Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C>[CH2:39]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=2[N:9]=1)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Reactant: CCCCCCCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCCCCCCCCCCCCCCOC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A 250 mL three neck round bottom flask was equipped with an overhead stirrer, thermocouple, temperature controller and nitrogen sweep then charged with 10.0 g (25.34 mmol) of bendamustine hydrochloride, 5.85 g (25.6 mmol, 1.01 eq) of pentadecanol, 5.3 g (25.6 mmol, 1.01 eq) of dicyclohexylcarbodiimide (DCC), 100 mL of MDC and 0.31 g (2.54 mmol, 0.1 eq) of DMAP. The reaction was stirred at room temperature overnight at which time an in process analysis indicated the reaction was complete. Solids were removed by vacuum filtration and washed with 25 mL of MDC. The filtrate was washed with saturated aqueous sodium bicarbonate solution (2×100 mL), DI water (1×100 mL) and brine (1×100 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo to an off-white solid. This solid was triturated with 25 mL of MDC and the solid impurities were removed by vacuum filtration and washed with 5 mL of MDC. The filtrate was concentrated to dryness in vacuo to yield 10.8 g (19.0 mmol, 75%) of the product as an off-white solid with an HPLC purity of 94.6A %. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=8.76 Hz, 1H), 7.08 (d, J=2.32 Hz, 1H), 6.78 (dd, J=2.4, 8.76 Hz, 1H), 4.05 (t, J=6.8 Hz, 2H), 3.72 (m, 4H), 3.69 (s, 3H), 3.63 (m, 4H), 2.91 (t, J=7.4 Hz, 2H), 2.49 (t, J=7.08 Hz, 2H), 2.18 (m, 2H), 1.60 (m, 2H), 1.32 (m, 24H), 0.88 (t, J=6.68 Hz, 3H).
Reaction SMILES: [CH2:1]1[CH2:20][O:19][C:18]2[C:3](=[CH:4][C:5]3[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14]Cl)[C:8](=[O:16])[CH2:7][C:6]=3[CH:17]=2)[O:2]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[CH2:29][CH:28]([NH:35][CH3:36])[CH2:27][CH2:26]2>>[CH2:1]1[CH2:20][O:19][C:18]2[C:3](=[CH:4][C:5]3[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:35]([CH3:36])[CH:28]4[CH2:27][CH2:26][C:25]5[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=5)[CH2:29]4)[C:8](=[O:16])[CH2:7][C:6]=3[CH:17]=2)[O:2]1
Reactant: O=C1Cc2cc3c(cc2CCN1CCCCl)OCCO3
Reactant: CNC1CCc2cc(OC)c(OC)cc2C1
Product: COc1cc2c(cc1OC)CC(N(C)CCCN1CCc3cc4c(cc3CC1=O)OCCO4)CC2

Procedure:
The title compound is prepared from 1-[7,8-ethylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-chloropropane and 6,7-dimethoxy-2-methylamino-1,2,3,4-tetrahydronaphthalene analogously to Example 1. Mp: 152°-157° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:14][O:15][C:16]([C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1)=[O:17].C(N(C(C)C)CC)(C)C>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:14][O:15][C:16]([C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12])=[O:17]
Reactant: O=C(CCl)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCCN1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloroacetic benzyl ester (1.8 g, 9.75 mmol) in DCM (50 mL) is added (S)-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.51 g, 11.70 mmol), diisopropylethylamine (4.09 mL, 23.40 mmol) and tetrabutylammonium iodide (3.60 g, 9.75 mmol) and the resulting mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the residue purified by column chromatography using a gradient of 2-45% EtOAc/heptane to give (S)-1-benzyloxycarbonylmethyl-pyrrolidine-2-carboxylic acid methyl ester; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.81-2.05 (m, 3H), 2.13-2.24 (m, 1H), 2.78-2.84 (m, 1H), 3.15-3.20 (m, 1H), 3.57-3.69 (m, 3H), 3.70 (s, 3H), 5.15 (s, 2H), 7.36 (m, 5H).
Reaction SMILES: [N:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH3:19]>C(O)(C)C>[CH3:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[NH:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cc1cnccc1Cl
Reactant: Nn1ccc2ccccc21
Agent: Cl
Solvent: CC(C)O
Product: Cc1cnccc1Nn1ccc2ccccc21

