Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[O:16])[NH:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].O>CN(C=O)C>[C:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[O:16])[N:15]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc2c1CCCC(=O)N2
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)CCCc2c(OC(C)=O)cccc21
Yield: 99 %

Procedure:
6-acetoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzoazepine (252 mg) was dissolved in DMF (5 ml), and the resultant solution was stirred at room temperature. Potassium carbonate (509 mg) and methyl bromoacetate (0.22 ml) were added to the solution at room temperature. After disappearance of the raw materials was confirmed, water (20 ml) was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The resultant organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated. The resultant residue was purified by column chromatography (silica gel:hexane/ethyl acetate=1/1) to obtain the object compound ml (333 mg, yield 99%).
Reaction SMILES: [CH3:1][S@:2](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[N:7][CH:6]=1.Br[C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[C:29]2=[O:36]>>[O:35]=[C:30]1[C:29](=[O:36])[C:28]2[C:32](=[CH:33][CH:34]=[C:26]([C:12]#[C:11][C:9]3[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=3)[C:4]([N:3]=[S@@:2]([CH3:1])(=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH:27]=2)[NH:31]1
Reactant: C[Si](C)(C)C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc3c(c2)C(=O)C(=O)N3)c1)c1ccccc1
Yield: 22.2 %

Procedure:
In a manner similar to that described in Example 443, (S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (150 mg, 0.42 mmol) and 5-bromoisatin (116 mg, 0.46 mmol) were reacted to give the title compound as a reddish oil (40 mg).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[C:12]([CH3:17])([CH3:16])[C:13](Br)=[O:14]>C(Cl)Cl>[CH3:16][CH:12]1[CH2:17][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:13]1=[O:14]
Reactant: CC(C)(Br)C(=O)Br
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1Cc2ccccc2C1=O
Reaction time: 2 h

Procedure:
17.3 g (125 mmol) of AlCl3 were added to a solution of 3.91 g (50 mmol) of benzene in 30 ml of analytical grade methylene chloride, while cooling with ice. 11.9 g (52 mmol) of 2-bromoisobutyryl bromide were then added, and stirring was continued at 0° C. for 1 hour and at room temperature for 2 hours. The mixture was heated under reflux for a further 15 hours and then worked up analogously to Example A. The crude product was chromatographed on 100 g of silica gel (hexane/methylene chloride 1:1). The yield was 5.1 g (70%).
Reaction SMILES: [OH:1][C@H:2]([CH3:46])[CH2:3][NH:4][C:5]([CH3:45])([CH3:44])[CH2:6][C:7]([NH:9][C@H:10]1[C:16](=[O:17])[N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:21][CH:20]=2)[C:14]2[CH:40]=[CH:41][CH:42]=[CH:43][C:13]=2[S:12][CH2:11]1)=[O:8].[C:47]([O:51][C:52]([NH:54][CH2:55][C:56](O)=[O:57])=[O:53])([CH3:50])([CH3:49])[CH3:48]>>[C:47]([O:51][C:52]([NH:54][CH2:55][C:56]([O:1][C@H:2]([CH3:46])[CH2:3][NH:4][C:5]([CH3:45])([CH3:44])[CH2:6][C:7]([NH:9][C@H:10]1[C:16](=[O:17])[N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])=[CH:21][CH:20]=2)[C:14]2[CH:40]=[CH:41][CH:42]=[CH:43][C:13]=2[S:12][CH2:11]1)=[O:8])=[O:57])=[O:53])([CH3:50])([CH3:49])[CH3:48]
Reactant: C[C@@H](O)CNC(C)(C)CC(=O)N[C@@H]1CSc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)OC(C)(C)C)cc2)C1=O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CSc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)OC(C)(C)C)cc2)C1=O)OC(=O)CNC(=O)OC(C)(C)C

Procedure:
This intermediate is prepared from the intermediate obtained in Step B and N-t-butoxycarbonyl glycine according to the procedure described in Example 9, Step C.
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:12](OC(=O)C)(=[O:14])[CH3:13].O>C(O)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:12](=[O:14])[CH3:13])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1ccc(NC(C)=O)cc1
Yield: 96 %

