Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:22]=[C:23]([C@:27]2([NH:34][C:35]([NH2:37])=[S:36])[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2O)[CH:24]=[CH:25][CH:26]=1.O>O1CCCC1>[Br:20][C:21]1[CH:22]=[C:23]([C:27]23[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[S:36][C:35]([NH2:37])=[N:34]3)[CH:24]=[CH:25][CH:26]=1
Reactant: NC(=S)N[C@@]1(c2cccc(Br)c2)CCOC[C@@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC1=NC2(c3cccc(Br)c3)CCOCC2S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
Diethyl azodicarbonate (13.0 mL) was added dropwise to a solution of triphenylphosphine (7.51 g) in tetrahydrofuran (200 mL) in an ice bath. The mixture was warmed to room temperature and stirred for 30 minutes. The reaction solution was cooled to 0° C., and a solution of (±)-[(3R*,4R*)-4-(3-bromophenyl)-3-hydroxytetrahydropyran-4-yl]thiourea (6.33 g) in tetrahydrofuran (44 mL) was added dropwise. The mixture was stirred overnight while gradually warming to room temperature. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain a crude product. The resulting crude product was purified by silica gel column chromatography again to obtain the title compound (3.55 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[C:7]1[N:11]([CH3:12])[CH:10]=[N:9][CH:8]=1.[Li][CH2:19]CCC.[C:23]1(=[O:28])[O:27][CH2:26][CH:25]=C1.O>O1CCCC1.CCCCCC.C(=O)=O>[CH3:19][N:9]1[C:8]([C:7]2([CH:6]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH2:25][CH2:26][O:27][C:23]2=[O:28])=[CH:12][N:11]=[CH:10]1
Reactant: O=C1C=CCO1
Reactant: Cn1cncc1C(c1cccs1)c1cccs1
Reactant: [Li]CCCC
Agent: O=C=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cn1cncc1C1(C(c2cccs2)c2cccs2)CCOC1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
16.4 g (52.5 mmol) of 5-dithiophenylmethyl-1-methylimidazole are dissolved in 240 ml of tetrahydrofuran and cooled to -78° C. 52.5 mmol of n-BuLi in 32 ml of hexane are added dropwise to this. After 30 minutes at -78° C., 4.9 ml (69.8 mmol) of γ-crotonolactone are added and, after a further 1.5 hours, 250 ml of water are added dropwise while cooling in dry ice, and the mixture is allowed to warm to room temperature. It is then washed with ethyl acetate, acidified with glacial acetic acid and again extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue obtained in this way (13.8 g) is chromatographed on silica gel with dichloromethane/methanol (9:1). 6.6 g (16.6 mmol, 32%) of 3-(1-methylimidazol-5-yl-(dithiophenyl)methylbutyrolactone are obtained as a white powder of melting point 80° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.CCCCCC.C([Li])CCC.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(OCC)C>[C:32]1([NH:38][C:39]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:3]=2)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
1.0 g (0.0029 mol) of 2-bromo-4-methoxy-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 15 ml of diethyl ether. The solution was cooled in a dry ice-acetone bath in an argon atmosphere and mixed with 1.9 ml of a 1.69M-hexane solution of n-butyl lithium (0.0029×1.1 mol; hereinafter referred to merely as “BuLi”), followed by stirring for about 10 minutes. After 0.86 g (0.0029×2.5 mol) of phenyl isocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the solution was removed from the bath and stirred at room temperature for about 30 minutes. The reaction solution was mixed with about 5 ml of 1.2N aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated sodium bicarbonate water and saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The fraction was concentrated and then subjected to precipitation using hexane, thereby obtaining an aimed product.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][NH:8][C:7]=2[C:6](=[O:12])[NH:5][C:4]1=[O:13])[CH3:2].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH2:25]([N:8]1[C:7]2[C:6](=[O:12])[NH:5][C:4](=[O:13])[N:3]([CH2:1][CH3:2])[C:11]=2[N:10]=[CH:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 80 °C

