)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 119.3 %

Procedure:
To a solution of 2,7-dichlorofluorene (1.0 g, 4.3 mmol) in 3 mL of THF was added n-BuLi (2 mL, 5.0 mmol) at -78° C. under argon and the solution was stirred at -78° C. for 0.5 hours. A solution of C2H5I (0.78 g, 5.0 mmol) in 1 mL of THF was poured into the solution and stirred at -78° for 15 min, quenched with NH4Cl solution, concentrated and extracted the residue with ethyl acetate, dried with MgSO4 and evaporated to get the crude product which was purified by silica gel column chromatography using hexane as the eluent to obtain 1.35 g (74%) of 2,7-dichloro-9-ethylfluorene was a white solid, mp 80°-83° C.: IR: 3435, 1453, 1422, 1296, 1160, 1072, 885, 807 cm-1.H1NMR (CDCl3, 300 MHz) δ 7.2-7.8 (m, 6H), 3.9-4.1 (t, 1H), 2.0-2.2 (m, 2H), 0.6-0.8 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.O.[Br:16]Br>C(O)(=O)C>[Br:16][C:12]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:14])[N:9]2[CH3:13])=[N:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc2c(n1)CCC(=O)N2C
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1nc2c(cc1Br)N(C)C(=O)CC2
Temperature: 60 °C
Yield: 82.1 %

Procedure:
To a solution of 0.6 g (3.1 mmol) 6-methoxy-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one in 8 ml of acetic acid was added 8 ml of water. To this mixture was added 0.32 ml (6.2 mmol) of bromine. The reaction mixture was heated to 60° C. for 1 hour. The reaction mixture was cooled to room temperature and poured into 50 ml of water. The suspension was extracted with ethyl acetate. The ethyl acetate extracts were dried (Na2SO4) and evaporated. The residue was chromatographed on silica using chloroform as the elutant. Appropriate fractions were combined and evaporated to yield 0.69 g of 7-bromo-6-methoxy-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one. TLC Rf=0.8 (10:1 ethyl acetate/chloroform). 1H NMR (CDCl3) δ 7.42 (s, 1H), 4.0 (s, 3H), 3.3 (s, 3H), 3.0 (m, 2H), 2.7 (m, 2H). Mass Spectrum: m/e=271.2, 273.2 (p+1,3).