Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:32][Si](C)(C)C.CCOCC>CC(CC)=O>[ClH:32].[CH3:31][N:2]([CH3:1])[C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2cccc(F)c2)CCC(CC(=O)NCCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Solvent: CCOCC
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The less polar diastereoisomer of 2-[4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]-N-[2-(1H-indol-3-yl)ethyl]acetamide (86 mg, 0.204 mmol) was dissolved in ethyl methyl ketone (5 ml), and chlorotrimethylsilane (0.038 ml, 0.3 mmol) was added. After 1 h ether (30 ml) was added to the reaction mixture and the mixture was stirred at RT for 30 min. The hydrochloride was isolated as a colourless solid in a yield of 94% (87 mg) with an m.p. of 135-140° C. (Example 50).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][OH:4].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C1(C)C=CC=CC=1>[C:28]([O:4][CH2:3][CH:2]([CH3:1])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CO)CC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)OCC(C)CC1CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a cooled (0° C.), stirred solution of 2-methyl-3-cyclohexylpropanol (40.3 g., 0.26 mol.), dimethylaminopyridine (2.5 g., 0.02 mol.), and triethylamine (38.4 g., 0.38 mol.) in 200 ml of toluene was added acetic anhydride (39.4 g. 0.39 mol) over 30 minutes. The resulting solution was allowed to warm to room temperature and stirred for an additional 1.5 hours. The reaction mixture was washed twice with 125 ml portions of 2 N aqueous sodium chloride, dried over magnesium sulfate and concentrated to a colorless oil which was distilled to obtain 72 g. 98% yield; bp 67-71° C. at 0.6 mm. Odor: very pleasant fruity, rosy, floral. Mass Spectrum from 5508-36. MS (El) m/z (relative intensity) 155 (M+−C2H3O, 2), 138 (M+−C2H4O2, 15).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:13][N:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:28][N:14]([CH3:13])[CH2:15][CH2:16][N:17]([S:2]([CH3:1])(=[O:4])=[O:3])[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(NCCN(C)C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N(CCN(C)C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (0.105 ml, 1.350 mmol) was added to a stirred solution of triethylamine (0.282 ml, 2.024 mmol) and methyl 4-{[2-(dimethylamino)ethyl]amino}benzoate (0.15 g, 0.675 mmol) in CH2Cl2 (2 ml) and the mixture was stirred at room temperature for overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over Na2SO4 filtered and the solvent was evaporated under reduced pressure. The product was purified by reversed phase HPLC (20-100% MeCN/H2O with 0.05% TFA). MS cal'd 301 (MH+), exp 301(MH+).
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=O)=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.S(Cl)(Cl)=O.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>C(Cl)Cl>[CH2:23]([N:25]([CH2:26][CH3:27])[C:16]([C:12]1[CH:13]=[CH:14][C:15]2[C:2](=[O:1])[C:3]3[C:8]([O:9][C:10]=2[CH:11]=1)=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:18])[CH3:24]
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3oc2c1
Reactant: CCNCC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc2c(=O)c3ccccc3oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.6 %

Procedure:
A sample of compound 5a, (13.4 g, 55.6 mmol) was suspended in 220 mL CH2Cl2 and 24.4 mL (330 mmol) of thionyl chloride was added. The mixture was refluxed over 6 h, adding approximately 10 mL of additional thionyl chloride per hour until the reaction became homogeneous. At that time, the thionyl chloride and solvent were removed under vacuum and the remaining residue was diluted with an additional 220 mL CH2Cl2. To the suspension was added 100 mL ice cold 1.5 N NaOH, 100 mL CH2Cl2, and 17 mL (166 mmol) diethyl amine. After stirring for 15 min at room temperature, the phases were separated, and the organic phase was washed with HCl and brine, dried over magnesium sulfate, filtered and concentrated to yield Compound 6a (14.7 g, 49.8 mmol). MS m/z(MH+)296.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.[Cl-].[NH4+].O1CCCC1.O>CO.[Fe]>[NH2:16][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Sc1ccc(O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(Br)ccc1Sc1ccc(O)cc1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A mixture of the product from Example 238A (0.302 g, 0.926 mmol), iron powder (0.208 g, 3.7 mmol, 4.0 eq) and ammonium chloride (0.059 g, 1.11 mmol, 1.2 eq) in a mixture of methanol (6 mL), tetrahydrofuran (6 mL), and water (2 mL) was heated under reflux for 5 hours and then cooled to room temperature. The reaction mixture was filtered through Celite and the filter pad was rinsed with methanol (25 mL). The filtrate was evaporated under reduced pressure to leave a brown glassy solid (0.27 g, 99%) that was utilized without further purification.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:42]3[N:41]=[CH:40][N:39]=[C:29]([NH:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:43][CH2:44][CH:45]([OH:48])CO)[C@@H:21]1[OH:49])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C(Cl)Cl>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:42]3[N:41]=[CH:40][N:39]=[C:29]([NH:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:43][CH2:44][CH:45]=[O:48])[C@@H:21]1[OH:49])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OCC(O)CO)[C@@H]1O)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OCC=O)[C@@H]1O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.2 %

