Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.Br[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25]>>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([S:10]([N:9]([CH2:23][C:24]([OH:26])=[O:25])[C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:12])=[O:11])=[N:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C(C)C)cn2)cn1
Product: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)cn1

Procedure:
prepared by reaction of 5-isopropyl-pyridine-2-sulfonic acid (6-methoxy-pyridin-3-yl)-amide with tert-butyl bromoacetate
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[CH:18]=[CH:19][S:20][C:16]=3[C:15]3[CH:14]=[CH:13][C:12]([C:21]#[N:22])=[CH:11][C:10]=3[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:24]O.[C:26]([O-:29])([O-])=[O:27].[K+].[K+]>CCO>[C:1]1([NH:7][C:8]2[C:17]3[CH:18]=[CH:19][S:20][C:16]=3[C:15]3[CH:14]=[CH:13][C:12]([C:21]4[NH:24][C:26](=[O:27])[O:29][N:22]=4)=[CH:11][C:10]=3[N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc2c(c1)nc(Nc1ccccc1)c1ccsc12
Reactant: NO
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=c1[nH]c(-c2ccc3c(c2)nc(Nc2ccccc2)c2ccsc23)no1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 21.7 %

Procedure:
4-(phenylamino)thieno[3,2-c]quinoline-7-carbonitrile (1.0 eq, 27 mg, 0.0897 mmol) and hydroxylamine hydrochloride (10 eq, 62 mg, 0.892 mmol) and K2CO3 (10 eq, 124 mg, 0.896 mmol) were mixed in EtOH (0.5 ml) and the mixture heated under microwave at 100° C. for 10 min. The solid were removed by filtration and washed with EtOH. The solvents were removed in vacuo. The crude material was suspended in chloroform (0.5 ml). Ethyl chloroformate (20 ul) and triethylamine (20 ul) were added and the mixture stirred at room temperature for 10 min. CH2Cl2 was added and the organic phase was washed with brine. The organic phase was dried over Na2SO4 and the solvent removed. The crude material was suspended in NMP (1 ml) and heated under microwave at 160° C. for 10 min. The material was purified by preparative HPLC. Genevac evaporation afforded 3-(4-(phenylamino)thieno[3,2-c]quinolin-7-yl)-1,2,4-oxadiazol-5(4H)-one as an off-white solid (7 mg, 22% yield).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:23](O)=[O:24])[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]=1[O:12]C1C=CC=CC=1.C(N=C=NCCCN(C)C)C.ON1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2N=N1.[CH2:47]([NH:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:55]([N:54]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:23](=[O:24])[C:8]1[CH:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:11]([O:12][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:10]([S:19]([NH2:22])(=[O:20])=[O:21])[CH:9]=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCNc1cc(C(=O)N(Cc2ccccc2)Cc2ccccc2)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
Bumetanide (960 mg, 2.6 mmol) was dissolved in dimethyiformamide (DMF, 10 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 560 mg, 3.6 mmol) was added. After 10 minutes 1-hydroxybenzotriazole (HOBt, 392 mg, 2.9 mmol) was added and the solution was stirred for an additional 10 minutes. Dibenzylamine (1 mL, 5.2 mmol) was added and the reaction was stirred for 2 hours, at which time the reaction was complete by LC/MS. The reaction was poured into saturated ammonium chloride (20 mL) and extracted with ethyl acetate (2×100 mL). The ethyl acetate, was washed with saturated sodium bicarbonate, water and brine, and dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure to yield 1.0 g (75%) of N,N-dibenzyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzamide as white solid.
Reaction SMILES: [CH2:1]([CH:7]([C:12](=[O:33])[CH2:13][CH:14]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)C.[BH4-].[Na+]>C1COCC1>[CH2:1]([CH:7]([CH:12]([OH:33])[CH2:13][CH:14]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCC(CC(=O)C(CCCCCC)C(=O)OC)OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCCCCCC(CC(O)C(CCCCCC)C(=O)OC)OC1CCCCO1
Temperature: -5 °C
Yield: 98.9 %

