Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][N:39]([CH3:45])[CH:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[CH3:38][N:39]([CH3:45])[CH:40]1[CH2:44][CH2:43][N:42]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CN(C)C1CCNC1
Product: CN(C)C1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)C1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and dimethyl-pyrrolidin-3-yl-amine according to conditions described in general procedure C. Mp: 108-110° C.; 1H NMR (400 MHz, CDCl3) δ 1.61-1.77 (m, 6 H), 1.80-2.2.15 (m, 2 H), 2.17-2.27 (m, 6 H), 2.72 (bs, 1 H), 3.20-3.91 (m, 4 H), 3.25-3.27 (m, 4 H), 5.82-5.84 (bd, 1 H), 6.73-6.77 (m, 1 H), 6.97 (d, J=8.0 Hz, 1 H), 7.29-7.34 (m, 2 H), 7.46-7.64 (m, 2 H), 7.88-8.00 (m, 3 H), 8.13-8.20 (m, 2 H), 8.22 (d, J=5.5 Hz, 1 H).
Reaction SMILES: C[OH:2].[CH3:3][C:4]1[O:8][C:7]([CH2:9][CH:10]([OH:12])[CH3:11])=[CH:6][CH:5]=1.ClCl>O>[CH3:11][C:10]1[O:12][C:5]([CH2:4][CH3:3])=[C:6]([OH:2])[C:7](=[O:8])[CH:9]=1
Reactant: Cc1ccc(CC(C)O)o1
Reactant: CO
Agent: ClCl
Solvent: O
Product: CCc1oc(C)cc(=O)c1O
Temperature: -15 °C
Yield: 30 %

Procedure:
In a three necked round bottom flask were combined 28 ml of methanol and 38 ml of water. The solution was cooled to -15° C. and 0.166 mole of 5-methyl-2-(2-hydroxy-propyl)furan (J. Org. Chem., 26, 1673, 1960) and 0.416 mole of chlorine were added simultaneously. During the addition, the reaction was maintained between -16° and -8° C. When addition was completed, the solution was warmed to 80° C. and refluxed for about 3 hours. Upon cooling to room temperature, the pH was adjusted to 2.1 and extracted with chloroform (3×100 ml). The combined organic layers were washed with water, brine and dried over magnesium sulfate. The organic solution was filtered and evaporated to give a thick dark solid. The solid was recrystallized twice from methanol to give 8.06 grams (30% yield) of white solid. Sublimation yielded pure product, m.p. 157°-159° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(N(CC)CC)C.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH3:18][S@:10](=[O:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N:9][C:7](=[O:8])[C:6]1[CH:19]=[C:2]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH:3]=[N:4][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a degassed solution of 10.0 mL DMF at room temperature was added (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (1.02 g, 3.0 mmol), triethylamine (1.3 mL, 9.0 mmol), trimethylsilylacetylene (0.83 mL, 6.0 mmol), and dichlorobis(triphenylphosphine)palladium(II) (211 mg, 0.3 mmol). After 15 minutes added copper(I) iodide (29 mg, 0.15 mmol) and continued reaction for 4 hours. The reaction was then partitioned between EtOAc and H2O. The EtOAc layer was washed with saturated NaHCO3, brine, dried with anhydrous Na2SO4 and rotary evaporated to 20 ml volume. The solution was placed overnight in the refrigerator and the resulting solid filtered and rinsed with 40% EtOAc/hexane to give the title compound (674 mg) as a tan solid. The filtrate was evaporated and purified by chromatography (silica gel, eluting with hexane/EtOAc) to give an additional 301 mg of the title compound. The product lots were combined and purified by chromatography (silica gel, eluting with hexane/EtOAc) to give the title compound as a tan solid (959 mg, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([O:52][CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2].Cl>CO>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OCOC(=O)C(C)(C)C)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: CCOc1nc2cccc(C(=O)OCOC(=O)C(C)(C)C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To 2.0 g of pivaloyloxymethyl 2-ethoxy-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methylbenzimidazole-7-carboxylate were added 30 mL of methanol and 6 mL of 1N-hydrochloric acid and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure and extracted using ethyl acetate and water. The organic layer was separated and concentrated under reduced pressure to give an oil. This oil was purified by silica gel chromatography (100 mL, methylene chloride-methanol=10:1) to provide 1.13 g of pivaloyloxymethyl 2-ethoxy-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylbenzimidazole-7-carboxylate (yield 80%).
