Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@@H:16]3[O:17]C(C)(C)[O:19][C@@H:15]3[C@@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[O:13]2)=[C:5]([NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:4]=1.C(N(CC)CC)C.[CH3:49][CH:50]([S:52](Cl)(=[O:54])=[O:53])[CH3:51]>ClCCl>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][NH:27][C:5]2[N:4]=[C:3]([CH2:2][NH:1][S:52]([CH:50]([CH3:51])[CH3:49])(=[O:54])=[O:53])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:12]2[O:13][C@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[C@@H:15]([OH:19])[C@H:16]2[OH:17])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)C(C)C)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (Preparation 10) (140 mg, 0.25 mmol) and triethylamine (0.05 ml, 0.36 mmol) in anhydrous dichloromethane (1 ml) was treated with a solution of 2-propanesulphonyl chloride (40 mg, 0.28 mmol) in anhydrous dichloromethane (1 ml). The mixture was stirred at room temperature for 18 hours during which time the solvent was allowed to evaporate off freely. The residue was dissolved in ethanol (1 ml), treated with hydrochloric acid (1 M, 1 ml) and heated at 60° C. for 4 hours. The solvent was removed under reduced pressure and the residue was azeotroped with ethanol (×2). The residue was then purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (95:5 by volume) gradually changing to dichloromethane:methanol (90:10 by volume) to give a solid which was triturated with diethyl ether, diluted with pentane, filtered and dried to afford the title compound as a solid (28 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:4][CH:3]=1.[Mg].II.IC(I)C.[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[CH2:49][CH2:48][C:47](=[O:50])[CH2:46][CH2:45]3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[CH2:49][CH2:48][C:47]([OH:50])([C:2]4[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:4][CH:3]=4)[CH2:46][CH2:45]3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COCCCCOc1ccc(Br)cc1
Reactant: O=C1CCN(c2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cc2)CC1
Agent: CC(I)I
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCCCOc1ccc(C2(O)CCN(c3ccc(N4CCN(C(=O)OCc5ccccc5)CC4)cc3)CC2)cc1
Temperature: 0 °C
Yield: 47.5 %

Procedure:
To the solution of 1-bromo-4-(4-methoxybutoxy)benzene (4.94 g) and magnesium (463 mg) in tetrahydrofuran (50 ml) was added iodine at room temperature. The solution was refluxed for 7.5 hours, during which period diiodoethane was added to the mixture. After cooling to 0° C., 4-[4-(4-oxopiperidin-1-yl)phenyl]piperazine-1-carboxylic acid benzyl ester (4.94 g) in tetrahydrofuran (20 ml) was added dropwise with stirring to the solution. The mixture was stirred at room temperature for 2 hours. The reaction mixture was added to a mixture of ammonium chloride solution and ethyl acetate. The organic layer was taken, washed with brine, sodium hydrogen carbonate solution and brine and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (50:1 dichloromethane-methanol elution) to give 4-[4-[4-hydroxy-4-[4-(4-methoxybutoxy)phenyl]piperidin-1-yl]phenyl]piperazine-1-carboxylic acid benzyl ester (3.42 g).
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][N:19]=[C:20](I)[N:13]2[N:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:36]2[CH2:37][CH2:38][O:39][CH2:40][CH:41]=2)O1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][CH:9]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][N:19]=[C:20]([C:36]3[CH2:41][CH2:40][O:39][CH2:38][CH:37]=3)[N:13]2[N:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(OCc1ccccc1)c1nn2c(I)ncc2c(=O)[nH]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(OCc1ccccc1)c1nn2c(C3=CCOCC3)ncc2c(=O)[nH]1
Temperature: 125 °C
Yield: 75.7 %

Procedure:
To a solution of compound 12 (300 mg, 0.75 mmol) in dioxane (2 mL) was added a solution of Cs2CO3 (492 mg, 1.51 mmol) in H2O (0.5 mL) dropwise, followed by addition of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (318 mg, 1.5 mmol) and Pd(PPh3)4 (86 mg, 0.075 mmol). The reaction mixture was degassed by purging with N2 for 15 min. Then the reaction was heated to 125° C. under microwave heating for 40 min. After removal of the solvent, the residue was purified by chromatography on silica gel column (eluted with PE/EtOAc=10:1 to 1:5) to afford compound 13 (200 mg, 75% yield) as white solid. LC-MS: m/z 353 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.82 (br. s, 1H), 7.91 (s, 1H), 7.37˜7.32 (m, 5H), 7.19 (br. s, 1H), 4.61 (m, 2H), 4.49 (q, J=6.8 Hz, 1H), 4.40 (m, 2H), 3.95 (t, J=5.2 Hz, 2H), 2.78 (m, 2H), 1.58 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]2[C:8](=[C:9]([F:12])[C:10]=1[F:11])[C:7](=[NH:13])[NH:6][C:5]2=N.Cl.[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:24]1[S:25][CH2:26][C:27](=[NH:29])[N:28]=1.Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:1].[NH:13]=[C:7]1[C:8]2[C:4](=[C:3]([F:15])[C:2]([Cl:1])=[C:10]([F:11])[C:9]=2[F:12])[C:5](=[C:26]2[S:25][C:24]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]3[CH3:17])=[N:28][C:27]2=[NH:29])[NH:6]1
Reactant: CC1CCCCN1C1=NC(=N)CS1
Reactant: N=C1NC(=N)c2c(F)c(Cl)c(F)c(F)c21
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Product: CC1CCCCN1C1=NC(=N)C(=C2NC(=N)c3c(F)c(F)c(Cl)c(F)c32)S1

