Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].CN(C)C=O.C([Li])CCC.C([O:21][C:22]([C:24]1[N:25]([CH3:40])[C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:27]2[C:32]=1[CH:31]=[CH:30][C:29]([Cl:33])=[CH:28]2)=O)C>CCCCCC>[ClH:33].[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][C:22]([C:24]1[N:25]([CH3:40])[C:26]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[C:27]2[C:32]=1[CH:31]=[CH:30][C:29]([Cl:33])=[CH:28]2)=[O:21])[CH3:2]
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCN(CC)CCNC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Product: Cl
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A solution of 2.3 g. of 2-diethylaminoethylamine in 25 ml. of dimethylformamide is treated under an atmosphere of argon at 5°-10° C. with 0.02 mol. of butyllithium (10 ml. of a 2-M solution in hexane). Then, there is added at 20°-25° C. a solution of 3.2 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid ethyl ester in 15 ml. of dimethylformamide, the hexane is removed by distillation and the mixture is subsequently stirred at 120° C. for 1 hour. After cooling, the mixture is poured on to 200 ml. of ice-water, the separated oil extracted with methylene chloride and the extract washed with water and evaporated to dryness. The residue is dissolved in 100 ml. of diethyl ether and the solution obtained extracted with 0.5 -N hydrochloric acid. The ethereal phase contains unreacted starting material which can be recovered after concentration of the solution. The aqueous acid extract is made alkaline with concentrated ammonia solution at 0° -5° C. and the separated oil extracted with diethyl ether. The ethereal extract is washed with water, dried over sodium sulfate and concentrated to dryness. The residual base is dissolved in 5 ml. of acetone and treated with excess ethereal hydrochloric acid. The hydrochloride which crystallizes out is removed by filtration and washed with diethyl ether, and there is obtained 5-chloro-2-metyl-3-phenylisoindole-1-carboxylic acid [2-(diethylamino)ethyl]amide hydrochloride having a melting point of 211°-214° C. (decomposition).
Reaction SMILES: [CH:1]12[C:9](=[C:10]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)[C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[CH:26]=[CH2:27].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[CH:1]12[C:9](=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:18]3[CH:23]=[CH:22][C:21](/[CH:27]=[CH:26]/[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:20][CH:19]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2
Reactant: Oc1ccc(C(=C2C3CCCC2CCC3)c2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2C3CCCC2CCC3)c2ccc(O)cc2)cc1
Temperature: 85 °C
Yield: 91.9 %

Procedure:
Compound 43 (0.32 g, 0.834 mmol), t-butyl acrylate (0.734 mL, 5.01 mmol), P(o-tolyl)3 (0.11 g, 0.359 mmol), Pd(OAc)2 (0.0394 g, 0.175 mmol) and Et3N (0.7 mL, 5.01 mmol) were added to a flask containing CH3CN (13 mL) and the stirred reaction mixture was heated at 85° C. for 24 h under a nitrogen atmosphere. The reaction mixture was allowed to cool at RT and then partitioned between water and EtOAc. The layers were separated, and the organic phase washed with brine, dried (MgSO4), filtered, and the filtrate was concentrated to give an oily residue. The crude oil was adsorbed onto silica and purified by flash column chromatography on silica gel with a hexanes:EtOAc gradient (100:0 to 50:50) to give compound 44 as a yellow foam (0.33 g, 92%). 1H NMR (400 MHz, DMSO-d6): δ 1.45-1.53 (m, 10H), 1.72-1.73(m, 7H), 1.96-2.01(m, 2H), 2.53-2.64 (m, 4H), 6.42 (d, J=16.1 Hz, 1H), 6.66 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.3 Hz, 2H), 7.08 (d, J=8.1 Hz, 2H), 7.48 (d, J=16.1 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 9.30 (s, 1H).
Reaction SMILES: BrC1C=C(N[C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)C=CC=1.NC1C=C(OC)C(OC)=CC=1C(OC)=[O:27].C(N)=O>O>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[NH:12][C:11](=[O:27])[N:10]=[CH:9]2
Reactant: COC(=O)c1cc(OC)c(OC)cc1N
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1OC
Solvent: NC=O
Solvent: O
Product: COc1cc2cnc(=O)[nH]c2cc1OC

