Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([SH:36])=[CH:32][CH:31]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:1][C:2]1[C:3]([C:4](=[O:6])[S:36][C:33]2[CH:34]=[CH:35][C:30]([CH3:29])=[CH:31][CH:32]=2)=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][N:10]=1
Reactant: Cc1ncc(-c2ccccc2)cc1C(=O)O
Reactant: Cc1ccc(S)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(SC(=O)c2cc(-c3ccccc3)cnc2C)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a 0° C. solution of 2-methyl-5-phenylnicotinic acid (100 mg, 0.40 mmol) in CH2Cl2 (4 mL) was added oxalyl chloride (344 μL, 4.0 mmol). The mixture was stirred at 40° C. After 3 hours, the mixture was concentrated to dryness, dissolved in benzene (2×5 mL) and concentrated again. After dissolving the crude residue in CH2Cl2 (2 mL) at 0° C., pyridine (1 mL, 0.92 M in CH2Cl2), 4-dimethylaminopyridine (10 mg, 0.08 mmol) and 4-methylthiophenol (60 mg, 0.48 mmol) were added. The mixture was then allowed to warm to room temperature. After stirring for 2 hours, the mixture was diluted with EtOAc, washed with 1N HCl, brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash chromatography (100-80% hexanes/EtOAc gradient) to afford the title compound. LRMS (APCI) calculated for C20H18NOS [M+H]+, 320.1; found 320.1
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:29][O:30][C:31]1[C:32](=[O:55])[C:33]([CH3:54])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][C:51](=[O:53])[CH3:52])=[C:45]([CH:49]=2)[C:46](O)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]>C(Cl)Cl>[CH3:1][N:2]([C:46](=[O:47])[C:45]1[CH:49]=[C:41]([CH2:40][C:34]2[C:35](=[O:39])[C:36]([O:37][CH3:38])=[C:31]([O:30][CH3:29])[C:32](=[O:55])[C:33]=2[CH3:54])[CH:42]=[CH:43][C:44]=1[O:50][C:51](=[O:53])[CH3:52])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:7][CH:8]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: CNc1ccc(C(F)(F)F)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)N(C)c3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.5 %

Procedure:
N-Methyl-4-trifluoromethylaniline (0.200 g, 1.143 mmol), triethylamine (0.116 g, 1.143 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.193 g, 1.143 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.285 g, 0.762 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.140 g, 0.263 mmol, 35%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:12][CH:11]3[C:13]([CH3:15])([CH3:14])[CH:7]([CH2:8][NH:9][CH2:10]3)[CH2:6]2)[CH2:3][CH2:2]1.[NH2-].[Li+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25](Cl)[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:9]2[CH2:8][CH:7]3[C:13]([CH3:15])([CH3:14])[CH:11]([CH2:12][N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:6]3)[CH2:10]2)=[CH:23][CH:24]=1
Reactant: CC1(C)C2CNCC1CN(CC1CC1)C2
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [NH2-]
Solvent: CN(C)C=O
Product: CC1(C)C2CN(CC3CC3)CC1CN(C(c1ccc(F)cc1)c1ccc(F)cc1)C2
Temperature: 60 °C
Reaction time: 4 h
Yield: 84.1 %