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:24])[CH2:7][N:8]([CH:21]1[CH2:23][CH2:22]1)[S:9]([C:12]1[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=1[Cl:20])(=[O:11])=[O:10])C>O.C1COCC1>[CH:21]1([N:8]([CH2:7][C:6]([OH:24])=[O:5])[S:9]([C:12]2[C:13]([Cl:20])=[CH:14][C:15]([Cl:19])=[CH:16][C:17]=2[Cl:18])(=[O:11])=[O:10])[CH2:22][CH2:23]1
Reactant: CCOC(=O)CN(C1CC1)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN(C1CC1)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl

Procedure:
A soln. of lithium hydroxide (298 mg, 12.5 mmol) in water (15 ml) was added to a soln. of [cyclopropyl-(2,4,6-trichlorobenzenesulfonyl)-amino]-acetic acid ethyl ester (2.91 g, 7.5 mmol) in THF (25 ml) and the mixture was stirred at RT for approx. 18 h. The mixture was concentrated i. vac. and water was added to the residue. The alkaline residue was extracted with MC (2×50 ml). The aqueous phase was adjusted to pH 1-2 with conc. hydrochloric acid and extracted with EtOAc (3×30 ml). These combined organic phases were dried with Na2SO4 and concentrated i. vac. Toluene was repeatedly added to the residue and the mixture concentrated i. vac. Yield: 1.77 g (65%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)=[O:5])[CH3:2].[CH3:24][O:25][C:26]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:27]=1[NH2:28]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[NH:28][C:27]1[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:26]=1[O:25][CH3:24])=[O:5])[CH3:2]
Reactant: COc1ccc(C)cc1N
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1cc(C)ccc1OC)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 but using intermediate B and 2-methoxy-5-methylaniline. After completion, the reaction mixture was extracted with HCl and washed with a saturated NaHCO3 solution. The organic was dried (Na2SO4), filtered and concentrated. The product was used without further purification. tR: 1.40 min (LC-MS 2); ESI-MS: 520.1/522.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:24])[S:12][C:13]=2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([F:35])[CH:34]=1)[C:29](Cl)=[O:30]>>[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([F:35])[CH:34]=1)[C:29]([NH:24][C:11]1[S:12][C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)=[O:30]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccc([N+](=O)[O-])cc2)cc1
Product: COc1ccc(-c2nc(NC(=O)c3cc(F)cc(F)c3)sc2Cc2ccc([N+](=O)[O-])cc2)cc1
Yield: 66.7 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-methoxy-phenyl)-5-(4-nitro-benzyl)-thiazol-2-ylamine prepared in Example 6 and 3,5-difluorobenzoyl chloride prepared in the step 1 of Example 16 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (20:1-10:1) to obtain a product as a white solid in a yield of 66.7%, mp: 189-190└. 1H-NMR (CDCl3, 400 MHz) δ: 3.76 (3H, s, OCH3), 4.34 (2H, s, CH2), 6.72 (2H, d, J=8.68 Hz, ArH), 6.85 (1H, t, 3JFH=8.40 Hz, ArH), 7.18 (2H, d, 3JFH=5.32 Hz, ArH), 7.25 (2H, d, J=8.68 Hz, ArH), 7.40 (2H, d, J=8.40 Hz, ArH), 8.21 (2H, d, J=8.40 Hz, ArH), 12.05 (1H, br, CONH); EI-MS m/e (%): 481.1 (M+, 100), 141.0 (63); HREI-MS Calcd. for C24H17F2N3O4S: 481.0908. found: 481.0902. Anal. Calcd. for C24H17F2N3O4S: C, 59.87; H, 3.56; N, 8.73. found: C, 59.98; H, 3.80; N, 8.67.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH:34]([NH:37]O)([CH3:36])[CH3:35].O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][NH:37][CH:34]([CH3:36])[CH3:35])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: CC(C)NO
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 46.5 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]-benzazepine-4,10(1H,9H)-dione (300 mg, 1.03 mmol) (compound of Example 9) and 1,1′-carbonyldiimidazole (251 mg, 1.55 mmol) in N,N-dimethylformamide (12 mL) was stirred for 1 hour. In one portion N-isopropylhydroxylamine hydrochloride (345 mg, 3.09 mmol) was added and the solution was stirred for 55 minutes at room temperature. To the resulting solution was added water (40 mL) giving a precipitate which was separated by filtration. This Crude product was purified by flash chromatography eluting with chloroform:2-propanol (98:2-96.5:3.5) to give the title compound (167 mg, 47% yield, m.p. 224° C.).
