Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C@@H:11]([OH:20])[CH2:10][CH2:9]4)[C@H:6]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])[C:31]([O:33]CC)=[O:32])[CH2:5][C:4]=2[CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C@@H:11]([OH:20])[CH2:10][CH2:9]4)[C@H:6]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][CH2:38][C:39]([F:44])([F:45])[C:40]([F:41])([F:42])[F:43])[C:31]([OH:33])=[O:32])[CH2:5][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(CCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12)CCCC(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 60 °C
Yield: 96.5 %

Procedure:
Ethyl 11-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoate (660 mg, 1.03 mmol) was dissolved in a mixed solvent of ethanol (10 ml) and water (2.0 ml). To this solution, NaOH (820 mg, 20.5 mmol) was added, and the resulting mixture was heated for 4 hours at 60° C. After cooling, 2N aqueous hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then filtered. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to give 11-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid (613 mg, Yield 97%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]#[N:15])=[C:7]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)([O-])=O.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCO>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]#[N:15])=[C:7]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(C(F)(F)F)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A mixture of 6.0 g (16.8 mmol) of 6-nitro-4-(3-trifluoromethylphenylamino)quinoline-3-carbonitrile and 18.9 g (83.8 mmol) of SnCl2.2H2O in 240 mL of EtOH was refluxed under N2 for 1 hr. Ice water was added followed by NaHCO3 to pH 8. The mixture was stirred for 2 hr and then extracted with CHCl3. Darco was added and the extracts were filtered through anhyd MgSO4 and evaporated. The residue was filtered through silica gel with 10% MeOH in CHCl3. Solvent evaporation and drying in vacuo (40° C.) gave 4.87 g of 6-amino-4-(3-trifluoromethylphenylamino)quinoline-3-carbonitrile as a brown solid: mass spectrum (electrospray, m/e): M+H 329.1.
Reaction SMILES: [NH2:1][C:2](=NO)[C:3]1[CH:4]=[C:5]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.[NH2:27]C(=NO)C1C=C(C(NCC2C=CC(CCC(OCC)=O)=CC=2)=O)C=CC=1>>[NH2:27][N:1]=[CH:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCc1ccc(CNC(=O)c2cccc(C(N)=NO)c2)cc1
Reactant: CCOC(=O)CCc1ccc(NC(=O)c2cccc(C(N)=NO)c2)cc1
Product: CCOC(=O)CCc1ccc(NC(=O)c2cccc(C=NN)c2)cc1

Procedure:
The compound of Example 14 was reduced under conditions similar to the conditions described in Example 15, replacing the compound of Example 13 with the compound of Example 14.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[N:20]1[CH:28]=[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:22]2=[N:21]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[N:20]1[CH:28]=[C:23]2[CH:24]=[N+:25]([O-:9])[CH:26]=[CH:27][C:22]2=[N:21]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cccc(Cl)c1-n1cc2cnccc2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1ccc2nn(-c3c(F)cccc3Cl)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
mCPBA (2.38 g, 13.88 mmol) was added to a cooled 0° C.) solution of 2-(2-chloro-6-fluorophenyl)-2H-pyrazolo[4,3-c]pyridine (2.27 g, 9.2 mmol) in DCM (55 mL) under nitrogen. The reaction was stirred for 3 hours, warmed to room temperature, and stirred for an additional 2 hours. Sodium thiosulfate (sat. aq.) was added and the layers were partitioned. The organic layer was washed with sodium hydrogen carbonate (sat. aq.) and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (5-10% methanol in DCM) to afford the title compound as a beige solid (2.13 g, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.90 (dd, J=1.8, 0.9 Hz, 1H), 8.87 (s, 1H), 7.95 (dd, J=7.5, 1.8 Hz, 1H), 7.83 (dt, J=7.5, 1.0 Hz, 1H), 7.74 (td, J=8.3, 5.8 Hz, 1H), 7.65-7.63 (m, 2H).
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[NH2:9][CH2:10][CH:11]([OH:13])[CH3:12].C(N(CC)CC)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([Si:5]([CH3:7])([CH3:6])[O:13][CH:11]([CH3:12])[CH2:10][NH2:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)CN
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CN)O[Si](C)(C)C(C)(C)C
Reaction time: 16 h

