Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[Si](C)(C)C.C[Si]([CH:10]1[CH2:14][CH:13](Br)[O:12][C:11]1([Si](C)(C)C)[P:16]([OH:19])([OH:18])=[O:17])(C)C.[P:24]([O:33]C(C)C)([O:29]C(C)C)[O:25]C(C)C.C[Si](OP(C1CCC(P(OC(C)C)(OC(C)C)=O)O1)(O[Si](C)(C)C)=O)(C)C>>[P:16]([C:11]1([P:24]([OH:33])([OH:29])=[O:25])[CH2:10][CH2:14][CH2:13][O:12]1)([OH:19])([OH:18])=[O:17]
Reactant: C[Si](C)(C)C1CC(Br)OC1([Si](C)(C)C)P(=O)(O)O
Reactant: CC(C)OP(OC(C)C)OC(C)C
Agent: CC(C)OP(=O)(OC(C)C)C1CCC(P(=O)(O[Si](C)(C)C)O[Si](C)(C)C)O1
Agent: C[Si](C)(C)Br
Product: O=P(O)(O)C1(P(=O)(O)O)CCCO1

Procedure:
To make 2,5-diphosphonotetrahydrofuran (i.e. n is 2), step (a) is suitably accomplished by adding dimethyl phosphite to a cool slurry of sodium hydride in 2,5-dimethoxytetrahydrofuran under an inert atmosphere such as nitrogen or argon and heating the resulting reaction mixture to form 2-phosphono-5-methoxytetrahydrofuran as a first intermediate. Step (b) is suitably accomplished by adding bromotrimethyl silane to said first intermediate and stirring the resulting mixture under an inert atmosphere such as nitrogen or argon, thereby forming di-(trimethylsilyl)2-phosphono-5-bromotetrahydrofuran as a second intermediate. Step (c) is suitably accomplished by adding triisopropyl phosphite to said second intermediate and heating the mixture under an inert atmosphere such as nitrogen or argon, thereby forming 2-(di-(trimethyl silyl)phosphono)-5-(diisopropylphosphono)-tetrahydrofuran. Diphosphonotetrahydrofuran may be produced by adding a concentrated acid, such as hydrochloric acid to the 2-(di-(trimethyl silyl)phosphono)-5-(diisopropylphosphono)-tetrahydrofuran and refluxing the acid solution. 2,6-Diphosphonotetrahydropyran (i.e. n is 3) and 2,7-Diphosphonooxepane (i.e. n is 4) may be produced in similar fashion, respectively using 2,6-dimethoxytetrahydropyran and 2,7-dimethoxyoxepane rather than 2,5-dimethoxytetrahydrofuran as a starting material.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].CS(O[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29][CH2:28]1)(=O)=O>O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:35])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:29][CH2:28]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: O=c1ccc2ccc(Cl)nc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(Cl)nc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution of 7-chloro-1,8-naphthyridin-2(1H)-one [J. Org. Chem. 1990, 55, 4744-4750] in dry DMF (20 mL) (540 mg, 3.0 mmol) at 0° C. was treated with sodium hydride (144 mg, 60% in mineral oil, 3.6 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was cooled using an ice bath. A solution of 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1yl}ethyl methanesulfonate in DMF (Intermediate 6), 0.33 mmol/mL, 10 mL, 3.3 mmol) was then added over 1 hour. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with water and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated sodium chloride solution (3×10 mL), dried over sodium sulfate and evaporated. Chromatography on silica gel using methanol in dichloromethane (0-15%) gave the title compound as a brown foam (711 mg, 58%).
Reaction SMILES: C([Li])CCC.[C:6]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:32]1[CH2:36][CH2:35][N:34]=[C:33]1[C:37]1[CH:51]=[CH:50][C:40]([CH2:41]P(=O)(OCC)OCC)=[CH:39][CH:38]=1>CCCCCC.O1CCCC1>[O:32]1[CH2:36][CH2:35][N:34]=[C:33]1[C:37]1[CH:38]=[CH:39][C:40]([CH:41]=[C:28]2[CH2:27][CH2:26][N:25]([C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)=[CH:50][CH:51]=1
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CCOP(=O)(Cc1ccc(C2=NCCO2)cc1)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C(=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1)c1ccc(C2=NCCO2)cc1
Temperature: -60 °C
Reaction time: 0.42 h

