Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3](=[O:10])[O:2]1.[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([O:19][C:3](=[O:10])[CH2:4][C:5]1([C:1]([OH:11])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: O=C1CC2(CCCC2)C(=O)O1
Solvent: Cc1ccccc1
Product: O=C(CC1(C(=O)O)CCCC1)OCc1ccccc1
Temperature: 100 °C
Reaction time: 19 h
Yield: 60.5 %

Procedure:
To a solution of 2-oxaspiro[4.4]nonane-1,3-dione (3 g, 19.46 mmol) in toluene (2 ml), BnOH (2.023 ml, 19.46 mmol) was added. The reaction mixture was allowed to stir at 100° C. for 19 hours, and the reaction mixture was concentrated under reduced pressure. The obtained residue was recrystallized in DCM (15 ml) and 2,2,4-trimethylpentane (100 ml). The obtained colorless crystal was washed with a 10% solution of DCM/heptane (20 ml). The obtained solid was dried under reduce pressure to give 1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxylic acid (3.09 g); Retention time=1.56 minutes (condition A); 1H NMR (400 MHz, CDCl3) δ ppm 1.24 (t, J=7.2 Hz, 3H) 1.58-1.81 (m, 6H) 2.19-2.25 (m, 2H) 2.75 (s, 2H) 5.11 (s, 2H) 7.28-7.37 (m, 5H) 11.80 (br s, 1H).
Reaction SMILES: C([NH:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:54]/[O:55][CH2:56][F:57])/[C:27]([NH:29][C@@H:30]2[C:52](=[O:53])[N:32]3[C:33]([C:49]([O-:51])=[O:50])=[C:34](/[CH:37]=[CH:38]/[CH2:39][N+:40]([C@@H:43]([C:46](=[O:48])[NH2:47])[CH2:44][OH:45])([CH3:42])[CH3:41])[CH2:35][S:36][C@H:31]23)=[O:28])[N:22]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C(OCC)C>C1(OC)C=CC=CC=1>[NH2:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:54]/[O:55][CH2:56][F:57])/[C:27]([NH:29][C@@H:30]2[C:52](=[O:53])[N:32]3[C:33]([C:49]([O-:51])=[O:50])=[C:34](/[CH:37]=[CH:38]/[CH2:39][N+:40]([C@@H:43]([C:46](=[O:48])[NH2:47])[CH2:44][OH:45])([CH3:42])[CH3:41])[CH2:35][S:36][C@H:31]23)=[O:28])[N:22]=1
Reactant: C[N+](C)(C/C=C/C1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OCF)c3nsc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1)[C@H](CO)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CCOCC
Product: C[N+](C)(C/C=C/C1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OCF)c3nsc(N)n3)[C@H]2SC1)[C@H](CO)C(N)=O
Reaction time: 1 h
Yield: 99.6 %

Procedure:
The compound (500 mg) of Example 38 was suspended in anisole (3 ml), followed by an addition of trifluoroacetic acid (3.5 ml) under ice cooling. The resulting mixture was stirred for 1 hour at the same temperature, followed by a further addition of trifluoroacetic acid (1.5 ml). The resulting mixture was stirred for 1 hour. Ethyl ether was added, and a precipitate thus formed was collected by filtration to obtain the target product (350 mg). Its infrared spectrum and NMR spectrum were consistent with those of Example 10.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:7]=1.BrC1C=CC([N+]([O-])=O)=CC=1C(OC)=O.[Cl:37]C1C=CC(OC)=C(B(O)O)C=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:37][C:4]1[C:5]([O:21][CH3:22])=[C:6]([C:8]2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:7]=[CH:2][CH:3]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(F)ccc1OC
Reactant: COc1ccc(Cl)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cccc(Cl)c1OC
Yield: 35 %

Procedure:
This compound was prepared in a manner similar to that of methyl (5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylate) (EXAMPLE 107) from methyl 2-bromo-5-nitrobenzoate (0.58 g, 2.2 mmol), (PPh3)4Pd (77 mg, 0.066 mmol), and 5-chloro-2-methoxyphenylboronic acid (0.54 g, 2.9 mmol) to afford 245 mg (35%) of methyl (3'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate) as a clear oil. Data for methyl (3'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate): 1H NMR (400 MHz, CDCl3) 8.79 (d, J=2.4, 1H), 8.40 (dd, J=8.4, 2.4, 1H), 7.57 (d, J=8.5, 1H), 7.45 (m, 1H), 7.15 (m, 2H), 3.75 (s, 3H), 3.47 (s, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=1.C1C(=O)N([Br:24])C(=O)C1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[C:14]([Br:24])[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1-c1nc2ccccc2s1
Product: Nc1ncc(Br)cc1-c1nc2ccccc2s1