Procedure:
5′-O-tert-butyldiphenylsilyl-N6-benzoyl-2′-O-(2,3-dihydroxypropyl)-adenosine (5.59 g, 8.17 mmol) was dissolved in dry CH2Cl2 (40.42 mL). To this NaIO4 adsorbed on silica gel (Ref. J. Org. Chem. 1997, 62, 2622-2624) (16.34 g, 2 g/mmol) was added and stirred at ambient temperature for 30 minutes. Reaction monitored by TLC (5% MeOH in CH2Cl2). Reaction mixture was filtered and the filtrate washed thoroughly with CH2Cl2. Dichloromethane layer evaporated to get the title compound (5.60 g) that was used in the next step without purification. Rf 0.3 (5% MeOH in CH2Cl2).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[F:24][C:25]1[CH:26]=[C:27]([Mg]Br)[CH:28]=[C:29]([F:31])[CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([C:4]([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH2:14][CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][C@H:17]4[CH3:21])=[CH:11][C:10]=3[CH:22]=2)=[O:5])[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Product: C[C@@H]1CCCN1CCc1cc2cc(C(=O)c3cc(F)cc(F)c3)ccc2o1

Procedure:
The product from Example 71E and 3,5-difluorophenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.45 (d, 3H), 1.75 (m, 1H), 2.13 (m, 2H), 2.35 (m, 1H), 3.30 (m, 4H), 3.56 (m, 1H), 3.82 (m, 2H), 6.88 (s, 1H), 7.38 (dd, 2H), 7.30 (m, 3H), 7.63 (dd, 1H), 7.80 (dd, 1H), 8.05 (d, 1H); MS (ESI) m/z 370 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[O:22]C)[O:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=1[CH3:18])([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH3:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([CH3:14])[C:8]=1[O:7][C:6]1[CH:19]=[CH:20][C:21]([OH:22])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-nitrobenzene (500 mg, 1.59 mmol) in CH2Cl2 (12 mL was added boron tribromide (1 M in CH2Cl2, 3.2 mL, 3.2 mmol). The resulting mixture was stirred 1 h at RT then quenched with water (15 mL) and 1 M HCL (10 mL). After stirring 30 min at RT, the solution was extracted with CH2Cl2 (3×20 mL). Combined extracts were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound of Step B. The title product of Step B was used in the next step without further purification. MS (APCI−) Calc.: 301, Found: 300.2 (M−1).
Reaction SMILES: C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[NH2:11][C@H:12]1[C@@H:16]2[O:17][C:18]([CH3:21])([CH3:20])[O:19][C@@H:15]2[C@@H:14]([O:22][CH2:23][CH2:24][OH:25])[CH2:13]1.C(=O)(O)[O-].[Na+].[Cl:31][C:32]1[C:37]([NH2:38])=[C:36](Cl)[N:35]=[C:34]([S:40][CH2:41][CH2:42][CH3:43])[N:33]=1.C(O)CC(C)C>C1(C)C=CC=CC=1.O>[NH2:38][C:37]1[C:36]([NH:11][C@H:12]2[C@@H:16]3[O:17][C:18]([CH3:20])([CH3:21])[O:19][C@@H:15]3[C@@H:14]([O:22][CH2:23][CH2:24][OH:25])[CH2:13]2)=[N:35][C:34]([S:40][CH2:41][CH2:42][CH3:43])=[N:33][C:32]=1[Cl:31]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCO)C[C@H]2N
Reactant: CCCSc1nc(Cl)c(N)c(Cl)n1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)CCO
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Temperature: 105 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
A flask was charged with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt (17 g), sodium bicarbonate (21.2 g), 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (10 g) and isoamyl alcohol (30 mL). The mixture was heated to about 100-110° C. and maintained at the same temperature for about 10-12 hours and completion of the reaction was monitored by TLC. After completion of reaction the mixture was cooled to room temperature then filtered and the bed was washed with isoamyl alcohol (10 mL). The filtrate was subjected to complete distillation under vacuum at about 65-70° C. to afford the crude. Then water (100 mL) and toluene (100 mL) were charged. The mixture was stirred for about 20 minutes and layers were separated. The organic layer was separated and washed with water (100 mL). The organic layer was separated and subjected to complete distillation under vacuum at 60-65° C. followed by cooling to room temperature and subsequent addition of n-heptane (150 mL). The mixture was stirred for about 4-5 hours followed by isolation of solid by filtration and washing with n-heptane (20 mL). The solid isolated was subjected to drying under vacuum at 50-55° C. to afford the title compound in about 82% yield having HPLC purity of about 99%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[H-].[Na+].C(Cl)Cl.CCOC(C)=O>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([O:15][CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc(Cl)nc(N3CCOCC3)n2)CC1
Yield: 81.3 %

