Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:5][Si:4]([Cl:7])(Cl)[CH2:3][CH2:2]1.NC(N)=O.[C:12]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[CH2:13][OH:14]>C1COCC1>[Cl:7][Si:4]1([O:14][CH2:13][C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:5][CH2:1][CH2:2][CH2:3]1
Reactant: O=C(CO)OCc1ccccc1
Reactant: Cl[Si]1(Cl)CCCC1
Agent: NC(N)=O
Solvent: C1CCOC1
Product: O=C(CO[Si]1(Cl)CCCC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of cyclotetramethylenedichlorosilane (0.5 mL; 3.82 mMol) in dry THF (5 mL) was added urea (0.275 g; 4.58 mmol). The mixture was then cooled to 0° C. and benzyl glycolate (0.54 mL; 3.82 mmol) was then added dropwise over a 7 minute span. The mixture was then taken off the ice bath and allowed to stir at room temperature for 1 hour. The biphasic mixture was then concentrated under high vacuum and diluted with chloroform. The aqueous layer was then soaked up with excess Na2SO4 and the mixture was filtered. The filtrate was concentrated to a light yellow crude liquid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][NH:10][S:9]2(=[O:15])=[O:14])=[CH:5][CH:4]=1.[I:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[I:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:10]1[S:9](=[O:15])(=[O:14])[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=2)[C:12](=[O:13])[CH2:11]1
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)cc1
Reactant: OCc1cccc(I)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(Cc3cccc(I)c3)S2(=O)=O)cc1
Temperature: 25 °C

Procedure:
A solution of the title B compound, 2-(4-methoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (1.02 g, 3.98 mmol), 3-iodo-benzyl alcohol (1.01 mL, 7.95 mmol) and triphenylphosphine (2.10 g, 8.0 mmol) in THF (50 mL) is cooled to 5° C. and treated with a solution of diethyl azodicarboxylate (1.26 mL, 8.0 mmol) in THF (10 mL). The reaction is allowed to warm to RT over 16 h. The reaction mixture is concentrated to yield a yellow oil. This is chromatographed on a 110 g silica gel RediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 0:100 (EtOAc:CH2Cl2) to 5:95 over 25 min. Fractions containing product are combined and concentrated to yield an oil, which spontaneously crystalizes. Trituration with Et2O yields 5-(3-iodo-benzyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a white solid: mp=98-100° C.
Reaction SMILES: [OH:1][CH:2]([CH:5]1[C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH:6]1[O:22][Si](C(C)(C)C)(C)C)[CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C.Cl>[OH:1][CH:2]([CH:5]1[C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH:6]1[OH:22])[CH2:3][CH3:4]
Reactant: CCC(O)C1C(O[Si](C)(C)C(C)(C)C)CCC12CCN(C(=O)OC(C)(C)C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(O)C1C(O)CCC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 1-(1-hydroxyprop-1-yl)-2-(tert-butyldimethylsilyloxy)-8-azaspiro[4.5]decane-8-carboxylate (0.248 g, 0.58 mmol) in THF (15 mL) was added 1M tetrabutylammonium fluoride in THF (2.3 mL, 2.3 mmol). The solution was stirred at room temperature for 4 h and was then diluted with ethyl acetate, poured into IN HCl, and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with 50% ethyl acetate in hexanes to afford the title compound (0.18 g) as a mixture of isomers.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@H:15]([N:21]3[CH2:25][C:24]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])=[CH:23][C:22]3=[O:34])[CH2:16][CH:17]([CH3:20])[CH2:18][CH3:19])=[N:9]2)[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@H:15]([N:21]2[CH2:25][C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])=[CH:23][C:22]2=[O:34])[CH2:16][CH:17]([CH3:20])[CH2:18][CH3:19])=[N:9]1
Reactant: CCC(C)C[C@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cl
Solvent: C1CCOC1
Product: CCC(C)C[C@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
A solution of (R)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (prepared in Example 252, 600 mg, 1.16 mmol) in tetrahydrofuran (25 mL) was treated with 2N aqueous hydrochloric acid (12 mL) and stirred at room temperature for 2 h. At this time the mixture was concentrated in vacuo and the residue partitioned between 17% ethyl acetate/hexanes and water. The layers were separated and the organic layer was washed with brine and dried with sodium sulfate. The mixture was filtered and concentrated in vacuo which afforded (R)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (500 mg, 90.4%) as a fluffy powder: HR-ES-MS (m/z) calculated for C23H29ClN4O5 [M+H]+ 477.1899, observed 477.1896. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86 (br. s., 3H), 1.29 (br. s., 6H), 1.78 (br. s., 2H), 3.14-3.58 (m, 4H), 3.70-3.93 (m, 2H), 4.09 (dd, J=13.4, 2.6 Hz, 1H), 4.21 (d, J=18.4 Hz, 1H), 4.58 (d, J=18.4 Hz, 1H), 4.69-4.79 (m, 1H), 4.79 (s, 1H), 6.41 (br. s., 1H), 7.37 (t, J=7.2 Hz, 1H), 7.41-7.58 (m, 3H), 7.65 (d, J=7.8 Hz, 1H), 10.70 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:34]([O:40][CH2:41]I)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36].C(OCC)(=O)C>CN(C)C(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH2:41][O:40][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:25]=[N:24][CH:23]=[N:22][CH:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C\c4cncnc4)CS[C@H]23)cs1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCOC(=O)C1=C(/C=C\c2cncnc2)CS[C@@H]2[C@H](NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12