Procedure:
Following the procedure described in Example 9, part B above but using equivalent amounts of 5-chloro-4,6,7-trifluoro-1,3-diiminoisoindoline and 2-(2-methylpiperidino)-4-imino-2-thiazoline hydrochloride in place of 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, there is obtained as the product 1-imino-5-chloro-4,6,7-trifluoro-3-[2-(2-methylpiperidino)-4-imino-2-thiazolin-5-ylidene]isoindoline hydrochloride.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[C:13]([O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH2:22][CH2:21]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2nccs2)CC1
Temperature: 120 °C
Yield: 26.7 %

Procedure:
6.91 g (75.0 mmol) potassium carbonate was added to a solution of 1.35 ml (15.0 mmol) 2-bromothiazole and 3.00 g (15.0 mmol) piperidin-4-yl-carbamic acid-tert-butyl ester in DMF (50 ml) and heated to 120° C. for 8 h. Subsequently, the solvent was removed in vacuo and the residue taken up by chloroform. This solution was washed with water and brine in turn, dried over MgSO4, filtered and concentrated in vacuo. Column chromatography (SiO2, chloroform) was carried out on the residue, yielding 1.14 g (4.0 mmol, 27%) (1-thiazol-2-yl-piperidin-4-yl)-carbamic acid-tert-butyl ester.
Reaction SMILES: [OH:1][CH:2]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:30])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)=[O:6].[H-].[Na+].[CH3:37]I>C1COCC1>[CH3:37][O:1][CH:2]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:30])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:29])[F:27])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)=[O:6]
Reactant: CI
Reactant: CC(C)(C)C(O)CNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(CNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.2 %

Procedure:
To a solution of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-3,3-dimethylbutyl)amide (81.6 mg, 0.17 mmol) in THF (1.0 mL) was added sodium hydride (5.0 mg, 0.19 mmol), followed by methyl iodide (15 mL, 0.26 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and then the solvent was removed. The gummy material was diluted with dichloromethane (5 mL), washed with water (2×2 mL), dried over MgSO4 and filtered off the solid. After the solvent was concentrated into dryness, the crude material was subjected to column chromatography eluted sequentially with ethyl acetate:hexane (1:1) and ethyl acetate to obtain 25.3 mg (30%) of the product as solid. m.p. 65-68° C. 1H NMR (300 MHz, CDCl3) δ 7.73-7.69, 7.62, 7.53, 7.33, 6.98-6.93, 4.18-3.59, 3.48, 3.41, 3.37-3.26, 3.18, 3.03-2.98, 1.76, 0.98, 0.75. 13C NMR (75 MHz, CDCl3) δ 167.6, 166.4, 158.9, 149.8, 149.3, 134.3, 132.4, 129.5, 129.4, 129.3, 129.1, 127.2, 126.9-126.7, 112.7, 88.1, 61.7, 61.4, 52.7, 52.0, 46.4, 44.7, 44.6, 44.5, 44.4, 41.3, 41.2, 40.5, 35.8, 35.3, 35.0, 26.0, 25.9, 25.7. MS (ES+) m/z 508 (M+1).
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[C:4]([CH3:16])([CH3:15])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.CC1(C)C(C)(C)OB([C:26]2[CH:43]=[CH:42][C:29]([O:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)=[CH:28][CH:27]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[O:5][C:4]([CH3:16])([CH3:15])[C:3](=[O:17])[C:2]=2[C:26]2[CH:27]=[CH:28][C:29]([O:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)=[CH:42][CH:43]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Yield: 76 %