Procedure:
The title compound was prepared from 3-benzothiazol-2-ylpyridin-2-ylamine (22.7 g, 100 mmol) and NBS (17.8 g, 100 mmol) as a brown solid following the General Procedure for the Bromination of Aminopyridines with NBS. 1H NMR (CDCl3, 300 MHz): δ=7.17 (brs, 2H), 7.41 (t, J=6.9 Hz, 1H), 7.50 (t, J=6.9 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.95 (d, J=2.4 Hz, 1H), 8.03 (d, J=2.1 Hz, 1H), 8.20 (d, J=2.1 Hz, 1H). MS(ES+): m/z=305.98/307.94 (91/100) [MH+]. HPLC: tR=3.62 min (nonpolar—5 min, ZQ3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH2:32]([N:35]([CH2:40][CH:41]=[CH2:42])[C:36](=[O:39])[CH:37]=[CH2:38])[CH:33]=[CH2:34]>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:32][CH:33]=[CH2:34])[CH2:40][CH:41]=[CH2:42])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=CCN(CC=C)C(=O)C=C
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Product: C=CCN(CC=C)C(=O)C=Cc1cc(C)c(N(Cc2cccnc2)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1
Yield: 53.7 %

Procedure:
In the same manner as described in Example 203, 550.4 mg (1.0 mmol) of the product of Example 89 and 453.6 mg (3.0 mmol) of N,N-diallylacrylamide provided 309 mg (53%) of the desired product as a yellow gum. Electrospray Mass Spec 576(M+H).
Reaction SMILES: [N+](C1C=C([C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)=[O:11])C=CC=1)([O-])=O.C([N-]C(C)C)(C)C.[Li+].C1CCCCC1.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>O1CCCC1.O>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:18]2[CH:19]=[C:20]3[C:12]([CH:10]=[O:11])=[CH:13][N:14]([S:47]([C:44]4[CH:45]=[CH:46][C:41]([CH3:51])=[CH:42][CH:43]=4)(=[O:49])=[O:48])[C:15]3=[N:16][CH:17]=2)[CH:22]=1
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1c[nH]c2ncc(-c3cccnc3)cc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3cc(-c4cccnc4)cnc32)cc1
Reaction time: 0.5 h

Procedure:
To (3-nitro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (536, 291 mg, 0.85 mmol) in tetrahydrofuran (7 mL) was added 1.5 M of lithium diisopropylamide in cyclohexane (676 μl, 1.59 mmol) at −78° C. under an atmosphere of nitrogen. After 30 minutes, p-toluenesulfonyl chloride (209 mg, 1.10 mmol) was added in tetrahydrofuran and the reaction was stirred for three hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. All solids were filtered and purified by silica gel column chromatography eluting with 60% ethyl acetate in hexane to give the compound (537, 182 mg, 43%). MS(ESI)[M+H+]+=499.2.
Reaction SMILES: [CH3:1][SiH2:2][O:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[CH2:8]=[CH:9]C.[C:11]1(C)C=CC=CC=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH2:5]([Si:4]([CH3:7])([CH3:6])[O:3][SiH:2]([CH3:11])[CH3:1])[CH2:8][CH3:9]
Reactant: C=CC
Reactant: C[SiH2]O[Si](C)(C)C
Reactant: Cc1ccccc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCC[Si](C)(C)O[SiH](C)C
Temperature: 50 °C