Procedure:
The title compound was prepared from 1H-indol-1-amine and 4-chloro-3-methylpyridine hydrochloride in isopropanol at 90° C. for 6 hours in substantially the same manner as in Example 1, m.p. 78°-80° C.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]([C:19]4[C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:21][O:22][C:23]=4[CH3:24])=[N:17][N:18]=3)=[CH:10][CH:9]=2)=[O:7])[CH:5]=[CH:4]N=C1.[CH:31]1(N)CC1>O1CCCC1>[CH:5]1([NH:1][C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]([C:19]4[C:20]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[N:21][O:22][C:23]=4[CH3:24])=[N:17][N:18]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:31]1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(=O)n3ccnc3)cc2)o1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(=O)NC3CC3)cc2)o1
Temperature: 80 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a suspension of imidazol-1-yl-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-methanone (200 mg, 0.50 mmol) in tetrahydrofuran (2 mL) was added cyclopropylamine (37 mg, 0.65 mmol) and the mixture was stirred for 3 h at 80° C. After cooling to ambient temperature the resulting suspension was concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20) afforded the title compound (149 mg, 77%) as a white solid. MS: m/e=387.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][O:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.Cl.[CH3:20][NH2:21]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH3:20])[C:5]2[CH2:10][O:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2OCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CN
Agent: Cl
Product: CNc1nc(Cl)nc2c1COC2c1ccc(F)cc1
Yield: 60.8 %

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (Preparation M) (250 mg, 0.877 mmol) and methanamine hydrochloride (89 mg, 1.315 mmol) were combined and purified as per Preparation Ia to give 2-chloro-7-(4-fluorophenyl)-N-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine (149 mg, 0.533 mmol, 60.8% yield). LC-MS (M+H)+=280.0. 1H NMR (500 MHz, MeOD) δ ppm 7.31-7.44 (2H, m), 7.05-7.17 (2H, m), 5.80-5.95 (1H, m), 4.94-5.21 (2H, m), 2.93-3.07 (3H, m).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:16]1.CO.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[C@H:15]1[CH2:16][CH2:17][C@H:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:19][CH2:20]1
Reactant: COCOc1ccc([C@H]2CC[C@H](CC(=O)OC)CC2)c(OCOC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added cis/trans-methyl {4-[2,4-bis(methoxymethoxy)phenyl]cyclohexyl}acetate (1.00 g, 2.84 mmol) and methanol (20 ml). The stirred solution was heated to reflux temperature and aqueous hydrochloric acid (20 ml, 1 M) was added in aliquots (4×5 ml) at 10 min intervals. After 2 hr, the reaction mixture was cooled to room temperature and saturated aqueous sodium bicarbonate (50 ml) added. The reaction mixture was poured into a separating funnel containing ethyl acetate (100 ml) and water (30 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give a white solid. Purification via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 1:2, v/v) afforded the title compound (0.51 g, 69%) as a mixture of diastereoisomers. m/z (ES+) 265 (M+H+); δH(CD3OD) 1.33-1.91 (9H, m), 2.30 (2H, m), 2.79 (1H, m), 3.72 (3H, s), 6.28 (2H, m), 6.95 (1H, m).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.[CH3:17][CH:18]1[CH2:23][NH:22][CH2:21][CH2:20][NH:19]1>CN(C)C=O>[CH3:17][CH:18]1[NH:19][CH2:20][CH2:21][N:22]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH2:23]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CN(c2ccc([N+](=O)[O-])cn2)CCN1
Reaction time: 1 h

Procedure:
872 mg (6.31 mmol) of potassium carbonate were added to a solution of 500 mg (3.15 mmol) of 2-chloro-5-nitropyridine in 7 ml of dimethylformamide. After that, a solution of 350 mg (3.32 mmol) of 2-methylpiperazine in 3 ml of dimethylformamide was slowly added dropwise to the reaction mixture while cooling with ice (exothermic reaction). The reaction mixture was stirred for 1 hour while cooling with ice and then stirred overnight at room temperature. After the solvent had been evaporated to dryness, the residue was taken up in water and this mixture was extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness, with 3-methyl-1-(5-nitropyridin-2-yl)piperazine (Yield: 650 mg, 89% of theory) being obtained.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]=[C:16]=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:18]([C:20]1([CH2:35][CH3:36])[C:23](=[O:24])[NH:22][CH:21]1[O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[CH3:19].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:35]([C:20]1([CH2:18][CH3:19])[C:23](=[O:24])[N:22]([C:16]([NH:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:17])[CH:21]1[O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[CH3:36]
Reactant: O=C=NCc1ccccc1
Reactant: CCC1(CC)C(=O)NC1Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC1(CC)C(=O)N(C(=O)NCc2ccccc2)C1Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
Triethylamine (1.26 mL, 9.1 mmol), 4-dimethylaminopyridine (20 mg, 0.2 mmol), and benzyl isocyanate (1.12 mL, 9.1 mmol) were successively added to a solution of 4-(3,3-diethyl-4-oxo-2-azetidinyl)oxy-nitrobenzene (1.2 gm, 4.6 mmol) in methylene chloride (10 mL). The solution was stirred at room temperature for 1.5 hours, then ethyl acetate (100 mL) was added. The solution was sucessively washed with 1N hydrochloric acid (3×20 mL), 1N sodium bicarbonate solution (3×20 mL), water (20 mL), and saturated salt solution (20 mL), 1N sodium solution was dried over anhydrous sodium sulfate and the solvent removed by rotoevaporated. The product was purified by flash column chromatography on silica gel eluted with 15% ethyl acetate in hexanes and recrystallized from ethyl acetate/hexanes as a white solid (mp. 96°-97° C.; 1.3 gm, 70% yield): 1H-NMR δ (CDCl3) 1.04 (3H, t, J=7 hz), 1.08 (3H, t, J=7 Hz), 1.76-2.10 (4H, m), 4.47 (2H, d, J=6 hz), 5.76 (1H, s), 7.26-7.44 (7H, m), 8.24 (2H, d, J=9 Hz; ir (thin film) 1780, 1720 cm-1.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][NH:7][C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[CH:52](O)=O.C=O.[OH-].[Na+]>C(#N)C>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][N:7]([CH3:52])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)CN[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)CN(C)[C@H](C)[C@@H](O)[C@]1(C)O

