Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]([F:19])([F:18])[C:3]([F:17])([F:16])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[Cl:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1.Cl>CS(C)=O.[Cu]>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]([F:19])([F:18])[C:3]([F:17])([F:16])[O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=2[O:14][CH3:15])=[CH:23][CH:22]=1
Reactant: Clc1ccc(I)cc1
Reactant: COc1cc([N+](=O)[O-])ccc1OC(F)(F)C(F)(F)Br
Agent: [Cu]
Agent: Cl
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1OC(F)(F)C(F)(F)c1ccc(Cl)cc1
Temperature: 160 °C
Reaction time: 18 h
Yield: 26.3 %

Procedure:
Under a dry argon atmosphere a stirred mixture of 4-(2-bromo-1,1,2,2-tetrafluoroethoxy)-3-methoxynitrobenzene (5.0 g, 0.014 mole), 4-chloroiodobenzene (3.4 g, 0.014 mole), and copper powder (4.6 g, 0.072 mole, 200 mesh) in dimethyl sulfoxide (75 mL) was heated at about 160° C. for approximately three hours. The reaction mixture was allowed to cool to room temperature and stirred for an additional 18 hours. The cool mixture was poured into 200 mL of 2N hydrochloric acid, the resultant mixture was extracted with three 100 mL portions of methylene chloride. The extracts were combined and washed in succession with 2N hydrochloric acid, an aqueous, saturated, sodium chloride solution, and 2N aqueous sodium hydroxide. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving an oil. This oil was purified by column chromatography on silica gel, eluting with n-heptane:toluene (90:10), to yield 1.4 g of 4-[2-(4-chlorophenyl)-1,1,2,2-tetrafluoroethoxy]-3-methoxynitrobenzene as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:18][O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Br)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:18][O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:15][CH:12]2[CH2:11][CH2:10][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:17]=[CH:16][C:5]=4[N:6]=3)[CH2:14][CH2:13]2)[CH:23]=1
Reactant: COC(=O)Cc1cccc(CBr)c1
Reactant: NC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(CNC2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A mixture of 1-(6-chlorobenzothiazole-2-yl)piperidine-4-ylamine (500 mg), (3-bromomethylphenyl)acetic acid methyl ester (454 mg), potassium carbonate (284 mg) and dimethylformamide (6 mL) was stirred at room temperature for 1 hour. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (434 mg). Yield: 55%.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=1.Cl[C:23]1[C:28]([C:29]#[N:30])=[CH:27][CH:26]=[CH:25][N:24]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:23]2[N:24]=[CH:25][CH:26]=[CH:27][C:28]=2[C:29]#[N:30])[O:17][N:16]=1
Reactant: N#Cc1cccnc1Cl
Reactant: Cc1sc(-c2ccccc2)nc1COc1cc(CO)on1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1sc(-c2ccccc2)nc1COc1cc(COc2ncccc2C#N)on1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.4 %

Procedure:
To a mixture of [3-(5-methyl-2-phenyl-4-thiazolylmethoxy)-5-isoxazolyl]methanol (1.80 g), 2-chloro-3-cyanopyridine (0.83 g) and N,N-dimethylformamide (80 mL) was added sodium hydride (60%, oil, 0.26 g) under ice-cooling. The reaction mixture was stirred at room temperature for 5 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (2.08 g, 86%) of 2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 135-136° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=1[CH2:19][N:20]1[CH2:24][C@@H:23]([CH3:25])[C@@:22]([CH2:42][C:43]([O:45]C(C)(C)C)=[O:44])([C:26](=[O:41])[NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]=3)[CH2:30][CH2:29]2)[CH2:21]1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[C:10]=1[CH2:19][N:20]1[CH2:24][C@@H:23]([CH3:25])[C@@:22]([CH2:42][C:43]([OH:45])=[O:44])([C:26](=[O:41])[NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]=3)[CH2:30][CH2:29]2)[CH2:21]1
Reactant: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)(F)F)C[C@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(CC2=CCCCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)(F)F)C[C@]1(CC(=O)O)C(=O)NC1CCN(CC2=CCCCC2)CC1
Reaction time: 2 h
Yield: 67 %