Procedure:
3.5 g 3-cyclopropylmethyl-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane were dissolved in 25 ml dimethylformamide, and 0.8 g lithium amide were added to the solution. The reaction mixture was then maintained at a temperature of 60° C. for one hour and subsequently allowed to cool. After cooling, a solution of 8 g bis-(4-fluorophenyl)methyl chloride in 10 ml dimethylformamide was added in drops, and the reaction mixture was stirred for a further 4 hours at 40° C. Then aqueous citric acid solution was added to the reaction mixture, and the mixture was worked up as described in Example 1. 5.8 g 7-[bis-(4-fluorophenyl)methyl]-3-cyclopropylmethyl-9,9-dimethyl-3,7diazabicyclo[3,3,1]nonane were obtained as an oleaginous base.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=1>ClCCl>[OH:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:3]2([CH2:2][NH:1][S:31]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)(=[O:33])=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7]2)=[CH:10][CH:11]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: NCC1(Cc2ccc(CCO)cc2)CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCC1(Cc2ccc(CCO)cc2)CCCC1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a mixture of 300 mg (1.086 mmol) of 2-(4-{[1-(aminomethyl)-cyclo-pentyl]methyl}phenyl)ethanol (EP 472 449), 30 ml of dichloromethane and 537.6 μl (3.857 mmol) of triethylamine is added dropwise, at −20° C., a solution of 310.1 mg (1.222 mmol) of 3-pyridinesulfonyl chloride in 10 ml of dichloromethane. The mixture is allowed to warm to room temperature slowly (over 3 hours) and is stirred for a further 2 hours. The reaction medium is then washed with water and dried over Na2SO4. After concentrating the organic phase under vacuum, the oil obtained is purified by flash chromatography on silica gel with a dichloromethane/methanol mixture (99/1). 266 mg of an amorphous white solid are obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]1([CH2:26][C:27]([NH2:29])=[O:28])[CH2:23][S:22](=[O:25])(=[O:24])[CH2:21]1>>[NH2:29][C:27](=[O:28])[CH2:26][C:20]1([NH:19][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])[CH2:21][S:22](=[O:24])(=[O:25])[CH2:23]1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: NC(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (130 mg, 43%); MS (ESI, m/z): 422.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]([NH2:20])=O)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH2:23][CH2:24]N.C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:9])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:20]3[CH2:24][CH2:23][CH2:22][N:21]=[C:18]23)=[CH:6][CH:7]=1
Reactant: NC(=O)C1(c2ccc(F)cc2)OC(=O)c2ccccc21
Reactant: NCCCN
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(O)(c2ccc(F)cc2)C2=NCCCN12
Temperature: 25 °C

Procedure:
A mixture of 1-(4-fluorophenyl)-3-oxo-1,3-dihydro-2-benzofuran-1-carboxamide (17 g), 1,3-diaminopropane (25 mL), and toluene (125 mL) was heated at reflux for 19 h in a flask equipped with a water separator. The mixture was cooled to ambient temperature and extracted with water, and evaporated to dryness. The residue was crystallized from ethanol to give the title compound (26 g) as a solid, m.p. 126-128° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[H-].[Na+].[CH3:42]I>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]([C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]([CH3:39])([CH3:38])[CH2:36][O:37][CH3:42])=[CH:32][CH:33]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CI
Reactant: CCCc1nc(CC)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC(C)(C)COC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a solution of 4′-({2-ethyl-1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.48 g) in N,N-dimethylformamide (10 mL) was added sodium hydride (0.07 g, 60%), and the mixture was stirred for 15 min. Then methyl iodide (0.11 mL) was added, and the mixture was further stirred for 2 hr. Small pieces of ice were added to the reaction mixture, and the mixture was stirred for 15 min, diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 48%).
Reaction SMILES: [CH2:1]=O.[OH:3][CH2:4][C:5]([CH2:10][OH:11])([CH3:9])[C:6]([OH:8])=[O:7]>>[CH3:9][C:5]1([C:6]([OH:8])=[O:7])[CH2:10][O:11][CH2:1][O:3][CH2:4]1
Reactant: C=O
Reactant: CC(CO)(CO)C(=O)O
Product: CC1(C(=O)O)COCOC1

Procedure:
Synthesis of the acetal (formal) of formaldehyde and 2,2-bis(hydroxymethyl)propanoic acid yielding 5-methyl-1,3-dioxane-5-carboxylic acid.
Reaction SMILES: C(C(Cl)=O)COCC(COCCC(Cl)=O)(COCCC(Cl)=O)COCCC(Cl)=O.O1CCCC1.N[C:36]1[CH:37]=[C:38]([C:46]([O:48][CH3:49])=[O:47])[CH:39]=[C:40]([CH:45]=1)[C:41]([O:43][CH3:44])=[O:42].C(N(CC)CC)C>CN(C)C=O>[C:41]([O:43][CH3:44])(=[O:42])[C:40]1[CH:45]=[CH:36][CH:37]=[C:38]([C:46]([O:48][CH3:49])=[O:47])[CH:39]=1.[C:41]([O:43][CH3:44])(=[O:42])[C:40]1[CH:45]=[CH:36][CH:37]=[C:38]([C:46]([O:48][CH3:49])=[O:47])[CH:39]=1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Agent: O=C(Cl)CCOCC(COCCC(=O)Cl)(COCCC(=O)Cl)COCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 227.5 %

