Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2]C=C.C([CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C>>[CH:1]([C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:10]=[CH2:9])=[CH2:2]
Reactant: CC(C)(C)C=Cc1ccccc1
Reactant: C=CC=C
Product: C=Cc1ccccc1C=C

Procedure:
A second reactor (7.6 L, purchased from Chemineer, Inc.) was used to make poly(t-butyl styrene) (“PtBuSt”). The second reactor was first charged with 0.51 lbs of t-butyl styrene, followed by 3 lbs of hexane. Polymerization was initiated at 57° C. by adding 3 ml of 1.6 M oligomeric oxolanyl propanes in hexane and 4 ml of 1.54 M n-butyllithium in hexane. The polymerization was then allowed to continue for approximately two hours. The GPC analysis indicated that the PtBuSt in the solution had an Mn of 48,880 and an Mw/Mn of 1.12. Then, the PtBuSt/hexane solution was charged into the polybutadiene solution prepared in the first reactor as described above. After thoroughly mixing, 450 ml of the mixed solution, which was still chemically alive, was placed into a clean, dry, nitrogen purged closed bottle. Polymerization was then extended by charging 24 ml of a styrene/hexane blend (containing 33 weight percent styrene) to form a polystyrene (“PS”) block on the PBd and PtBuSt blocks. After approximately half an hour, the resulting diblock copolymers (i.e., PBd-PS and PtBuSt-PS) formed spherical micelles in the hexane solution (about 14 weight percent solid aggregated) with the styrene blocks directed toward the center of the micelle structures and the butadiene and t-butylstyrene blocks as tails extending therefrom. After forming the micelles, 1 ml of divinyl benzene (“DVB”) was added to the bottle in order to polymerize and crosslink the polystyrene core.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:28])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[N:6]=[CH:7][C:8]2=[O:28])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reaction time: 0.75 h

Procedure:
A solution of tert-butyl {1-[2-(7-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 141, 240 mg, 0.62 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (15 mL). After 45 minutes, the reaction was concentrated to dryness, the residue taken up in methanol/chloroform (15:85, 30 mL) and washed with saturated sodium bicarbonate solution. The aqueous layer was re-extracted with methanol/chloroform (15:85, 3×30 mL. The combined organic phases were dried over magnesium sulfate and concentrated to dryness to give 170 mg (quantitative) of the crude product as an oil.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([O:14][Si](C)(C)C)=[CH2:13])[CH3:10].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.O1CCCC1.O.[Ti](Cl)(Cl)(Cl)Cl.[Ti]>[OH:8][C@H:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:14]
Reactant: C=C(OCC)O[Si](C)(C)C
Reactant: O=Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Ti]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@H](O)c1ccccc1
Temperature: -20 °C
Yield: 70 %

Procedure:
The compound of Example 45 shown in Table 9 (14 mg, 0.05 mmol) was added to titanium tetrachloride (9.5 mg, 0.05 mmol) in toluene (1.0 ml), and the resultant mixture was stirred until the mixture became uniform. After titanium was coordinated with the compound, the solvent was removed through evaporation under reduced pressure at room temperature. The resultant residue was dissolved in anhydrous tetrahydrofliran (10 ml), and the solution was cooled to −20° C. Separately, benzaldehyde (106 mg, 1.0 mmol) and 1-ethoxy-1-trimethylsiloxyethene (192 mg, 1.2 mmol) were dissolved in anhydrous tetrahydrofuran (2 ml), and the resultant solution was added to the above solution, and then the resultant mixture was stirred at −20° C. for one day. Tetrahydrofuran (2 ml) containing trifluoroacetic acid in an amount of 10 w/w% was added to the resultant reaction mixture, and the mixture was returned to room temperature. The reaction mixture was diluted with water, and then subjected to extraction with ether. The organic layer was washed with salt water, and dried over anhydrous magnesium sulfate. After removal of the solvent, the resultant oily product was purified through silica gel chromatography, to thereby yield colorless oily ethyl (S)-3-hydroxy-3-phenylpropionate ([α]D20-25.5 (cl, CHCl3)) at a yield of 70%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:11][CH3:12]>>[CH2:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:12]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCBr
Product: CCn1ccc2ccccc21