Reaction SMILES: Cl.[C:2](SCC1C=CC=CC=1)(=[NH:4])[CH3:3].[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]2[CH2:24][S:23][C:22]([NH2:25])=[N:21]2)[CH:17]=[CH:18][CH:19]=1.C(SCC1C=CC=CC=1)(=N)C>C(O)C.O>[NH2:25][C:22]1[S:23][CH2:24][CH:20]([C:16]2[CH:15]=[C:14]([NH:13][C:2](=[NH:4])[CH3:3])[CH:19]=[CH:18][CH:17]=2)[N:21]=1
Reactant: CC(=N)SCc1ccccc1
Reactant: NC1=NC(c2cccc(N)c2)CS1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=N)Nc1cccc(C2CSC(N)=N2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
0.15 g of benzyl ethanimidothioate hydrochloride and then 5 cm3 of ethanol are added, under an inert atmosphere and at a temperature in the region of 0° C., to a stirred solution of 0.14 g of 4-(3-aminophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine in 15 cm3 of ethanol. The mixture is stirred for 1 hour at about 0° C. and then for 2 hours at a temperature in the region of 20° C. A further 0.030 g of benzyl ethanimidothioate is added to complete the reaction, after which the mixture is maintained at a temperature in the region of 45° C. for 24 hours. The reaction medium is evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is taken up in 30 cm3 of water and the solution is washed with 30 cm3 of dichloromethane. The aqueous solution is concentrated under the above conditions and the solid obtained is then triturated from diethyl ether, filtered, air-dried and purified by chromatography at atmospheric pressure on a column of silica gel (particle size 40-63μ; mass 63 g), eluting with a dichloromethane/methanol/aqueous ammonia mixture (12/3/0.5 by volume). The fractions containing the expected product are collected. These fractions are combined and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.100 g of [3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl]-(1-iminoethyl)amine is obtained in the form of a white solid melting at 180° C. 1H NMR spectrum (250 MHz, (CD3)2SO-d6, with addition of a few drops of CD3COOD-d4, δ in ppm): 2.28 (unres. mult.: 3H); 3.18 (dd, J=12.5 and 8.5 Hz: 1H); 3.80 (dd, J=12.5 and 8.5 Hz: 1H); 5.30 (t, J=8.5 Hz: 1H); 7.21 (broad d, J=8.5 Hz: 1H); 7.27 (broad s 1H); 7.36 (broad d, J=8.5 Hz: 1H); 7.49 (broad t, J=8.5:Hz: 1H).
Reaction SMILES: [NH:1]1[C:5]2(CCCCC2)[CH:4]=CS1(=O)=O.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22](=[O:33])(=[O:32])[NH:23][C:24]3([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:25]=2[CH3:26])=[CH:17][CH:16]=1.C(N)C>C(O)C>[CH2:5]([NH:1][CH2:26][C:25]1[C:24]2([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[NH:23][S:22](=[O:33])(=[O:32])[C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=1)[CH3:4]
Reactant: O=S1(=O)C=CC2(CCCCC2)N1
Reactant: CC1=C(c2ccc(CBr)cc2)S(=O)(=O)NC12CCCCC2
Agent: CCN
Solvent: CCO
Product: CCNCC1=C(c2ccc(C)cc2)S(=O)(=O)NC12CCCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Ethylaminomethyl-3-(4-methylphenyl)-2-thia-1-azaspiro[4.5]dec-3-ene 2,2-dioxide, shown below, was prepared according to the methods described in Examples 1 and 2. Bromination with N-bromosuccinimide afforded a mixture of 4-bromomethyl-3-4-methylphenyl)-2-thia-1-azaspiro[4.5]dec-3-ene 2,2-dioxide and 3-(4-bromomethyl-phenyl)-4-methyl-2-thia-1-azaspiro[4.5]dec-3-ene 2,2-dioxide. The raw mixture (400 mg) was dissolved in ethanol (10 mL) and ethylamine (70% in water, 5 mL) was added. The solution was stirred overnight at room temperature, concentrated