Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[C:19]1[S:20][CH:21]=[CH:22][N:23]=1>CN(C)C=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[CH2:16][CH2:17]1
Reactant: c1ccc2cc(CN3CCNCC3)ccc2c1
Reactant: Clc1nccs1
Solvent: CN(C)C=O
Product: c1ccc2cc(CN3CCN(c4nccs4)CC3)ccc2c1
Yield: 54.9 %

Procedure:
In a manner similar to that described above, but starting from 45.2 g (0.2 mole) of 1-(2-naphthylmethyl)-piperazine and 12 g (0.1 mole) of 2-chlorothiazole in 150 ml of dimethylformamide at 150° C., there were obtained 17 g of 1-(2-naphthylmethyl)-4-(2-thiazolyl)-piperazine as beige crystals melting at 83°-84° C.
Reaction SMILES: [CH:1]1([O:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:36])[C@@H:15]([NH:25]C(OCC3C=CC=CC=3)=O)[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.[Pd]>[CH:1]1([O:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:36])[C@@H:15]([NH2:25])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(C(=O)OC2CCC2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC[C@H](N)C(=O)N1CCN(C(=O)OC2CCC2)CC1
Reaction time: 12 h

Procedure:
To a solution of 11.1 g 4-((S)-2-Benzyloxycarbonylamino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid cyclobutyl ester in 80 ml ethyl acetate were added 0.6 g Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 12 h. The reaction mixture was filtrated over a plug of Celite, washed with ethanol and concentrated to give the crude product which was used in the subsequent reaction. Yield: 7.2 g.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:14][C:13]=3[CH:25]=2)[S:3]1.[BH4-].[Na+].O>CO.O1CCCC1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]([OH:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:14][C:13]=3[CH:25]=2)[S:3]1
Reactant: O=C1NC(=O)C(Cc2ccc3oc(C(=O)c4ccccc4)nc3c2)S1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc3oc(C(O)c4ccccc4)nc3c2)S1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
1.3 g of 5-[(2,4-dioxothiazolidin-5-yl)methyl)-2-(benzoyl)benzoxazole are dissolved in a mixture of 30 ml of methanol and 6 ml of tetrahydrofuran, and 0.14 g of sodium borohydride is added thereto. After the mixture is stirred at room temperature for 5 minutes, water is added thereto. The solution is extracted with ethyl acetate, and the extract is evaporated to remove the solvent. The residue is crystallized with ether, whereby 0.64 g of 5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-(α-hydroxybenzyl)benzoxazole is obtained as colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[O:14][CH3:15].[C:16]1([CH:23]=CC(O)=[CH:19][CH:18]=1)O.C=CC=C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:19][CH:18]=[CH:16][CH2:23][C@H:10]2[N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[O:14][CH3:15]
Reactant: Oc1ccc(O)cc1
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1OC
Agent: C=CC=C
Solvent: Cc1ccccc1
Product: COc1ccc([C@@H]2CC=CC[C@H]2[N+](=O)[O-])cc1OC
Temperature: 160 °C
Reaction time: 144 h

Procedure:
50.0 g of 3,4-dimethoxy-ω-nitrostyrene and 1.0 g (9.1 mmol) of hydroquinone are suspended in 200 ml of abs. toluene and treated at −70° C. with 55.0 g (1.02 mol) of liquid 1,3-butadiene. The mixture is stirred at 160° C. for 6 days in an autoclave and then cooled. Some of the solvent is removed on a rotary evaporators and the resulting precipitate is filtered off with suction and recrystallized in ethanol. M.p.: 113.5-115.5° C.
Reaction SMILES: CC1C=C[C:5]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]C2)=[C:6]([NH:8]C(N2CCN(C)CC2)=O)C=1>P(Cl)(Cl)(Cl)=O>[NH:18]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:20]=[N:8][CH:6]=[CH:5]1
Reactant: Cc1ccc(N2CCc3ccccc32)c(NC(=O)N2CCN(C)CC2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: C1=CNc2ccccc2C=N1
Temperature: 25 °C