Procedure:
6.25 ml of a 1.6M solution of n-butyllithium in hexane followed, after stirring for 20 minutes, by 3.4 g of N-trityl-4-piperidone (prepared from 4-piperidone hydrochloride hydrate and trityl chloride) in 20 ml of tetrahydrofuran are added dropwise at -60° C. to 2.97 g of diethyl 4-(2-oxazolin-2-yl)benzylphosphonate. The mixture is stirred at -60° C. for 25 minutes. The reaction solution is then allowed to warm to ambient temperature and is stirred for a further 1.5 hours at this temperature. The reaction solution is then stirred into 150 ml of ice-water, the mixture is extracted three times with 150 ml of ethyl acetate, and the organic phase is dried and evaporated down. The residue is purified by column chromatography on Silica gel (petroleum ether/ethyl acetate=1:1, v/v). 1.7 g of the title compound of melting point 110°-115° C. are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[N:14][C:15]([N:19](C(OC(C)(C)C)=O)[NH:20][C:21](OC(C)(C)C)=O)=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:35]1[N:36]=[CH:37][N:38]([C:40](C2C=CC=CC=2)([C:47]2C=CC=CC=2)C2C=CC=CC=2)[CH:39]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:60]C>CN(C=O)C>[CH2:3]([N:10]1[C:18]2[CH:17]=[CH:16][C:15]3[N:14]([C:21]([CH3:60])=[N:20][N:19]=3)[C:13]=2[CH:12]=[C:11]1[C:35]1[N:36]=[CH:37][N:38]([CH2:40][CH3:47])[CH:39]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)n2Cc2ccccc2)n1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cnc(-c2cc3c(ccc4nnc(C)n43)n2Cc2ccccc2)c1
Reaction time: 0.17 h
Yield: 59.6 %

Procedure:
Sodium hydride (3.1 mg, 0.078 mmol, 60% in mineral oil) was added to a solution of 6-benzyl-7-(1H-imidazol-4-yl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (5.1 mg, 0.016 mmol, from Example 74) in DMF (0.20 mL). After 10 minutes, iodoethane (3.7 μL, 0.046 mmol, Aldrich) was introduced and the reaction was allowed to proceed for 15 minutes, at which time it was quenched with water. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded product (3.4 mg, 61%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C@:9]1([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19]C(=O)C2C=CC=CC=2)=[N:10]1.[Cl:30][C:31]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[C:33](Cl)[N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:30][C:31]1[N:32]=[C:33]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:9]3([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:17])([F:16])[F:18])[O:12][C:11]([NH2:19])=[N:10]3)[CH:4]=2)[CH:34]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:36]=1
Reactant: O=C(NC1=N[C@](CF)(c2cc(O)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Reactant: Clc1cc(-c2ccccc2)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: NC1=N[C@](CF)(c2cc(Oc3cc(-c4ccccc4)cc(Cl)n3)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 100 °C
Yield: 2.9 %