Procedure:
The tetraacid chloride from Step I and dry tetrahydrofuran (50 mL), were mixed under an inert atmosphere and the mixture was cooled to 0° C. for at least 30 min. Dimethyl 5-aminoisophthalate (Aldrich, 2.65 g, 12.7 mmol) is then added as a solution in dry N,N-dimethylformamide (15 mL) in slowly, dropwise to the flask containing the tetraacid chloride chloride. Two successive rinses with tetrahydrofuran (10 mL) were done to quantitatively transfer all of the amine to the acid chloride flask. Triethylamine (2.6 mL, 18.7 mmol) was then added and the reaction is then allowed to slowly warm to room temperature and stir overnight. After removing the tetrahydrofuran by rotary evaporation, the crude residue is then dissolved in 140 mL of diethyl ether, and is washed with deionized water (40 mL), saturated sodium bicarbonate (40 mL), 5% citric acid (40 L), and brine (40 mL). The diethyl ether layer is then dried over sodium sulfate, filtered through glass wool, the solvent removed by rotary evaporation, and dried in vacuo to give crude tetramethyl bis isophthalate (5.61 g) as a viscous, yellow syrup. The diester thus obtained is used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([S:9][C:10]2[NH:14][N:13]=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].[CH3:15]S(C)=O.C(=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[N+:1]([C:4]1[S:8][C:7]([S:9][C:10]2[N:14]=[N:13][N:12]([CH3:15])[N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc(Sc2nnn[nH]2)s1
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnc(Sc2ncc([N+](=O)[O-])s2)n1
Reaction time: 8 h

Procedure:
5-[(5-Nitrothiazol-2-yl)mercapto]tetrazole (2.44 g) is dissolved in 20 mL of dimethyl formamide, or a mixture of dimethylformamide and dimethylsulfoxide, containing 1.4 g of potassium carbonate and 1.3 g of methyl iodide. After stirring overnight the mixture is diluted with 40 ml of water. The precipitate is collected by vacuum filtration, dried and purified by high performance liquid chromatography on a reversed phased C-18 column using a gradient of acetonitrile in water to give 0.5 g of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]1[CH:18]=[C:19]([CH:31]=[CH:32][C:33]=1[F:34])[O:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]([NH2:29])[CH3:28])=[CH:23][C:22]=1[CH3:30]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH:27]([C:24]3[CH:25]=[N:26][C:21]([O:20][C:19]4[CH:31]=[CH:32][C:33]([F:34])=[C:17]([F:16])[CH:18]=4)=[C:22]([CH3:30])[CH:23]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1Oc1ccc(F)c(F)c1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1Oc1ccc(F)c(F)c1
Yield: 57 %