Procedure:
Trifluoroacetic acid (1.5 ml, 20.3 mmol) was added to a solution of tert-butyl 2-[(3R*,4S*)-1-{[2-chloro-6-(trifluoromethyl)phenyl]methyl}-3-{[1-(cyclohex-1-en-1-ylmethyl)piperidin-4-yl]carbamoyl}-4-methylpyrrolidin-3-yl]acetate obtained in Example 4i (353 mg, 0.577 mmol) in dichloromethane (400 μl), which was stirred at mom temperature for two hours. The reaction mixture was concentrated under reduced pressure and purified by ODS column chromatography (elution solvent: methanol/water) to give the title compound (215 mg, yield 67%).
Reaction SMILES: [CH2:1]([NH:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>CCOCC.C(#N)C>[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:31])[N:15]([CH2:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([CH2:7][N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([N:22]([CH3:32])[CH3:21])=[CH:24][CH:25]=3)=[O:31])[CH2:13][CH2:12]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:25][CH:24]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: CCCCCNC[C@H]1CC[C@H](CNCCCCC)CC1
Solvent: CC#N
Solvent: CCOCC
Product: CCCCCN(C[C@H]1CC[C@H](CN(CCCCC)C(=O)Nc2ccc(N(C)C)cc2)CC1)C(=O)Nc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Trans-1,4-bis[(normalpentylamino)methyl]cyclohexane, 0.56 g, was dissolved in 10 ml of ether. A solution of 0.81 g of 4-dimethylaminophenyl isocyanate in 20 ml of acetonitrile was added. The reaction mixture was stirred at room temperature for 10 hours. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to provide 1.10 g (yield: 89%) of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[CH:18][C:13]=2[CH:12]=1)=[O:10].C(N(C(C)C)CC)(C)C.Cl.[NH2:41][CH:42]([CH3:47])[C:43]([CH3:46])([OH:45])[CH3:44]>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]2[N:15]=[C:16]([NH:41][CH:42]([CH3:47])[C:43]([OH:45])([CH3:46])[CH3:44])[N:17]=[CH:18][C:13]=2[CH:12]=1)=[O:10]
Reactant: CC(N)C(C)(C)O
Reactant: CS(=O)(=O)c1ncc2cc(C(=O)Cc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(Nc1ncc2cc(C(=O)Cc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1)C(C)(C)O
Temperature: 120 °C