Procedure:
9-Deoxo-9a-aza-9a-homoerythromycin A (73.5 g —0.1 mole) was dissolved in 250 ml acetonitrile. To this solution, formic acid (19 ml, 0.5 mole) followed by formaldehyde (37%, 20 ml, 0.25 mole) were added and refluxed for 24 hours. The pH of the reaction mixture was adjusted with alkali (NaOH solution) to 10.5 and filtered to remove particles. To the filtered acetonitrile solution, an equal volume of water was added to precipitate Azithromycin monohydrate as cube shaped crystals. The crystals were filtered and dried under vacuum at 50° C. to give 65 g of Azithromycin monohydrate having water content of 5% (water content measured by the Karl Fischer titration method). This sample of Azithromycin monohydrate crystals has a characteristic solid state (KBr pellet) IR spectrum (FIG. 1) and a characteristic X-ray diffraction pattern (FIG. 2).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:13][O:14][CH2:15][CH2:16][OH:17])[CH3:12])=[CH:7][N:6]=1)([CH3:3])[CH3:2].O[C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]2=[O:49])=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:13][O:14][CH2:15][CH2:16][O:17][C:19]2[CH:51]=[CH:50][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[N:26]([C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]3=[O:49])=[CH:21][CH:20]=2)[CH3:12])=[CH:7][N:6]=1)([CH3:2])[CH3:3]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc(OC(C)C)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(OC(C)C)nc1
Yield: 81.4 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 1.02 g of 2-[1-(2-isopropoxy-5-pyridyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 32), 2.00 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 1.24 g of triphenylphosphine and 784 mg of diethyl azodicarboxylate, 2.39 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH:11]([C:16]([F:19])([F:18])[F:17])[C:12](=[O:15])[CH2:13]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+].CN(C=O)C>CCOCC>[N:21]([CH2:13][C:12](=[O:15])[CH:11]([C:16]([F:19])([F:18])[F:17])[CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CC(C(=O)CBr)C(F)(F)F)OCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: [N-]=[N+]=NCC(=O)C(CC(=O)OCc1ccccc1)C(F)(F)F
Yield: 81.2 %

Procedure:
Stir a mixture of 290 mg (0.82 mmol) of the bromo-ketoester of Example 5, 91 mg (1.4 mmol) of NaN3, and 4 ml of dry DMF at 25° C. for 1 hour. Dilute the mixture with ether, wash several times with water and then brine, dry over MgSO4, and remove the solvent in vacuo to give 210 mg of the desired azide (VII, R=CF3, R1,R2 =H, R3 =C6H5CH2) as an oil.
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:9]=[N:10][N:11]3[C:16]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[CH3:25])=[C:15]([C:26](OCC)=[O:27])[CH:14]=[N:13][C:12]=23)(=[O:7])=[O:6])[CH2:3][CH2:2]1.Cl.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[CH:1]1([NH:4][S:5]([C:8]2[CH:9]=[N:10][N:11]3[C:16]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[CH3:25])=[C:15]([C:26]([N:42]4[CH2:43][CH2:44][CH:39]([C:36]5[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=5)[CH2:40][CH2:41]4)=[O:27])[CH:14]=[N:13][C:12]=23)(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC3CC3)cnn2c1Nc1ccc(F)cc1C
Agent: Cl
Product: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(c3ccc(F)cc3)CC2)cnc2c(S(=O)(=O)NC3CC3)cnn12
Yield: 14.9 %