Procedure:
A mixture of 4-bromo-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2 g, 0.0067 mol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (2.43 g, 0.0067 mol), and Cs2CO3 (11 g, 0.034 mol) in toluene (25 mL) and water (8 mL) was degassed. Pd(dppf)Cl2(1.1 g, 0.0013 mol) was then added under an inert atmosphere and the mixture was degassed again. The reaction mixture was refluxed for 3 h, filtered through a pad of Celite®. The filtrate was diluted with EtOAc (100 mL), washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (2.3 g, 74%) as solid. 1H NMR (500 MHz, d6-DMSO): δ 8.42 (d, J=7.6 Hz, 1H), 8.06-7.99 (m, 2H), 7.95 (t, J=7.2 Hz, 1H), 7.72 (t, J=7.2 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H); 7.18 (d, J=7.4 Hz, 2H), 7.12 (d, J=7.2 Hz, 2H), 6.89 (d, J=7.2 Hz, 2H), 5.38 (s, 2H), 3.79 (s, 3H).1.42 (s, 6H). MS: M+H: m/z=452.1; M+Na: m/z=474.2. HPLC: 96%, Column: Eclipse XDB-C18, 150×4.6 mm, Sum. Mobile Phase: 0.1% TFA in Water (A), AcN (B), Flow rate: 1.5 ml/min (Gradient)
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:23]=[C:8]2[C:9]([C:15](=[O:22])[CH:16](C)[C:17](OC)=O)=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[N:7]2[N:6]=1)[CH3:4].Cl>CO>[CH2:3]([C:5]1[CH:23]=[C:8]2[C:9]([C:15](=[O:22])[CH2:16][CH3:17])=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[N:7]2[N:6]=1)[CH3:4]
Reactant: CCc1cc2c(C(=O)C(C)C(=O)OC)ccc(OC)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(=O)c1ccc(OC)n2nc(CC)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
A 1 mol/L aqueous sodium hydroxide solution (12 mL) was added to a solution of the compound of Example 184 (460 mg) in methanol (30 mL). The mixture was stirred at room temperature for 2 days. Subsequently, diluted hydrochloric acid was added to make the mixture acidic. Methanol was evaporated and the residue was extracted with ethyl acetate (×2). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and subsequent purification of the residue by silica gel column chromatography (hexane:ethyl acetate=2:3) afforded the title compound as a pale green powder (295 mg).
Reaction SMILES: C1(CC(Cl)=O)C=CC=CC=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1)[NH2:15].[C:34]1([CH2:40][C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.C(O)C>[C:34]1([CH2:40][C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:44]([NH:43][C:41](=[O:42])[CH2:40][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[S:45])[CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cc1ccccc1)N=C=S
Agent: O=C(Cl)Cc1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
2-Phenylethanoyl isothiocyanate was prepared using commercially available 2-phenylethanoyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-phenylethanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (41 mg, yield 53%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1
Reactant: Brc1nccs1
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(c2nccs2)CC1
Temperature: 100 °C

Procedure:
A mixture of methyl piperidine-4-carboxylate (2.045 g), 2-bromothiazole (1.64 g), and Cs2CO3 (5.86 g) in N,N-dimethylformamide (15 mL) was heated at 100° C. overnight.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([N+]([O-])=O)[C:13]=1[C:14]#[N:15])([O-:11])=[O:10]>>[OH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:8][C:16]1[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[C:13]=1[C:14]#[N:15]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OCCCCCCO
Product: N#Cc1c(OCCCCCCO)cccc1[N+](=O)[O-]
Yield: 88 %

Procedure:
Prepared as in Example 197c from hexane-1,6-diol and 2,6-dinitrobenzonitrile in 88% yield as a pale yellow solid. MS 265 (MH+).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[OH:19][CH2:20][C@@H:21]1[CH2:29][C@@H:28]2[C@@H:24]([CH2:25][N:26]([C:30](=[O:41])[C@H:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[CH3:32])[CH2:27]2)[C@@:23]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[F:49])([OH:42])[CH2:22]1>ClCCl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:19][CH2:20][C@@H:21]2[CH2:29][C@@H:28]3[C@@H:24]([CH2:25][N:26]([C:30](=[O:41])[C@H:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[O:39][CH3:40])[CH3:32])[CH2:27]3)[C@@:23]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])([OH:42])[CH2:22]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](CO)C[C@@](O)(c3ccccc3F)[C@@H]2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](COS(=O)(=O)c3ccc(C)cc3)C[C@@](O)(c3ccccc3F)[C@@H]2C1
Reaction time: 18 h
Yield: 59.7 %

Procedure:
4.2 g of p-toluenesulphonyl chloride and then 3.1 cm3 of triethylamine are added at room temperature to a solution of 1.17 g of (3aS,4S,6R,7aR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol in 30 cm3 of dichloromethane. The reaction mixture is stirred at this temperature for 18 hours, then washed with twice 25 cm3 of water and then with 25 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2.8 cm, height 25 cm), eluting under a pressure of 0.8 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60:40 by volume) and collecting fractions of 25 cm3. Fractions 22 to 35 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.95 g of (3aS,4S,6R,7aR)-6-p-toluenesulphonyloxymethyl-4-(2-fluorophenyl)-2-[(S)-2-(2-methoxyphenyl) propionyl]perhydroisoindol-4-ol is obtained in the form of a thick white foam.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13](Cl)=[O:14])[CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C(C)=CC=CC=1>C(Cl)(Cl)Cl.[Pd]>[CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([CH:13]=[O:14])[CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)Cl)cccc2c1=O
Agent: [Pd]
Solvent: Cc1ccccc1C
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2)oc2c(C=O)cccc2c1=O

