Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CC[N:4]([CH:8]([CH3:10])C)[CH:5](C)[CH3:6].C[N:12](C)[C:13]([Cl:15])=[O:14].C(O)(C(F)(F)F)=O.C[N:25](C=O)C>CC#N>[N:25]1[CH:10]=[CH:8][N:4]=[CH:5][C:6]=1[C:13]([NH2:12])=[O:14].[ClH:15]
Reactant: CN(C)C(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C=O
Agent: Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cnccn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The mixture of (R)-tert-butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (87, 240 mg, 0.71 mmol), 4-(1-methylpiperidin-4-yl)aniline (280 mg, 1.42 mmol), fine-powder cesium carbonate (930 mg, 2.84 mmol), Pd(OAc)2 (32 mg, 0.14 mmol), BINAP (88 mg, 0.14 mmol) in 20 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 2 hours. The mixture was cooled to RT, diluted with 100 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 15% MeOH in chloroform to isolate (R)-tert-butyl 1-(5-cyano-6-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate (204) in >90% yield. It was dissolved in 30 mL MeOH and 3 mL DMSO. To it were added two NaOH solid bead (about 200 mg) and then 1 mL 30% H2O2. The mixture was stirred at RT for 2 hours, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was diluted with 120 mL EtOAc, washed with water, concentrated in vacuo to dryness to give crude (R)-tert-butyl 1-(5-carbamoyl-6-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate (205). It was treated with 40 mL commercial 4N HCl in dioxane for 40 min, and concentrated in vacuo to afford crude (R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (206) hydrochloride. Crude 206 hydrochloride (60 mg, 0.12 mmol) was dissolved in 3 mL DMF. To it were added DIEA (210 μL, 1.2 mmol) and dimethylcarbamoyl chloride (34 μL, 0.36 mmol). The mixture was stirred at RT for 1.5 hour, acidified with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-O-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (207) as HCl salt (36 mg). MS found for C25H36N8O2 as (M+H)+ 481.2, (M−H)− 479.3. UV: λ=268, 277, 306, 336, 372 nm.
Reaction SMILES: S(O)(O)(=O)=O.[CH2:6]1[C:15]2[C:10](=[C:11]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1.[CH2:21]1C2C(=C(NS(C)(=O)=O)C=CC=2)CC[NH:22]1.S(=O)(=O)(O)O.Cl.C(N(CC)C(C)C)(C)C.N#CBr>C(#N)C.O>[C:21]([N:7]1[CH2:8][CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:6]1)#[N:22]
Reactant: CS(=O)(=O)Nc1cccc2c1CCNC2
Agent: Cl
Agent: N#CBr
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1cccc2c1CCN(C#N)C2
Temperature: 20 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a stirred slurry of N-(1,2,3,4-tetrahydro-5-isoquinolyl)methanesulfonamide hemisulfate (prepared analogously to the compound of Example 19(b) in WO 98/30560, but using sulphuric acid in the final step in place of hydrochloric acid; 240 g, 0.88 mol) in acetonitrile (2400 ml) at 0° C. was added N,N-diisopropylethylamine (326 ml, 1.88 mmol). Cyanogen bromide (99.2 g, 0.94 mol) was added over a period of 20 minutes keeping the temperature below 10° C. The resulting slurry was allowed to warm to 20° C. and stirred at this temperature for 18 hrs. After this time, water (2400 ml) was added and the resulting mixture extracted with CH2Cl2 (2×2500 ml). The combined organic phases were washed with water (2000 ml) and evaporated to dryness. The resulting solid was reslurried in CH2Cl2 (360 ml) and the solid collected by filtration to yield 158 g (72%) of the title compound.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:25]2[CH:24]=[C:9]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:23])[C:19]([F:21])([F:22])[F:20])[CH:14]=[CH:15][CH:16]=3)[CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: Nc1ccc(Oc2cccc(NC(=O)C(F)(F)F)c2)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3cccc(NC(=O)C(F)(F)F)c3)cc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
