Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]1[O:10][C:9]2[CH:11]=[C:12]3[C:17](=[CH:18][C:8]=2[NH:7][C:6]1=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]3.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH:5]3[O:10][C:9]4[CH:11]=[C:12]5[C:17](=[CH:18][C:8]=4[NH:7][C:6]3=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]5)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: O=C1Nc2cc3c(cc2OC1CCCBr)CCCC3
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2cc3c(cc2OC1CCCN1CCN(c2ccc(F)cc2)CC1)CCCC3
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 59.3 %

Procedure:
A mixture of 2-(3-bromopropyl)-6,7,8,9-tetrahydro-2H-naphtho[2,3-b][1,4]oxazin-3(4H)-one (3.1 g), 1-(4-fluorophenyl)piperazine (2.3 g), triethylamine (1.5 ml) and N,N-dimethylformamide (DMF)(100 ml) was stirred at 80° C. for 1.5 hour, which was diluted with ice-water and subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), from which the solvent was distilled off. The residue was recrystallized from chloroform-ethyl acetate to give 2.4 g (59.3%) of 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-6,7,8,9-tetrahydro-2H-naphtho[2,3-b][1,4]oxazin-3(4H)-one as colorless crystals, m.p. 164°-165° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13](CC2C=CC(OC)=CC=2)[C:14]2[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=2)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:43]=[C:44]([N:46]2[C:50]([CH3:51])=[N:49][N:48]=[N:47]2)[CH:45]=1)[NH2:42]>CO>[C:11]([C:8]1[N:6]2[N:7]=[C:2]([NH:42][C:41]3[CH:43]=[C:44]([N:46]4[C:50]([CH3:51])=[N:49][N:48]=[N:47]4)[CH:45]=[C:39]([O:38][CH3:37])[CH:40]=3)[CH:3]=[C:4]([NH:13][C:14]3[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=3)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[C:5]2=[N:10][CH:9]=1)#[N:12]
Reactant: COc1ccc(CN(c2cccc(C(=O)NCCN(C)C)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Reactant: COc1cc(N)cc(-n2nnnc2C)c1
Solvent: CO
Product: COc1cc(Nc2cc(Nc3cccc(C(=O)NCCN(C)C)c3)c3ncc(C#N)n3n2)cc(-n2nnnc2C)c1

Procedure:
Example 255 was prepared from 253D and 3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)aniline following the procedure as described in Example 6. HPLC: Rt=3.11 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=512.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][CH:17]=[CH:16][CH2:15][CH:14]([CH2:19][S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]2[C:27]([OH:29])=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH:30][NH:31]C(C1C(COC(=O)C)CC=CCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O>>[OH:30][NH:31][C:27]([CH:13]1[CH:14]([CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH:16]=[CH:17][CH2:18][N:12]1[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])=[O:29]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(COC(C)=O)C2C(=O)NO)cc1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(CSc3ccccc3)C2C(=O)O)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(CSc3ccccc3)C2C(=O)NO)cc1

Procedure:
1-(4-Methoxy-benzenesulfonyl)-3-phenylsulfanylmethyl-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid hydroxyamide was synthesized from 1-(4-Methoxy-benzenesulfonyl)-3-phenylsulfanylmethyl-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid in the same manner as the procedures used for the preparation of Acetic acid 2-hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepin-3-ylmethyl ester: MS (M+H)+ =449, (M+NH4)+ =466.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:5][CH2:4][NH:3]1.CCN=C=NCCCN(C)C.Cl.[CH:28]1([C:32]2[C:40]([C:41]3[NH:45][C:44]([CH2:46][CH3:47])=[N:43][N:42]=3)=[CH:39][C:35]([C:36](O)=[O:37])=[C:34]([CH3:48])[CH:33]=2)[CH2:31][CH2:30][CH2:29]1>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:28]1([C:32]2[C:40]([C:41]3[NH:45][C:44]([CH2:46][CH3:47])=[N:43][N:42]=3)=[CH:39][C:35]([C:36]([N:3]3[CH2:4][CH2:5][CH:6]([C:8]4[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=4)[CH2:7][CH:2]3[CH3:1])=[O:37])=[C:34]([CH3:48])[CH:33]=2)[CH2:29][CH2:30][CH2:31]1
Reactant: CCc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Reactant: CC1CC(c2ccc(C#N)cc2)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3C)c(C)cc2C2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.9 %