Procedure:
In an example, A1 was prepared essentially as described in Barker, AJ. European Patent Application 0 566 226 A1, Oct. 20, 1993; and Gazit et al., Bioorg. Med. Chem. 4:1203-1207, 1996. Briefly, methyl 2-amino-4,5-dimethoxybenzoate was treated with formamide at 180° C. The reaction was cooled and diluted with water. The precipitate was collected by filtration, washed with water and dried to give 6,7-dimethoxyquinazolone, which was treated with thionyl chloride and dimethylformamide at reflux, concentrated, and stirred with sodium bicarbonate solution. The resulting solid was collected and crystallized from hexane to give 4-chloro-6,7-dimethoxyquinazoline, which was refluxed with 3-bromoaniline in ethanol, cooled, treated with 1 normal NaOH and the resulting solid collected by filtration to yield 4-(3-bromophenylamino)-6,7-dimethoxyquinazoline (A1).
Reaction SMILES: [CH2:1](OC1C=CC(C2C=CC(=O)NN=2)=CC=1OC)C(C)C.[CH2:21]([O:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:35]=[CH:36][C:37](=[O:40])[NH:38][N:39]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:22](C)C.C(OC1C=C(C2C=CC(=O)NN=2)C=CC=1OC)C.COC1C=C(C2C=CC(=O)NN=2)C=CC=1OCCC>>[CH:21]([O:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:35]=[CH:36][C:37](=[O:40])[NH:38][N:39]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])([CH3:22])[CH3:1]
Reactant: COc1ccc(-c2ccc(=O)[nH]n2)cc1OCC(C)C
Reactant: COc1cc(-c2ccc(=O)[nH]n2)ccc1OCC(C)C
Agent: CCCOc1ccc(-c2ccc(=O)[nH]n2)cc1OC
Agent: CCOc1cc(-c2ccc(=O)[nH]n2)ccc1OC
Product: COc1ccc(-c2ccc(=O)[nH]n2)cc1OC(C)C

Procedure:
The following are obtained analogously: 6-(4-isobutoxy-3-methoxyphenyl)-3[2H ]pyridazinone, m.p. 184°, 42.2% of theory, 6-(3-isobutoxy-4-methoxyphenyl)-3[2H]pyridazinone, m.p. 186°, 58.4% of theory, 6-(3-ethoxy-4-methoxyphenyl )-3[2H]pyridazinone, m.p. 171°, 73.1% of theory and 6-(3-methoxy-4-n-propoxyphenyl)-3[2H ]pyridazinone, m.p. 173°, 66.3% of theory.
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([CH3:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:11][CH:12]1[CH2:16][CH2:15][CH:14]([CH3:17])[C:13]1=[O:18]>>[CH3:11][C:12]12[C:13](=[O:18])[C:14]([CH3:17])([CH2:15][CH2:16]1)[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2]2
Reactant: Cc1ccccc1C(Br)Br
Reactant: CC1CCC(C)C1=O
Product: CC12CCC(C)(Cc3ccccc3C1)C2=O

Procedure:
A process for the preparation of the compounds of the present invention which are substituted by alkyl substituents, e.g., methyl substituents in the 6 and/or 9 positions, begins with the treatment of an α,α-dihaloxylene with an alkylated or dialkylated derivative of the appropriate cycloalkanone-enamine. Thus, for example, α,α-dibromoxylene is treated with the pyrrolidine enamine of 2,5-dimethylcyclopentanone to produce the corresponding 6,9-dimethyl-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene-11-one, followed by thallation as described hereinabove, to introduce the corresponding 2'-hydroxy compound and subsequent conversion to the oxime, followed by catalytic reduction to the desired D,L-11-endo-amino-6,9-dimethyl-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)SC)#[N:2].[CH2:20]([NH2:22])[CH3:21]>C(O)C>[C:1]([N:3]=[C:4]([NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[NH:22][CH2:20][CH3:21])#[N:2]
Reactant: CCN
Reactant: COc1ccc2c(c1)C(N=C(NC#N)SC)CCC2
Solvent: CCO
Product: CCNC(=NC#N)NC1CCCc2ccc(OC)cc21