Procedure:
The compound (100 mg) of Example 16 was dissolved in N,N-dimethylacetamide (2 ml), followed by the addition of pivaloyloxymethyl iodide (50 mg). They were reacted for 1 hour. Ethyl acetate (50 ml) was added. The resulting mixture was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. Ether was added to the residue and the resulting solid was collected by filtration, whereby the title compound (80 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.S(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Product: OCCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
After a mixture of 3-(4-chlorophenyl)propionic acid (5.00 g, 27.0 mmol) and thionyl chloride (3 ml) was refluxed for 2 hours, an excess of the thionyl chloride was distilled away under reduced pressure. The resultant residues were dissolved in tetrahydrofuran (200 ml), dropped slowly to a suspension of LiAlH4 in tetrahydrofuran at 0° C. and stirred at room temperature for 1 hour. Water and 1 N aqueous sodium hydroxide were added to the reaction mixture, and after insolubles were filtered off, the filtrate was dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, whereby 4.6 g 3-(4-chlorophenyl)propyl alcohol was obtained as oily matter.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.[Cl:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([S:21](Cl)(=[O:23])=[O:22])=[CH:16]2.C(N(C(C)C)CC)(C)C.ClC1C=CC=C2C=1C=CC=C2S(Cl)(=O)=O>C(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([S:21]([N:3]1[CH2:4][CH:5]3[CH2:8][CH2:9][CH:1]([CH2:7][CH2:6]3)[CH2:2]1)(=[O:22])=[O:23])=[CH:16]2
Reactant: C1CC2CCC1CNC2
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cccc2c1
Agent: O=S(=O)(Cl)c1cccc2c(Cl)cccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1ccc2c(Cl)cccc2c1)N1CC2CCC(CC2)C1
Reaction time: 8 h