Procedure:
To a solution of 2-(2-chloro-phenyl)-1-[7-(4-fluorophenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanone, 31, (0.036 g, 0.080 mmol) in N-methylpyrrolidinone (2 mL) is added diisopropylethylamine (0.071 mL, 0.410 mmol) and 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.035 g, 0.240 mmol). The mixture is heated to 120° C. for 4 hours. The reaction crude product is then purified by preparative HPLC to afford the desired product as a yellowish solid: 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 7.54 (s, 1H), 7.42-7.38 (m, 1H), 7.32-7.10 (m, 7H), 4.36 (s, 2H), 3.92-3.82 (m, 1H), 1.26 (d, J=9.1 Hz, 6H), 1.20 (d, J=6.8 Hz, 3H); ESI+ MS: m/z (rel intensity) 467.0 (100, M++H).
Reaction SMILES: [H-].[Na+].CCOP(OCC)([CH2:8][C:9]#[N:10])=O.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][C:23]2=O)=[CH:18][CH:17]=1.O>O1CCCC1>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][C:23]2=[CH:8][C:9]#[N:10])=[CH:18][CH:17]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)C(=CC#N)CCC2
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a solution of 60% sodium hydride (6.24 g, 156 mmol) in tetrahydrofuran (100 ml) was gradually added dropwise, under ice-cooling, diethyl cyanomethyl phosphonate (30.4 g, 172 mmol). The mixture was stirred for 15 minutes. To the reaction mixture was then added dropwise a solution of 7-methoxy-1-tetralone (25.2 g, 143 mmol) in THF (50 ml). The reaction mixture was heated for 3 hours under reflux. The reaction mixture was poured into water, and the organic layer was subjected to extraction with chloroform. The extract solution was washed with brine and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=9:1) to give the above-titled compound (a mixture of isomers) (28 g, yield 98%, oil). The above-titled compound (a mixture of isomers) was further purified by a silica gel column chromatography (hexane:ethyl acetate=98:2) to fractionally refine the respective isomers.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=CC(C2N(C([N:71]3[CH2:76][CH2:75][CH:74]([CH2:77][CH2:78][S:79]([CH3:82])(=[O:81])=[O:80])[CH2:73][CH2:72]3)=O)[C@@](C3C=CC(Cl)=CC=3)(C)[C@@](C3C=CC(Cl)=CC=3)(C)N=2)=C(OCC)C=1)(C)(C)C>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:71]3[CH2:76][CH2:75][CH:74]([CH2:77][CH2:78][S:79]([CH3:82])(=[O:81])=[O:80])[CH2:73][CH2:72]3)=[O:36])[C@@:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CCS(C)(=O)=O)CC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 2) was reacted with 4-(2-methanesulfonyl-ethyl)-piperidine hydrochloride (example 53) to give the title compound. HR-MS (ES, m/z) calculated for C36H46Cl2N5O4S [(M+H)+] 714.2642, observed 714.2644.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])([OH:3])=[O:2].[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[C:1]([C:4]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:5]=1[O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])([OH:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(Oc1ccc(Cl)cc1C(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Product: CC(Oc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-])C(=O)O

Procedure:
To a solution of 220 g of 2-(2-carboxy-4-chlorophenoxy) propionic acid in 550 ml of concentrated sulfuric acid is added dropwise a mixed liquid of 44 ml of fuming nitric acid and concentrated sulfuric acid under stirring with keeping at a temperature below 10° C. After the addition, the reaction mixture is stirred below 10° C. for 3 hours and poured into 10 1 of ice-cold water. The precipitated crystals are collected by filtration, washed with 2 1 of water four times and them dried to give 190 g of 2-(2-carboxy-4-chloro-6-nitrophenoxy)propionic acid, melting at 190° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](I)[CH2:28][CH3:29].O>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:27][CH2:28][CH3:29])[CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCI
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCN(C(=O)OC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 26.7 %

Procedure:
A solution of benzyl 4-[(tert-butoxycarbonyl)amino]piperidine-1-carboxylate obtained in Example (241a) (1.00 g, 2.99 mmol) in THF (5 mL) was added to a suspension of sodium hydride (55%) (261 mg, 5.98 mmol) in THF (25 mL) at 0° C. Subsequently, propyl iodide (1.46 mL, 15.0 mmol) was added at 0° C., and the mixture was stirred at room temperature for 22 hours. Thereafter, sodium hydride (55%) (130 mg, 2.99 mmol) and propyl iodide (0.58 mL, 5.98 mmol) were added, and the mixture was heated under reflux for 22 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Thereafter, the combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=5/1) to obtain 301 mg of the title compound as a pale yellow oily substance (27%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C>[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Cc1ccccc1B(O)O
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)c1[nH]c2ccccc2c1-c1ccccc1C