Procedure:
95.0 g (0.64 mol) of p-normalbutylaniline was dissolved in 170 ml of glacial acetic acid. 81.3 g (0.80 mol) of acetic anhydride was then added dropwise to the solution at a temperature of 30° C. After the completion of dropwise addition, the reaction mixture was then allowed to undergo reaction at a temperature of 40° C. for 1 hour. The reaction solution was then poured into 600 ml of water. The resulting crystal was filtered off, washed with water, and then dried. The crystal thus obtained was then recrystallized from a mixture of 120 ml of toluene and 1,000 ml of n-hexane to obtain 117.5 g (yield: 96.4%) of p-normalbutylacetanilide. The melting point of the crystal was from 105.5° C. to 106.0° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14](COCC[Si](C)(C)C)[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(OC([N:38]1[CH2:42][CH2:41][C:40]2([CH2:46][CH2:45][NH:44][CH2:43]2)[CH2:39]1)=O)(C)(C)C>>[CH2:39]1[C:40]2([CH2:46][CH2:45][NH:44][CH2:43]2)[CH2:41][CH2:42][N:38]1[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(I)c3)nc12
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)C1
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(N4CCC5(CCNC5)C4)c3)nc12

Procedure:
1-{2-[3-(2,7-Diaza-spiro[4.4]non-2-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared starting from 1-[2-(3-iodo-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one and 2,7-diaza-spiro[4.4]nonane-2-carboxylic acid tert-butyl ester following general procedures as described in these Examples. M+H=404.
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.N[C:15]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=C[NH:17][N:16]=1>C(O)(=O)C>[CH2:23]([O:22][C:20]([C:19]1[CH:15]=[N:16][N:17]2[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:13]=12)=[O:21])[CH3:24]
Reactant: CN(C)C=CC(=O)c1ccccc1
Reactant: CCOC(=O)c1c[nH]nc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccccc3)ccnc12

Procedure:
A mixture of 17.5 g. of 3-dimethylaminoacrylophenone and 15.52 g. of 3-amino-4-carbethoxypyrazole in 50 ml. of glacial acetic acid is refluxed for 4 hours and then evaporated. The residue is treated as described in Example 1, giving the desired product, m.p. 129°-130° C.
Reaction SMILES: [Cl:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([Cl:13])=[CH:5][C:3]=1[NH2:4].[F:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:16]=1[C:17]([N:19]=[C:20]=[O:21])=[O:18].CCCCCC>C1C=CC=CC=1>[Cl:1][C:2]1[C:8]([C:9]([F:11])([F:10])[F:12])=[CH:7][C:6]([Cl:13])=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:17](=[O:18])[C:16]1[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:15]=1[F:14])=[O:21]
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1Cl
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: c1ccccc1
Solvent: CCCCCC
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)cc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of 2,5-dichloro-3-trifluoromethyl aniline (0.6 g) in 10 ml of dry benzene was added dropwise a solution of 2,6-difluorobenzoylisocyanate (0.5 g) in 5 ml of dry benzene under water-cooling and the solution was stirred for one hour at room temperature. 50 ml of n-hexane was added to the above solution and the precipitated crystal was filtered. The crystal was washed with n-hexane to obtain the desired product 0.9 g. (m.p. 205°-207.5° C.)
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[N:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]4[CH:29]=[N:30][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:32][CH:33]=4)[C:23]3=[O:38])[CH2:18][CH2:17]2)=[N:14][CH:15]=1>CC(O)=O>[Cl:1][C:12]1[C:13]([N:16]2[CH2:17][CH2:18][CH:19]([N:22]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]4[CH:29]=[N:30][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:32][CH:33]=4)[C:23]3=[O:38])[CH2:20][CH2:21]2)=[N:14][CH:15]=[C:10]([Cl:9])[N:11]=1
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4cnc(Cl)cn4)CC3)C2=O)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(Cl)nc4Cl)CC3)C2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
N-Chlorosuccinimide (0.013 g, 0.098 mmol) was added to a suspension of (S)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)-3-(6-(methylsulfonyl)pyridin-3-ylamino)pyrrolidin-2-one (0.034 g, 0.075 mmol) in AcOH (0.3 mL). The mixture was stirred at ambient temperature for 1 hour and then at 50° C. for 1 hour. Acetic acid was removed with a stream of nitrogen. The residue was vigorously stirred in a mixture of 10% Na2S2O3 (1 mL) and EtOAc (1 mL) for 40 minutes. The mixture was partitioned between EtOAc (30 mL) and saturated NaHCO3 (20 mL). Solids which did not dissolve were collected by filtration of the suspension through a 0.45 μm nylon membrane to provide (S)-1-(1-(3,5-dichloropyrazin-2-yl)piperidin-4-yl)-3-(6-(methylsulfonyl)pyridin-3-ylamino)pyrrolidin-2-one (0.011 g, 0.023 mmol, 30%). Mass spectrum (apci) m/z=485.0 (M+H) 487.0. Optical purity of the product was not determined.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:13][CH3:14])[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:28][CH2:29][CH:30]([OH:32])[CH3:31]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][C:4]1[CH:3]=[CH:2][N:28]([CH2:29][CH:30]([OH:32])[CH3:31])[C:5]=12
Reactant: CC(O)CN
Reactant: COc1cccc2c1CC(CC=O)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1Cc1ccn(CC(C)O)c1-2
Reaction time: 0.58 h
Yield: 28.8 %