Procedure:
A stirred mixture of 35.1 (0.10 mole) of N-[5-methyl-2-(2,3-dihydro-1H-indol-1-yl)phenyl]-4-methyl-1-piperazinecarboxamide of Example 5c in 500 ml of phosphorus oxychloride was refluxed for 6 hours under nitrogen, then cooled to room temperature. The excess phosphorus oxychloride was removed at aspirator pressur with gentle warming. The residue was chilled in an ice-bath (with exclusion of moisture), and then treated first with 250 ml of ice-cold 2N-NaOH, then with 500 ml of chloroform. The mixture was stirred vigorously until all the material passed into solution. The organic phase was separated, washed thrice with water, and concentrated in vacuo to an oil. This was dissolved in 100 ml of boiling acetone, then allowed to crystallize at room temperature to afford 13.5 9 (41% overall yield) of 9-methyl-6-(4-methyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo 3,2,1-jk][1,4]-benzodiazepine, m.p. 160°-162° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Na].[OH:8][CH:9]([CH:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[CH2:10][N+:11]([O-])=O.O.[OH-].[Na+]>O1CCCC1>[OH:8][CH:9]([CH:14]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][NH2:11]
Reactant: COc1ccccc1OC(c1ccccc1)C(O)C[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1OC(c1ccccc1)C(O)CN
Yield: 47.8 %

Procedure:
To a suspension of 0.55 g of LiAlH4 in 18 ml of anhydrous tetrahydrofuran there was added dropwise at 30° C. over 4 hours 1 g of 2-hydroxy-1-nitro-3-phenyl-3-(2-methoxy-phenoxy)-propane sodium salt in 70 ml of anhydrous tetrahydrofuran. After the addition, the mixture was cooled and decomposed with water, 15% NaOH, water. It was then filtered; the solid was washed with tetrahydrofuran and the solvent evaporated to dryness. The residue was dissolved in ethyl ether and extracted with 3% HCl, made alkaline with 20% NaOH NaOH and re-extracted with ethyl ether. The organic solution was then washed with water, dried over Na2SO4, filtered and evaporated to dryness. A small quantity of isopropyl ether was then used to ground it to obtain 2-hydroxy-3-(2-methoxy-phenoxy)-3-phenyl-propylamine (0.4 g); melting point 84°-110° C. (R=47.2%) as mixture of two diasteroisomers. The mixture was separated by column chromatography on silica gel (phase: CHCl3 /CH 3 OH/32% NH4OH-150/50/2) to obtain two distinct diastereoisomers having melting point of 126°-129° C. (diastereoisomer with Rf<) and 105°-110° C. respectively (diastereoisomer with Rf>).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](O)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[N:12]=[C:13]2[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:9][C:10]=1[F:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1cn(C2CC2)c2nc(O)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Temperature: 25 °C

Procedure:
A suspension of 0.19 g (0.72 mmole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1,8 -naphthyridine-3-carboxylic acid in 2 mL of phosphorus oxychloride was heated at reflux for 1/2 hour. The resulting solution was cooled to room temperature and the solvent was removed in vacuo. The residue was triturated with ice-water and the resulting solid was removed by filtration, washed with water, then ether and dried in vacuo to give 0.11 g of the title compound, mp 209°-212° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1.[NH:36]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][CH2:38][CH2:37]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:36]3[CH2:42][CH2:41][C:40](=[O:43])[NH:39][CH2:38][CH2:37]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Br)cc2)[C@@H](c2ccc(Br)cc2)N1C(=O)Cl
Reactant: O=C1CCNCCN1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Br)cc2)[C@@H](c2ccc(Br)cc2)N1C(=O)N1CCNC(=O)CC1