Procedure:
The title compound was prepared from the coupling of 3-azabicyclo[3.2.2]nonane and 5-chloro-2-naphthalenesulfonyl chloride. 3-Azabicyclo[3.2.2]nonane (0.31 g, 2.5 mmol) and diisopropyl ethyl amine (1.0 ml, 5.7 mmol) were dissolved in 10 ml chloroform. 5-Chloro-1-naphthalenesulfonyl chloride (0.50 g. 1.9 mmol) in 20 ml chloroform was added dropwise to the solution. After stirring overnight, the solution was washed with saturated sodium bicarbonate solution and brine. Drying over magnesium sulfate and evaporation followed by recrystallization with isopropyl ether/methanol gave 0.50 g (76% yield) of a yellow solid: mp 138°-139° C.; 1H NMR (CDCl3): 8.39 (d, J=8.9, 1 H, H3), 8.33 (d, J=1.7, 1 H, H1), 7.91-7.84 (m, 2 H, H4 and H6), 7.72 (d, J=7.5, 1 H, H8), 7.52 (t, J=7.9, 1 H, H7), 3.31 (d, J=4.2, 4 H, N (CH2R)2), 2.09 (s, 2 H, N(CH2CHR)2), 1.75-1.61 (m, 8 H, alkyl H's); anal calcd for C18H20 2 NO2SCl; C, 61.79; H, 5.76; N, 4.00; found: C, 61.89; H, 5.80; N. 4.08.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])[NH:6][C:7]=1[CH3:8].Br[C:19]1[N:23]([CH3:24])[N:22]=[N:21][N:20]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:19]3[N:23]([CH3:24])[N:22]=[N:21][N:20]=3)[CH2:16][CH2:17]2)=[O:10])[NH:6][C:7]=1[CH3:8]
Reactant: Cn1nnnc1Br
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3nnnn3C)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Example 123 by coupling 4-bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 57) with 5-bromo-1-methyl-1H-tetrazole (Can. J. Chem. 1971, 49, 2139).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([O:17][CH3:18])=[O:16])=[N:6][C:7]=1[CH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([O:17][CH3:18])=[O:16])=[N:6][C:7]=1[CH:8]1[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]1
Reactant: COC(=O)c1ccc(F)c(C2CCC(=O)CC2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(F)c(C2CCC(O)CC2)n1
Temperature: 25 °C

Procedure:
To a 0° C. solution of methyl 5-fluoro-6-(4-oxocyclohexyl)picolinate (1.0 equiv.) win MeOH (0.08 M) was added NaBH4. The solution was allowed to warm to room temperature overnight then partitioned between ethyl acetate and brine, the organic phase was dried over magnesium sulfate, filtered, and concentrated to give methyl 5-fluoro-6-(4-hydroxycyclohexyl)picolinate as a mixture of two isomers (5:1). LC/MS=254.2 (M+H), Rt=0.63 min.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[CH3:29][C:30](C)([O-:32])[CH3:31].[Li+].C(C1OC1)Br>CN(C)C(=O)C>[CH2:29]([CH2:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1])[CH:30]1[O:32][CH2:31]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)[O-]
Agent: BrCC1CO1
Agent: [Li+]
Solvent: CC(=O)N(C)C
Product: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CCC1CO1
Temperature: 10 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Cholesterol (5.80 g; 15 mmol; Sigma, St. Louis, Mo.) was dissolved in 76 ml dry N,N-dimethylacetamide (DMAc) under a flow of dry argon. The solution was cooled to 10° C. and 15 ml (15 mmol) of a 1.0M solution of lithium tert-butoxide in hexanes (Sigma) was added. After further cooling to 5° C., 10 ml (117 mmol) of freshly distilled epibromohydrin was added and the mixture was stirred at 3-5° C. for 2 hours. The temperature was allowed to slowly rise to 21-23° C. and the reaction was allowed to continue for another hour. The reaction mixture was then diluted with 500 ml of 0.5% aqueous KHCO3 and extracted with 350 ml n-heptane and then twice more with 100 ml n-heptane. The combined organic layers were dried over Na2SO4. After filtration from the desiccant, the solvent was removed in vacuo. The syrupy residue (7.3 g) was purified by flash-chromatography on silica gel employing elution with hexane, hexane/toluene (1:1 mixture), and toluene. The fractions containing pure glycidyl-cholesterol (thin layer chromatography (TLC)-monitoring) were pooled and dried in vacuo until crystallization occurred. The procedure yielded 4.25 g glycidyl-cholesterol (64%). The product displayed an Rf of 0.38 by TLC (silica gel, n-heptane/ethyl acetate, 85:15 by volume). The signals (only those produced by the glycidyl group not present in the starting cholesterol) obtained by IH NMR analysis of the product are as follows: 2.62 and 2.87 (both m, 1H and 1H, two non-equivalent H of oxirane CH2), 3.15 (m, 1H, CH), and 3.47 and 3.72 (both m, 1H and 1H, diastereotopic H of CH2O).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:47]([O:49][C:50]([C:52]1[C:60]2[N:59]=[C:58]([NH2:61])[NH:57][C:56]=2[CH:55]=[C:54]([S:62]([CH2:65][CH3:66])(=[O:64])=[O:63])[CH:53]=1)=[O:51])[CH3:48]>CN(C=O)C>[CH2:47]([O:49][C:50]([C:52]1[C:60]2[NH:59][C:58]([NH:61][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:57][C:56]=2[CH:55]=[C:54]([S:62]([CH2:65][CH3:66])(=[O:64])=[O:63])[CH:53]=1)=[O:51])[CH3:48]
Reactant: CCOC(=O)c1cc(S(=O)(=O)CC)cc2[nH]c(N)nc12
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(S(=O)(=O)CC)cc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12