Procedure:
A solution of 2.04 g of (RS)-2-(2-oxoethyl)-4-methoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 3.13 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 35 minutes, during which the solvent was reduced to a volume of 25 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:4). There was obtained 0.7 g (29%) of (RS)-1-(5-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol as a brown oil which was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11]([NH2:13])=[O:12])[CH2:8]1.[C:19](OC=O)(=[O:21])C.C([O-])=O.[Na+].C(Cl)(=O)C>CCOCC>[CH:19]([NH:13][C:11]([N:9]1[CH2:8][CH:7]([O:6][C:5]2[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[CH2:10]1)=[O:12])=[O:21]
Reactant: CC(=O)OC=O
Reactant: NC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Agent: O=C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)Cl
Product: O=CNC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 54 h
Yield: 61 %

Procedure:
A mixture of 0.524 g (0.002 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide and 1.5 ml of formic acetic anhydride (prepared by reacting sodium formate and acetyl chloride in ether at 23°-27° C. for 5.5 hr, filtering and evaporating off the ether) was stirred at room temperature for about 54 hr. The mixture was evaporated to dryness and the residue was partitioned between 7 ml methylene chloride and 2 ml water. The methylene chloride layer was separated, dried over sodium sulfate and evaporated to dryness. The residue was triturated with ether and the mixture subjected to filtration to give a solid white filter cake weighing 0.398 g after drying. The solid was stirred with more ether for 10 minutes and the mixture filtered to give 0.350 g (61%) white powder, m.p. 117.5°-119° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].[O:26]=[C:27]1[NH:31][C:30](=[O:32])[CH:29]([CH2:33][C:34]2[CH:44]=[CH:43][C:37]([O:38][CH2:39][C:40](O)=[O:41])=[CH:36][CH:35]=2)[S:28]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:26]=[C:27]1[NH:31][C:30](=[O:32])[CH:29]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:38][CH2:39][C:40]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:41])=[CH:43][CH:44]=2)[S:28]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: COc1ccc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)cc1
Yield: 93.5 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-methoxyphenoxy)phenyl]-N-methylcarbamate (2.0 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (2.0 g), diethyl cyanophosphonate (1.3 g), triethylamine (0.81 g) and anhydrous tetrahydrofuran (50 ml) and the reaction mixture was purified to give the desired product (3.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[C:14]([NH2:20])[CH:13]=2)[CH:10]=1)=[O:4].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=S)=[CH:24][CH:23]=1.CI>CO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]3[N:18]([CH3:19])[C:29]([NH:28][C:25]4[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=4)=[N:20][C:14]=3[CH:13]=2)[CH:10]=1)=[O:4]
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: CNc1ccc(Oc2cncc(C(=O)OC)c2)cc1N
Solvent: CO
Solvent: CI
Product: COC(=O)c1cncc(Oc2ccc3c(c2)nc(Nc2ccc(Br)cc2)n3C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the methyl5-[3-amino-4-(methylamino)phenoxy]pyridine-3-carboxylate (1 eq) in methanol (8 ml) was treated with 4-bromophenylisothiocyanate (1 eq) and stirred at 60° C.-65° C. for 2 hours. The reaction mixture was cooled down to room temperature and methyl iodide (1 eq) was added and stirred overnight at 60° C. The reaction was cooled down to room temperature, evaporated, taken up in ethyl acetate and washed with water and brine, dried, evaporated under reduced pressure. Column chromatography yielded methyl5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-3-carboxylate. MS: MH+=452
Reaction SMILES: [N:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[C:15]1([Li])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.ClCCl.[O-2].[O-2].[Mn+4]>[C:15]1([C:2]2[CH:3]=[CH:4][C:5]3[C:14](=[C:13]4[C:8](=[CH:7][CH:6]=3)[CH:9]=[CH:10][CH:11]=[N:12]4)[N:1]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [Li]c1ccccc1
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1ccc(-c2ccc3ccc4cccnc4c3n2)cc1