Procedure:
To a round-bottom flask was added a solution of 4-(2-methylpiperidin-4-yl)benzonitrile (compound 176.3, 210 mg, 0.940 mmol, 1.00 equiv, 90%) in N,N-dimethylformamide (2 mL). EDC.HCl (404 mg, 2.11 mmol, 2.00 equiv), 4-dimethylaminopyridine (257 mg, 2.10 mmol, 2.00 equiv), and 4-cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 176.4, 300 mg, 1.05 mmol, 1.00 equiv) were added to the reaction mixture. The resulting solution was stirred for 4 h at 25° C., then diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 2×30 mL of NH4Cl (aq., sat.) and 2×30 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using silica gel column chromatography with dichloromethane/methanol (20:1) as eluent. The crude product (˜20 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (48% CH3CN up to 49% in 8 min, up to 100% in 3 min, down to 48% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 3.8 mg (1%) of the title compound as a white solid. m/z (ES+) 468 (M+H)+.
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[OH:11].[Br:12][CH2:13][CH2:14]O>>[Br:12][CH2:13][CH2:14][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: OCCBr
Product: BrCCOc1ccc2ccccc2c1

Procedure:
This example was prepared by substituting 1-naphthol with 2-naphthol and substituting 3-bromopropanol with 2-bromoethanol in EXAMPLE 31A.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[NH:5][C:6]([C:10]([O:12]CC)=[O:11])=[C:7]([CH3:9])[N:8]=1.CO>C1COCC1>[CH3:3][C:4]1[NH:5][C:6]([C:10]([OH:12])=[O:11])=[C:7]([CH3:9])[N:8]=1
Reactant: CCOC(=O)c1[nH]c(C)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C)c(C(=O)O)[nH]1
Temperature: 70 °C
Yield: 99 %

Procedure:
Lithium hydroxide (1.6 mL, 1.6 mmol, 1 M in H2O) was added to a solution of ethyl 2,4-dimethyl-1H-imidazole-5-carboxylate (54 mg, 0.32 mmol) in THF:MeOH (4.8 mL/1.6 mL). The reaction mixture was heated at 70° C. for 4 h. The solvent was evaporated and dried in vacuo to give the title compound (mg, >99%) as a white solid which was directly used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])[N:4]=1.O.[NH2:22][NH2:23].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([NH:22][NH2:23])=[O:15])[N:4]=1
Reactant: COc1cc(OC)nc(Oc2ccccc2C(=O)O)n1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)nc(Oc2ccccc2C(=O)NN)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.10 Gram of 2-(4,6-dimethoxypirimidin-2-yl)oxybenzoic acid was dissolved in 10 ml of tetrahydofuran, and 0.77 g of N,N'-carbonyldimidazole was added. After stirring at room temperature for 20 minutes, the reaction solution was cooled to 0° to 5° C. 0.72 Gram of hydrazine monohydrate was added with keeping this temperature. After stirring at 0° to 5° C. for 30 minutes, the reaction solution was pourd into water, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution twice and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was washed with diethylether to obtain 0.95 g of 2-(4,6-dimethoxypirimidin-2-yl)oxybenzohydrazide [present compound (1)].
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:7]([CH3:10])(=[O:9])=[O:8].[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(OCC)C>[C:25]([O:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:7]([CH3:10])(=[O:8])=[O:9])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(O)CCCN(CCCCCCC(=O)O)S(C)(=O)=O
Solvent: CCOCC
Product: CCCCCC(CCCN(CCCCCCC(=O)O)S(C)(=O)=O)OC(C)=O
Temperature: 60 °C

Procedure:
A mixture of 7-[N-(4-hydroxynonyl)methanesulfonamido]heptanoic acid (10.9 g., 0.03 mole) (Example 1, Step B) and acetic anhydride (6.1 g., 0.06 mole) is heated at 60° C. for 18 hours. The mixture is cooled and and taken up in 80 ml. of ethyl ether. The solution is extracted with an ice-cold solution of 8 g. of sodium hydroxide in 150 ml. of water. The basic solution is separated and acidified with concentrated hydrochloric acid. The crude product that separates is extracted into ether, washed with water and dried over sodium sulfate. The ether is evaporated and the residual oil is purified by chromatography on silica gel using 2% methanol in chloroform as the eluting solvent. There is obtained 7-[N-(4-acetoxynonyl)methanesulfonamido]heptanoic acid as a viscous oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]2[N:11]3[C:12](=[O:24])[NH:13][C:14]3[C:15]2=[N:21][NH:22][CH:23]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.[Cl-].[Na+]>CN1CCCC1=O>[CH:25]1([NH:28][C:12]([NH:13][C:14]2[C:15]([C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:8]([CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:9][C:10]=4[N:11]=3)=[N:21][NH:22][CH:23]=2)=[O:24])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: O=c1[nH]c2c[nH]nc2c2nc3ccc(CN4CCOCC4)cc3n12
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)NC1CC1
Temperature: 100 °C