To a solution of potassium thiocyanate (17.5 g, 180.0 mmol) in acetic acid (130 mL) was added a solution of N-[3-(4-aminophenoxy)phenyl]-2,2,2-trifluoroacetamide (13.0 g, 43.9 mmol) in acetic acid (20 mL), and the mixture was stirred at room temperature for 15 min. To the obtained solution was added dropwise a solution of bromine (7.71 g, 48.2 mmol) in acetic acid (30 mL) at room temperature over 30 min or longer and, after the completion of the dropwise addition, the mixture was stirred at room temperature for 13 hr. The resulting yellow solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), and basified with 8N aqueous sodium hydroxide solution. The aqueous layer was separated, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (200 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (10.3 g, 66%) as a yellow amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]([CH:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)([CH3:12])[CH3:11].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:14]2[CH:13]([C:10]([F:9])([CH3:12])[CH3:11])[CH2:17][O:16][C:15]2=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(F)C1COC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(F)C1COC(=O)N1c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
To the solution of 2,4-dichloropyrimidine (150 mg, 1.006 mmol) and 4-(2-fluoropropan-2-yl)oxazolidin-2-one (148 mg, 1.01 mmol) in DMF (4.5 mL), sodium hydride (60% wt. 89 mg, 2.21 mmol) was added to give a pale yellow mixture. The mixture was stirred at room temperature for 2 hr, diluted with EtOAc and stirred for additional 30 min. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic phase was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 12 g, EtOAc/heptane=0/100 to 80/20] providing 3-(2-chloropyrimidin-4-yl)-4-(2-fluoropropan-2-yl)oxazolidin-2-one (150 mg) as a brown solid. MS m/z 260.1 (M+H)+; Rt-0.72 min. 1H NMR (400 Mhz, CDCl3) δ ppm 8.51 (d, J=5.9 Hz, 1H), 8.17 (d, J=5.9 Hz, 1H), 5.14 (dd, J=17.4, 8.0 Hz, 1H), 4.66 (d, J=9.4 Hz, 1H), 4.43-4.52 (m, 1H), 1.42-1.52 (m, 3H), 1.30-1.40 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:22]([OH:23])=[CH:21][C:5]2[C:6]([CH3:20])([CH3:19])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([Cl:18])[CH:10]=4.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:43][C:44]1([CH3:51])[O:48][C@H:47]([CH2:49]O)[CH2:46][O:45]1.C1(C)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[Cl:18][C:11]1[CH:10]=[C:9]2[C:14]([C:15]3[C:16](=[O:17])[C:4]4[CH:3]=[C:2]([Br:1])[C:22]([O:23][CH2:49][C@H:47]5[CH2:46][O:45][C:44]([CH3:51])([CH3:43])[O:48]5)=[CH:21][C:5]=4[C:6]([CH3:20])([CH3:19])[C:7]=3[NH:8]2)=[CH:13][CH:12]=1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CC1(C)c2cc(O)c(Br)cc2C(=O)c2c1[nH]c1cc(Cl)ccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](COc2cc3c(cc2Br)C(=O)c2c([nH]c4cc(Cl)ccc24)C3(C)C)O1
Temperature: 40 °C
Reaction time: 12 h
Yield: 68.3 %

Procedure:
Under nitrogen atmosphere, 9-bromo-3-chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S2-4, 112 mg, 0.29 mmol) and triphenylphosphine (227 mg, 3 eq.) were added with THF (2 ml), and ((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (114 mg, 3 eq.) and 2.19 N toluene solution (0.4 mL, 3 eq.) of diethyl azodicarboxylic acid were added dropwise thereto, followed by stirring at 40° C. for 12 hr under nitrogen atmosphere. The residues obtained from the reaction solution after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/dichloromethane) to obtain the title compound (white powder, 100 mg).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:18]([O:19][CH2:20][CH:21]=[CH2:22])[C@H:17]([O:23][C@@H:24]2[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:25]2[NH:34][C:35](=[O:37])[CH3:36])[C@@H:16]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:15][C@@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[O-2].[Ba+2].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].[CH2:60](Br)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C)C=O.C(Cl)(Cl)Cl>[C:1]([NH:4][C@@H:5]1[C@@H:18]([O:19][CH2:20][CH:21]=[CH2:22])[C@H:17]([O:23][C@@H:24]2[O:31][C@H:30]([CH2:32][O:33][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C@@H:28]([O:29][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:26]([O:27][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C@H:25]2[NH:34][C:35](=[O:37])[CH3:36])[C@@H:16]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:15][C@@H:6]1[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: C=CCO[C@@H]1[C@@H](NC(C)=O)[C@@H](OCc2ccccc2)O[C@H](COCc2ccccc2)[C@H]1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Agent: [Ba+2]