Procedure:
A compound E-1 was synthesized by the following method. 1,10-phenanthroline (9.64 g) was reacted with phenyl lithium (100 ml) (1.07 M cyclohexane/ether solution) at 0° C. for 1.5 hours in toluene (250 ml) and treated by a conventional method. The resulting product was reacted with manganese dioxide (93.0 g) at room temperature for 56 hours in dichloromethane (300 ml) and treated by a conventional method to obtain 9.44 g of 2-phenyl-1,10-phenanthroline. To 25 ml of a THF solution of 1,3-dibromobenzene (0.34 ml) was added an t-butyl lithium (1.53 M pentane solution) (7.35 mL) at −78° C., and the resulting mixture was stirred for 1 hour, and then its temperature was raised to 0° C. The resulting solution was added to 85 ml of a THF solution of the obtained 2-phenyl-1,10-phenanthroline (1.44 g), and the resulting mixture was stirred at room temperature for 20 hours, and treated by a conventional method. The resulting product was reacted with manganese dioxide (8.50 g) at room temperature for 23 hours in dichloromethane (85 ml) and treated by a conventional method to obtain 1.08 g of a compound E-1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: FC(F)(F)c1cccc(I)c1
Product: FC(F)(F)c1cccc(-n2ccc3ccc(Cl)cc32)c1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-iodo-3-(trifluoromethyl)benzene: ESMS m/e: 295.6 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[C:14]([CH3:22])[C:13]=2[CH:23]=1)C1C=CC=CC=1>C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])=[C:14]([CH3:22])[C:13]=2[CH:23]=1
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(OCc3ccccc3)cc12
Solvent: CCO
Product: Cc1c(C(=O)C(C)C)oc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.2 %