Procedure:
7-Morpholin-4-ylmethyl-2,4-dihydro-1,2,4,5a,10-pentaaza-cyclopenta[a]fluoren-5-one (1.0 wt, prepared as outlined above in Example 66 of WO 2006/070195) and 1-methyl-2-pyrrolidinone (3.0 vol) are charged to a suitably sized flange flask equipped with a mechanical stirrer, condenser and thermometer. Cyclopropylamine (0.351 wt) is added at 15 to 30° C. under nitrogen. The contents are then heated to 95 to 105° C. and stirred at this temperature until the reaction is judged complete by 1H NMR analysis. Once complete, the reaction mixture is cooled to 16 to 25° C. and added slowly (approximately 2 to 3 hours) to stirred ca. 13% w/w sodium chloride solution (11.5 vol) whilst maintaining the mixture at 16 to 25° C. A precipitate is formed. The transfer of the reaction mixture is completed with a 1-methyl-2-pyrrolidinone (0.5 vol) rinse at 16 to 25° C. The precipitated solid is collected by filtration, washed with water (0.5 vol) and pulled dry on the filter until deemed suitable for handling. The solid is suspended in ethyl acetate (5.0 vol) and water (6.0 vol) and stirred at 16 to 25° C. for 60 to 70 minutes. The solid is collected by filtration, sequentially washed with ethyl acetate (1.0 vol) and mixed heptanes (2×2.0 vol) and dried on the filter until deemed suitable for handling. The solid is suspended in ethyl acetate (4.0 vol) and stirred at 15 to 25° C. for at least 60 minutes. The solid is collected by filtration, washed with ethyl acetate (1.0 vol) and pulled dry on the filter to yield crude 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea (60 to 80% w/w) as a dark brown/red solid.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[CH2:15][S:14][CH2:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:23]([O:27][C:28]([NH:30][C@H:31]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C@@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:25])([CH3:24])[CH3:26])[C:32]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:8]4[CH2:15][S:14][CH2:13][C:9]=4[N:10]=[CH:11][N:12]=3)[CH2:2][CH2:3]2)=[O:33])=[CH:37][CH:38]=1
Reactant: c1nc2c(c(N3CCNCC3)n1)CSC2
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3c2CSC3)CC1
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of 4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine (0.28 g, 1.3 mmol) in CH2Cl2 (20 mL) was added triethylamine (5 mL) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.38 g, 1.3 mmol). After stirring for 30 minutes, HBTU (0.57 g, 1.5 mmol) was added. The mix was stirred at room temperature for 1 hour. The solvent was removed and the residue was subject to silica gel chromatography, eluting with hexane/ethyl acetate (1:1) to give (R)-tert-butyl 3-(4-chlorophenyl)-1-(4-(5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (0.62 g, 98%). 1H NMR (CDCl3, 400 MHz) δ 8.49 (s, 1H), 5.38-5.35 (m, 1H), 3.70-3.50 (m, 6H), 3.27-3.13 (m, 2H), 2.98-2.92 (m, 2H), 1.42 (s, 9H). MS (APCI+) [M+H]+ 505.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[NH:11][C:12]([I:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].IC>CO>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[N:11]([CH3:17])[C:12]([I:15])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c(I)ccc1OCc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CO
Product: Cn1c(I)ccc(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
To a solution of 3-(benzyloxy)-6-iodopyridin-2(1H)-one (20.48 g, 62.6 mmol) in methanol (626 mL) was added potassium carbonate (8.56 g, 62.6 mmol) and iodomethane (3.91 mL, 62.6 mmol), and the resulting mixture was stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure, and the resulting residue was partitioned between water and ethyl acetate. The aqueous layer was removed and discarded. The organic layer was collected, dried over anhydrous magnesium sulfate, and purified using silica gel chromatography to afford 3-(benzyloxy)-6-iodo-1-methylpyridin-2(1H)-one (15.4 g, 45.1 mmol, 72% yield). ES-MS (M+H)+=342.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:7][N:6]([S:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])(=[O:10])=[O:9])[CH:5]([CH2:20][C:21]([NH:23][C@H:24]2[C:33]3[C:28](=[CH:29][C:30]([CH:34]=O)=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]2)=[O:22])[C:4](=[O:36])[NH:3]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[C:52]([NH2:56])([CH3:55])([CH3:54])[CH3:53]>CCOC(C)=O>[C:52]([NH:56][CH2:34][C:30]1[CH:29]=[C:28]2[C:33](=[CH:32][CH:31]=1)[CH:24]([NH:23][C:21](=[O:22])[CH2:20][CH:5]1[C:4](=[O:36])[NH:3][C:2]([CH3:37])([CH3:1])[CH2:7][N:6]1[S:8]([C:11]1[C:12]([CH3:19])=[CH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])(=[O:10])=[O:9])[CH2:25][CH2:26][CH2:27]2)([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)N
Reactant: Cc1cc(C)c(S(=O)(=O)N2CC(C)(C)NC(=O)C2CC(=O)N[C@@H]2CCCc3cc(C=O)ccc32)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(S(=O)(=O)N2CC(C)(C)NC(=O)C2CC(=O)NC2CCCc3cc(CNC(C)(C)C)ccc32)c(C)c1
Temperature: 85 °C