Procedure:
Using ethyl 3-(N-cyclopropylsulfamoyl)-7-(4-fluoro-2-methylphenylamino)-pyrazolo[1,5-a]pyrimidine-6-carboxylate (0.496 g, 1.145 mmol) obtained in step 1 and 4-(4-fluorophenyl)piperidine hydrochloride (0.072 g, 0.335 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.0283 g, 3%) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[CH:6][N:5]([CH3:8])[N:4]=1.[CH3:9][NH2:10]>O1CCOCC1>[CH3:9][NH:10][CH2:2][C:3]1[N:7]=[CH:6][N:5]([CH3:8])[N:4]=1
Reactant: CN
Reactant: Cn1cnc(CCl)n1
Solvent: C1COCCO1
Product: CNCc1ncn(C)n1
Temperature: 80 °C
Yield: 80 %

Procedure:
A solution of 3-chloromethyl-1-methyl-1H-1,2,4-triazole (from Example 1, Step c; 600 mg, 4.6 mmol) in 40% aqueous methylamine and 1,4-dioxane (5 ml) was stirred and heated at 80° C. in a sealed tube for 16 hours. Upon cooling the whole mixture was evaporated (azeotroping with ethanol). The residue was purified by chromatography on silica gel, eluting with dichloromethane-methanol-aqueous ammonia (60:8:1→40:8:1) to give the title compound (440 mg, 80%) as a pale yellow oil. 1H NMR (250 MHz, d6-DMSO) δ 3.61 (2H, s), 3.81 (3H, s), 8.35 (1H, s); MS (ES+) m/e 127 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[C:4]([F:19])[CH:3]=1.IC.[C:22](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:22])[CH:17]=2)=[O:11])=[C:4]([F:19])[CH:3]=1
Reactant: O=C(/C=C/c1ccc(Cl)cc1F)c1ccc(=O)[nH]c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)/C=C/c2ccc(Cl)cc2F)ccc1=O

Procedure:
In analogy to example 161, step 1, (E)-5-(3-(4-chloro-2-fluorophenyl)acryloyl)pyridin-2(1H)-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a yellow solid, MS (ESI+): m/z=292.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]12[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2.[CH:19](OCC)=[CH2:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[NH4+].[Cl-]>C1COCC1>[CH:19]([O:1][C:2]12[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH2:20]
Reactant: C=COCC
Reactant: CC1CC(=O)C2CCCCCCCCCC2(O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=COC12CCCCCCCCCC1C(=O)CC(C)C2
Temperature: 40 °C
Reaction time: 2 h
Yield: 19.3 %

Procedure:
A mixture of 1 g (4 mmol) of (16) and 0.46 ml (4.8 mmol) ethyl vinyl ether in 2 ml THF was stirred at room temperature in the presence of 201 mg (0.8 mmol) pyridinium p-toluenesulfonate (PPTS) for 4 hours. The mixture was stirred at 40° C. for 2 h and 0.46 ml (4.8 mmol) ethyl vinyl ether were added. After 6 hours at 40° C. the reaction the mixture was hydrolyzed with 3 ml of a saturated aqueous NH4Cl solution. After extraction with 50 ml diethyl ether the combined organic phases were washed (H2O), dried (Na2SO4) and the solvent was evaporated. Flash chromatography, using SiO2 (105 g) and n-pentane/diethyl ether=95:5 as eluent, afforded 215 mg (yield: 19%) of (26).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]=[C:28]=[S:29]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:19][C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[C:28]([NH:27][CH3:26])=[S:29])[CH2:14][CH2:13]1)[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN=C=S
Reactant: C[C@H](CCNC(=O)OC(C)(C)C)N1CCC(NCc2ccsc2)CC1
Solvent: ClCCl
Product: CNC(=S)N(Cc1ccsc1)C1CCN([C@H](C)CCNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following general procedure H: to ((R)-3-{4-[(Thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (1.0 g, 2.72 mmol) in dry CH2Cl2 (20 ml) was added methylisothiocyanate (223 μl, 3.26 mmol). The reaction mixture was then allowed to stir at room temperature overnight under N2 pressure to yield {(R)-3-[4-(3-methyl-1-thiophen-3-ylmethyl-thioureido)-piperidin-1-yl]-butyl}-carbamic acid tert-butyl ester as yellow oil.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[C:10]([OH:21])[CH:9]=1)=[O:7])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[CH3:33][C:34]([CH3:41])([CH2:39][CH3:40])[CH2:35][C:36](Cl)=[O:37]>>[CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[C:10]([O:21][C:36](=[O:37])[CH2:35][C:34]([CH3:41])([CH3:33])[CH2:39][CH3:40])[CH:9]=1)=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)CC(=O)Oc1ccc(C(=O)CNC(C)C)cc1O
Reactant: CCC(C)(C)CC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CCC(C)(C)CC(=O)Oc1cc(C(=O)CNC(C)C)ccc1OC(=O)CC(C)C

Procedure:
Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with 3,3-dimethylpentanoyl chloride there is obtained 3-(3,3-dimethylpentanoyloxy)-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-(3,3-dimethylpentanoyloxy)-4-(isovaleryloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.