Procedure:
A mixture of 2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine (0.47 g, 2 mmol), tert-butyl 4-hydroxy-1-piperidinecarboxylate (0.40 g, 2 mmol), and a small excess of NaH (58 mg, 2.4 mmol) in THF (20 mL) was stirred at room temperature overnight. The reaction was quenched with water, and the mixture was extracted with EtOAc. Chromatography on silica eluting with CH2Cl2/EtOAc (9:1) gave 0.65 g (81% yield) of tert-butyl 4-(4-chloro-6-morpholino-1,3,5-triazin-2-yloxy)piperidine-1-carboxylate as a white solid: mp (i-Pr2O) 150-152° C.; 1H NMR (CDCl3) δ 5.18 (tt, J=7.7, 3.8 Hz, 1H), 3.87 (m, 2H), 3.83 (m, 2H), 3.78-3.71 (m, 6H), 3.30 (ddd, J=13.5, 8.3, 3.8 Hz, 2H), 1.95 (m, 2H), 1.78 (m, 2H), 1.46 (s, 9H); Anal. Calcd. for C17H26ClN5O4: C, 51.06; H, 6.55; N, 17.51. Found: C, 51.21; H, 6.28; N, 17.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:32](Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.CO>C(Cl)Cl>[CH3:32][O:24][C:23](=[O:25])[CH2:22][CH2:21][N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[CH:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[N:17]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCn1ccc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, methanol (20 μL, 0.49 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 3-{3-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid methyl ester (28 mg, 55%) as a white solid: ESI-LRMS m/e calcd for C22H28ClN3O5S [M+] 481.1, found 482.5 [M+H+]; 1H NMR (400 MHz, CDCl3), δ ppm 1.08-1.21 (m, 2H, CH2), 1.40-1.95 (m, 8H, 4×CH2), 2.13-2.28 (m, 1H, CH), 2.82 (t, J=6.5 Hz, 2H, COCH2), 3.26 (s, 3H, SO2CH3), 3.54 (t, J=7.6 Hz, 1H, CH), 3.67 (s, 3 H, CO2CH3), 4.27 (t, J=6.5 Hz, 2H, NCH2), 6.62 (d, J=2.3 Hz, 1H, Ar), 7.30 (d, J=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 7.89 (s, 1H, NH), 8.08 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]([CH2:6][CH2:7][OH:8])[CH2:2]1.[CH2:9]([N:18]=[C:19]=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17]>C1(C)C(C)=CC=CC=1>[O:1]1[CH2:5][CH2:4][N:3]([CH2:6][CH2:7][O:8][C:16]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:18][C:19]([O:8][CH2:7][CH2:6][N:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[O:20])=[O:17])[CH2:2]1
Reactant: OCCN1CCOC1
Reactant: O=C=NCCCCCCN=C=O
Solvent: Cc1ccccc1C
Product: O=C(NCCCCCCNC(=O)OCCN1CCOC1)OCCN1CCOC1