Procedure:
2-[5,5-Dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-2(R,S)-yl]-N-(6-formyl-1,2,3,4-tetrahydro-naphthalen-1(R)-yl)-acetamide (Step b, 550 mg, 1.0 mmol) was dissolved in 1,2-dicholoethane (10 mL) and tert-butylamine (1.5 mL). NaBH(OAc)3 (1.5 g, 6.0 mmol) was added to the reaction, and heated to 85° C. in a sealed tube for 18 h. The mixture was cooled to RT, diluted with EtOAc (25 mL), washed with sat. NaHCO3 solution (2×), and brine, dried over MgSO4, filtered, and concentrated in vacuo to provide a residue which was purified by column chromatography (SiO2, 10% MeOH in CH2Cl2+1% NH3) to provide the title compound. ESMS 583.4 (M+H), 581.5 (M−H).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]([F:37])([C:33]([F:36])([F:35])[F:34])[CH2:4][C:5]([F:32])([F:31])[CH2:6][C:7]([F:30])([F:29])[CH2:8][CH:9]([C:25]([F:28])([F:27])[F:26])[CH2:10][CH:11]([C:21]([F:24])([F:23])[F:22])[CH2:12][CH:13]([C:17]([F:20])([F:19])[F:18])[CH2:14][CH2:15]I.C(O)C.[S-:43][C:44]#[N:45].[K+]>C(O)(=O)C>[F:1][C:2]([F:39])([F:38])[C:3]([F:37])([C:33]([F:36])([F:35])[F:34])[CH2:4][C:5]([F:32])([F:31])[CH2:6][C:7]([F:30])([F:29])[CH2:8][CH:9]([C:25]([F:28])([F:27])[F:26])[CH2:10][CH:11]([C:21]([F:24])([F:23])[F:22])[CH2:12][CH:13]([C:17]([F:20])([F:19])[F:18])[CH2:14][CH2:15][S:43][C:44]#[N:45]
Reactant: N#C[S-]
Reactant: FC(F)(CC(CC(CC(CCI)C(F)(F)F)C(F)(F)F)C(F)(F)F)CC(F)(F)CC(F)(C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: N#CSCCC(CC(CC(CC(F)(F)CC(F)(F)CC(F)(C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Reaction time: 8 h
Yield: 94.4 %

Procedure:
According to scheme (27) above, in a flask that can be equipped with an agitator, thermocouple and a reflux condenser, 20 grams (27 mmol) of 1,1,1,2,4,4,6,6-octafluoro-2,8,10,12-tetrakis(trifluoromethyl)-14-iodotetradecane (see, e.g. Published Patent Applications), 20 ml of absolute ethanol, 3.9 grams (40.5 mmol) of potassium thiocyanate (KSCN) and 0.5 ml of glacial acetic acid (HOAc) can be placed to form a mixture. The mixture can be heated to reflux (84.7 C) and maintained stirring for overnight. The mixture can be concentrated in vacuo to afford what can be observed as a thick yellow slurry. The slurry can be extracted with 300 ml of diethyl ether and decanted twice and filtered to afford a wet cake and a filtrate. The wet cake can be washed with three 100 ml portions of diethyl ether and the filtrates combined. The combined filtrates can be concentrated in vacuo to afford 17.12 grams (94.6% yield) of the 1,1,1,2,4,4,6,6-octafluoro-2,8,10,12-tetrakis(trifluoromethyl)-14-thiocyanatotetradecane product that can be observed as a light yellow oil. The product structure can be confirmed by NMR and/or chromatographic analysis.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: C1CNCCN1
Reactant: Clc1nc2ccccc2s1
Solvent: Cc1ccccc1
Product: c1ccc2sc(N3CCNCC3)nc2c1
Temperature: 0 °C