Procedure:
The title compound is prepared in 57% yield (190 mg, off white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (220 mg, 0.79 mmol, Step-1 of Intermediate-1) and 1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (260 mg, 0.87 mmol, Amine-44, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][CH2:17]O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:38]N1C(=O)CCC1=O>C(Cl)Cl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][CH2:17][Br:38])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CCCO)cc1OC1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCCBr)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3.3 g (13.2 mmol) of 3-(3-cyclopentoxy-4-methoxyphenyl)-1-propanol in 75 mL of dry methylene chloride at 0° C. under a nitrogen atmosphere was added 4.3 g (16.4 mmol) of triphenylphosphine followed by a slow, portionwise addition of N-bromosuccinimide over a 5 minute period. The reaction mixture was stirred at 0° C. for 1.5 hours at the end of which time the mixture was quenched with excess methanol and stirred for an additional 10 minutes. Concentration of the mixture to dryness followed by liquid chromatography purification using 200 g of silica gel and elution 50% chloroform in hexane provided an analytically pure oil upon drying in vacuo.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])[CH2:12][CH:11]([C:22](O)=[O:23])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:38]=[C:39]([O:41][CH2:42][CH3:43])[NH2:40]>CN(C=O)C.O1CCOCC1>[CH2:42]([O:41][C:39]1[N:40]=[C:22]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])[CH2:12]2)[O:23][N:38]=1)[CH3:43]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CC(O)C3)C2)cc1
Reactant: CCOC(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOc1noc(C2CC(c3ccc(CC)cc3)CN(C(=O)N3CC(O)C3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 80.0 mg (0.241 mmol) of the carboxylic acid from Example 14A in 0.97 ml of DMF and 1.93 ml of 1,4-dioxane were added, at 60° C., 99.8 mg (0.615 mmol) of 1,1′-carbonyldiimidazole, and the mixture was stirred for 3 h. Subsequently, the mixture was admixed with 50.1 mg (0.481 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and then stirred at RT for 2 h and then at 120° C. for 2.5 h. The reaction solution was concentrated under reduced pressure and purified directly by means of preparative HPLC. Yield: 33.1 mg (33% of theory)
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH2:5][CH:4]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.[OH:23]S(O)(=O)=O>C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH:1]([C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH2:5][CH:4]=1)=[O:23]
Reactant: O=S(=O)(O)O
Reactant: N#CC1=CCSc2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: O=CC1=CCSc2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.5 g of 4-cyano-2H-1-benzothiopyrane in 2 ml of benzene are reacted with 2 ml of a 20% solution of diisobutylaluminium hydride in toluene and the mixture stirred for 4 hours at room temperature. The resulting mixture is poured onto 20% H2SO4 and the organic phase separated, washed with saturated aqueous NaCl and dried over MgSO4. After concentration by evaporation the product is purified by chromatography over kieselgel (eluant hexane/ethyl acetate).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[NH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23].C(=O)([O-])O.[Na+].Cl>COCCO>[C:6]([C:5]1[CH:14]=[CH:15][C:2]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:3]([N+:16]([O-:18])=[O:17])[CH:4]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCC(=O)O
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CCNc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 100.7 %

Procedure:
4-Chloro-3-nitrobenzophenone (10 g.) was added to a mixture of 3-aminopropionic acid (β-alanine) (10.1 g.) and sodium hydrogen carbonate (9.6 g.) in 2-methoxyethanol (100 ml.) which was then heated under reflux for 4 hours. The mixture was cooled, poured into ice-water (250 ml.) and brought to pH 3 by addition of concentrated hydrochloric acid. The solid obtained was filtered, washed with water and air-dried to give 3-(4-benzoyl-2-nitroanilino)propionic acid (12.1 g), m.p. 170°-5° C.
Reaction SMILES: ClC1C=CC([C:8](=[O:18])[CH:9]([Br:17])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[CH:12][CH:11]=2)=CC=1.[F:19]C(F)(F)C1SC(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2)N=1.ClC1C=CC(CC(O)=O)=CC=1.[F:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>ClC1C=CC=CC=1>[F:53][C:54]1[CH:59]=[CH:58][C:57]([C:8](=[O:18])[CH:9]([Br:17])[C:10]2[CH:15]=[CH:14][C:13]([F:19])=[CH:12][CH:11]=2)=[CH:56][CH:55]=1
Reactant: FC(F)(F)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)s1
Reactant: O=C(c1ccc(Cl)cc1)C(Br)c1ccc(Cl)cc1
Reactant: Fc1ccccc1
Agent: O=C(O)Cc1ccc(Cl)cc1
Solvent: Clc1ccccc1
Product: O=C(c1ccc(F)cc1)C(Br)c1ccc(F)cc1

Procedure:
The above acetophenones are prepared as in Steps I and II of Example 2. (1) Substituting phenylacetic acid for p-chlorophenylacetic acid and benzene for chlorobenzene affords 2-bromo-2-phenylacetophenone. (2) The preparation of p-chloro-2-bromo-2-(p-chlorophenyl)acetophenone is described in Steps I and II of Example 2. (3) Substituting p-fluorophenylacetic acid for p-chlorophenylacetic acid and fluorobenzene for chlorobenzene affords p-fluoro-2-bromo-2-(p-fluorophenyl)acetophenone. (4) Substituting p-isopropoxyphenylacetic acid for p-chlorophenylacetic acid and isopropoxybenzene for chlorobenzene affords p-isopropoxy-2-bromo-2-(p-isopropoxyphenyl)acetophenone. (5) Substituting m,p-dimethoxyphenylacetic acid for p-chlorophenylacetic acid and m,p-dimethoxybenzene for chlorobenzene affords m,p-dimethoxy-2-bromo-2-(m,p-dimethoxyphenyl)acetophenone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[O:10]1[CH2:14][CH2:13][O:12][CH:11]1[CH2:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25].O1CCOC1CCCCCCCCOC1C=C(C=CC=1)C=O>>[O:10]1[CH2:14][CH2:13][O:12][CH:11]1[CH2:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:24]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[OH:25])[CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1cccc(OCc2cccc(CC3OCCO3)c2)c1
Reactant: Fc1cccc([Mg]Br)c1
Agent: O=Cc1cccc(OCCCCCCCCC2OCCO2)c1
Product: OC(c1cccc(F)c1)c1cccc(OCc2cccc(CC3OCCO3)c2)c1