Procedure:
A mixture of 59.74 g of 3-methyl-8-chlorocarbonylflavone (obtained from 3-methylflavon-8-carboxylic acid and thionyl chloride, white crystals, m.p. 156°-156.5° C.), 200 ml of xylene, 6 g of 5% palladium on barium sulfate and 0.4 ml of quinoline-S, maintained under stirring and under hydrogen flow, was heated for 6-7 hours at 85°-90° C. Upon completion of the reaction, the mixture was cooled, diluted with chloroform (20 ml), filtered, the solvent was evaporated under vacuum, and 260 ml of 20% sodium hydrogensulfite (W/V) and 600 ml of water were added to the residue. The mixture thus obtained was heated at reflux for 2 hours and then filtered while hot. The cooled filtrate was extracted several times with ethyl ether (4×200 ml), concentrated hydrogen chloride added and then heated to 95°-100° C. for 2 hours. After cooling, the solid thus formed was filtered and washed with water. The product (II) was obtained in a global yield equal to 78% of theoretical (41.46 g) and could be used as such in further syntheses. After recrystallization from methyl-tert-butyl-ether, it melted at 124°-126° C.
Reaction SMILES: [O-:1][Si:2]([O-:4])=[O:3].[Na+:5].[Na+].[OH-:7].[Na+]>>[Si:2]([O:7][Si:2]([O-:4])([O-:3])[O-:1])([O-:4])([O-:1])[O-:3].[Na+:5].[Na+:5].[Na+:5].[Na+:5].[Na+:5].[Na+:5]
Reactant: O=[Si]([O-])[O-]
Reactant: [OH-]
Agent: [Na+]
Product: [O-][Si]([O-])([O-])O[Si]([O-])([O-])[O-]

Procedure:
400 g of a commercially available water glass solution having an SiO2 :Na2O ratio of 2:1 and a solids content of 45% by weight, prepared by hydrothermal digestion of sand with sodium hydroxide solution, were dehydrated in a laboratory hot-air spray tower (inlet temperature 220° C., outlet gas temperature 120° C.) to give an amorphous sodium disilicate having an ignition loss of 16.8% by weight at 620° C. 8 g of the amorphous sodium disilicate were then heat-treated for 1 h in a muffle furnace at 620° C. and then rapidly cooled. The X-ray reflections (position and intensity) required for the phase calculation are given in Table 1. According to the above formulae, the percentage distribution among the crystalline phases is:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:4][C:3]1=[O:14].O=C1N(C(OCC2C=CC=CC=2)=O)[C@H:19](C(O)=O)[CH2:18]N1.ICC.[H-].[Na+]>CN(C)C=O>[CH2:18]([N:4]1[CH:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:6][N:2]([CH3:1])[C:3]1=[O:14])[CH3:19]
Reactant: O=C(O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Reactant: CN1CC(C(=O)OC(C)(C)C)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN1C(=O)N(C)CC1C(=O)OC(C)(C)C
Temperature: -10 °C
Yield: 76 %

Procedure:
A stirred solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (0.501 g, 2.5 mmol) (prepared as described in step (i) of Example 49 from 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate, itself prepared as described in step (ii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in N,N-dimethylformamide (10 ml) was cooled to −10° C. under argon and treated with iodoethane (0.404 ml, 5.00 mmol). Sodium hydride (60% dispersion in oil) (0.100 g, 2.500 mmol) was added portion wise. The mixture was allowed stirred warm to room temperature over 3 hours. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (20 ml) and brine (10 ml). The aqueous layer was re-extracted with ethyl acetate (20 ml) and the organic extracts were combined, washed with saturated sodium hydrogen carbonate solution (20 ml), water (2×20 ml) and brine (20 ml), dried and evaporated. The residue was purified by silica gel chromatography eluting with 25-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-ethyl-1-methyl-2-oxo-4-imidazolidinecarboxylate (433 mg, 76%). LC/MS [M+H]+=229. (ii) A solution of 1,1-dimethylethyl 3-ethyl-1-methyl-2-oxo-4-imidazolidinecarboxylate (433 mg, 1.897 mmol) in TFA/DCM (1:2, 6 ml) was stirred at room temperature for 18 hours. The solution was evaporated and the residue was co-evaporated with dichloromethane and dried to give crude 3-ethyl-1-methyl-2-oxo-4-imidazolidinecarboxylic acid, (assume ˜1.9 mmol). LC/MS [M+H]+=173.