Procedure:
7.76 g of methyl 2-hexyl-3-oxo -5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate are dissolved in 500 ml of THF while gassing with argon, treated with 20 ml of ethanol and cooled to -5° C. 5.3 g of NaBH4 are added portionwise while stirring in such a manner that the temperature does not exceed 0° C. After stirring for 3 hours the excess sodium borohydride is filtered off, the reaction mixture is hydrolyzed (to pH 6) with 2N hydrochloric acid in the cold and the solvent is evaporated off. The residue is extracted with ether and the ethereal phase is dried and evaporated. There are obtained 7.71 g of methyl 2-hexyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:18][C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>O>[ClH:3].[CH2:24]([O:23][C:21](=[O:22])[CH2:20][N:11]1[C:12]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:18]=[C:10]1[C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)[CH3:25]
Reactant: Clc1ccc(-c2nc3cccnc3[nH]2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cn1c(-c2ccc(Cl)cc2)nc2ncccc21
Product: Cl
Temperature: 25 °C

Procedure:
Under a nitrogen flow, sodium hydride (1.76 g, 0.044 mole, 60% in oil) was washed with hexaxnes (~75 ml) and decanted. Dimethylformamide (150 ml) was added and the 2-(4-chlorophenyl)-3H-imidazo [4,5-b]pyridine (9.16 g, 0.04 mole) was added in portions. The reaction mixture was heated at 70°-85° C. for 1 1/2 hours. Ethyl bromoacetate (6.68 g, 0.04 mole) was added in dropwise and the reaction mixture was allowed to stir at room temperature over the weekend. The reaction mixture was poured into water and the precipitate was collected by filtration, washed with water, and dried under high vacuum at 50 ° C. overnight (78.6% crude yield). A 1.5-g sample was dissolved in ethyl acetate, acidified with ethereal hydrogen chloride, and the crystalline precipitate was collected by filtration, washed with ethyl acetate, and dried under high vacuum to give 1.55 g. The sample was recrystallized from acetonitrile to give 1.16 g after drying under high vacuum at 75° C. over the weekend, mp 199°-200° C. with decomposition.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[CH:7][C:8]1[O:9][C:10]2[C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=[CH:22][C:11]=2[C:12]=1[CH2:13][CH2:14][O:15]C1CCCCO1)(=[O:3])[CH3:2].CCCCCC.C(OCC)(=O)C>CO.[Pd]>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][C:10]2[C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=[CH:22][C:11]=2[C:12]=1[CH2:13][CH2:14][OH:15])(=[O:3])[CH3:2]
Reactant: COC(=O)COc1cccc2c(CCOC3CCCCO3)c(C=CCOC(C)=O)oc12
Agent: [Pd]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c(CCO)c(CCCOC(C)=O)oc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49.6 %

Procedure:
Methyl (2-(3-acetoxy-1-propenyl)-3-(2-tetrahydropyranyloxyethyl)benzofuran-7-yloxy)acetate (199 mg) was dissolved in methanol (4 ml) and 5% Pd/C (28 mg) was added to the solution, followed by stirring the solution at room temperature for 1.5 hours under hydrogen atmosphere. After filtering the reaction solution through Celite, the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (solvent: hexane/ethyl acetate=1/1)using silica gel to obtain the desired compound (80 mg, yield: 50%).
Reaction SMILES: [S].[Br:2][C:3]1[CH:4]=[C:5](S)[CH:6]=[CH:7][CH:8]=1.[C:10]1([SH:16])C=CC=[CH:12][CH:11]=1.ClCCC(O)=[O:21]>>[Br:2][C:3]1[CH:4]=[C:5]([CH:11]([CH3:12])[C:10]([OH:21])=[S:16])[CH:6]=[CH:7][CH:8]=1
Reactant: Sc1ccccc1
Reactant: O=C(O)CCCl
Reactant: Sc1cccc(Br)c1
Agent: [S]
Product: CC(C(O)=S)c1cccc(Br)c1