Procedure:
tert-Butyl-chloro-dimethyl-silane (2.6 g 17 mmol) was dissolved in DCM (20 mL). 1-Amino-propan-2-ol (1.2 g, 16 mmol), triethylamine (2.2 mL, 16 mmol) and a catalytic amount of DMAP were added. The reaction mixture was stirred for 16 h. Water (10 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (2×100 mL). The combined organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The product was isolated as an oil. Yield: 2.4 g, 80%.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:7](=[C:9]([C:15]([OH:17])=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH:8]=1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[C:1]([C:4]1[O:5][C:6]2[C:7](=[C:9]([C:15]([Cl:21])=[O:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C(=O)O)c2cc(C(C)=O)oc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Cl)c2cc(C(C)=O)oc12

Procedure:
2-Acetyl-7-methoxybenzofuran-4-carboxylic acid (0.12 g) was suspended in anhydrous dichloromethane (4 ml) at room temperature under nitrogen and oxalyl chloride (0.1 ml) added followed by 3 drops of N,N-dimethylformamide. Evaporation in vacuo after 2 h afforded the title compound as a yellow solid (~0.5 g). TLC Rf 0.60 (50% ethyl acetate in hexane)
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(=O)OC(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([C:15]1[CH:16]=[C:17]([F:23])[C:18]([F:22])=[C:19]([F:21])[CH:20]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)c1cc(F)c(F)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCC(=O)c1cc(F)c(F)c(F)c1
Yield: 88.1 %