Procedure:
0.30 g (1.5 mmol) of isoquinoline-3-carboxylic acid and 800 mg (2.1 mmol) HBTU were dissolved in 3.0 mL of DMF and 0.6 mL of DIEA and treated with 0.28 g (0.94 mmol) of 2-amino-6-ethylsulfonyl-1H-benzoimidazole-4-carboxylic acid ethyl ester as described in general procedure A to produce 6-ethylsulfonyl-2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid ethyl ester. LCMS: 453 (M+1)+.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH:14]([C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]>C1C=CC=CC=1>[CH2:20]([O:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH:14][C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[CH2:21][CH:22]([CH3:23])[CH3:24]
Reactant: CC(C)CCOCCCCC(O)c1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)CCOCCCC=Cc1ccc2c(c1)OCO2

Procedure:
0.07 g (0.37 millimol) of p-toluenesulphonic acid-monohydrate are added to 2.2g (0.0075 mol) of 1-(1-hydroxy-5-isopentyloxy-pentyl)-3,4-methylenedioxybenzene, dissolved in 150 cc of benzene. The solution is rapidly heated to boiling temperature and boiled at reflux over the course of 20 minutes and using a DeanStark-trap. After cooling, the benzene solution is extracted with saturated sodium bicarbonate solution, subsequently with water and saturated sodium chloride solution and dried with sodium sulphate. The solution is evaporated and the residue chromatographed on silica gel with hexane/ethyl acetate (97:3), whereupon the 1-(5-isopentyloxy-1-pentenyl)-3,4-methylenedioxybenzene is obtained as a pure, colourless oil. nD20 = 1.5248
Reaction SMILES: [C:1]1([C@@H:7]([NH2:9])C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CN)CCCCC1.BrCC(N(C)C)=O.Br[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28]>>[CH:1]1([CH2:7][NH:9][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C(CBr)N1CCOCC1
Agent: CN(C)C(=O)CBr
Agent: NCC1CCCCC1
Product: O=C(CNCC1CCCCC1)N1CCOCC1

Procedure:
By following the procedure of section (a) of this example but replacing (S)-1-phenylethylamine with twice the equivalent amount of (cyclohexylmethyl)amine and replacing 2-bromo-N,N-dimethylacetamide with an equivalent amount of 4-(2-bromo-1-oxoethyl)morpholine, 4-{2-[(cyclohexylmethyl)amino]-1-oxoethyl}morpholine [1H NMR(CDCl3) δ 3.76-3.54 (m,3H), 3.43-3.33 (m,4H), 2.45 (d, J=6.6 Hz,2H), 2.41 (broad s,1H), 1.84-0.84 (m, 11H)] was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8](SC)=[N:7][C:6]=2[CH:18]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[Cl:26]([OH:30])(=[O:29])(=[O:28])=[O:27]>C(O)(=O)C.O>[Cl:26]([OH:30])(=[O:29])(=[O:28])=[O:27].[Cl:26]([OH:30])(=[O:29])(=[O:28])=[O:27].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[N:7][C:6]=2[CH:18]=1
Reactant: CSC1=Nc2cc(Cl)ccc2N(C)c2cscc21
Reactant: CN1CCNCC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CN1CCN(C2=Nc3cc(Cl)ccc3N(C)c3cscc32)CC1

Procedure:
A solution of 0.7 g. of 7-chloro-4-methyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in 3.5 ml. of N-methylpiperazine is treated with 1-2 drops of glacial acetic acid and heated under reflux for 4 days. The solution is concentrated to dryness and the residue is warmed with dilute acetic acid. The acidic solution is filtered, cooled and made alkaline with concentrated ammonium hydroxide. The sticky precipitate is collected and dissolved in chloroform. The dried chloroform solution is concentrated under reduced pressure to give an oil. An ethanolic solution of the oil is treated with 70% perchloric acid and is diluted with water. The precipitate is collected and recrystallized from ethanol to give a white solid, m.p. 212°-215° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>C(#N)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(F)cc1
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(F)cc2)cc1
Yield: 102 %