and the residue was dissolved in CH2Cl2, washed with water and extracted with 0.5 M HCl. After addition of NaOH and extraction with CH2Cl2 the organic layer was dried (Na2SO4) and evaporated. The two products were separated by column chromatography (CH2Cl2/acetone 9:1) and the title compound compound [4-Ethylaminomethyl-3-(4-methylphenyl)-2-thia-1-azaspiro[4.5]dec-3-ene 2,2-dioxide] was isolated as white crystals. Yield: 80 mg, 24%; MS (IS): 334 [MH]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:34][C:35]([F:46])([F:45])[C:36]([NH:38][C:39]1[CH:43]=[CH:42][S:41][C:40]=1[I:44])=[O:37].[C:47]([O:51][C:52]([N:54]1[CH2:59][CH:58]=[C:57]([CH2:60]O)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48]>O1CCCC1>[C:47]([O:51][C:52]([N:54]1[CH2:55][CH:56]=[C:57]([CH2:60][N:38]([C:39]2[CH:43]=[CH:42][S:41][C:40]=2[I:44])[C:36](=[O:37])[C:35]([F:34])([F:45])[F:46])[CH2:58][CH2:59]1)=[O:53])([CH3:50])([CH3:48])[CH3:49]
Reactant: O=C(Nc1ccsc1I)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(CO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(CN(C(=O)C(F)(F)F)c2ccsc2I)CC1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 62.9 %

Procedure:
Triphenylphosphine (2.29 g) was dissolved in tetrahydrofuran (50 ml) and the solution was cooled to −10° C. under argon. Diisopropylazodicarboxylate (1.70 ml) was added dropwise over 10 min and the resulting mixture was stirred at −10° C. for 20 min (formation of a white precipitate). 2,2,2-Trifluoro-N-(2-iodo-thiophen-3-yl)-acetamide (2.25 g) dissolved in a minimum volume of tetrahydrofuran was added, followed by 4-Hydroxymethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (J. Org. Chem. 2001, 66, 5545-5551, 1.49 g) dissolved in a minimum volume of tetrahydrofuran. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The solution was then concentrated in vacuo and the residue subjected to silica gel chromatography (cyclohexane:ethyl acetate 93:7) to afford 4-{[(2-Iodo-thiophen-3-yl)-(2,2,2-trifluoro-acetyl)-amino]-methyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a colourless oil (2.27 g). 1H NMR (400 MHz, CDCl3) 1.5 (s, 9H), 2.15 (m, 2H), 3.43 (m, 1H), 3.52 (m 1H), 3.75 (d, J=19 Hz, 1H), 3.77 (m, 2H), 4.76 (d, J=17 Hz, 1H), 5.41 (s, 1H), 6.68 (br d, J=5.5 Hz, 1H), 7.42 (d, J=5.5 Hz, 1H); MS (ES+) 417 (M+H+—CO2-isobutene), 458 (M+H+-isobutene).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH2:20]([N:23]=[C:24]=[S:25])[CH:21]=[CH2:22].Cl>O>[CH2:20]([N:23]1[C:10](=[O:12])[CH:2]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:1][C:24]1=[S:25])[CH:21]=[CH2:22]
Reactant: C=CCN=C=S
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCN1C(=O)C(Cc2ccccc2)NC1=S
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A flask equipped with a magnetic stirrer was charged with phenylalanine (15.8 g, 0.100 mol), triethylamine (11.1 g, 0.11 mol) pyridine (100 mL), and water (50 mL). Allyl isothiocyanate (10.4 g, 0.11 mol) was added to the flask, and the mixture was kept at 40-450 for 4 hr. the mixture was cooled to room temperature and was then extracted with 3×200 mL of toluene. The aqueous phase was mixed with concentrated hydrochloric acid (16 mL, 0.19 mol) and boiled gently for 45 min. The reaction mixture was stirred rapidly as it cooled to room temperature. It was further cooled in an ice-water bath for 20 min, and the solid that had formed was collected and washed with water.