Procedure:
Tert-butyl 5-oxo-5-(3,4,5-trifluorophenyl)pentylcarbamate (0.18 g, 0.54 mmol) was stirred in trifluoroacetic acid/dichloromethane 1:1 (8 mL) for 1 hour then concentrated. The residue was dissolved in ethyl acetate (40 mL) and washed with saturated sodium chloride/2M aqueous sodium hydroxide 10:1 (11 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to provide 5-amino-1-(3,4,5-trifluorophenyl)pentan-1-one (0.11 g, 88% yield) as an oil. MS (EI) for C11H12F3NO: 232 (MH+).
Reaction SMILES: N#N.[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:5])[CH3:4].OS(O)(=O)=O.[C:18]([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CO>[CH3:18][O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][C:3](=[O:5])[CH3:4]
Reactant: CC(=O)CCCCC(=O)O
Reactant: O=C([O-])[O-]
Agent: N#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCCCC(C)=O
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask under inert atmosphere (N2), a solution of 5-acetylvaleric acid (7.54 g, 50.21 mmol) in a mixture of CH2Cl2 (35 mL) and MeOH (14 mL) was treated with conc. H2SO4 (0.14 mL, 2.51 mmol) and the reaction mixture was stirred at reflux for 24 h. The mixture was cooled to rt and sat. aq. Na2CO3 was added. The aq. layer was extracted with CH2Cl2 and the combined organic layers were washed with water, dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:1→1:2 hept-EA) gave the title compound as an orange oil.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CS(C)=O>[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:3]2[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[C@@H:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:5]=34)[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CS(C)=O
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2OC[C@@H]4C)C[C@H]1NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A mixture of (3S)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (0.5 g), anhydrous dimethyl sulfoxide (10 ml) and cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.54 g) was stirred for 2 hours at 90°-100° C. and then concentrated. The resulting residue was dissolved in chloroform and the solution was washed with 10% aqueous citric acid solution further washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The resulting precipitate was triturated in methanol and collected by filtration to give the title compound (0.67 g) as yellowish powder, mp 206°-207° C.
Reaction SMILES: [C:1]1([CH:6]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:44][C:45]1[CH:46]=[C:47]([CH:59]=[CH:60][C:61]=1[F:62])[CH2:48][C:49]1([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:51][CH2:50]1>CN(C=O)C.N1C=CC=CC=1.C(OCC)(=O)C>[C:1]1([CH:6]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)[C:7]([NH:44][C:45]2[CH:46]=[C:47]([CH:59]=[CH:60][C:61]=2[F:62])[CH2:48][C:49]2([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:50][CH2:51]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(N)c2)CC1
Reactant: O=C(O)C(C1=CCCC1)N1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(NC(=O)C(C3=CCCC3)N3CCc4ccccc4C3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 mg (0.39 mmol) of rac-cyclopent-1-en-1-yl(3,4-dihydroisoquinolin-2(1H)-yl)acetic acid were initially charged in 2.6 ml of DMF/pyridine (3:1), 192 mg (0.51 mmol) of HATU were added and the mixture was stirred at RT for 30 min. 103 mg (0.39 mmol) of tert-butyl 1-(3-amino-4-fluorobenzyl)cyclopropanecarboxylate were then added, and the reaction mixture was stirred at RT overnight. The mixture was then purified directly by preparative HPLC (RP18 column; acetonitrile/water gradient with addition of 0.1% TFA, 10:90→95:5; run time 38 min). The product obtained in this manner was taken up in ethyl acetate and washed repeatedly with 1 N hydrochloric acid. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. This gave 103 mg (purity 72%, 37% of theory) of the title compound which was reacted without further purification.
Reaction SMILES: [BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].[O:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]1[C:23]1[S:24][CH:25]=[CH:26][N:27]=1>CO>[OH:9][C@@H:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][C@H:11]1[C:23]1[S:24][CH:25]=[CH:26][N:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(c2nccs2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](c2nccs2)C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Add sodium tetraborohydride (535.9 mg, 14.2 mmol) to a solution of tert-butyl 4-oxo-3-(thiazol-2-yl)piperidine-1-carboxylate (4.0 g, 14.2 mmol) in MeOH (175 mL) and stir at ambient temperature for 45 minutes. Quench the reaction mixture with water (100 mL). Concentrate under vacuum to remove MeOH. Extract the aqueous residue with EtOAc (3×100 mL), combine the organic extracts and sequentially wash with water (100 mL) then brine (100 mL). Dry over sodium sulphate; filter; collect the filtrate; and concentrate under vacuum to give the title compound as a mixture of diastereomer pairs (3.9 g). MS (m/z): 285 (M+1).
Reaction SMILES: C(Cl)CCl.[CH:5]1[CH:6]=[CH:7][C:8]2[N:13](O)N=[N:11][C:9]=2[CH:10]=1.[C:15]([C:19]1[CH:20]=[CH:21][C:22]([O:36][CH3:37])=[C:23]([CH:35]=1)[C:24]([NH:26][C:27]1[C:28]([C:32](O)=[O:33])=[N:29][NH:30][CH:31]=1)=[O:25])([CH3:18])([CH3:17])[CH3:16].C1(N)C(N)=CC=CC=1>CN(C=O)C>[NH2:13][C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][C:9]=1[NH:11][C:32]([C:28]1[C:27]([NH:26][C:24](=[O:25])[C:23]2[CH:35]=[C:19]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH:20]=[CH:21][C:22]=2[O:36][CH3:37])=[CH:31][NH:30][N:29]=1)=[O:33]
Reactant: COc1ccc(C(C)(C)C)cc1C(=O)Nc1c[nH]nc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: Nc1ccccc1N
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(C)C)cc1C(=O)Nc1c[nH]nc1C(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.9 %