Procedure:
1-[(4S,5R)-4,5-Bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-[1,4]diazepan-5-one was prepared from (4S,5R)-4,5-bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12b) and [1,4]diazepan-5-one (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 695.3 [(M+H)+]
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9](=[O:11])[CH3:10]>>[CH:5]1[CH:6]=[CH:7][C:2](/[CH:1]=[CH:10]/[CH:9]=[O:11])=[CH:3][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: CC=O
Product: O=C/C=C/c1ccccc1

Procedure:
As shown in Scheme 1, benzaldehyde derivative 1-1 can be reacted with acetaldehyde in the presence of either an acid or a base catalyst to afford cinnamic aldehyde 1-2. Reaction of cinnamic aldehyde 1-2 with an organometallic compound such as a Grignard reagent R8MgX1 [wherein X1 is halo such as Cl or Br], followed by oxidation of the intermediate alcohol to ketone and by reduction of the C═C bond to a C—C single bond under a hydrogenation condition (for example, in the presence of Pd/C catalyst), affords ketone 1-3. Reaction of ketone 1-3 with amine 1-4 under reductive amination condition (such as in the presence of a borohydride reducing reagent) affords compound 1-5.
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[CH2:34](Br)CCCCCCCCCCCCCCCCCCC.C([Mg]Br)=CCCCCCCCCC>>[CH3:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:34]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCCCCBr
Agent: CCCCCCCCCC=C[Mg]Br
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC

Procedure:
In accordance with (1--1) and (1-2) of Example 1, using eicosanyl bromide and undecenylmagnesium bromide as the raw material, a similar reaction was carried out to obtain hentriacontane as the intermediate product and then by another reaction 1,1,1-trichlorodotriacontane was obtained. One gram of the thus obtained, 1,1,1-trichlorodotriacontane dissolved in 6 ml of n-butyl alcohol was placed in a 50-ml conical flask and 1.4 ml of distilled water and 2.5 g of potassium hydroxide were added to the solution in the flask. The mixture was heated to a temperature of 60° C. to make reaction for 30 hours under agitation. Then, iced water was added to the reaction mixture to cool the mixture, and after neutralizing with an aqueous dilute hydrochloric acid, the separated precipitate was collected by filtration and dried to obtain 0.82 g of the product. After recrystallizing from benzene, 0.52 g of dotriacontanoic acid melting at 95.5° C. was obtained with a yield of 60%.
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][C:44]([NH:46][CH3:47])=[O:45]>C1COCC1.C(Cl)Cl.O>[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:43][C:44]([NH:46][CH3:47])=[O:45])[CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Reactant: CNC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CNC(=O)CN1CCC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)CC1
Reaction time: 3 h
Yield: 82.1 %

Procedure:
To a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 375 TFA salt (300 mg, 0.59 mmol) in THF (5 mL) was added potassium carbonate (285 mg, 2.10 mmol) followed by 2-bromo-N-methylacetamide (99 mg, 0.65 mmol). The reaction mixture was stirred for 3 hours before being diluted with DCM and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was triturated with diethyl ether to give 508 as a brown solid (226 mg, 82%). LCMS: RT=3.21 min, [M+H]+=467. 1 H NMR δ (ppm) (DMSO-d6): 8.28 (1 H, d, J=8.19 Hz), 8.10 (1H, s), 7.75-7.68 (1 H, m), 7.10 (1 H, dd, J=8.24, 1.81 Hz), 6.96 (1 H, d, J=1.76 Hz), 5.86-5.77 (1 H, m), 4.36 (2 H, t, J=5.02 Hz), 3.42 (2 H, t, J=5.03 Hz), 2.91-2.87 (4 H, m), 2.64 (3 H, d, J=4.74 Hz), 2.55-2.45 (1 H, m), 2.19-2.17 (2H, m), 1.76-1.75 (4 H, m), 1.55 (6 H, d, J=6.59 Hz)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[C:4]([CH:19]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=2[F:33])C(OC)=O)[CH:3]=1.[OH-].[Li+]>CO.O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[CH:9]=[CH:10][C:5]2=[C:4]([CH2:19][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=2[F:33])[CH:3]=1
Reactant: COC(=O)C(c1ccc([N+](=O)[O-])cc1F)c1cc(Cl)nc2c1ccn2COCC[Si](C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(Cc3ccc([N+](=O)[O-])cc3F)cc(Cl)nc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
358 mg (0.72 mmol) of methyl (6-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)(2-fluoro-4-nitrophenyl)acetate are dissolved in 6 ml of methanol. 21 mg (0.87 mmol) of lithium hydroxide and 2 drops of water are added, and the mixture is stirred at RT for 20 hours. The mixture is concentrated under reduced pressure, dichloromethane and water are added and the organic phase is separated off and dried over sodium sulfate. The solvent is removed under reduced pressure and the product is purified by chromatography on silica gel (mobile phase: dichloromethane). This gives an oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[F:17][C:18]([F:23])([F:22])[CH2:19][NH:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:21][NH:20][CH2:19][C:18]([F:23])([F:22])[F:17])[N:3]=1
Reactant: NNCC(F)(F)F
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: FC(F)(F)CNNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[2,2,2-trifluoroethylhydrazino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,2,2-trifluoroethylhydrazine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[C:4](Cl)(=[O:14])[C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:11])=[O:10])=[CH:7][CH:6]=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:11])=[O:10])=[CH:7][CH:6]=1)=[O:14])[CH3:2]
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: CCO
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(C(=O)Cl)cc1