Procedure:
The title compound was prepared according to general procedure A described in Scheme 1 from indole and bromoethane. The crude material was used directly without further purification
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][NH:22][C:21]3=[O:25])[N:17]2C(OC(C)(C)C)=O)=[CH:12][CH:11]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][NH:22][C:21]3=[O:25])[NH:17]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3F)cc2)CC[C@]12CCNC2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCC[C@]12CC[C@H](c1ccc(OCc3ccccc3F)cc1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
1,1-Dimethylethyl (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D26, 30 mg) was dissolved in dry DCM (1.5 ml). At 0° C. TFA (0.4 ml) was added and the mixture was stirred at room temperature for 1 h. The mixture was evaporated and the residue purified via a SCX cartridge affording the title compound (23 mg) as a yellowish oil. Rt (HPLC) 3.61 min; MS: (ES/+) m/z: 341 [MH+]. C20H21FN2O2 requires 340.
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].P(Cl)(Cl)(Cl)=O.[CH3:11][C@:12]12[CH2:29][CH2:28][C@H:27]3[C@@H:17]([C:18](=[O:30])[CH:19]=[C:20]4[C@:25]3([CH3:26])[CH2:24][CH2:23][CH2:22][CH2:21]4)[C@@H:16]1[CH2:15][CH2:14][C:13]2=[O:31]>C(Cl)(Cl)Cl.C(OCOCC)C>[CH2:1]=[C:21]1[CH2:22][CH2:23][CH2:24][C@@:25]2([CH3:26])[C:20]1=[CH:19][C:18](=[O:30])[C@@H:17]1[C@@H:27]2[CH2:28][CH2:29][C@@:12]2([CH3:11])[C@H:16]1[CH2:15][CH2:14][C:13]2=[O:31]
Reactant: C[C@]12CCCCC1=CC(=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCOCC
Product: C=C1CCC[C@@]2(C)C1=CC(=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 80.6 %

Procedure:
A suspension of 1.0 g of sodium acetate in 30 ml of chloroform, 30 ml of formaldehyde diethylacetal, and 3.8 ml of phosphorus oxychloride is combined with 1.0 g of 5-androstene-7,17-dione and refluxed for 61/2 hours. Under agitation, a saturated soda solution is then added dropwise until alkaline reaction occurs in the aqueous phase. The organic phase is separated, washed with water, dried over sodium sulfate, and concentrated under vacuum. The crude product is purified on 200 g of silica gel with a hexane/ethyl acetate gradient (0-50% ethyl acetate), thus isolating 840 mg of 4-methylene-5-androstene-7,17-dione, mp 131.5°-132° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH3:14])[N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH:3]=1>C(O)C.[Pd]>[CH3:14][N:8]([N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[C:4]1[CH:3]=[CH:2][N:7]=[CH:6][N:5]=1
Reactant: CN(c1cc(Cl)ncn1)n1cccc1
Agent: [Pd]
Solvent: CCO
Product: CN(c1ccncn1)n1cccc1
Yield: 138.1 %

Procedure:
6-Chloro-N-methyl-N-(1H-pyrrol-1-yl)-4-pyrimidinamine (7.2 g), in 200 ml of ethanol (100%) was hydrogenated under atmospheric pressure at room temperature in the presence of 10% Pd/C (2.0 g) and MgO (1.6 g). When the reaction was complete, the mixture was filtered through celite, and the filtrate evaporated to yield a solid (8.3 g) which was eluted with 10% ethyl acetate/DCM on a silica gel column via flash chromatography. The desired fractions were evaporated to yield 3.74 g (63.3%) of a solid, N-Methyl-N-(1H-pyrrol-1-yl)-4-pyrimidinamine, m.p. 97°-99° C.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC[O-].[Na+].C(O)C.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>ClCCl>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:19][CH:18]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CSCc1ccc(C)cc1