Procedure:
A mixture of EXAMPLE 31B (1.08 g), ortho-tolylboronic acid (1.1 g), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (140 mg) in dimethoxyethane:2N aqueous Na2CO3 (25 mL:5 mL) was stirred under nitrogen at 80° C. for 16 hours, diluted with ethyl acetate and was washed with water and brine. The organic phase was dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel with 0-10% ethyl acetate/hexanes.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][N:18]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[C:17](=[O:28])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].OO.[OH:33]S(O)(=O)=O>C(O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][N:18]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]([NH2:24])=[O:33])[C:17](=[O:28])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2CC(=O)N(c3cccc(C#N)c3)C2)cc1OC1CCCC1
Reactant: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2CC(=O)N(c3cccc(C(N)=O)c3)C2)cc1OC1CCCC1
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of 3-[4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]benzonitrile (12.5 mg, 0.033 mmol) in ethanol (0.5 mL) was added 2 μL of a 25% NaOH solution, followed by 29 μL of 35% H2O2. The temperature of the reaction mixture was kept at 50° C. for 3 h. Upon completion, 5% H2SO4 was added until the mixture was neutral (pH 7). The reaction mixture was extracted with EtOAc and dried with MgSO4. Purification on silica gel afforded the product as a white solid. Yield: 94%.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[O:28][C:29]=1[CH3:30]>>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:27]1[O:28][C:29]([CH3:30])=[C:25]([CH2:24][N:11]2[C:12]3[C:8](=[CH:7][C:6]([CH2:5][CH:4]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:3]([OH:2])=[O:22])=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)[N:26]=1
Reactant: COC(=O)C(Cc1ccc2[nH]ccc2c1)Oc1ccccc1
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCl
Product: Cc1oc(-c2ccccc2Cl)nc1Cn1ccc2cc(CC(Oc3ccccc3)C(=O)O)ccc21

Procedure:
In analogy to the procedure described in example 44, rac-3-(1H-indol-5-yl)-2-phenoxy-propionic acid methyl ester (preparation 7) was reacted with 4-chloromethyl-2-(2-chloro-phenyl)-5-methyl-oxazole to give rac-3-{1-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-2-phenoxy-propionic acid as off-white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8](N)[CH2:9][NH2:10].C=O>C(Cl)Cl>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH2:8][CH2:9][NH:10]1
Reactant: Oc1ccccc1
Reactant: NCCN
Agent: C=O
Solvent: ClCCl
Product: c1ccc2c(c1)CCNO2
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a suitably equipped glass resin reactor equipped with stirrer is charged 450 parts phenol, 450 parts methylene chloride and 144 parts of ethylene diamine. The temperature of the reaction mixture is adjusted to 25° C. and 595 parts of 50% formalin is added while maintaining the temperature below 30° C. The reaction mixture is stirred for 2 hours at 30° C. after formaldehyde addition is complete. It is then heated to atmospheric reflux, refluxed for 3 hours and allowed to cool and separate into two layers. The upper water layer is withdrawn and discarded. The lower organic layer is reheated to atmospheric reflux and distilled to remove solvent. Heating is continued with the gradual reduction of pressure until a temperature of 70° C. at about 5.0 kPa pressure is reached. Cellosolve (450 parts) is added to the resin slowly, keeping the temperature near 70° C. A uniform yellow solution forms which is cooled and filtered. The product has 66% closed dihydroxybenzoxazine ring and a calculated equivalent wt. of 224. The solution has a solids content of 60.2%.
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=[O:4].[CH2:6](O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CC>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:4]
Reactant: CCCCCCCCCCO
Reactant: O=C(O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)CBr
Reaction time: 1.5 h
Yield: 117.4 %

Procedure:
20 g of bromoacetic acid, 22 g of n-decyl alcohol, and 2.5 g of p-toluenesulfonic acid were added to 150 ml of toluene, and the azeotropic dehydration was carried out for 1.5 hours. After cooling the mixture by allowing it to stand, the toluene was removed under reduced pressure and then vacuum distillation was performed, to obtain 41 g of n-octyl bromoacetate (121° C., 10 mmHg).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][NH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19]>C1COCC1.C(Cl)Cl>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][N:15]([CH3:14])[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1ccc2nc(Br)sc2c1
Reactant: CNCCN(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CCN(C)c1nc2ccc([N+](=O)[O-])cc2s1
Yield: 0.1 %