Procedure:
p-Ethoxycarbonylbenzoyl chloride is prepared according to the method of M. J. Dewar and J. P. Schroeder, J. Org. Chem., 30, 2297 (1965), by the gradual addition of a small amount of ethyl alcohol to a boiling solution of terephthaloyl chloride in benzene. After removal of the solvent the residue is distilled under reduced pressure to give the acyl chloride which boils at 102°-105° C. at 0.4 mm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)[CH:5]=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[NH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]1[N:7]=[C:2]([NH2:1])[C:3]([N+:20]([O-:22])=[O:21])=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1ccc([N+](=O)[O-])c(N)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCNc1ccc([N+](=O)[O-])c(N)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
195 mg (0.56 mmol) of tert-butyl {3-[(6-amino-5-nitropyridin-2-yl)amino]propyl}carbamate (Example 56A) are dissolved in 6 ml of dichloromethane, and 656 mg (5.6 mmol) of trifluoroacetic acid are slowly injected. The mixture is stirred at RT for 16 h and then all the volatile constituents are removed in vacuo. 185 mg (96% of theory) of the product are obtained.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1.C(N(C(C)C)CC)(C)C.[Br:31][C:32]1[CH:46]=[CH:45][C:35]([O:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClC(Cl)C>[Br:31][C:32]1[CH:46]=[CH:45][C:35]([O:36][C:37]2[CH:44]=[CH:43][C:40]([CH2:41][N:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]3[CH2:4][N:3]([CH2:11][C:12]3[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)[CH3:2])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1
Reactant: O=Cc1ccc(Oc2ccc(Br)cc2)cc1
Reactant: COC(=O)c1ccc(CN(C)CC2CCCCN2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: CN(Cc1ccc(C(=O)O)cc1)CC1CCCCN1Cc1ccc(Oc2ccc(Br)cc2)cc1
Reaction time: 0.5 h
Yield: 13.2 %