Procedure:
A solution of 5.5 g of N-cyano-N'-(1,2,3,4-tetrahydro-7-methoxy-1-naphthyl)-S-methylisothiourea and 10 ml of 70 percent aqueous ethylamine in 100 ml of ethanol was heated at reflux for 37 hours. The solvent was removed by evaporation in vacuo, and the residue was chromatographed on silica gel, using ethyl acetate as eluent. The ethyl acetate was removed from the eluate by evaporation in vacuo, and the residue was crystallized from toluene to give N"-cyano-N-ethyl-N'-(1,2,3,4-tetrahydro-7-methoxy-1-naphthyl)guanidine as 2.7 g of white, crystalline solid, mp 130°-131°.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][CH3:5].C([O:11][CH3:12])=O.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>CN(C=O)C>[CH3:5]/[C:4](=[CH:12]\[O:11][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])/[C:3]([O:7][CH3:8])=[O:6]
Reactant: COC=O
Reactant: CCC(=O)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C(C)=C/OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
To a suspension of 10.6 g (250 mmol) of sodium hydride (60% in oil) in 150 ml of DMF was added dropwise a mixture of 20 g (226 mmol) of methyl propionate and 20.4 g (340 mmol) of methyl formate under ice cooling and stirred at room temperature overnight. To the reaction mixture was added portionwise 34.6 g (181 mmol) of p-toluenesulfonyl chloride under ice cooling and stirred at room temperature for 1 hour. After dilution with tert-butyl methyl ether, the solution was washed sequentially with water and saturated NaCl solution, dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1 to obtain 11.0 g of (E)-methyl 2-methyl-3-(p-toluenesulfonyloxy)-2-propenoate.
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][NH:11][CH2:10][C@@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25](Br)[CH:26]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]>>[C:16]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25]([N:11]3[CH2:12][C@H:13]([CH3:14])[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C@H:9]([CH3:15])[CH2:10]3)[CH:26]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: COc1cc2c(cc1Br)N(C(C)=O)CC2
Reactant: C[C@@H]1CNC[C@H](C)N1Cc1ccccc1
Product: COc1cc2c(cc1N1C[C@@H](C)N(Cc3ccccc3)[C@@H](C)C1)N(C(C)=O)CC2
Yield: 43 %

Procedure:
The title compound was prepared in 43% yield from cis-1-benzyl-2,6-dimethylpiperazine (Org. Prep. Proc. 1976, 8, 19) and D1 using a similar procedure to Description 2.
Reaction SMILES: O[CH2:2][C:3]([CH3:25])=[CH:4][CH2:5][CH2:6][C:7]([CH3:24])=[CH:8][CH2:9][CH2:10][C:11]([CH3:23])=[CH:12][CH:13]=[C:14]([CH:20]([CH3:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.C(Cl)(Cl)(Cl)[Cl:52]>>[Cl:52][CH2:2][C:3]([CH3:25])=[CH:4][CH2:5][CH2:6][C:7]([CH3:24])=[CH:8][CH2:9][CH2:10][C:11]([CH3:23])=[CH:12][CH:13]=[C:14]([CH:20]([CH3:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(=CC=C(C)CCC=C(C)CCC=C(C)CO)C(C)C
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)C(=CC=C(C)CCC=C(C)CCC=C(C)CCl)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 14-hydroxy-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenoate (713 mg, 2.03 mmol) in dry carbon tetrachloride (2 ml) was added triphenylphosphine (787 mg, 3.00 mmol), and the mixture was heated under reflux with stirring for 2 hours. After confirmation of disappearance of the starting material, the mixture was cooled to room temperature, and n-hexane was added thereto. Insoluble triphenylphosphine oxide was filtered and washed with n-hexane. The liltrate and the washing were combined and condensed. The resultant residue was added to a small amount of n-hexane, filtered, and washed to remove the residual triphenylphosphine oxide. The filtrate and the washing were combined and condensed to give as a residue the aimed ethyl 14-chloro-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenoate. The product was used in the subsequent reaction without purification.
Reaction SMILES: CCO.C(Cl)(=O)C.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]([OH:27])[C:25]#[N:26])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N[C:29]1[C:34]([OH:35])=[CH:33][CH:32]=[CH:31][N:30]=1>C(Cl)(Cl)Cl>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH:24]([C:25]2[O:35][C:34]3[C:29]([N:26]=2)=[N:30][CH:31]=[CH:32][CH:33]=3)[OH:27])=[CH:20][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#CC(O)CCc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ncccc1O
Solvent: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: OC(CCc1ccc(OCc2ccccc2)cc1)c1nc2ncccc2o1
Reaction time: 0.33 h