Procedure:
The title compound was prepared as described in Example 10 Step 2 with 3-fluorophenylmagnesium bromide and 3-((3-((1,3-dioxolan-2-yl)methyl)benzyl)oxy)-benzaldehyde replacing 2-thienylmagnesium bromide and 3-(8-(1,3-dioxolan-2-yl)octyloxy)benzaldehyde, respectively.
Reaction SMILES: [CH:1]1[C:17]2[C:5](=[C:6]3[CH:48]=[CH:47][CH:46]=[CH:45][C:7]3=[C:8]3[C:16]=2[CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=2)[C:14]2[C:9]3=[C:10]3[CH:44]=[CH:43][CH:42]=[CH:41][C:11]3=[C:12]3[CH:40]=[CH:39][CH:38]=[CH:37][C:13]3=2)[CH:4]=[CH:3][CH:2]=1.C([O:51][C:52](=O)[CH2:53][C:54](=[O:64])[C:55]1[CH:60]=[C:59]([F:61])[C:58]([F:62])=[CH:57][C:56]=1[F:63])C.C.CO>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.C(Cl)Cl.CO>[F:63][C:56]1[CH:57]=[C:58]([F:62])[C:59]([F:61])=[CH:60][C:55]=1[C:54](=[O:64])[CH2:53][C:52]([O:36][CH2:35][C:32]1[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:15]2[C:14]3[C:9](=[C:10]4[CH:44]=[CH:43][CH:42]=[CH:41][C:11]4=[C:12]4[CH:40]=[CH:39][CH:38]=[CH:37][C:13]4=3)[C:8]3[C:16]2=[C:17]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=[C:6]2[CH:48]=[CH:47][CH:46]=[CH:45][C:7]2=3)=[CH:34][CH:33]=1)=[O:51]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F
Reactant: OCc1ccc(OCCCCCCCCCCC2c3c(c4ccccc4c4ccccc34)-c3c2c2ccccc2c2ccccc32)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(CC(=O)c1cc(F)c(F)cc1F)OCc1ccc(OCCCCCCCCCCC2c3c(c4ccccc4c4ccccc34)-c3c2c2ccccc2c2ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-[[10-(17H-Tetrabenzo[a,c,g,i]fluoren-17-yl)decyl]oxy]benzenemethanol (8) (44.9 mg, 0.071 mmol) and DMAP (3.2 mg, 0.026 mmol) were added to an oven-dried flask and dissolved in freshly distilled toluene (8 mL). 3-Oxo-3-(2,4,5-trifluoro-phenyl)-propionic acid ethyl ester (7) (46.2 mg, 0.19 mmol) was added and the resultant solution refluxed under an atmosphere of nitrogen for 20 hours. The reaction was cooled to room temperature and solvent removed in vacuo to yield an orange oil. This was dissolved in DCM/methanol (3:2, 25 mL). Charcoal (prewashed with toluene, 510 mg) was added and the suspension stirred at room temperature for 15 minutes. Methanol was added in portions (total 45 mL) and stirring continued until TLC analysis showed that none of the desired product was present in the supernatant liquid. The supernatant was removed by centrifugation and the charcoal residue then suspended in toluene (40 mL). The suspension was then stirred at 40° C. for 15 minutes and the supernatant removed by centrifugation. This was repeated with fresh toluene until no fluorescent products were detected in the supernatant by TLC. The toluene washes were combined and solvent removed in vacuo. The yellow residue was purified by flash column chromatography using DCM as eluent to yield the desired product (35.2 mg, 60%).