Procedure:
180 g (1 mol) of 3-ethylxanthine were initially introduced into 1000 ml of dimethylformamide, the mixture was heated to 80° C. with stirring and, after the introduction of 88 g (0.64 mol) of potassium carbonate, treated dropwise with 133 g (1.05 mol) of benzyl chloride in the course of 1 hour. It was then stirred at 100° C. for 2 hours, treated with 1000 ml of water, and the precipitated product was filtered on a suction filter, washed with water until salt-free and dried in a vacuum drying oven at 100° C. If necessary, a further purification can be carried out by reprecipitating from 1 N sodium hydroxide solution using 4 N hydrochloric acid analogously to Example 1a).
Reaction SMILES: C([O:3][C:4]([C:6]([CH3:33])([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=1)[CH2:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[O:5])C.[OH-].[Na+].O1CCCC1>CO.C(OCC)(=O)C>[C:4]([C:6]([CH3:33])([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=1)[CH2:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([OH:5])=[O:3]
Reactant: CCCCCCCCc1ccc(CCC(C)(CCP(=O)(OCC)OCC)C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCc1ccc(CCC(C)(CCP(=O)(OCC)OCC)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 82.6 %

Procedure:
To a solution of (±)-diethyl 3-ethoxycarbonyl-3-methyl-5-(4-(octyl)phenyl)pentylphosphonate (0.211 g, 0.437 mmol) in methanol (2 ml) was added 1N aqueous sodium hydroxide (1.3 ml, 1.3 mol). Tetrahydrofuran was added as necessary to keep the substrate in solution. The reaction was heated to 50° C. for 16 h then warmed to 70° and stirred at this temperature for 20 h. The reaction was diluted with ethyl acetate (30 ml) and washed with 2N aq HCl (20 ml), saturated aqueous sodium chloride (20 ml), dried over magnesium sulfate and concentrated to give a colorless oil (0.164 g): MS m/e 455.2 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([OH:8])=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.[C:24](=[O:26])=[O:25]>C1COCC1.O>[O:8]=[C:5]1[NH:6][CH:7]=[C:2]([C:24]([OH:26])=[O:25])[CH:3]=[C:4]1[C:9]([F:12])([F:11])[F:10]
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1c[nH]c(=O)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-3-(trifluoromethyl)pyridin-2-ol (0.960 g, 3.97 mmol, Aldrich) in THF (20 mL) at −78° C. under N2 was slowly added n-butyllithium solution, 1.6 M in hexane (5.45 mL, 8.73 mmol). After addition, the mixture was stirred at −78° C. for 30 min. Then, dry ice was added and the mixture was stirred at −78° C. for 30 min and at rt for 30 min. Water (20 mL) was then added slowly, and the mixture was stirred at rt for 15 min. The aqueous phase was collected and acidified (pH=5-6) using concentrated HCl. The mixture was extracted with EtOAc (3×15 mL). The combined organic layers were dried (MgSO4), concentrated, and dried in vacuo to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 208 (M+H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:31])[C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.CN(C=O)C>C(OCC)(=O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:31])[C:23](=[O:30])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1ccccc1

Procedure:
1.4 g (3.3 mmol) of N-[4′-(2,4-dioxo-thiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-methylbenzamide, 30 ml of DMF and 25 ml of ethyl acetate are introduced into a three-necked flask. The reaction medium is degassed, 1.4 g of palladium-on-charcoal (10%) are introduced and the mixture is hydrogenated under atmospheric pressure at 60° C. The reaction medium is filtered and evaporated, and the residue obtained is purified by chromatography on a column of silica eluded with a mixture of dichloromethane and methanol (99/1). After evaporation of the solvents, 300 mg (21%) of N-[4′-(2,4-dioxo-thiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbenzamide with a melting point of 70-71° C., are collected.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14](SC)=[CH:13][CH:12]=2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OO.[C:25](O)(=O)C.[S:29](=[O:32])([OH:31])[O-].[Na+]>O>[CH3:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([S:29]([CH3:25])(=[O:32])=[O:31])=[CH:13][CH:12]=2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S([O-])O
Reactant: CC(=O)O
Reactant: CSc1ccc(-c2c(S(C)(=O)=O)ccc(C(=O)O)c2C)cc1
Agent: OO
Agent: [Na+]
Solvent: O
Product: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1-c1ccc(S(C)(=O)=O)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 2.2 g (6.5 mmol) of 2-methyl-4-methylsulfonyl-3-(4-methylthiophenyl)benzoic acid, 2.2 mL (19.6 mmol) of 30 percent hydrogen peroxide, and 25 mL of acetic acid was heated to 80° C. with stirring for 1 hour and was then allowed to stand overnight. The mixture was diluted with water, treated with sodium bisulfite, and then extracted with a mixture of ether and ethyl acetate. The extract was concentrated by evaporation under reduced pressure and the residue was diluted with dichloromethane. The resulting mixture was filtered and the solids that were collected were washed with ethyl acetate. The filtrate was found to contain only about 0.5 g of impure product and was discarded. The solids were dissolved (a slow process) in a mixture of ethyl acetate and water and the organic phase was separated and concentrated by evaporation under reduced pressure. The resulting solid residue was diluted with hexane and the insoluble solids were recovered by filtration and dried to obtain 2.1 g (88 percent of theory) of the title compound as a white powder melting at 214-215° C.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][O:2]2.CC1([O:17]C(=O)C)CCCC=C1>[Pd+2]>[CH:1]12[CH:9]([OH:17])[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][O:2]2
Reactant: CC(=O)OC1(C)C=CCCC1
Reactant: C1CC2CCOC(C1)C2
Agent: [Pd+2]
Product: OC1C2CCCC1OCC2