Procedure:
To a solution of 4-fluoroaniline (200.0 g (1.80 mol) in pyridine (155.0 g (1.96 mol)) and acetonitrile (155 ml), under cooling with ice and with stirring, p-toluenesulfonyl chloride (360.3 g (1.89 mol)) was added. After stirring for 20 hours at room temperature, water (1500 ml) was added to the reaction mixture to bring about separation of crystals. The crystals were filtered and washed with water to give 486.6 g (102%) of 4′-fluoro-p-toluenesulfonanilide as pale red crude crystals.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=1>>[CH2:25]([O:24][C:18]1[CH:17]=[C:16]([Cl:15])[CH:21]=[CH:20][C:19]=1[CH2:22][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCOc1cc(Cl)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CCCCOc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-butoxyphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 0.95 (3H, t, J=7.2 Hz), 1.41-1.48 (2H, m), 1.74-1.79 (2H, m), 4.01 (2H, t, J=6.4 Hz), 5.23 (2H, s), 5.77 (1H, d, J=1.6 Hz), 6.90 (1H, d, J=2.0 Hz), 6.95 (1H, dd, J=1.6 Hz, 7.6 Hz), 7.34 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=0.8 Hz, 4.8 Hz), 7.57 (1H, d, J=1.6 Hz), 8.04 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H19ClN4O2, 383; Found, 383.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:13]2[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cncc(Br)c2)cn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
3,5-Dibromopyridine (500 mg, 2.11 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (400 mg, 1.9 mmol), 1,1′bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (172 mg, 0.211 mmol), and potassium phosphate tribasic (1.34 g, 6.33 mmol) were combined in a 20 mL microwave vial and dissolved in dioxane (9 mL) and water (1 mL). The vial was sealed and flushed with argon. The reaction mixture was stirred at 90° C. for 2 hours. The vial was then cooled to ambient temperature and diluted with ethyl acetate. The organic layer was washed with water, brine, and then dried over anhydrous magnesium sulfate. The solution was then filtered and concentrated in vacuo. The crude material was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 8.58 (s, 1H), 8.44 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 3.91 (s, 3H). LRMS (ESI) calc'd for C9H8BrN3 [M+H]+: 238. Found: 238.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>C(NCC)C.[Pd](Cl)Cl.[Cu]I>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[C:34]#[C:33][CH2:32][CH2:31][OH:35]
Reactant: C#CCCO
Reactant: COc1ccc(Br)c(OC)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COc1ccc(C#CCCO)c(OC)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
1-Bromo-2,4-dimethoxybenzene (10 g 0.046 mol), palladium chloride (0.2 g 0.11 mmol) and triphenylphosphine (0.6 g 0.0023 mol) were dissolved in diethylamine (100 mL) under a nitrogen atmosphere. Copper (I) iodide (0.44 g 0.0023 mol) and 3-butyn-1-ol (7 mL 0.092 mol) were added into the reaction mixture at once. The mixture was stirred overnight at 55° C. under a nitrogen atmosphere. The catalyst was filtered off from the reaction mixture and the same amount of palladium chloride, triphenylphosphine, copper (I) iodide and 3-butyn-1-ol were added. The reaction mixture was stirred and heated at 85° C. for 48 hours. Then the solvent was removed at reduced pressure and water (approx. 100 mL) was added to the residue. The mixture was extracted with ethyl acetate (350 mL) passed through a pad of silica gel and concentrated. The product was purified by flash chromatography (silica gel, 1:1 hexanes/ethyl acetate). Compound 75 (4.2 g, 24%) was isolated as a brown oil. 1H NMR (300 MHz, CDCl3) δ 2.24 (t, 1H), 2.73 (t, 2H), 3.80 (br s, 5H), 3.87 (s, 3H), 6.43 (m, 2H), 7.30 (m, 1 H).