Procedure:
Suspend 2-bromo-6-nitrobenzthiazole (5.00 g, 19.3 mmol) in THF (150 mL). Add N,N, N-trimethylethylene diamine (5.2 g, 40.0 mmol) and stir at room temperature for 6 h. Dilute with CH2Cl2, wash with saturated sodium bicarbonate (2×) and brine, and concentrate in vacuo to afford the crude title compound (5.79 mg, 100%). Carry the crude product on as is. 1H NMR (400 MHz, CDCl3): δ 8.50 (d, 1H, J=2.2 Hz), 8.19 (dd, 1H, J=8.8, 2.2 Hz), 7.49 (d, 1H, J=9.2 Hz), 3.73 (m, 2H), 3.27 (s, 3H), 2.64 (t, 2H, J=6.8 Hz), 2.33 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[CH2:7][CH:8]([OH:37])[C:9]([CH3:36])([CH3:35])[C:10](=[O:34])[CH:11]([CH3:33])[CH:12]([O:24][C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26])[CH:13]([CH3:23])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:44](Cl)([CH2:49][CH3:50])([CH2:47][CH3:48])[CH2:45][CH3:46]>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6](=[O:38])[CH2:7][CH:8]([O:37][Si:44]([CH2:49][CH3:50])([CH2:47][CH3:48])[CH2:45][CH3:46])[C:9]([CH3:36])([CH3:35])[C:10](=[O:34])[CH:11]([CH3:33])[CH:12]([O:24][C:25]([O:27][CH2:28][C:29]([Cl:30])([Cl:32])[Cl:31])=[O:26])[CH:13]([CH3:23])[CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(COCc1ccccc1)C(OC(=O)OCC(Cl)(Cl)Cl)C(C)C(=O)C(C)(C)C(O)CC(=O)OC(C)(C)C
Reactant: CC[Si](Cl)(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(CC(=O)OC(C)(C)C)C(C)(C)C(=O)C(C)C(OC(=O)OCC(Cl)(Cl)Cl)C(C)COCc1ccccc1
Reaction time: 3 h
Yield: 510.4 %

Procedure:
To a solution of 70 (37.6 mg, 6.3 μmol) and imidazole (9.4 mg, 13.8 μmol) in DMF (0.4 mL) at 0° C. was added TESCl (11.6 μL, 69.3 μmol). After 3 h, the mixture was diluted with sat aq NaHCO3. The aqueous layer was extracted three times with hexanes. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient hexane to hexane/EtOAc 93:7) to yield, in order of elution, 71 (22.9 mg, 51%), and recovered 70 (12.9 mg, 34%) as clear oils. 7: 1H NMR (400 MHz, CDCl3) δ 0.66 (q, J=7.9 Hz, 6H), 0.96 (t, J=7.9 Hz, 9H), 1.01 (s, 3H), 1.05 (d, J=5.2 Hz, 3H), 1.07 (d, J=5.3 Hz, 3H), 1.35 (s, 3H). 1.44 (s, 9H), 2.05-2.11 (m, 2H), 2.50 (dd, J=3.5 and 17.2 Hz, 1H), 3.35 (dd, J=5.9 and 9.0 Hz, 1H), 3.49 (dd, J=4.0 and 9.0 Hz, 1H), 3.53 (dd, J=3.8 and 6.7 Hz, 1H), 4.18 (dd, J=3.5 and 6.5 Hz, 1H), 4.45 (s, 2H), 4.65 (d, J=11.9 Hz, 1H), 4.79 (d, J=11.9 Hz, 1H), 4.97 (dd, J=3.7 and 8.1 Hz, 1H), 7.29-7.52 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 5.3, 7.3, 10.9, 14.9, 21.3, 22.6, 28.4, 35.9, 41.1, 42.7, 53.7, 71.9, 73.7, 75.7, 80.1, 80.9, 95.1, 127.9, 128.0, 128.7, 138.6, 154.3, 171.7, 215.7; IR (film, NaCl, cm−1) 2956, 2876, 1732, 1694, 1456, 1366, 1257, 1154, 1098, 988, 835, 774, 741; LRMS (ESI) calcd for C33H53O8SiCl3Na [M+Na+] 733.2, found 733.3. [α]23D=−16.1 (c=0.1, CHCl3).