Procedure:
When m is 0, n is 2 or p is 3, the ring system is a 2-oxabicyclo[3.3.1]nonane, another subclass of the invention. For example, a compound of subclass XVI of formula XVIp below ##STR31## in which R2, R5 and R6 are methyl in formula 1 can be prepared by treating 3-methyl-3-acetoxycyclohex-1-ene with a malonic ester in the presence of palladium(II), the resulting cyclohexene diester is hydrolyzed, decarboxylated, and treated with methyl Grignard reagent. The resulting cyclohexenylalkanol is epoxidized and cyclized to yield the 2-oxabicyclo[3.3.1]nonan-9-ol, which is treated with WCH2X in which X is halogen to yield the desired ether XVIp. Alternatively, 3-methyl-2-cyclohexen-1-carboxylic acid is converted to 3-methyl-2-cyclohexen-1-acetic acid by methods analogous to those of the literature and described for compounds of formula XIp, the resulting acid is treated with methyl Grignard, and the resulting alcohol is subjected to epoxidation-cyclization to yield 2-oxabicyclo[3.3.1]nonan-9-ol.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6]1[CH:7]=[C:8]([N+:29]([O-:31])=[O:30])[CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][C:12]([C:16]#[N:17])=[C:11]2[N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[CH:23]=1)C(=O)C.C(=O)([O-])[O-].[K+].[K+].C(=O)=O>C1COCC1.CO>[Br:28][C:24]1[CH:23]=[C:22]([NH:18][C:11]2[C:10]3[C:15](=[C:6]([CH2:5][N:2]([CH3:3])[CH3:1])[CH:7]=[C:8]([N+:29]([O-:31])=[O:30])[CH:9]=3)[N:14]=[CH:13][C:12]=2[C:16]#[N:17])[CH:27]=[CH:26][CH:25]=1
Reactant: CNC
Reactant: CC(=O)N(c1cccc(Br)c1)c1c(C#N)cnc2c(CBr)cc([N+](=O)[O-])cc12
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)Cc1cc([N+](=O)[O-])cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of dimethylamine in THF (2.0 M; 115 ml; 230 mmol) at 0° C. was added a solution of 8-bromomethyl 4-[(3-bromophenyl)-N-acetylamino]-6-nitro-quinoline-3-carbonitrile (11.6 g, 23 mmol) in 115 ml of THF during 15 m. After warming to 25° C. the mixture was stirred for 2 h. The THF was evaporated off, and the residue was refluxed in 230 ml of methanol with 12.7 g (92 mmol) of potassium carbonate for 1 h. The mixture was cooled, saturated with CO2, and concentrated. The residue was partitioned with methylene chloride and water. The organic layer was washed with water, dried, and concentrated. The residue was subjected to chromatography on silica gel with methylene chloride-ethyl acetate-methanol-triethylamine to give 6.0 g yellow solid, mp 223-226° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11](=O)[CH3:12])[CH:6]=[CH:7][CH:8]=1.[C:14]1(=[O:21])[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15]1.C([O-])(=O)C.[NH4+:26]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:15]3[C:14](=[O:21])[CH2:19][CH2:18][CH2:17][C:16]=3[NH:26][C:11]([CH3:12])=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: [NH4+]
Reactant: O=C1CCCC(=O)C1
Reactant: COc1cccc(C=CC(C)=O)c1
Agent: CC(=O)[O-]
Solvent: CCO
Product: COc1cccc(C2C=C(C)NC3=C2C(=O)CCC3)c1
Yield: 36 %