Procedure:
A slurry of methyl 4-((methyl(piperidin-2-ylmethyl)amino)methyl)benzoate hydrochloride salt (200 mg, 0.58 mmol) in dichloroethane (6 mL) was stirred as diisopropylethylamine (225 mg, 1.74 mmol) was added. After 30 minutes, 4-(4-bromophenoxy)benzaldehyde (160 mg, 0.58 mmol) was added to the reaction mixture. After 20 minutes, solid triacetoxyborohydride (147 mg, 0.7 mmol) was added and the reaction was stirred for 17 hours. Solvent was removed under reduced pressure. The residue was dissolved in a mixture of THF and methanol and treated with lithium hydroxide to give a basic solution. The reaction was stirred for 17 hours, concentrated to dryness, and purified by reverse phase preparative HPLC using a gradient of acetonitrile in water containing 0.1% TFA. Relevant fractions were combined to give 40 mg of 4-[[[[(RS)-1-[[4-(4-bromophenoxy)phenyl]methyl]-2-piperidinyl]methyl]methylamino]methyl]benzoic acid; 1NMR (400 MHz, DMSO-d6) δ 7.93 (d, 2H), 7.57 (d, 2H), 7.52 (m, 4H), 7.06 (d, 2H), 6.96 (d, 2H), 4.61 (dbr, 2H), 4.18 (dbr, 2H), 3.24 (m, 1H), 2.34 (s, 3H), 2.00 (m, 1H), 1.63 (m, 5H) ppm.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1.C(Cl)(Cl)[Cl:28].ClN1C(=O)CCC1=O>O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1([C:13]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:14]([Cl:28])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH2:12]1
Reactant: ClC(Cl)Cl
Reactant: ClCCCCOC1(C(=Cc2ccccc2)c2ccccc2)C=CC=CC1
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Product: ClCCCCOC1(C(=C(Cl)c2ccccc2)c2ccccc2)C=CC=CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine (E and Z)-1-(4-chlorobutoxy)phenyl-1,2-diphenyl ethylene (20.2 mol) and chloroform (60 L). Add N-chlorosuccinimide (7 kg, 52.4 mol). Heat to reflux. After 18 hours, cool to ambient temperature and add water. Separate the organic layer and extract with aqueous saturated sodium carbonate solution. Separate the organic layer and evaporate in vacuo to give (E and Z)-1-(4-chlorobutoxy)phenyl-2-chloro-1,2-diphenyl ethylene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(C(C)C)c1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(C(C)C)c1)C(O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
While stirring zinc chloride (3.99 g, 29.3 mmol) in diethyl ether (30 ml), sodium borohydride (2.22 g, 58.6 mmol) was added at room temperature, and the mixture was stirred as it was for 2 hrs. The insoluble material in the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. To the obtained solution was added a solution of ethyl 3-(4-fluorophenyl)-2-(3-isopropylbenzyl)-3-oxopropionate (5.016 g, 14.65 mmol) in diethyl ether (30 ml) under ice-cooling, and the mixture was stirred at 0° C. for 20 min. To the reaction solution was added dilute hydrochloric acid by small portions to decompose excess zinc borohydride, and the mixture was extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:55]1[CH:60]=[CH:59][CH:58]=[C:57]([C:61](O)=[O:62])[CH:56]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[N:55]1[CH:60]=[CH:59][CH:58]=[C:57]([C:61]([N:15]2[CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:13][CH2:14]2)=[O:62])[CH:56]=1
Reactant: O=C(O)c1cccnc1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccnc1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
To a solution of 1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 1) (100 mg, 0.340 mmol) in DMF (5 ml) was added HOBT.H2O (52.0 mg, 0.340 mmol), HBTU (129 mg, 0.340 mmol), 3-pyridinecarboxylic acid (41.8 mg, 0.340 mmol) and DIPEA (0.178 ml, 1.019 mmol). The reaction mixture was stirred for 2 hours at room temperature. Reaction mixture was transferred to a 100 ml round bottom flask and was reduced to dryness in vacuo. The residue was dissolved in DCM (50 ml) and was transferred to a separating funnel then washed with saturated NaHCO3 solution (5 ml), twice. The organic layer was collected and dried with dried magnesium sulphate. The solid was removed by filtration and the filtrate collected in a 250 ml round bottom flask and reduced to dryness in vacuo. The residue was then dissolved in 1.8 ml 1:1 MeCN/DMSO and purified by MDAP in 2 batches. The fractions containing desired product were combined in a 250 ml round bottom flask and reduced in vacuo to yield the title compound (63 mg).