Agent: [O-2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: C=CCO[C@@H]1[C@@H](NC(C)=O)[C@@H](OCc2ccccc2)O[C@H](COCc2ccccc2)[C@H]1O[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1NC(C)=O
Reaction time: 24 h

Procedure:
To a solution of benzyl 2-acetamido-4-O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-3-O-allyl-6-O-benzyl-2-deoxy-α-D-glucopyranoside (624 mg, 0.97 mmol) in N,N-dimethylformamide (15 ml) are added barium oxide (670 mg), barium hydroxide octahydrate (223 mg), and benzyl bromide (1.04 ml, 8.74 mmol). The reaction mixture is stirred for 20 hours at room temperature at which time additional barium oxide (335 mg), barium hydroxide octahydrate (112 mg) and benzyl bromide (0.52 ml) are added. Stirring is continued for 24 hours at room temperature. The reaction mixture is then diluted with chloroform (100 ml), washed successively with 60% aqueous acetic acid, saturated sodium bicarbonate, and water, dried (sodium sulfate), and evaporated. The residue is applied to a column of silica gel (90 g) that is eluted with 4:1 chloroform-ethyl acetate. Combination and evaporation of the appropriate fractions affords benzyl 2-acetamido-4-O-(2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-D-glucopyranosyl)-3-O-allyl-6-O-benzyl-2-deoxy-α-D-glucopyranoside as a white solid; yield 612 mg (69%), [α]D25 +58° (c, 1.1, chloroform). The 300 MHz nmr spectrum in chloroform-d is in accord with the desired structure.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.O>C1COCC1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C1COCCN1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In THF (250 ml) was dissolved 4-nitrobenzylbromide (25.0 g), and to the mixture was added morpholine (25.2 ml) at 0° C. The reaction mixture was stirred for 15 hours at room temperature. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give 4-(4-nitrobenzyl)morpholine (25.5 g) as pale yellow crystals. A portion of the crystals was recrystallized from diisopropylether to give pale yellow crystals which were used for various analyses. mp 79-80° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([I:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH2:14][CH2:15]Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:29][CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32]>>[CH2:31]([CH:30]([N:29]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([I:12])[C:6]=3[N:5]=[C:4]([CH3:13])[C:3]=2[CH2:14][CH2:15]1)[CH2:33][CH3:34])[CH3:32]
Reactant: Cc1nc2c(I)cccc2c(Cl)c1CCCl
Reactant: CCC(N)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCC(CC)N1CCc2c(C)nc3c(I)cccc3c21

Procedure:
4-Chloro-3-(2-chloroethyl)-8-iodo-2-methylquinoline (900 mg, 2.46 mmol) was dissolved in 3-aminopentane (10 mL), followed by adding p-toluenesulfonic acid (900 mg). The mixture was sealed at 200° C. for six hours. Water was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over magnesium sulfate, and then evaporated. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (450 mg, 1.18 mmol) as white crystals.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][C@@H:10]([CH3:25])[C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[CH:26]1[CH:31]=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=[O:40])=CC=1.C(=O)([O-])O.[Na+]>O.C(O)CO>[CH2:26]1[CH2:31][O:40][C:12]([C@@H:11]2[C@:15]3([CH3:24])[C@H:8]([C@H:7]4[C@H:18]([C:17](=[O:23])[CH2:16]3)[C@:19]3([CH3:22])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:21][CH2:20]3)[CH2:5][CH2:6]4)[CH2:9][C@H:10]2[CH3:25])([CH3:13])[O:14]1
Reactant: c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@@]21C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: C[C@@H]1C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]2(C)[C@H]1C1(C)OCCO1

Procedure:
A mixture of 3α-hydroxy-16α-methyl-5α-pregnane-11,20-dione (1.00 g), benzene (50 ml), ethylene glycol (5 ml) and toluene-4-sulphonic acid monohydrate (50 mg) was brought to reflux under a Dean and Stark water separator and refluxed for 5 hr, then poured into saturated aqueous sodium hydrogen carbonate (50 ml) and the layers separated. The aqueous portion was extracted with additional benzene (50 ml) and the combined organic portions washed with water (2×50 ml), dried and evaporated to a white foam (1.12 g). A portion of this material (1.00 g) was crystallised from ether-petroleum ether (b.p. 60°-80°) to afford the title compound (581 mg), m.p. 122°-124°, [α]D +37.2°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:17][CH2:18][CH2:19]Br>CN(C=O)C>[Br:17][CH2:18][CH2:19][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCBr)cc1
Reaction time: 8 h
Yield: 84.8 %

Procedure:
1-(4-hydroxyphenyl)ethanone (8.2 g, 60.2 mmol), potassium carbonate (15.2 g, 110.1 mmol), and KI (1.0 g, 6.0 mmol) in 100 DMF was stirred for 5 min, then 1,2-dibromoethane (60 ml, 696.2 mmol) was added. The mixture was stirred overnight, evaporated, diluted with EtAc/Hexane (1:1), washed with 0.1 M HCl/NaCl (conc), dried over MgSO4, filtered, evaporated and purified by SiO2 chromatography eluted with EtAc/Hexane (1:3 to 2:3) to afford 12.41 g (85.2%) of the title compound. 1H NMR (CDCl3) 7.87 (ddd, 2H, J=2.8, 4.9, 9.7 Hz), 6.88 (ddd, 2H, J=2.8, 4.9, 9.6 Hz), 4.29 (t, 2H, J=6.2 Hz), 3.59 (t, 2H, J=6.2 Hz); 13C NMR 196.88, 162.11, 131.15, 130.54, 113.80, 68.06, 29.50, 26.62; MS m/z+264.80 (M+Na), 266.80 (M+2+Na).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4](P(OCC)(OCC)=O)[CH2:5][CH:6]([CH3:8])[CH3:7].[H-].[Na+].[CH:20](=O)[CH:21]([CH3:23])[CH3:22].O>O1CCCC1.CCOCC>[CH3:1][O:2][C:3](=[O:17])[C:4]([CH2:5][CH:6]([CH3:7])[CH3:8])=[CH:20][CH:21]([CH3:23])[CH3:22]
Reactant: CCOP(=O)(OCC)C(CC(C)C)C(=O)OC
Reactant: CC(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(=CC(C)C)CC(C)C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
4-Methyl-2-(diethylphosphono)pentanoic acid methyl ester (28 g, 0.1M) prepared as in Example (1) in dry tetrahydrofuran (200 ml) was stirred under nitrogen whilst sodium hydride (2.2 g, 80% dispersion in oil; 0.11M) was added portion wise at 23° C. The reaction was stirred for 30 minutes and isobutyraldehyde (72 g, 1M) added with cooling to maintain the temperature below 30° C. The reaction was stirred for 16 h at 20° C. and water (20 ml) added. The organic phase was diluted with ether and then washed successively with aqueous sodium hydrogen carbonate, water and aqueous citric acid (1M), dried over sodium sulphate and concentrated in vacuo. Vacuum distillation of the resulting oil afforded E and Z 2-(2-methylpropyl)-4-methyl-pent-2-enoic acid methyl ester (12.5 g) b.p. 60°-70° C. at 0.5 mm Hg as a colourless oil δ(CDCl3) 0.86 and 0.88 (6H, each d, each J=7 Hz CH2CH(CH3)2); 1.0-1.02 (6H, each d, each J=7 Hz, CHCH(CH3)2); 1.6-1.85 (1H, m, CH2CH) 2.1 and 2.2 (2H, each d, each J=7 Hz, CH2) 2.55 and 2.75 (1H, each m, C=CHCH); 3.74 (3H, s, OCH3); 5.58 and 6.59 (1H, each d, each J=9 Hz, C=CH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[H-].[Na+].[CH3:12][O:13][CH2:14][CH2:15]Cl.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:12][O:13][CH2:14][CH3:15])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COCCCl
Reactant: Cc1ccc(O)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCOc1ccc(C)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
12.1 g (65 mmol) of 3-bromo-4-methylphenol are placed in 100 ml of dry dimethylformamide in a round-bottomed flask and under a stream of nitrogen. At 0° C., 3.1 g (78 mmol) of 60% sodium hydride are added slowly. After 1 hour, 7.3 ml (78 mmol) of methoxyethyl chloride are added dropwise. The mixture is stirred at room temperature overnight. It is then poured into water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (85/15) to give 13.2 g (83%) of the expected product in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([I:11])=[CH:9][NH:8][C:6]=2[N:7]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.O>C(Cl)Cl.CN(C1C=CC=CN=1)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=3)(=[O:21])=[O:20])[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(I)c[nH]c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a suspension of 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.80 g, 8.92 mmol) and p-toluenesulfonyl chloride (1.65 g, 8.66 mmol) in CH2Cl2 (30 mL), triethylamine (3.0 mL, 21.6 mmol) and dimethylaminopyridine (0.047 g, 0.38 mmol) were added. The mixture was stirred at room temperature for 2 h. Water and CH2Cl2 were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine as a solid (4.00 g). MS 468.2 and 470.2 (M+H)