Procedure:
In round-bottomed flask were added N-((4S,6S)-4-(2-fluoro-5-hydroxyphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (225 mg, 0.543 mmol), 2,6-dichloro-4-phenylpyridine (146 mg, 0.652 mmol), cesium carbonate (230 mg, 0.706 mmol) in DMSO (1358 μl). The flask was heated in 100° C. oil bath for 7 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was back extracted with EtOAc (2×) and the combined organics was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 50% EtOAc in hexane, followed by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 15 min, then neutralized with saturated NaHCO3 and extracted with DCM, to provide (4S,6S)-4-(5-((6-chloro-4-phenylpyridin-2-yl)oxy)-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (8 mg, 0.016 mmol, 2.96% yield) as a off-white solid.
Reaction SMILES: Br[C:2]1[C:3](=[O:24])[N:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:5]([CH3:16])[C:6]=1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH:25]1([C:2]2[C:3](=[O:24])[N:4]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[N:5]([CH3:16])[C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:27][CH2:26]1
Reactant: OB(O)C1CC1
Reactant: Cn1c(CCc2ccc(F)cc2)c(Br)c(=O)n1-c1ccc(F)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(CCc2ccc(F)cc2)c(C2CC2)c(=O)n1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 19.6 %

Procedure:
Into a sealable tube under argon was added 4-bromo-2-(4-fluoro-phenyl)-5-[2-(4-fluoro-phenyl)-ethyl]-1-methyl-1,2-dihydro-pyrazol-3-one (0.312 g), cyclopropylboronic acid (0.139 g), potassium phosphate (0.924 g), tricyclohexyl phosphine (0.034 g) and toluene (3.0 mL). To this was added palladium acetate (0.013 g) and the tube was sealed and stirred at 100° C. for 20 hours. The reaction vessel was then cooled and the diluted with water/EtOAc. The phases were separated and the aqueous phase was extracted with further EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated in vacuo to afford a crude residue. Flash column chromatography over silica gel using ISCO combiflash chromatography and eluting with EtOAc/heptane afforded the desired 4-cyclopropyl-2-(4-fluoro-phenyl)-5-[2-(4-fluoro-phenyl)-ethyl]-1-methyl-1,2-dihydro-pyrazol-3-one (0.055 g) as a white crystalline solid. MS (ESI+): 315.1 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].C(O)(=O)C.[N:17]([O-])=O.[Na+]>O>[F:1][C:2]([F:11])([F:12])[C:3]1[C:4]2[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:6][N:17]=1
Reactant: O=N[O-]
Reactant: Nc1ccccc1CC(F)(F)F
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1n[nH]c2ccccc12
Temperature: 25 °C

Procedure:
18.9 parts of 2-(2,2,2-trifluoro-ethyl)-aniline are dissoved in 700 parts by volume of glacial acetic acid. 14 parts by volume of a 50% aqueous solution of sodium nitrite are poured at one go into this well stirred solution. The temperature of the mass rises from 20° C. 27° C. The stirring is maintained at ambient temperature for about 15 hours, after which the intermediate diazo derivative has totally disappeared. A large part of the acetic acid is eliminated by distillation in vacuum so as to give a volume of about 100 parts. Then the solution is run into 160 parts of cold water with stirring. The precipitate of 3-trifluoromethyl-indazole formed is filtered off and washed with water: crude M.p. 98° C. It is recrystallised from boiling water for analysis. White needles of M.p. 104° C. (Kofler stage) are obtained; dry weight after recrystallisation 11.4 parts.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH3:27].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:26][CH3:27])=[O:10])=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:3]=1
Reactant: CCI
Reactant: O=C(O)Cc1ccc(Br)cc1OC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(Br)cc1OC1CCCCC1
Reaction time: 60 h
Yield: 85.6 %