Procedure:
117 g (1 mol) of 2-(1,3-oxazolidin-3-yl)-ethanol are reacted with 84 g (0.5 mol) of hexamethylene diisocyanate in 20 g of xylene by the method described in Example 1. This reaction is catalyzed by the addition of 0.05 g of Sn(II) octoate and is carried out first at 30° C and later at 50° C. The product obtained, which is about 90% pure, is solid at room temperature, but a pourable liquid at 50° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO.C(OCC)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)c1c[nH]cc1-c1ccc(N)cc1
Yield: 44.6 %

Procedure:
0.2 g (0.769 mmol) of ethyl 4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate is added at a temperature in the region of 20° C. to a suspension of 0.02 g (0.188 mmol) of 10% palladium on carbon in 15 cm3 of methanol. After hydrogenating for 20 hours in an autoclave under 3 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered, the catalyst is rinsed with three times 5 cm3 of methanol and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is stirred in 10 cm3 of diethyl ether and then filtered and dried under reduced pressure (2.7 kPa) to give 0.079 g of ethyl 4-(4-aminophenyl)-1H-pyrrole-3-carboxylate, in the form of a brown solid; EI: m/z=230 (M+) base peak, m/z=202 (M-C2H4+), m/z=157 (M-C2H5O+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:22]1([CH3:26])[CH:23]=[CH:24][CH:25]=[C:20]([C:19]2[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=[CH:17][N:18]=2)[CH:21]=1
Reactant: Cc1cccc(-c2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(-c2nccnc2N2CCNCC2)c1
Reaction time: 2 h

Procedure:
Dissolve 3′-m-tolyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (3.3 g, 9.32 mmol) in DCM (10 mL). Add cold (from refrigerator) trifluoroacetic acid (42.6 g, 28.8 mL). Stir for 2 hr. at room temperature. Partition reaction mixture between methylene chloride and 5N NaOH (pH aqueous=14). Separate layers. Extract aqueous layer with methylene chloride (2×20 mL). Combine organic layers, dry over anh. sodium sulfate, filter and concentrate to give the title preparation (2.35 g, 99%). MS (ES): m/z=255 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[CH3:12][O:13][C:14]([C:16]1[N:20]([CH:21]2C3C(=CC=CC=3)C=[CH:23][C:22]2([CH3:32])[CH3:31])[CH:19]=[N:18][CH:17]=1)=[O:15]>C(Cl)Cl>[CH3:12][O:13][C:14]([C:16]1[N:20]([CH:21]2[C:3]3[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=3)[CH:8]3[O:10][CH:23]3[C:22]2([CH3:32])[CH3:31])[CH:19]=[N:18][CH:17]=1)=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cncn1C1c2ccccc2C=CC1(C)C
Solvent: ClCCl
Product: COC(=O)c1cncn1C1c2ccccc2C2OC2C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.9 %