Procedure:
The compounds of this invention in which X is sulfur are available by bromo replacement of the corresponding 2-amino-5-bromothiochromanes. The latter are available by a sequence of reactions beginning with m-bromothiophenol. The thiophenol is treated in base with β-chloropropionic acid to produce m-bromophenylthiopropionic acid. The acid then is cyclized with polyphosphoric acid or with thionyl chloride or phosgene and a Lewis acid to produce a mixture of 5-bromo-4-thiochromanone and 7-bromo-4-thiochromanone. The thiochromanone mixture is reduced using, for example, sodium borohydride, to produce 4-bromo-1,2-benzothiapyran which is then oxidized with an organic peroxide to the corresponding sulfoxide having an epoxy group in the 3,4 position. Upon treatment with a Lewis acid, 5-bromo-3-thiochromanone sulfoxide is formed which can be reduced to the corresponding thiochromanone using dimethyl sulfide in the presence of trifluroacetic anhydride, oxalyl chloride, thionyl chloride, and the like, or reductively aminated to the 3-amino-5-bromothiochromane sulfoxide by treatment with the appropriate amine and sodium borohydride. The latter is reduced to the desired 3-amino-5-bromothiochromane using trifluoroacetic anhydride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22]1(O)[CH2:26][CH2:25][CH2:24][CH2:23]1.CO>ClCCl>[CH:22]1([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: OC1CCCC1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: ClCCl
Solvent: CO
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OC1CCCC1
Yield: 77 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using cyclopentanol (31 μL, 0.34 mmol) as the coupling partner. Chromatography (1:1 methanol:dichloromethane) through SiO2 yielded 47 mg (77%) of the titled compound as fine white needles. ESI-MS m/z 360 (MH+), 358 (M−H−).
Reaction SMILES: CS(O[CH2:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=O)=O.CN(C=O)C.[N-:33]=[N+:34]=[N-:35].[Na+]>O>[N:33]([CH2:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:27])=[N+:34]=[N-:35]
Reactant: Cc1noc(COS(C)(=O)=O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(CN=[N+]=[N-])c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottomed flask was added crude (4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methyl methanesulfonate (30.8 mg, 0.076 mmol), DMF (2 mL), and sodium azide (4.93 mg, 0.076 mmol). The reaction was stirred at room temperature for 2 h before diluting with water and extracting with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated to afford crude (2-(5-(azidomethyl)-3-methylisoxazol-4-yl)phenyl) (4-chlorophenyl)methanone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1)=[O:17].Br[CH2:27]C(C1C=C(CC)C=CN=1)=O>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16]([C:18]1[CH:23]=[C:22]([CH2:24][CH3:27])[CH:21]=[CH:20][N:19]=1)=[O:17]
Reactant: CCc1ccc2[nH]c(C(=O)c3cc(C)ccn3)c(CC(=O)OC)c2c1
Reactant: CCc1ccnc(C(=O)CBr)c1
Product: CCc1ccnc(C(=O)c2[nH]c3ccc(CC)cc3c2CC(=O)OC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-ethyl-2-(phenylsulfonylamino)cinnamate (Example 133, step 2) and 2-bromoacetyl-4-ethylpyridine (Preparation is described in Example 57).
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[S:37]([CH3:40])(=[O:39])=[O:38])[N:27]=[C:26]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]2[CH3:47])[N:25]=1.[CH:48]1([NH:51][C:52](=[O:69])[NH:53][C:54]2[CH:59]=[CH:58][C:57](B3OC(C)(C)C(C)(C)O3)=[CH:56][CH:55]=2)[CH2:50][CH2:49]1>>[CH:48]1([NH:51][C:52]([NH:53][C:54]2[CH:59]=[CH:58][C:57]([C:24]3[CH:29]=[C:28]([C:30]4[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=4[S:37]([CH3:40])(=[O:39])=[O:38])[N:27]=[C:26]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]4[CH3:47])[N:25]=3)=[CH:56][CH:55]=2)=[O:69])[CH2:50][CH2:49]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1

Procedure:
Method as described for intermediate 5 using (S)-4-(4-chloro-6-(5-fluoro-2-(methylsulfonyl)phenyl)pyrimidin-2-yl)-3-methylmorpholine (intermediate 16) and 4-(3-cyclopropylureido)phenyl boronic acid pinacol ester. Material was purified by prep HPLC (low pH) to afford a brown solid, (43 mg, 17%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([OH:12])[CH3:11].Br[C:14]1[C:15]([NH2:21])=[N:16][CH:17]=[C:18]([Br:20])[N:19]=1>>[Br:20][C:18]1[N:19]=[C:14]([O:12][CH:10]([C:3]2[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[C:15]([NH2:21])=[N:16][CH:17]=1
Reactant: CC(O)c1c(Cl)ccc(F)c1Cl
Reactant: Nc1ncc(Br)nc1Br
Product: CC(Oc1nc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
5-Bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine was prepared following procedure 2 from 1-(2,6-dichloro-3-fluoro-phenyl)-ethanol and 3,5-dibromo-pyrazin-2-ylamine.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4]O.N1C=CN=C1.[C:11]([Si:15](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:14])([CH3:13])[CH3:12].[OH2:29]>CN(C)C=O>[Si:15]([O:29][CH:2]([I:1])[CH2:3][CH3:4])([C:11]([CH3:14])([CH3:13])[CH3:12])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCCI
Reactant: O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCC(I)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 20 h