Procedure:
A mixture of anhydrous EtOH (3.6 mL) and CHCl3 (4.0 mL) at 0° C. was treated with acetyl chloride (3.4 mL, 47.6 mmol, 16.2 equiv) and was stirred for 20 min. A solution of 4-(4-(benzyloxy)phenyl)-2-hydroxybutanenitrile (S50, 750 mg, 2.94 mmol, 1 equiv) in 9 mL of CHCl3 was added dropwise and the reaction was stirred for 20 h at 25° C. The reaction mixture was concentrated and the crude product was dissolved in anhydrous EtOH. 2-Amino-3-hydroxypyridine (370 mg, 3.36 mmol, 1.1 equiv) was added and the reaction mixture was warmed at reflux overnight. Concentration followed by column chromatography (SiO2, 2.5×8 cm, 0-4% MeOH—CHCl3 gradient) afforded S51 (130 mg, 0.36 mmol, 13%) as a tan oil: 1H NMR (CDCl3, 600 MHz) 8.52 (d, 1H, J=4.8 Hz), 7.78 (d, 1H, J=7.9 Hz), 7.43 (d, 2H, J=7.0 Hz), 7.39 (t, 2H, J=7.9 Hz), 7.34-7.31 (m, 1H), 7.28-7.26 (m, 1H), 7.14 (d, 2H, J=8.3 Hz), 6.87 (d, 2H, J=8.3 Hz), 5.07-5.00 (m, 1H), 5.00 (s, 2H), 2.84-2.81 (m, 2H), 2.36-2.30 (m, 2H); 13C NMR (CDCl3, 150 MHz) 157.0, 154.6, 146.1, 143.0, 137.0, 133.0 (2C), 129.4, 128.5, 127.8, 127.4, 120.2, 118.8, 114.7, 69.9, 67.0, 36.9, 30.1; IR (film) νmax 3380, 2926, 1665, 1612, 1557, 1511, 1454, 1410, 1382, 1239, 1177, 1092, 1026, 831, 785, 737, 700 cm−1.
Reaction SMILES: N12CCCN=C1CCCCC2.[N+:12]([C:15]1[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(NC1C=CC(S([N:41]=[N+:42]=[N-])(=O)=O)=CC=1)(=O)C>C1COCC1>[N+:41](=[C:21]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1)[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[N-:42]
Reactant: C=CCOC(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=CCOC(=O)C(=[N+]=[N-])c1cccc([N+](=O)[O-])c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (10.6 g, 10.5 ml, 69.6 mmol, Eq: 1.04) in THF (59.0 ml) at 5° C. was added dropwise a solution of allyl 2-(3-nitrophenyl)acetate (intermediate B3a) (14.8 g, 66.9 mmol, Eq: 1.00) and 4-acetamidobenzenesulfonyl azide (16.6 g, 68.9 mmol, Eq: 1.03) in THF (118 ml) within 40 min and the mixture was stirred at 23° C. for 18 h protected from light. Quenched with sat. NH4Cl-sol., diluted with ethyl acetate, separated phases, the organic layer was washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left an orange semisolid, diluted with diethyl ether, filtered the solid off, washed with diethyl ether, the filtrate was concentrated in vacuum to give an orange semisolid. The crude material was purified by flash chromatography (silica gel, 300 g, 25% to 30% EtOAc in heptane) to give the title compound as a yellow solid (15.62 g, 94%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2([C:12]([F:15])([F:14])[F:13])[N:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C)C=O>[F:13][C:12]([F:15])([F:14])[C:9]1([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][N:20]2[C:16](=[O:26])[C:17]3[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19]2=[O:21])[NH:11][NH:10]1
Reactant: FC(F)(F)C1(c2cccc(CBr)c2)N=N1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(C2(C(F)(F)F)NN2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
A mixture of 3-(3-bromomethyl-phenyl)-3-trifluoromethyl-3H-diazirine, (140 mg, 0.5 mmol) and potassium phthalimide (95 mg, 0.5 mmol) in dimethylformamide (1.5 mL) was stirred at room temperature for 3 hrs. Dimethylformamide was removed in vacuo. The residue was extracted with CH2Cl2, washed with water, then dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by column chromatography (SiO2, 1:1 CH2Cl2/pentane) to provide 140 mg (Yield 82%) of the title compound as a solid; 1H NMR (300 MHz, CDCl3) δ ppm: 4.80 (2H, s) 7.09-7.21 (2H, m) 7.32 (1H, t, J=7.9 Hz) 7.41-7.49 (2H, m) 7.66-7.71 (2H, m) 7.81-7.85 (2H, m); LC/MS m/z 346 (M+H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:24])[N:5]2[C:10]3[CH:11]=[CH:12][N:13](S(C4C=CC(C)=CC=4)(=O)=O)[C:9]=3[N:8]=[CH:7][C:6]=12.[CH:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26].CCO.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.[Pd]>[CH3:24][C:4]1[N:5]2[C:10]3[CH:11]=[CH:12][NH:13][C:9]=3[N:8]=[CH:7][C:6]2=[C:2]([C:30]2[CH:31]=[CH:32][C:27]([CH:25]=[O:26])=[CH:28][CH:29]=2)[N:3]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(Br)nc(C)n23)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccc(C=O)cc2)c2cnc3[nH]ccc3n12
Temperature: 150 °C
Yield: 76.2 %