Procedure:
An 80 mL Fischer-Porter high pressure bottle was charged with tetramethyldisiloxane (10.0 g), toluene (10.0 g) and Wilkinson's catalyst ((PPh3)3RhCl, 40 ppm), stirred and brought to 50° C. The bottle was attached to a manifold and pressurized with propylene (40 psig) and maintained at 50° C. for 2 h. The pressure was vented, and the reaction was sampled for GC analysis; found M′MR product and MRMR byproduct (40:60). The resulting mixture of materials was used without further purification, yield 14.1 g.
Reaction SMILES: C(C=C)=O.C1(C=CC(O)=CC=1)O.[CH3:13][P:14]([O:18][CH2:19][CH3:20])[O:15]CC.[CH2:21]([O:23][CH:24]([O:31][CH2:32][CH3:33])[CH2:25][CH2:26]P(C)(=O)[O-])[CH3:22]>C(O)C>[CH2:21]([O:23][CH:24]([O:31][CH2:32][CH3:33])[CH2:25][CH2:26][P:14]([CH3:13])(=[O:15])[O:18][CH2:19][CH3:20])[CH3:22]
Reactant: CCOP(C)OCC
Reactant: CCOC(CCP(C)(=O)[O-])OCC
Agent: C=CC=O
Agent: Oc1ccc(O)cc1
Solvent: CCO
Product: CCOC(CCP(C)(=O)OCC)OCC
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
Into a 100 ml. red flask was introduced 12.5 g. of acrolein, and 15 mg. of hydroquinone and 45 ml. of anhydrous ethyl alcohol were added thereto. The resulting mixture was stirred at -10° C. in a stream of nitrogen and then 13.6 g. of diethyl methylphosphonite was added dropwise thereto over 20 minutes. After stirring further for 30 minutes at the same temperature, the mixture was stirred for 2 hours at 0° C. and subsequently for 4 hours at room temperature, followed by further reaction at 70° C. for 12 hours. After the reaction mixture thus obtained was concentrated by evaporation of the ethanol under reduced pressure, the residue was subjected to distillation under reduced pressure to give a fraction boiling at 85° to 91° C./0.17 mmHg. and thus was obtained 12.2 g. of a light-yellow oil of ethyl, 3,3-diethoxypropylmethylphosphinate.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:6][CH2:5]1.Cl[CH2:23][O:24][CH3:25].O>CN(C)C=O>[CH3:23][O:24][CH2:25][N:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:6][CH2:5][C:4]1=[O:3]
Reactant: O=C1CCN(c2ccccc2F)c2ccccc2N1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCN1C(=O)CCN(c2ccccc2F)c2ccccc21
Reaction time: 1 h
Yield: 237.5 %

Procedure:
Under argon atmosphere, 60% sodium hydride (0.38 g) was suspended in N,N-dimethylformamide (5 ml), a solution of 2-oxo-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.89 g) in N,N-dimethylformamide (15 ml) was added dropwise over 15 minutes under ice-cooling, the mixture was stirred for one hour at same temperature. Chloromethylmethyl ether (0.89 g) was added thereto, the resultant mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, extracted with chloroform, the organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 5.26 g of the titled compound as colorless amorphous (Yield: 98.4%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9][C@H:8]1/[CH:32]=[CH:33]\[C:34]([NH2:36])=[O:35])=[O:6])[CH:2]=[CH2:3].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([SH:12])[CH2:9][C@H:8]1/[CH:32]=[CH:33]\[C:34]([NH2:36])=[O:35])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1/C=C\C(N)=O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1/C=C\C(N)=O
Reaction time: 0.5 h

Procedure:
To a solution of (Z)-3-[(2S,4S)-N-allyloxycarbonyl-4-tritylthiopyrrolidin-2-yl]acrylamide (1.02 g, 2.06 mmol) in methylene chloride (1 ml) were added trifluoroacetic acid (1 ml) and triethylsilane (0.33 ml, 2.07 mmol) under ice-cooling under nitrogen. The reaction mixture was stirred for 30 minutes at the same temperature, concentrated under reduced pressure, and diluted with methylene chloride (5 ml). The mixture was concentrated again, and extracted with ethyl acetate (50 ml). The organic layer was washed with 0.1M phosphate buffer (pH 5.7×2) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated to give (Z)-3 [(2S,4S)-N-allyloxycarbonyl-4-mercaptopyrrolidin-2-yl]acrylamide, which was used for the next reaction without purification. ##STR328##
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]1([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)=[O:6]
Reactant: NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Product: O=C(NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1)c1ccc(Cl)cc1Cl

Procedure:
From 2,4-dichlorobenzoic acid and 2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+): m/z=439.0, tR (minutes, Method E)=0.81
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Br:24][C:25]1[C:26]([CH2:33]Br)=[N:27][C:28]([S:31][CH3:32])=[N:29][CH:30]=1>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:33][C:26]3[C:25]([Br:24])=[CH:30][N:29]=[C:28]([S:31][CH3:32])[N:27]=3)[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CSc1ncc(Br)c(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reaction time: 1 h