Procedure:
A solution of 2-chlorobenzothiazole (5 g) in 20 mL of toluene is added dropwise to a refluxing solution of piperazine (20 g) in 150 mL of toluene. The solution is heated for an additional 24 hours, and after cooling at 0° C. for about 30 minutes, filtered. The filtrate is extracted with 10% acetic acid and the aqueous extracts are washed with ether, basified and extracted with dichloromethane. The dichloromethane layer is washed with water, dried and concentrated. The concentrated material is placed under vacuum overnight (6.8 g, m.p. 63-64° C.). 1H NMR (CDCl3) 7.62 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.29 (td, J=7.6, 1.2 Hz, 1H), 7.07 (t, J=8.0 Hz, 1H), 3.61 (t, J=5.2 Hz, 4H), 3.00 (t, J=5.2 Hz, 4H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([O-:18])(=O)=[O:16].[Na+].CC(C)=O.P(Cl)(Cl)([Cl:26])=O>CN(C)C(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([Cl:26])(=[O:18])=[O:16]
Reactant: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CC(C)=O
Product: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Temperature: 40 °C

Procedure:
59 g of sodium 2-(2-methoxyethoxy)-5-nitrobenzenesulfonate prepared as described in Synthesis Example 1 was added to a mixture of 200 ml of acetone and 75 ml of phosphorous oxychloride. 75 ml of N,N-dimethylacetamide was added dropwise to the mixture with stirring while the reaction mixture was maintained at 30°to 40° C. After completion of the addition, the mixture was allowed to stand with stirring until it cooled to room temperature. The reaction mixture was then poured into 600 ml of ice water, stirred for 30 minutes and the crystals thus precipitated were collected by filtration. The crystals were washed with 100 ml of water and air-dried. Yield:56 g; Melting Point: 74°-74.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Na+].[I-].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][O:23][CH3:24]>CN(C=O)C.O>[CH3:24][O:23][CH2:22][CH2:21][CH2:20][NH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COCCCBr
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCNc1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 39 %

Procedure:
Methyl 2-amino-3-nitrobenzoate (3.82 mmol, 0.75 g) in DMF (20 mL) was added NaI (8.40 mmol, 1.26 g). The reaction solution was stirred at 0° C. for 5 min and then added NaH (5.00 mmol, 0.20 g) at 0° C. The reaction solution was stirred at 0° C. for 30 min and then added 1-bromo-3-methoxypropane (5.00 mmol, 0.77 g). The reaction solution was heated to 80° C. and kept stirring at 80° C. for 6 hr. After cooling down the reaction solution was poured into H2O, extracted with EtOAc. The extract was washed with H2O, brine dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, EtOAc-hexane: 5:95) to afford methyl 2-(3-methoxypropylamino)-3-nitrobenzoate (44A) (1.49 mmol, 800 mg, yield: 78.1%). ESI-MS: m/z 269.3 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].[C:11]([NH:19][C:20](=[O:23])[CH2:21]Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O.CO>[C:11]([NH:19][C:20](=[O:23])[CH2:21][S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCl)NC(=O)c1ccccc1
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(CSc1ccc(O)cc1)NC(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
In a 200 ml four-necked flask equipped with a stirrer and a thermometer, 2.52 g (20 mmol) of 4-mercaptophenol, 1.32 g (20 mmol) of 85% potassium hydroxide and 50 ml of methanol were added at normal temperature. After confirming that potassium hydroxide had been dissolved, the inner temperature was cooled to 10° C. and 3.95 g (20 mmol) of N-benzoyl-chloroacetamide was added, followed by stirring at normal temperature for 3 hours. After the completion of the reaction, the reaction solution was acidified with hydrochloric acid and 50 ml of water was added, and then the deposited crystals were collected by filtration to obtain 5.0 g of N-benzoyl-(4-hydroxyphenylthio)acetamide. The yield was 87% and the melting point was 149–151° C.