Procedure:
To a microwave reaction vial containing 3-bromo-1-methyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.100 g, 0.247 mmol, Preparation #AB.1), 4-formylphenylboronic acid (0.074 g, 0.493 mmol, Lancaster) and SiliaCat® DPP-Pd (0.031 g, 0.025 mmol, Silicycle) in 1,4-dioxane (1.0 mL) and EtOH (1.0 mL) was added a solution of Cs2CO3 (0.177 g, 0.543 mmol) in water (0.3 mL). The mixture was heated in a microwave at 150° C. for 30 min. The mixture was filtered through a filtration tube with a polyethylene frit, and the resulting solid was rinsed with EtOAc (5 mL). The solid was dissolved in a 9:1 DCM/MeOH solution and filtered. The filtrate was concentrated under reduced pressure followed by drying overnight in a vacuum oven at about 65° C. to give the title compound (0.052 g, 76%): LC/MS (Table 2, Method c) Rf=1.67 min.; MS m/z: 277 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[C:28]=4[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])[CH:19]=3)[C:14](O)=[O:15])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:49][NH2:50]>>[C:44]([CH2:43][CH2:42][C:28]1[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:18]2[CH:17]=[C:13]([C:14](=[O:15])[NH:50][CH3:49])[CH:12]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[CH:19]=2)=[CH:32][CH:31]=[CH:30][C:29]=1[O:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])([OH:46])=[O:45]
Reactant: CN
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC
Product: CNC(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCCO3)c1

Procedure:
The title compound was prepared according to the general procedure described in Example 74 starting from 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid and methylamine.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[Br:12][CH:13](Br)[CH3:14]>O.CCOC(C)=O>[Br:12][CH2:13][CH2:14][O:11][C:6]1[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([Cl:10])[CH:7]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: CC(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1cc(Cl)cc(OCCBr)c1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To a solution of NaOH (2.45 g, 61.3 mmol) in water (20 mL) was added 3,5-dichlorophenol (5 g, 30.7 mmol). The solution was heated at reflux for 1 h and was cooled to room temperature. Dibromoethane (11.52 g, 61.3 mmol) was added and the reaction was heated at reflux for 24 h. The cooled solution was diluted with EtOAc and the organic solution was washed sequentially with HCl (1N, 1×), water (1×), and brine (1×). The organic solution was dried (MgSO4), filtered, and concentrated. Purification by flash chromatography (hexanes to 5% EtOAc in hexanes ) provided the title compound (3.79 g). 1H NMR (400 MHz, CDCl3) δ 6.98 (m, 1H), 6.82 (m, 2H), 4.25 (t, 2H), 3.61 (t, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([C:11](=[CH:20]OCC)[C:12]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])#[N:10]>>[C:9]([C:11](=[CH:20][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1)[C:12]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])#[N:10]
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Reactant: Nc1cccc(F)c1
Product: CCOC(=O)NC(=O)C(C#N)=CNc1cccc(F)c1