Procedure:
To a solution of (4-bromo-2-cyclohexyloxyphenyl)acetic acid (1.33 g) in N,N-dimethylformamide (13 ml) were added potassium carbonate (0.88 g) and iodoethane (1.33 g) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 2.5 days. The resulting mixture was poured into water and the aqueous layer was extracted with a mixture of hexane and ethyl acetate (1:1). The organic layer was washed successively with water (twice) and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/toluene=1:1 to 1:2) to give ethyl (4-bromo-2-cyclohexyloxyphenyl)acetate (1.24 g).
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([N:9]([CH2:32][CH2:33][CH3:34])[C:10]1[CH:11]=[C:12]([CH:30]=O)[C:13](=[O:29])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28])[CH2:7][CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:32]([N:9]([CH2:6][CH2:7][CH3:8])[C:10]1[CH:11]=[C:12]([CH:30]=[CH2:1])[C:13](=[O:29])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]1[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26])[CH2:33][CH3:34]
Reactant: [Li]CCCC
Reactant: CCCN(CCC)c1cc(C=O)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(N(CCC)CCC)c2cccc(-c3c(C)cc(C)cc3C)n2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
Methyltriphenylphosphonium bromide (0.46 g, 1.28 mmol) was suspended in tetrahydrofuran (10 mL). The solution was cooled to −78° C. n-Butyllithium (1.6M, 0.80 μL, 1.28 mmol) was added. After 0.5 h, the solution was warmed to 0° C. and stirred for an addition 0.5 h. The solution was cooled again to −78° C. and 1-(dipropylamino)-6-mesityl-4-oxo-4H-quinolizine-3-carbaldehyde (A) (0.050 g, 0.128 mmol) was added dropwise as a solution in tetrahydrofuran (0.5 mL). The reaction was warmed to −30° C. for 0.5 h. The reaction was quenched with water, extracted with ethyl acetate, dried, and concentrated. Flash chromatography (15% ethyl acetate/hexanes) gave the desired alkene (0.022 g, 45% yield) as a red oil.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][NH2:5].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.N1C=CC=CC=1>[C:18]([NH:5][CH2:4][CH2:3][C:2]([OH:1])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCC(O)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCCC(O)(c1ccccc1)c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To the solution of 58.0 g of 3-hydroxy-3,3-diphenylpropylamine in 700 ml of methylene chloride and 30.5 g of pyridine, that of 37.5 g of benzoyl chloride in 300 ml of methylene chloride is added dropwise during 2 hours while stirring and cooling with an ice-bath. Stirring is continued for 1 hour at 0°-5°, the mixture washed twice with 200 ml of N hydrochloric acid, 150 ml of 5% aqueous sodium hydroxide and 25 ml of water each, dried, evaporated and the residue triturated with diethyl ether, to yield the N-benzoyl-3-hydroxy-3,3-diphenylpropylamine melting at 140°-141°.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(Cl)Cl.B(F)(F)F.[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>S(=O)(=O)(O)O.O>[CH:10]1[C:2]2[C:1](=[O:11])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: FB(F)F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)c2ccccc21
Temperature: -40 °C
Yield: 82 %

Procedure:
22.2 g of phthalic anhydride (0.15 mole) were charged into a stainless steel autoclave at ambient temperature with 10 cm3 of methylene chloride. The autoclave was cooled with liquid nitrogen. 30 g of HF (1.5 mole) and 102 g of BF3 (1.5 mole) were introduced. The temperature was brought to -40° C. and 12.9 g of benzene (0.165 mole) were introduced during 15 minutes. The temperature was maintained at -40° C. for one hour under 15 bars pressure, followed by decompression and degasification under vacuum to evaporate HF, BF3 and CH2Cl2 ; 10% caustic soda was then added to give a pH of 9. The solution was filtered, then acidified by addition of concentrated HCl. The O.B.B. acid precipitated in the form of very pure white crystals. The whole of the O.B.B. acid obtained was treated for 1 hour at 150° C. in 100% sulfuric acid. After cooling and dilution with water, 25.6 g of anthraquinone of 99.8% purity were obtained, i.e., an overall chemical yield of 82%.
Reaction SMILES: COC(=O)/[CH:4]=[CH:5]\[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[CH3:14][CH2:15][O:16][C:17]([CH3:19])=[O:18]>>[CH2:15]([O:16][C:17]([C@@H:19]1[CH2:4][C@@H:5]1[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:18])[CH3:14]
Reactant: COC(=O)/C=C\c1ccc(Br)cc1
Reactant: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 42, Step 1, but using Z-3-(4-Bromo-phenyl)-acrylic acid methyl ester from Step 1 as starting material Flash chromatography (Hex:EtOAc 85:15) afforded the title compound as a oil.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:32]4[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(C(=O)Nc3ccc4nc(N(C)CCN(C)C)sc4c3)cc2)cc1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.15 g, 0.31 mmol) and 4-methoxyphenyl boronic acid (0.057 g, 0.38 mmol) to give 0.025 g (16%). LC/MS, Retention time=4.45 min; (m/z): calcd for C26H28N4O2S (M+H)+: 461.6; found: 461.0.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:31]=1.C(N(CC)CC)C>ClCCl>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([NH:29][C:7](=[O:8])[C:6]2[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])=[CH:31][C:32]=1[C:38]([F:39])([F:40])[F:41])#[N:35]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC(C)C)c1C(=O)Cl
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1cccc(OC(C)C)c1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-Isopropoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-isopropoxy-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[NH:15][C:16]1[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1)[C:6]([O:8][CH3:9])=[O:7])([O-:14])=[O:13]
Reactant: Cc1cccc(N)c1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(Nc2cccc(C)c2)c([N+](=O)[O-])c1
Yield: 73.3 %