Procedure:
(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 1, 326 mg, 1.041 mmol) was dissolved in THF (7 mL) and cooled in an ice bath. To this solution was added NaH (27.3 mg, 1.136 mmol) all at once. The resulting bubbling/foaming mixture was stirred in an ice bath for 1 h followed by addition of 5-bromo-4-(bromomethyl)-2-(methylthio)pyrimidine (Step C, 282 mg, 0.946 mmol) in THF (3 mL). The resulting yellow mixture was stirred in an ice bath and allowed to warm to ambient overnight. The reaction crude was then quenched by adding NH4Cl (aq., sat.). The resulting mixture was worked up with brine, dried (Na2SO4), filtered and evaporated to give a yellow oil. The oil was purified by flash chromatography (SiO2, Biotage 40M cartridge). The column was eluted with a EtOAc/hexanes gradient mixture (0% to 20%). Related fractions were pooled and evaporated into a colorless glass/gum as the titled compound. LCMS calc.=530.99; found=532.00.
Reaction SMILES: C(O)C.C(O)(=O)C.[CH3:8][C:9]1[S:32][C:12]2[N:13]=[C:14]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-])=O)[C:11]=2[CH:10]=1>[Fe].O>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]1[C:11]2[CH:10]=[C:9]([CH3:8])[S:32][C:12]=2[N:13]=[C:14]([N:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]2)[N:15]=1
Reactant: Cc1cc2c(-c3ccccc3[N+](=O)[O-])nc(N3CCNCC3)nc2s1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1cc2c(-c3ccccc3N)nc(N3CCNCC3)nc2s1
Yield: 81.3 %

Procedure:
Into a mixed solvent of 8 ml of ethanol, 3.5 ml of water and 4 ml of acetic acid, 1.25 g of 6-methyl-4-(2-nitrophenyl)-2-piperazinyl-thieno[2,3-d]pyrimidine is dissolved, and 1.5 g of iron powder is gradually added at 90° C. over one hour. After the reaction at 90° C. further for 20 minutes, 25 ml of ethanol and 6 ml of water are added. The reaction mixture is filtered by a Celite layer. The Celite layer is washed with hot ethanol and the washings and the filtrate are combined and distilled off under reduced pressure. The residue is treated with 20 ml of 10% aqueous solution of sodium carbonate and with 80 ml of chloroform and filtered by a Celite layer. The chloroform layer is separated and dried over anhydrous sodium sulfate. Chloroform is removed to concentrate and crystallization from chloroform/cyclohexane gives the desired product (0.93 g) which has a melting point of 232°-236° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([O:9]C=CC)=[CH:5][CH:4]=1.OCC(CO)(CO)CO.C(Cl)(Cl)(Cl)[Cl:25]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:25][C:7]1[CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=[CH:5][C:6]=1[OH:9]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC=COc1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OCC(CO)(CO)CO
Product: Oc1ccc(C(F)(F)F)cc1Cl
Reaction time: 2 h

Procedure:
A mixture of 0.5 mol of propenyl 4-trifluoromethylphenyl ether, 0.25 mol of pentaerythritol and 5 g of p-toluenesulphonic acid in 500 ml of carbon tetrachloride was stirred and refluxed under nitrogen for 40 minutes. The resulting solution was washed with 250 ml of water, and then dried by azeotroping 150 ml solvent in vacuo. After addition of 150 ml of fresh carbon tetrachloride, chlorine was passed into the solution for 2 hours, after which the solution was washed with 250 ml of water and the solvent was evaporated. The remaining product was purified by fractional distillation to give 74.8 g of 2chloro-4-trifluoromethylphenol, b.p: 52°-53.5° C. at 6 Torr., which was identified and shown by gas chromatography to have a purity of greater than 97%.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(Cl)([Cl:18])=O>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][C:13]([Cl:18])=[O:15])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)N1CCC(CCCC(=O)O)CC1
Product: CC(=O)N1CCC(CCCC(=O)Cl)CC1
Reaction time: 0.08 h

Procedure:
4-(1-Acetyl-4-piperidinyl)butyric acid (2.6 g, 12 mmol) was added in small portions to thionyl chloride (12 ml) with ice-bath cooling. After the mixture was stirred for 5 minutes, the excess thionyl chloride was distilled off and the residue was washed with hexane to provide 4-(1-acetyl-4-piperidinyl)butyryl chloride as light-yellow solid. Aluminum chloride (66,0 g, 0.49 mol) powders were added in small portions to a mixed solution of the above acid chloride and 3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.5 g, 10 mmol), obtained in Reference Example 3, in 1,2-dichloroethane (10 ml) with ice-bath cooling. This mixture was stirred at room temperature for 2 days, then poured in ice-water, and extracted with ethyl acetate. The extract was washed with saturated NaCl/H2O and dried over MgSO4 The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=9:1) to provide 4-(1-acetyl-4-piperidinyl)-1-(3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-butanone (3.7 g) as colorless crystals melting at 101-102° C.
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4]O.[Br:17]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCBr
Yield: 89.4 %