Reaction SMILES: Cl.C(O[C:7]([N:9](C)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=O)(C)(C)C>O1CCOCC1>[CH3:7][NH:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)CCOCCOCCOCCOCCN(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCCOCCOCCOCCOCCC(=O)OC
Reaction time: 12 h
Yield: 92.9 %

Procedure:
3 ml of a 4M solution of HCl in dioxane are added to 390 mg of methyl 3-[2-(2-{2-[2-((tert-butoxycarbonyl)(methyl)amino)ethoxy]ethoxy}ethoxy)ethoxy]propanoate in solution in 5.3 ml of dioxane. After 12 h at AT, the mixture is concentrated under RP and the residue is dissolved in a minimum of methanol and deposited on Mega BE-SCX, 10GM 60ML (Varian). After washing the phase with MeOH, the product of interest is eluted with a 2N solution of ammonia in methanol. The methanol/NH3 phase is concentrated under RP. 270 mg of methyl 3-(2-{2-[2-(2-(methylamino)ethoxy)ethoxy]ethoxy}ethoxy)propanoate are thus obtained. 1H NMR (400 MHz, d5-DMSO): 2.28 (s, 3H); 2.54 (t, J=6.2 Hz, 2H); 2.59 (t, J=5.9 Hz, 2H); 3.44 (t, J=5.9 Hz, 2H); 3.47 to 3.54 (m, 12H); 3.60 (s, 3H); 3.63 (t, J=6.2 Hz, 2H). LC/MS (A) (ELSD): rt=0.30 min; [M+H]+: m/z 294.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.Cl.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1([CH3:31])[CH3:30])(=[O:23])=[O:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:27]3[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:22])=[O:23])[C:25]([CH3:31])([CH3:30])[CH2:26]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC1(C)CNCCN1S(C)(=O)=O
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl
Product: CC1(C)CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN1S(C)(=O)=O

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-methanesulfonyl-2,2-dimethyl-piperazine hydrochloride salt using procedure C yielded 2-chloro-6-(4-methanesulfonyl-3,3-dimethyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to procedure A to yield the desired final compound which was purified using flash chromatography.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:7][CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9]([O:11]CC)=[O:10])C.[OH-].[Na+].Cl>C1COCC1>[CH2:18]([CH:5]([CH:6]=[CH:7][CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9]([OH:11])=[O:10])[C:4]([OH:22])=[O:3])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(C=CC(CCCC)C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCC(C=CC(CCCC)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
To a stirred solution of 435 mg (1.39 mmol) mixture of (E)-(2R,5S)- and -(2RS,5SR)-2,5-dibutyl-hex-3-enedioic acid diethyl ester in 10 ml THF was added 26 ml (26 mmol) of 1 M sodium hydroxide solution. After stirring for 72 h at room temperature, the reaction mixture was acidified to pH 3 by addition of 1 M hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were washed successively with water and with saturated brine, dried over sodium sulphate, and concentrated in vacuo to afford 346 mg (97%) of the title compound as a white crystalline solid. MS m/e (%): 255 ([M−H]−, 60), 211 ([M−H—CO2]−, 100).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)[CH2:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CO.O=[Pt]=O>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9](=[O:23])[CH2:10]2)=[N:15][CH:16]=1
Reactant: O=C1CN(c2ccc([N+](=O)[O-])cn2)CCN1Cc1ccccc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCN(Cc3ccccc3)C(=O)C2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
The 1-benzyl-4-(5-nitropyridin-2-yl)piperazin-2-one (B-14) (195 mg, 0.63 mmol) was stirred in EtOAc (30 mL) and MeOH (15 mL). The mixture was treated with PtO2 (72 mg) and stirred at RT under 1 atm of H2 for 1 h 10 min. Then, the reaction mixture was filtered over a pad of celite and concentrated to yield 4-(5-aminopyridin-2-yl)-1-benzyl-piperazin-2-one (B-15) (176 mg, 100% yield). MS (M+1): 283.2
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2([C:14]#N)[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C1C=CC(C2(C=[O:32])CCCC2)=CC=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2([CH:14]=[O:32])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reactant: N#CC1(c2cccc(C(F)(F)F)c2)CCCC1
Product: O=CC1(c2cccc(C(F)(F)F)c2)CCCC1

Procedure:
1-(3-(Trifluoromethyl)phenyl)cyclopentanecarbaldehyde (469) was synthesized from 1-(3-(trifluoromethyl)phenyl)cyclopentanecarbonitrile (468) following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbaldehyde (238).
Reaction SMILES: [Br:1][C:2]1[C:10]([Br:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].Br[CH2:27][C:28]#[C:29][Si:30]([CH3:33])([CH3:32])[CH3:31]>>[Br:1][C:2]1[C:10]([Br:11])=[C:9]2[C:5]([CH2:6][C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([CH2:27][C:28]#[C:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: C[Si](C)(C)C#CCBr
Reactant: CCOC(=O)COc1cc2c(c(Br)c1Br)C(=O)C(c1ccccc1)C2
Product: CCOC(=O)COc1cc2c(c(Br)c1Br)C(=O)C(CC#C[Si](C)(C)C)(c1ccccc1)C2

Procedure:
Reaction of ethyl (6,7-dibromo-1-oxo-2-phenyl-5-indanyloxy)acetate with 1-bromo-3-(trimethylsilyl)-2propyne according to the procedure of Example 1, STEP (b), affords the title compound.