Procedure:
The compound obtained in Step 1 (1.30 g, 6.53 mmol), m-toluidine (1.40 g, 13.1 mmol), and potassium carbonate (870 mg, 6.53 mmol) were dissolved in acetonitrile, and then stirred under reflux for 12 hours. The solvent was removed by concentration under reduced pressure, and then the precipitate generated by adding hexane thereto was filtered and washed with hexane, to obtain methyl 3-nitro-4-(m-tolylamino)benzoate as an orange solid (1.37 g, 73%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2.[F:22][C@@H:23]1[CH2:27][N:26]([C:28](=[O:40])[CH2:29]OS(C2C=CC=CC=2)(=O)=O)[C@H:25]([C:41]#[N:42])[CH2:24]1.[I-].[K+]>>[CH2:20]([O:19][C:17]([C:12]12[CH2:11][CH2:10][C:9]([NH:8][CH2:29][C:28]([N:26]3[CH2:27][C@@H:23]([F:22])[CH2:24][C@H:25]3[C:41]#[N:42])=[O:40])([CH2:16][CH2:15]1)[CH2:14][CH2:13]2)=[O:18])[CH3:21]
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 72.7 %

Procedure:
Using ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate trifluoroacetate (685 mg), (2S,4S)-4-fluoro-1-[2-(benzenesulfonyloxy)acetyl]pyrrolidine-2-carbonitrile (625 mg) and potassium iodide (33.2 mg), the same procedure was followed as in Example 7 to give (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]ac etyl]-4-fluoropyrrolidine-2-carbonitrile (511 mg, 73% yield). This compound was identical to the compound obtained in Example 7.
Reaction SMILES: C([C:5]([N:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[C:28]#[N:29])=[CH:15][C:14]1=[O:30])([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([C:28]#[N:29])=[C:21]([C:16]2[C:17]([O:19][CH3:20])=[CH:18][N:13]([CH:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=[O:7])[C:14](=[O:30])[CH:15]=2)[CH:26]=1
Reactant: COc1cn(C(CC(C)C)(C(=O)O)C(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC(C)C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
178 mg (purity 92%, 0.38 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methylpentanoic acid (racemate) were hydrolysed with TFA according to General Method 6A. Yield: 165 mg (purity 85%, 98% of theory)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])[CH2:20]Br>CCO>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])[CH2:20][S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1
Reactant: Fc1cc(CBr)cc(F)c1F
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Solvent: CCO
Product: Fc1cc(CSc2nnc(-c3ccc4[nH]cnc4c3)o2)cc(F)c1F

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and 3,4,5-trifluorobenzylbromide (0.20 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.