Procedure:
To a stirred mixture of 3-iodo-1-propanol (4.3 g, 23 mmol) and imidazole (3.74 g, 55 mmol) in dimethylformamide (20 ml) was added tert-butylchlorodiphenylsilane (6.8 g, 24.7 mmol) at ambient temperature and the reaction mixture was stirred for 20 hours. The reaction mixture was then poured into cold water. The combined extracts were washed with dilute hydrochloric acid, 5 percent sodium bicarbonate dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluted with CH2Cl2 :hexane (1:5, v:v) and further by distillation to afford the desired product as a colorless oil: b.p. 134-5° C./0.01 mmHg.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([O:15][N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C(CNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Reaction time: 8 h
Yield: 52.5 %

Procedure:
N-Benzyloxycarbonylglycine (10.9 g, 52.2 mmol) and N-hydroxysuccinimide (6.0 g, 52.2 mmol), were dissolved in dioxane (100 ml) and cooled in a cold water bath. N,N'-Dicyclohexylcarbodiimide (10.8 g, 52.2 mmol) was added and the mixture was stirred overnight. The white precipitate which formed was filtered, washed and air-dried (11.8 g, 100% of dicyclohexylurea). The filtrate was evaporated to dryness under reduced pressure, and the residual solid (16.2 g) was crystallized from ethyl acetate (50 ml) to give 8.4 g (53%) of crystalline N-(N-benzyloxycarbonylglycyloxy)succinimide, m.p. 110.5°-112° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[NH:19][CH:20]=[C:21]([CH:23]=O)[N:22]=1.[C:25](O)(=[O:27])C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:23][C:21]3=[CH:20][N:19]=[C:18]([CH3:17])[N:22]3[C:25]2=[O:27])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCC1CCN(Cc2ccccc2)CC1
Reactant: Cc1nc(C=O)c[nH]1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ncc2n1C(=O)N(CCC1CCN(Cc3ccccc3)CC1)C2
Yield: 48 %

Procedure:
To a suspension of 2-(1-benzyl-4-piperidinyl)ethanamine (5.5 g), 2-methylimidazole-4-carbaldehyde (2.8 g) and acetic acid (1.7 ml) in 1,2-dichloroethane (50 ml) was added sodium triacetoxyborohydride (8.1 g) under ice-cooling. The reaction mixture was returned to room temperature and mixed for 15 hours. Then, the reaction solution was washed with an aqueous potassium carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in THF (50 ml). To the reaction solution were added N,N′-carbonyldiimidazole (4.5 g) and DBU (4.2 g), and mixed at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified with basic silica gel column (ethyl acetate) to obtain the title compound as a colorless oil (4.0 g, 48%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([O:13][C:14]1[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20](Cl)=[O:21])=[CH:16][CH:15]=1)[CH:7]=[N:6]2.[C:28]([CH:31](C(=O)C(OC1C=CC(OC2C=NC3C(=CC=C(F)C=3)N=2)=CC=1)C)[C:32]([O:34][CH3:35])=[O:33])(=[O:30])[CH3:29].C(Cl)(=O)C(Cl)=O.[Na].COC(=O)CC(C)=O>>[C:28]([CH:31]([C:20](=[O:21])[CH:19]([O:18][C:17]1[CH:24]=[CH:25][C:14]([O:13][C:8]2[CH:7]=[N:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:27])([F:26])[F:1])[CH:4]=3)[N:9]=2)=[CH:15][CH:16]=1)[CH3:23])[C:32]([O:34][CH3:35])=[O:33])(=[O:30])[CH3:29]
Reactant: COC(=O)C(C(C)=O)C(=O)C(C)Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1
Reactant: CC(Oc1ccc(Oc2cnc3cc(C(F)(F)F)ccc3n2)cc1)C(=O)Cl
Agent: COC(=O)CC(C)=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na]
Product: COC(=O)C(C(C)=O)C(=O)C(C)Oc1ccc(Oc2cnc3cc(C(F)(F)F)ccc3n2)cc1