Reaction SMILES: C([S:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)C1C=CC=CC=1.Cl.[NH2:20]O.C([O-])(=O)C.O>C(O)C>[CH3:18][O:17][C:16]1[C:9]2[S:8][N:20]=[CH:11][C:10]=2[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(C=O)c1SCc1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cccc2cnsc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5 g of 2-benzylthio-3-methoxybenzaldehyde are dissolved in 40 ml of ethanol, and 3.9 g of hydroxylamine hydrochloride are added. 40 ml of acetate buffer (pH=5) are added to this solution, and the mixture is stirred for 30 minutes at room temperature. The mixture is poured into water and extracted using ethyl acetate. The organic phase is washed using saline, dried over sodium sulfate, filtered and concentrated. The resulting oil is added to a suspension of 1.6 g of phosphorus pentoxide in20 ml of methanesulfonic acid, and the mixture is stirred overnight at room temperature. The reaction mixture is poured onto ice and extracted using ethyl acetate. The organic phase is washed with saturated sodium hydrogen carbonate solution and with saline and dried over sodium sulfate, filtered and concentrated. After purification by chromatography, 7-methoxybenzisothiazole is obtained in the form of an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16][C:17]2[NH:18][C:19]3[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:20]=3[N:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].CCOCC>CCCCCC>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[F:27][C:23]1[C:24]([F:26])=[CH:25][C:19]2[N:18]=[C:17]([S:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[NH:21][C:20]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCSc2nc3cc(F)c(F)cc3[nH]2)CC1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc2nc(SCCN3CCNCC3)[nH]c2cc1F
Yield: 82 %

Procedure:
Under stirring in an ice-bath, 1-tert-butoxycarbonyl-4-[2-(5,6-difluorobenzimidazol-2-ylthio)ethyl]piperazine (7.26 g, 18.22 mmol) was added to trifluoroacetic acid (50 mL) over 15 minutes and dissolved. After the mixture had been stirred for ten minutes under cooling with ice, ether (100 mL) and hexane (100 mL) were added thereto, and the formed crystals were collected through filtration. The crystals were recrystallized from ethanol-ether, to thereby yield 1-[2-(5,6-difluorobenzimidazol-2-ylthio)ethyl]piperazine tris(trifluoroacetic acid) salt (9.58 g, yield 82%) as a pale yellow powder.
Reaction SMILES: C(N(CC)CC)C.O[CH2:9][C@H:10]([CH3:23])[CH2:11][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13]O.CS(Cl)(=O)=O.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.CCOC(C)=O>[CH2:29]([N:36]1[CH2:9][C@H:10]([CH3:23])[CH2:11][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: C[C@@H](CO)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
Triethylamine (0.932 mL, 6.69 mmol) was added to a solution of tert-butyl [(1S,3R)-4-hydroxy-1-(hydroxymethyl)-3-methylbutyl]carbamate (0.39 g, 1.7 mmol) in DCM (7.5 mL) at 0° C. Methanesulfonyl chloride (0.388 mL, 5.01 mmol) was then added dropwise to the resulting solution. After stirring at 0° C. for 1 h, the mixture was diluted with DCM (50 mL), washed with saturated aq. NaHCO3 (50 mL), dried over Na2SO4 and concentrated under reduced pressure. Benzylamine (3.65 mL, 33.4 mmol) was added to the resulting residue and mixture was stirred at 70° C. for 18 h, then cooled to room temperature. The reaction mixture was diluted with EtOAc (100 mL), washed with a 10% aq. K3PO4 (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-30% EtOAc in hexanes) to give the title compound as a white solid (0.34 g, 67%). LCMS calc. for C18H29N2O2 (M+H)+: m/z=305.2. found 305.2.