Procedure:
A solution of 1-(3-methoxyphenyl)but-1-en-3-one (2.07 g), 1,3-cyclohexanedione (1.37 g) and ammonium acetate (1.39 g) in ethanol (20 mL) was stirred at reflux for 10 hours. The reaction was worked up as described in Example 8 and purified by chromatography (10% v/v ethyl ether in methylene chloride) to yield the title compound (1.14 g) as an off-white solid. Recrystallization from ethanol/hexane gave analytically pure material, mp 164°-167° C.; NMR: 1.71 (s,3, CH3), 1.82-1.88 (m,2, CH2), 2.13-2.17 (m,2, CH2), 2.40-2.44 (m,2, CH2) 3.67 (s,3, CH3), 4.35 (d,1, J=4.8, CH), 4.60 (d,1, J=4.6, CH), 6.64-6.66 (m,2, Ar), 6.71 (d,1, J=7.7, Ar), 7.12 (dd,1, J=7.7, 3.8, Ar), 8.41 (s,1, NH); (CI, CH4)MS: m/z=270(M+1). Analysis for C17H19NO2.0.5H2O: Calculated: C, 73.36; H, 7.24; N, 5.03. Found: C, 73.49; H, 6.98; N, 4.93.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[CH2:11][CH2:10][CH2:9][NH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])(=O)=O.O>ClCCl>[Si:26]([NH:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[CH2:11][CH2:10][CH2:9][NH:8][C:6]=2[N:7]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: Nc1nc(Cl)c2c(n1)NCCC2
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Nc1nc(Cl)c2c(n1)NCCC2
Temperature: -37 °C
Reaction time: 1.5 h
Yield: 100000000 %

Procedure:
To a solution of 69 g (370 nmol) of 2-amino-4-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine in anhydrous dichloromethan (450 ml) was added 70 ml (500 mmol) of triethylamine, and then cooled to -37° C. Then, under inert gas atmosphere, to the reaction mixture was dropwise added 102 ml (450 mmol) of tertbutyldimethylsilyl trifluoromethanesulfonate over a period of 30 minutes, and the mixture was stirred at that temperature for 1.5 hours. The suspension turned to a red-colored solution. The reaction solution was poured into 300 ml of water. After usual work up, the product was extracted with 300 ml of dichloromethane. The combined dichloromethane layer was dried over potassium carbonate, and then the solvent was evaporated from the filtrate. To the resulting oily residue was added 300 ml of hexane, then heated to 80° C. with stirring. An insoluble oily residue then removed by decantation. The target compound was extracted with 200 ml of hexane from the oily residue. The combined hexane layer was evaporated to give 112 g (370 mmol) of 2-tert-butyldimethylsilylamino-4-chloro-5,6,7,8tetrahydropyrido[2,3-d]pyrimidine in the form of white crystals. (Yield 99%)
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1[S:10][C:9]2[C:11](=[O:15])[CH:12]([CH3:14])[CH2:13][C:8]=2[CH:7]=1.[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][C:7]1[C:8]2[CH2:13][CH:12]([CH3:14])[C:11](=[O:15])[C:9]=2[S:10][C:6]=1[CH3:5]
Reactant: Cc1cc2c(s1)C(=O)C(C)C2
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: Cc1sc2c(c1Br)CC(C)C2=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
To a suspension of 92.4 g (693 mmol) of AlCl3 (anhydrous powder) in 120 ml of CHCl3, 51.2 g (308 mmol) of 2,5-dimethyl-4,5-dihydro-cyclopenta[b]thiophen-6-one in 50 ml of CHCl3 was added at 0° C. over 0.5 hour. The reaction mixture was stirred for 10 minutes at this temperature; then a solution of 16.6 ml of Br2 (323 mmol) in 30 ml of CHCl3 was added dropwise over 1 hour. The resulting mixture was stirred for 1 hour at room temperature, and then poured over 1000 cm3 of ice. The organic layer was separated. The aqueous layer was extracted with 4×200 ml of CH2Cl2. The combined organic fractions were washed with 1000 ml of saturated aqueous Na2CO3, dried over K2CO3, passed through a short Silica Gel 60 column (40-63 μm, d 40 mm, 1 50 mm), and evaporated to dryness. Fractional distillation gave white crystalline product, b.p. 130° C./0.4 mm Hg. Yield 69.2 g (92%) of the title product contaminated with ca. 12% of 3-bromo-2,5-dimethyl-5,6-dihydro-cyclopenta[b]thiophen-4-one.
Reaction SMILES: [CH2:1]([C:11]1[C:18]2[S:17][C:16]3[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:20](C(O)=O)[S:21][C:15]=3[C:14]=2[S:13][C:12]=1C(O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C2C(=CC=CC=2)C=CC=1.C(=O)=O>[Cu].CCCCCC>[CH2:1]([C:11]1[C:18]2[S:17][C:16]3[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:20][S:21][C:15]=3[C:14]=2[S:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1c(C(=O)O)sc2c1sc1c(CCCCCCCCCC)c(C(=O)O)sc12
Agent: [Cu]
Agent: O=C=O
Solvent: c1ccc2ncccc2c1
Solvent: CCCCCC
Product: CCCCCCCCCCc1csc2c1sc1c(CCCCCCCCCC)csc12
Temperature: 255 °C
Yield: 44.6 %