Procedure:
In the same manner, 2-[4-(6-trifluoromethyl-2-quinoxalinyloxy)phenoxy]propionic acid chloride is prepared from the corresponding propionic acid and oxalyl chloride, and is then reacted with the sodium salt of methylacetoacetate to give methyl 2-acetyl-4-[4-(6-trifluoromethyl-2-quinoxalinyloxy)phenoxy]-3-oxopentanoate (XIV; X' is CF3 and X" is hydrogen). The pentanoate is then heated with sodium chloride and DMSO to yield 5-[4-(6-trifluoromethyl-2-quinoxalinyloxy)phenoxy]-2,4-hexanedione (XV; X' is CF3 and X" is hydrogen).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:28]1[CH:33]=[C:32]([OH:34])[CH:31]=[C:30]([CH:35]([OH:38])[CH2:36][NH2:37])[CH:29]=1>>[OH:38][CH:35]([C:30]1[CH:29]=[CH:28][CH:33]=[C:32]([OH:34])[CH:31]=1)[CH2:36][NH:37][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)(=[O:16])=[O:17])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NCC(O)c1cccc(O)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4cccc(O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and DL-norphenylephrine according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.35-1.50 (m, 2H), 1.80-2.00 (m, 2H), 2.06 (s, 3H), 2.50-2.90 (m, 5H), 3.45-3.60 (m, 2H), 4.55-4.65 (m, 1H), 5.55 (brs, 1H), 6.60-6.70 (m, 1H), 6.70-6.85 (m, 4H), 6.86 (d, J=9.3 Hz, 2H), 7.11 (t, J=7.8 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.68 (d, J=8.7 Hz, 2H), 9.35 (s, 1H), 10.33 (s, 1H); MS (ES) m/z: 525.4 (MH+); HRMS Calcd. for C27H33N4O5S(MH+): 525.2172. Found: 525.2177.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([F:14])[CH:7]=1>S(=O)(=O)(O)O>[Br:5][C:6]1[C:13]([N+:1]([O-:4])=[O:2])=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([F:14])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Product: O=Cc1cc([N+](=O)[O-])c(Br)cc1F
Reaction time: 2 h

Procedure:
Nitric acid (25 mL) is added dropwise to a solution of 4-bromo-2-fluorobenzaldehyde (5.12 g, 25.2 mmol) in sulfuric acid (25 mL). The mixture is stirred for 2 hours and then is poured over ice. Product is extracted into MTBE (100 mL). The organic layer is washed with saturated aqueous NaHCO3 (100 mL), dried (Na2SO4), and evaporated yielding 5.98 g of yellow solid. 1H NMR (DMSO-d6) δ 10.13, 8.49, 8.22.
Reaction SMILES: [Cl:1]Cl.C(=O)([O-])[O-].[Na+].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16]>>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:1])[C:11]=1[Cl:16].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:1])=[CH:12][C:11]=1[Cl:16]
Reactant: Clc1ccccc1Cl
Reactant: ClCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Clc1ccc(Cl)c(Cl)c1
Product: Clc1cccc(Cl)c1Cl

Procedure:
The o-dichlorobenzene and the catalyst are introduced into the reaction vessel and the chlorine is passed in until a certain density is reached. After completion of the reaction, the chlorination product is neutralised, for example with sodium carbonate, washed with water and distilled in vacuo. A mixture which essentially contains 1,2,3-trichlorobenzene and 1,2,4-trichlorobenzene is obtained; the two isomers can be separated by fractional distillation in the usual manner.
Reaction SMILES: [CH2:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][C:6](=[O:8])[C@H:5]([CH3:9])[O:4]1)[CH3:2].[BrH:16].BrBr>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][C:6](=[O:8])[C@H:5]([CH3:9])[O:4]1)[CH3:2]
Reactant: CCC1(c2ccccc2)OC(=O)[C@H](C)O1
Reactant: Br
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)C1(c2ccccc2)OC(=O)[C@H](C)O1

Procedure:
To a solution of 2-ethyl-2-phenyl-5(S)-methyl-1,3-dioxolane-4-one (1 mmol) and hydrogen bromide (0.1 mmol) in carbon tetrachloride (3 ml), bromine (1 mmol) was added and the temperature was kept at 15° C.