Procedure:
9.4 g of 55% 3-chloroperbenzoic acid are added to a solution of 8.5 g of 1-(1,2-dihydro-2,2-dimethylnaphthalen-1-yl)-5-imidazolecarboxylic acid methyl ester in 150 ml of methylene chloride and the mixture is stirred at room temperature for 2 hours. The precipitate is separated off and the filtrate is washed twice using 50 ml of sodium hydrogen carbonate solution (5%) each time, dried over magnesium sulfate and concentrated by evaporation. Chromatography of the residue on silica gel [eluant:ether/hexane (3:1)] yields 1.7 g of a mixture of 1,4-cis-1-(3,4-epoxy-2,2-dimethyltetralin-1-yl)-5-imidazolecarboxylic acid methyl ester and 1,4-trans-1-(3,4-epoxy-2,2-dimethyltetralin-1-yl)-5-imidazolecarboxylic acid methyl ester in a ratio of 1:1 (m.p. 60°-68° C.).
Reaction SMILES: BrC[CH2:3][CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6].[Mg].[C:10](=[O:12])=[O:11].[CH3:13]COCC>>[CH3:6][Si:5]([CH3:8])([CH3:7])[CH:4]([CH3:13])[CH2:3][C:10]([OH:12])=[O:11]
Reactant: O=C=O
Reactant: C[Si](C)(C)CCCBr
Reactant: CCOCC
Agent: [Mg]
Product: CC(CC(=O)O)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution containing 3 g (15.4 mmol) of (3-bromopropyl)trimethylsilane in 3 ml of dry ether was added to 0.375 g (15.4 mmol) of magnesium turnings in ether (40 ml final volume of solution). After 1 hour of reflux gazeous carbondioxide was bubbled through the reaction mixture (3 g, 77 mmol of dry ice). After 2 hours of stirring at room temperature the reaction mixture was partitioned between aqueous ammonium chloride and ether. The organic phase was separated, the aqueous phase was further acidified with hydrochloric acid 1N and extracted with ether. Ethereal phases were pooled and the solvent was removed under reduced pressure. Separation of the expected 4-trimethylsilyl-butanoic acid from dimer of starting (3-bromopropyl)trimethylsilane was finally performed by acid base extraction. 0.62 g of 3-(trimethylsilyl)-butanoic acid was isolated as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][NH:10][NH2:11].C(=O)(O)[O-].[Na+].[CH2:17]([CH2:21][C:22](=O)[CH3:23])[C:18]([CH3:20])=O.Cl>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:10]([N:11]2[C:22]([CH3:23])=[CH:21][CH:17]=[C:18]2[CH3:20])[CH3:9])=[CH:6][CH:7]=1
Reactant: CNN
Reactant: CC(=O)CCC(C)=O
Reactant: Clc1ccc(Cl)nn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C)n1N(C)c1ccc(Cl)nn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A mixture of water (300 ml), 3,6-dichloropyridazine (29.8 g; 0.2 mole), methylhydrazine (9.2 g; 0.2 mole), and sodium bicarbonate (17.8 g; 0.2 mole), is heated to the reflux temperature for two hours. After cooling to about 60° C., acetonylacetone (22.2 g; 0.2 mole) is added and stirring is prosecuted for further 1 hour. Then the mixture is neutralized with hydrochloric acid and the obtained precipitate is collected and crystallized from ethyl ether, yielding 28 g (59.2%) of 6-chloro-N-(2,5-dimethyl-1H-pyrrol-1-yl)-N-methyl-3-pyridazineamine, whose structure is confirmed by I.R. and NMR spectra. M.p. 93°-94.5° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH:15](O)[CH2:14]2)[CH2:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(N(S(F)(F)[F:37])CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH:15]([F:37])[CH2:14]2)[CH2:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(C2CC(=O)N(Cc3ccccc3)C2)CC(O)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C1(C2CC(=O)N(Cc3ccccc3)C2)CC(F)C1
Reaction time: 20 h
Yield: 80 %

Procedure:
A 495 mg (1.56 mmol) portion of 1-benzyl-4-[3-(ethoxycarbonyl)-1-hydroxycyclobutan-3-yl]-2-pyrrolidone (Isomer A) was dissolved in a mixed solvent consisting of 12 ml of toluene and 6 ml of dichloromethane to which, while cooling in an ice bath with stirring, was then added 839 μl (6.24 mmol) of diethylaminosulfur trifluoride, subsequently carrying out 20 hours of stirring at 40° C. While cooling in an ice bath with stirring, the reaction solution was alkalified by slowly adding saturated sodium bicarbonate aqueous solution and then mixed with chloroform to carry out separation of layers, and the resulting organic layer was washed with saturated brine. The aqueous layer was again extracted with chloroform, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure and the resulting residue was purified by a silica gel column chromatography (n-hexane:ethyl acetate=2:1) to give 400 mg (80.0%) of the title compound.