Procedure:
Compound 68 (8.6 g, 0.016 mol), copper powder (0.7 g) and quinoline (50 mL) were combined and heated at 250-260° C. in a Woods-metal bath. When no further bubbles of carbon dioxide gas could be detected (about 2 hours), the mixture was cooled to room temperature and hexane (200 mL) was added. This mixture was washed repeatedly with HCl (1-2 M in water) to remove quinoline. The organic layer was dried over MgSO4 and concentrated by evaporation, and the residue was purified by column chromatography (SiO2/hexanes) to yield compound 63 (3.4 g, 47.4%). 1H NMR (CD2Cl2) δ 6.97 (s, 2H), 2.73 (t, 4H), 1.78 (m, 4H), 1.27 (m, 28H), 0.88 (t, 6H). 13C NMR: 141.89, 136.75, 130.99, 120.57, 32.33, 30.02, 29.79 (m, overlap), 29.74, 29.15, 23.10, 14.28.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([OH:11])=O)=[N:7][CH:6]=[CH:5][N:4]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][CH:23]([NH2:25])[CH3:24].Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][CH:23]([NH:25][C:9]([C:8]1[C:3]([C:2]([F:1])([F:13])[F:12])=[N:4][CH:5]=[CH:6][N:7]=1)=[O:11])[CH3:24]
Reactant: CC(N)Cc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1nccnc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc(Cl)cc1Cl)NC(=O)c1nccnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.1 %

Procedure:
To a solution of 2-trifluoromethylpyrazine-3-carboxylic acid (0.25 g, 1.3 mmol), [2-(2,4-dichlorophenyl)-1-methylethyl]amine (0.27 g, 1.3 mmol) and 4-dimethylaminopyridine (0.19 g, 1.6 mmol) in chloroform (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.3 g, 1.6 mmol) and the mixture was stirred at room temperature for 12 hrs. After adding water and chloroform, the mixture was partitioned, and the organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give a desired compound (yield; 0.31 g, 63%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[S:17][CH:18]=[C:19]([CH3:24])[C:20]=1[C:21]([NH2:23])=[O:22]>>[CH3:24][C:19]1[C:20]([C:21]([NH2:23])=[O:22])=[C:16]([NH:15][C:12](=[O:14])[CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[N:4]=[CH:3][CH:2]=[N:1]3)[S:17][CH:18]=1
Reactant: O=C(O)Cc1cccc2nccnc12
Reactant: Cc1csc(N)c1C(N)=O
Product: Cc1csc(NC(=O)Cc2cccc3nccnc23)c1C(N)=O

Procedure:
The title compound was prepared from 2-(quinoxalin-5-yl)acetic acid and 2-amino-4-methylthiophene-3-carboxamide using protocol B. Method[1], MS(ESI) 327.0 [M+H], Retention time=1.644 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:37][CH:38](I)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][I:37])=[CH:16][CH:17]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[OH:22])[C:9]2=[O:30])=[CH:6][CH:7]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reactant: CCCCCCCC(I)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCCCCCI)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one are dissolved in 10 ml of absolute dimethylformamide. 120 mg of powdered potassium carbonate and 0.44 ml of diiodooctane are then added. The reaction solution is stirred at room temperature overnight. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified using an SiO2 cartridge (n-heptane; n-heptane/ethylacetate 4:1). The product is obtained as an oil. C32H36F2INO3 (647) MS (ESI): M+-18