Procedure:
To a solution of EDC (720 mg, 3.8 mmol), HOBt (510 mg, 3.8 mmol) and 4-(5-tert-butyl-2-methoxy-benzoylamino)-1H-pyrazole-3-carboxylic acid (1 g, 3.16 mmol) in DMF (25 ml) was added benzene-1,2-diamine (375 mg, 3.5 mmol) and the mixture stirred at room temperature for 5 hours. The mixture was reduced in vacuo and the residue partitioned between EtOAc (50 ml) and brine (2×50 ml). Undissolved precipitate was removed by filtration, the organic portions washed with saturated aqueous sodium hydrogen carbonate (50 ml), dried (MgSO4) and reduced in vacuo to yield 4-(5-tert-butyl-2-methoxy-benzoylamino)-1H-pyrazole-3-carboxylic acid (2-amino-phenyl)-amide as a pale yellow powder (848 mg, 66%). (LC/MS (acidic method): Rt 3.21 min, [M+H]+ 408).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]3[C:15]([OH:17])=O)[S:8][C:4]=2[CH:3]=1.[CH2:20]([N:27]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:27]1[CH2:31][CH2:30][C@H:29]([NH:32][C:15]([C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][N:9]2[C:7]2[S:8][C:4]3[CH:3]=[C:2]([Cl:1])[CH:19]=[CH:18][C:5]=3[N:6]=2)=[O:17])[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccc(Cl)cc2s1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Product: O=C(N[C@H]1CCN(Cc2ccccc2)C1)[C@@H]1CCCCN1c1nc2ccc(Cl)cc2s1

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-(6-chloro-1,3-benzothiazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 45] and (3S)-1-benzylpyrrolidin-3-ylamine [see J. Med. Chem. (1989), 31(8), 1586-1590] to afford (2S)-N2-[(3S)-1-benzylpyrrolidin-3-yl]-1-(6-chloro-1,3-benzothiazol-2-yl)-2-piperidinecarboxamide as a solid.
Reaction SMILES: O=C=[N:3][CH:4]1[CH2:13][C:12](C)(C)[CH2:11][C:6](C)(CN=C=O)[CH2:5]1.C1(O)C=CC=CC=1.N1C=CN=C1.CCO[CH2:32][CH2:33][O:34][C:35](C)=[O:36].C(N(CCO)CCO)CCC.C(C1OC1)Cl.C(OS(OCC)(=O)=O)C>C(O)C>[C:4]1([NH:3][C:35]([O:34][CH2:33][CH3:32])=[O:36])[CH:13]=[CH:12][CH:11]=[CH:6][CH:5]=1
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: CCOCCOC(C)=O
Agent: CCCCN(CCO)CCO
Agent: CCOS(=O)(=O)OCC
Agent: c1c[nH]cn1
Solvent: ClCC1CO1
Solvent: Oc1ccccc1
Solvent: CCO
Product: CCOC(=O)Nc1ccccc1

Procedure:
1.0 mol of isophorone diisocyanate is dissolved in 2.2 mol of phenol at 95°-100° C. after the addition of 0.5 imidazole. The mixture is kept as a liquid by the addition of 200 ml of ethylglycol acetate. 0.9 mol of butyldiethanolamine are added after a reaction time of four hours and the mixture is then distilled at a reaction temperature of 120° C. to remove everything which distils off at a vacuum of 5 torr. The residue is then dissolved in 200 ml of ethylglycol acetate and 400 ml of ethanol and quaternised at 60°-70° C., first with 0.5 mol of epichlorohydrin for three hours and then with 0.5 mol of diethylsulphate. The readily soluble cationic polyurethane with phenylurethane end groups obtained in this way is made up to a volume of 2000 ml with methanol and then stored at temperatures below 10° C.
Reaction SMILES: [CH3:1][C:2](C)=[CH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:26])[C:14]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[OH:15])[CH2:8][CH2:7]1.Cl.Cl.N[CH:31]1[CH2:36]CN(CC2CCCCCC2)C[CH2:32]1>>[CH:4]1([CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([NH:12][C:13](=[O:26])[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[OH:15])[CH2:10][CH2:11]2)[CH2:36][CH2:31][CH2:32][CH2:1][CH2:2][CH2:3]1
Reactant: NC1CCN(CC2CCCCCC2)CC1
Reactant: CC(C)=CCCN1CCC(NC(=O)C(O)(c2ccco2)C2CCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CC2CCCCCC2)CC1)C(O)(c1ccco1)C1CCCC1