Procedure:
3.1 g (13.6 mmol) of (3R,7R)-3,7,11-trimethyl-1-dodecanol are treated with 4.02 g (15.3 mmol) of N-bromosuccinimide and 2.62 g (14.7 mmol) of triphenylphosphine in 13 ml of methylene chloride according to the method described above in Example 10. After chromatography and distillation, there are obtained 3.54 g (90%) of (3R,7R)-bromo-3,7,11-trimethyldodecane. B.p. 90°/0.05 Torr; [α]D20 = -3.6 (c = 1.005, n-octane).
Reaction SMILES: [O:1]=C1CN(CC([O-])=O)C(=O)N1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[CH2:18][N:19]1[C:23](=[O:24])[C:22](=[O:25])[N:21]([CH2:26][C:27]([OH:29])=[O:28])[C:20]1=S)([O-:14])=[O:13].Cl>C(O)(=O)C>[OH:25][CH:22]1[N:21]([CH2:26][C:27]([OH:29])=[O:28])[C:20](=[O:1])[N:19]([CH2:18][C:17]2[CH:31]=[CH:32][CH:33]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:23]1=[O:24]
Reactant: O=C([O-])CN1CC(=O)NC1=O
Reactant: O=C(O)CN1C(=O)C(=O)N(Cc2cccc([N+](=O)[O-])c2)C1=S
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)N(Cc2cccc([N+](=O)[O-])c2)C(=O)C1O
Reaction time: 2 h

Procedure:
The above-prepared dioxoimidazolidine-1-acetate product of paragraph (2) (15 g) was suspended in a mixed solvent of acetic acid and hydrochloric acid and the mixture was heated to reflux with stirring for two hours. Then the mixture was concentrated in vacuo, ether-chloroform was added thereto. The crystals were dislodged from the wall of the reaction flask with a spatula. The solid was washed with ether and recrystallized from a mixed solvent of ethanol and water to give 8.1 g of 5-hydroxy-3-(3-nitrobenzyl)-2,4-dioxoimidazolidine-1-acetic acid [Compound 15]. The melting point, MS, IR, NMR, and elementary analysis for the compound were:
Reaction SMILES: [CH3:1][C:2]([CH3:12])([C:7](=[O:11])[CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4].[ClH:13].[CH2:14]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:29]=O.Cl>C(O)C>[ClH:13].[CH2:22]([N:21]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][C:8]([CH3:29])([CH3:9])[C:7](=[O:11])[C:2]([CH3:1])([CH3:12])[C:3]([O:5][CH3:6])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=O
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: COC(=O)C(C)(C)C(=O)C(C)C
Agent: Cl
Solvent: CCO
Product: COC(=O)C(C)(C)C(=O)C(C)(C)CN(Cc1ccccc1)Cc1ccccc1

Procedure:
To a mixture of 86 g. (0.50 mole) methyl 2,2,4-trimethyl-3-ketovalerate, 117 g. (0.64 mole) dibenzylamin hydrochloride and 19.8 g. (0.22 mole) paraformaldehyde is added a solution of 1 ml. of concentrated hydrochloric acid in 150 ml. 95% ethanol and the mixture is heated at reflux for four hours. The mixture is filtered, 500 ml. of hot acetone added to the filtrate and the resulting mixture cooled then refrigerated overnight. The precipitated product is collected by filtration, washed with acetone and dried.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[O:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[Cl:17][C:18]1[CH:23]=[C:22]([N:24]=C=O)[CH:21]=[C:20]([Cl:27])[CH:19]=1.[N:28]1[S:29][N:30]=[C:31]2[C:36]([NH2:37])=[CH:35][CH:34]=[CH:33][C:32]=12>>[N:28]1[S:29][N:30]=[C:31]2[C:36]([NH:37][C:10]([C@@H:9]3[CH2:13][C:14](=[O:16])[CH2:15][N:8]3[C:6]([NH:24][C:22]3[CH:23]=[C:18]([Cl:17])[CH:19]=[C:20]([Cl:27])[CH:21]=3)=[O:7])=[O:12])=[CH:35][CH:34]=[CH:33][C:32]=12
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: Nc1cccc2nsnc12
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Product: O=C1C[C@@H](C(=O)Nc2cccc3nsnc23)N(C(=O)Nc2cc(Cl)cc(Cl)c2)C1

Procedure:
Following the general method as outlined in Example 22, starting from l-(tert-butoxy-carbonyl)-4-oxoproline, 1,3-dichloro-5-isocyanatobenzene, and 2,1,3-benzothiadiazol-4-amine the title compound was obtained in 47% purity by LC/MS. MS(ESI+): m/z=450.6.