Procedure:
3-Fluoroaniline (0.05 mol) is reacted with α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide (0.05 mol) to yield α-cyano-β-(3-fluoroanilino)-N-ethoxycarbonylacrylamide, m.p. 169.5°-171.0°, which is heated at reflux in tetralin to yield 5-cyano-1-(3-fluorophenyl)uracil, m.p. 245.5°-246.5°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]2[CH2:10][CH:11]=[CH:12][CH2:13][CH:6]2[C:5]1=[O:14].[C:15]([O:30]CC(C)C)(=O)[CH:16]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:17]1[C:18]([O:20][CH2:21][CH:22](C)C)=[O:19]>>[C:18]([O:20][CH2:21][CH2:22][N:4]1[C:5](=[O:14])[CH:6]2[CH2:13][CH:12]=[CH:11][CH2:10][CH:7]2[C:8]1=[O:9])(=[O:19])[CH:17]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:16]1[C:15]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]2[CH2:10][CH:11]=[CH:12][CH2:13][CH:6]2[C:5]1=[O:14])=[O:30]
Reactant: CC(C)COC(=O)C1CCCCC1C(=O)OCC(C)C
Reactant: O=C1C2CC=CCC2C(=O)N1CCO
Product: O=C(OCCN1C(=O)C2CC=CCC2C1=O)C1CCCCC1C(=O)OCCN1C(=O)C2CC=CCC2C1=O
Yield: 101 %

Procedure:
N-(2-Hydroxyethyl)-1,2,3,6-tetrahydrophthalimide (195.2 g, 1 mol) was dissolved in diisobutyl hexahydrophthalate (142.2 g, 0.5 mol). The mixture was treated as described in example 1 to obtain 266 g of brown crude bis[2-(1,2,3,6-tetrahydrophthalimido)ethyl] hexahydrophthalate.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[H-].[Na+].[H][H].[CH3:25][S:26][CH2:27]Cl>CN(C=O)C.CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl.O>[CH3:25][S:26][CH2:27][O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: [H][H]
Reactant: CSCCl
Agent: CN(C)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CSCOc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 4 °C
Reaction time: 16 h

Procedure:
To a solution of estrone (2.0 g, 7.39 mmol) in anhydrous DMF under Ar (g), was added NaH (60% in oil, 0.26g, 11.0 mmol). After the evolution of hydrogen had ceased, the solution was cooled in an ice bath for the addition of CH3SCH2Cl (3.56 g, 36.9 mmol, 3.08 mL) and DMAP (0.09 g, 7.0 mmol). The solution was stirred in a cold room (4° C.) for 16 hours. The reaction was stopped with cold water, extracted with ethyl acetate, wash with water and brine, dry over MgSO4, filtered and concentrated under reduce pressure. The crude extract was purified by flash chromatography on silica gel column and eluted with EtOAc:hexanes (1:9), to give EM-1066 (0.7 g, 30%) as a white solide; Rf 0.5 (3:7 EtOAc/Hexanes); M.p.65° C.; [α]D26 +116.40 (c 1.06, CHCl3); IR (ν) 2919, 2864, 1735, 1604, 1577, 1497, 1448, 1375, 1282, 1255, 1211, 1151, 1051, 989, 885, 823, 787, 739,640-690, 579 cm−1; 1H NMR δ 2.24 (3H, s, CH3—S), 5.12 (2H, s, S—CH2—O), 7.21 (1H, d, J=2.8 Hz, 1′-CH), 6.76 (2H, dd, j1=2.8 Hz and J2=8.6 Hz, 2′-CH), 6.70 (1H, d, J=8.0 Hz, 4′-CH).