Procedure:
The title compound was prepared in the same manner as described in Step 4 of Example 22 using 2-cyclopentyl-2-(2-furyl)-2-hydroxyacetic acid obtained in Example 50 and 4-amino-1-(cycloheptylmethyl)piperidine dihydrochloride.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:4])=[O:3].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1COCC1>[N:26]1([C:8]([C:7]2[CH:6]=[C:5]([S:2]([NH2:1])(=[O:3])=[O:4])[CH:13]=[CH:12][CH:11]=2)=[O:10])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc(C(=O)N2CCOCC2)c1
Reaction time: 4 h
Yield: 51 %

Procedure:
To a solution of 3-(aminosulfonyl)benzoic acid (6 g, 0.029 mol) in THF (100 ml) at 0° C. is added CDI (5.8 g, 0.035 mol) and the mixture is stirred for 4 h. To this mixture morpholine (7.8 ml, 0.089 mol) is added dropwise and the mixture is stirred at room temperature for 15 h. The solvent is removed under vacuum and the residue is diluted with EtOAc (100 ml), washed with a 10% solution of sodium bicarbonate, water and brine. The solvent is removed under vacuum and the residue is taken up with small amount of water (15 ml) and stirred for 15 min. The solid is collected by filtration to afford 4 g (50%) of the title compound as a solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.88-7.90 (1H, m), 7.83 (1H, s), 7.64-7.65 (2H, m), 7.47 (2H, bs), 3.56-3.64 (6H, m), 3.28-3.34 (2H, m); HPLC (Max plot) 98%, Rt, 4.09 min; LC/MS: (ES+): 206.2.
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[C:4]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:19][C:18]1[CH:20]=[CH:21][C:15]([I:14])=[CH:16][CH:17]=1)#[CH:3]
Reactant: O=C([O-])OCC=Cc1ccccc1
Reactant: Nc1ccc(I)cc1
Product: C#CC(Nc1ccc(I)cc1)c1ccccc1
Reaction time: 12 h
Yield: 92.9 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and p-iodoaniline (0.220 g, 1.04 mmol). The reaction was conducted at room temperature for 12 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be 98/2. The mixture was purified by flash column chromatography on silica gel (1.5% ethyl acetate in hexanes) to give the title compound (0.303 g, 92%). HPLC analysis indicated the enantiomeric excess of the product was 96% [Diacel CHIRALCEL OD-H (0.46 cm×25 cm); hexane/2-propanol=99/1; flow rate=0.6 mL/min; detection wavelength=254 nm; TR=18.4 (major), 23.1 (minor) min]: [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.48-7.40 (m, 6H), 7.36 (s, J=4.6 Hz, 1H), 6.43 (dt, J=8.8, 2.4 Hz, 2H), 6.09 (ddd, J=16.8, 10.4, 6.0 Hz, 1H), 5.34 (dt, J=12.0, 1.3 Hz, 1H), 5.31 (dt, J=5.2, 1.2 Hz, 1H), 4.97 (d, J=5.6 Hz, 1H), 4.15 (br s, 1H). 13C NMR (100.59 MHz, CDCl3) δ 146.53, 141.10, 138.35, 137.51, 128.72, 127.53, 126.99, 116.28, 115.69, 78.32, 60.46. Anal. Calcd for C15H14NI: C, 53.75; H, 4.21; N, 4.18; I, 37.86. Found: C, 53.59; H, 4.27; N, 4.17; I, 38.04.
Reaction SMILES: CS(O)(=O)=O.[CH3:6][C:7]1([CH3:17])[O:12][CH2:11][C:10]([CH2:15][CH3:16])([CH2:13]O)[CH2:9][O:8]1.[I-:18].[Na+]>CC(CC)=O>[CH3:6][C:7]1([CH3:17])[O:12][CH2:11][C:10]([CH2:15][CH3:16])([CH2:13][I:18])[CH2:9][O:8]1
Reactant: CCC1(CO)COC(C)(C)OC1
Reactant: [I-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCC1(CI)COC(C)(C)OC1