Procedure:
To a solution of 1-[5-(benzyloxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropan-1-one (11.4 g) synthesized in Example A85(1) in ethanol (200 mL) was added palladium carbon-ethylenediamine complex (1.1 g) at room temperature. The reaction mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 16 hr, and the catalyst was filtered off. The filtrate was concentrated under reduced pressure to give a crude product (8.0 g, quantitative) of the title object compound as a colorless solid.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][Cl:21])[OH:19])[CH3:9].[C:22]([N:26]=[C:27]=[O:28])(=[O:25])[CH:23]=[CH2:24].O>ClCCl>[C:22]([NH:26][C:27]([O:18][CH:14]1[CH2:13][CH2:12][C:11]([CH2:20][Cl:21])([OH:19])[CH:10]([C:2]2([CH3:9])[O:1][CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])[CH:15]1[O:16][CH3:17])=[O:28])(=[O:25])[CH:23]=[CH2:24]
Reactant: COC1C(O)CCC(O)(CCl)C1C1(C)OC1CC=C(C)C
Reactant: C=CC(=O)N=C=O
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)NC(=O)OC1CCC(O)(CCl)C(C2(C)OC2CC=C(C)C)C1OC
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
To a solution of 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol (418 mg) in dichloromethane (5 ml) was added dropwise acryloylisocyanate (300 mg). The mixture was stirred for 30 minutes at room temperatures. To the reaction mixture was added water, which was subjected to extraction with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 20 g, developing solvent: hexane-ethyl acetate=4:1) to afford 4-O-(acryloylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol (200 mg, yield 38%) as colorless crystals.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([CH:24]2[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][CH2:25]2)[C:17]([C@@H:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])[CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:32]([NH2:34])[CH3:33]>>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([CH:24]2[CH2:29][CH2:28][C:27]([CH3:30])([CH3:31])[CH2:26][CH2:25]2)[C:17]([C@@H:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])[CH2:13][C@H:9]1[C:10]([NH:34][CH2:32][CH3:33])=[O:11])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CCN
Reactant: CC1(C)CCC(N(C(=O)[C@@H]2CCCO2)[C@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)CC1
Product: CCNC(=O)[C@@H]1C[C@H](N(C(=O)[C@@H]2CCCO2)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Step D of Example A1, using (4S)-1-BOC-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-L-proline (0.96 g, 2.2 mmol) prepared in Step B of Example A2 and commercially available ethylamine (0.95 g, 93%).
Reaction SMILES: O.[PH2:2]([O-:4])=[O:3].[Na+].[CH2:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH3:11].OO>C(O)C.S(=O)(=O)(O)O>[CH2:6]([PH:2](=[O:4])[OH:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=[PH2][O-]
Reactant: C=CCCCC
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCC[PH](=O)O
Yield: 82.1 %

Procedure:
To a mixture of 95.2 g (0.898 mol) of sodium hypophosphite hydrate in 600 mL 95% ethanol, 23.8 mL of concentrated sulfuric acid was added. 1-hexene (25.2 g, 0.30 mol) was added to the stirred mixture followed by 1.76 g (0.0155 mol) of 30% hydrogen peroxide. The resulting mixture was refluxed for 8 hs, and then another 1.14 g (0.0101 mol) of hydrogen peroxide was added and the reaction mixture was continued to reflux for another 8 hs. The resulting mixture was cooled, filtered, and then the ethanol was removed using a rotary evaporator. To the resulting residue, 200 mL water was added and then 50% sodium hydroxide solution was added until the solution became alkaline. The mixture was extracted twice with 200 mL diethyl ether, and the aqueous phase was then acidified with concentrated sulfuric acid. The aqueous layer was extracted with 200 mL ethyl acetate, and the organic layer was washed with saturated sodium chloride and then dried over anhydrous magnesium sulfate. The organic layer was decanted and the drying agent was washed with another 50 mL ethyl acetate. The combined organic layers were evaporated on a rotary evaporator. 37.0 g n-hexylphosphinic acid (82.4% yield) was obtained.
Reaction SMILES: Br[CH:2]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:3](=[O:12])[C:4]([CH3:11])([S:6][C:7]([F:10])([F:9])[F:8])[CH3:5].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1>C(#N)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH:2]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[C:3](=[O:12])[C:4]([CH3:11])([S:6][C:7]([F:10])([F:9])[F:8])[CH3:5])=[CH:15][CH:16]=1
Reactant: CC(C)(SC(F)(F)F)C(=O)C(Br)Oc1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Solvent: CC#N
Product: CC(C)(SC(F)(F)F)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Yield: 36.5 %

Procedure:
29 g (0.075 mol) of crude 1-bromo-1-(4-chlorophenoxy)-3-methyl-3-trifluoromethylthio-butan-2-one and 16 g (0.25 mol) of 1,2,4-triazole in 150 ml of acetonitrile were heated under reflux for 1 hour. Thereafter, the mixture was concentrated and the residue was taken up with methylene chloride/water. The organic phase was separated off, dried over sodium sulphate and concentrated again. The oil residue was chromatographed. 10.4 g (37% of theory) of 1-(4-chlorophenoxy)-3-methyl-1-(1,2,4-triazol-1-yl)-3-trifluoromethylthio-butan-2-one of melting point 66° C. were obtained.