Procedure:
A mixture of 2,2-dimethyl-5-ethyl-5-hydroxymethyl-1,3-dioxane methylsulphonate (6.0 g.) and sodium iodide (9.0 g.) in ethyl methyl ketone was refluxed, with stirring, for forty-eight hours. The solvent was removed in vacuo and the resulting oil was poured into water. The aqueous mixture was extracted with ether. The ethereal extracts were washed with 5% aqueous sodium thiosulphate solution and then water. The ethereal extracts were dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue was purified by column chromatography on silica, eluting with 1:10 ether: hexane. 2,2-Dimethyl-5-ethyl-5-iodomethyl-1,3-dioxane was obtained as a colourless oil (5.0 g.)
Reaction SMILES: [CH2:1]([N:3]([CH3:23])[C:4]([N:6]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][CH:8]([C:20](O)=[O:21])[CH2:7]1)=[O:5])[CH3:2].[Cl:24][C:25]1[CH:30]=[C:29]([C:31](=[N:33]O)[NH2:32])[CH:28]=[CH:27][N:26]=1>>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]2[N:33]=[C:20]([CH:8]3[CH2:9][CH:10]([C:12]4[CH:13]=[CH:14][C:15]([CH2:18][CH3:19])=[CH:16][CH:17]=4)[CH2:11][N:6]([C:4]([N:3]([CH2:1][CH3:2])[CH3:23])=[O:5])[CH2:7]3)[O:21][N:32]=2)[CH:28]=[CH:27][N:26]=1
Reactant: NC(=NO)c1ccnc(Cl)c1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N(C)CC)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccnc(Cl)c4)no3)CN(C(=O)N(C)CC)C2)cc1

Procedure:
64 mg (0.20 mmol) of 1-[ethyl(methyl)carbamoyl]-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 45A) and 38 mg (0.22 mmol, 1.1 eq.) of 2-chloro-N′-hydroxypyridine-4-carboximidamide were reacted according to the General Method 1. Yield: 13 mg (14% of theory)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[OH:9][CH2:10][C@H:11]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[Br:8][C:6]1[CH:7]=[C:2]([N:15]2[C@H:11]([CH2:10][OH:9])[CH2:12][CH2:13][C:14]2=[O:16])[CH:3]=[N:4][CH:5]=1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Brc1cncc(Br)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1CC[C@@H](CO)N1c1cncc(Br)c1
Temperature: 110 °C
Yield: 24.5 %

Procedure:
In a sealed tube, 3,5-dibromopyridine (0.5 g, 2.11 mmol) was combined with (S)-5-(hydroxymethyl)pyrrolidin-2-one (0.243 g, 2.11 mmol), copper (I) iodide (0.040 g, 0.021 mmol), potassium carbonate (0.583 g, 4.22 mmol) and N,N′-dimethylethylenediamine (0.037 g, 0.042 mmol) in 1,4-dioxane (20 mL). The reaction mixture was heated at 110° C. overnight. The mixture was cooled to room temperature, filtered through dicalite and washed with DCM. The residue was purified by silica gel flash chromatography eluting with a 0 to 10% MeOH-DCM gradient to give the title compound (0.140 g, 25%) as a light yellow oil. MS: 271.1, 273.1 (M+H+).