Procedure:
Ethyl 2-mercaptoacetate (8.5 cc) is added in the course of 15 minutes at a temperature in the region of 20° C. to a stirred solution, through which a stream of nitrogen is passed, of a 2M ethanolic solution of sodium ethylate (37.5 cc) and ethanol (50 cc). The mixture is left with stirring for 15 minutes at the same temperature, and α-bromo-p-xylene (13.9 g) is then added in the course of 20 minutes at a temperature in the region of 20° C. Stirring is maintained for 60 minutes at this temperature, and the reaction mixture is then evaporated to dryness at 50° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is dissolved in dichloromethane (100 cc), and the organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). Ethyl (4-methylbenzylthio)acetate (15.6 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[Cl:11].[CH3:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:12][C:13]1[N:18]=[C:17]([S:19][CH2:2][C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([Cl:10])[C:8]=2[Cl:9])[N:16]=[C:15]([OH:20])[CH:14]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(O)nc(SCc2c(Cl)ccc(Cl)c2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
In a 100 mL round bottom flask, 2-(bromomethyl)-1,3,4-trichlorobenzene (550 mg, 2.0 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (250 mg, 2.0 mmol), and potassium carbonate (306 mg, 2.2 mmol) were mixed in DMF (10 mL). The reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was added. The mixture was filtered and washed with water and ethyl acetate to provide the title compound as a white solid (450 mg, 70% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.11 (s, 3H), 5.43 (s, 2H), 5.89 (s, 1H), 6.57 (br, 1H), 7.56 (d, 1H), 7.71 (d, 1H); M+ 318, 320.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:13]CC2SC(C3C=CC(C(F)(F)F)=CC=3)=NC=2C)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([OH:12])=[O:11].[C:31]1(C)C(O)=CC=C[CH:32]=1.S(Cl)(Cl)(=O)=O.[Sn]>>[SH:13][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH2:31][CH3:32])=[O:11])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O
Reactant: Cc1ccccc1O
Agent: [Sn]
Solvent: O=S(=O)(Cl)Cl
Product: CCOC(=O)COc1ccc(S)cc1C

Procedure:
As an alternative synthesis method of GW501516, it is disclosed, as illustrated in the following scheme (2), that the compound (13) of GW501516 can be prepared by introducing ethyl acetate group to o-cresol (14), reacting the resulted compound (15) with sulfonyl chloride, reducing the resulted compound (16) with tin (Sn) under acidic condition to form ethyl (4-mercapto-2-methyl phenoxy)acetate (17), reacting it with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl phenyl)thiazole (11) together with an excessive cesium carbonate to obtain the ethyl ester intermediate (18) of GW501516, and deprotecting the ester group of the intermediate compound with 1N lithium hydroxide.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:18])[CH:15]=NO)[CH:10]=[CH:11][CH:12]=1>>[Br:6][C:7]1[CH:8]=[C:9]2[C:10]([C:15](=[O:2])[C:14](=[O:18])[NH:13]2)=[CH:11][CH:12]=1
Reactant: O=C(C=NO)Nc1cccc(Br)c1
Reactant: O=S(=O)(O)O
Product: O=C1Nc2cc(Br)ccc2C1=O
Temperature: 90 °C
Yield: 98 %

Procedure:
To concentrated sulfuric acid (275 mL) at 50° C. was added N-(3-bromo-phenyl)-2-hydroxyimino-acetamide (55 g, 0.2272 mol). The temperature was raised to 90° C. and maintained for 3 hours. The reaction mixture was added to ice cold water to provide a yellow precipitate. The precipitate was filtered and dried to provide the title compound as a yellow solid (50 g, 98%). This material was taken for next step without any further purification.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3].CC1(C)C(C)(C)OB([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[OH:56])O1.C([O-])([O-])=O.[K+].[K+]>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]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=6[OH:56])[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(Br)c5)nn34)c(Cl)c21
Reactant: CC1(C)OB(c2ccccc2O)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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(-c6ccccc6O)c5)nn34)c(Cl)c21
Temperature: 90 °C

Procedure:
To a 2-5 ml microwave tube was added (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.240 g, 0.375 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.124 g, 0.563 mmol), and 2M aqueous K2CO3 (0.375 ml, 0.750 mmol) in 1,4-dioxane (3.0 ml) and water (0.75 ml). The reaction was sparged with nitrogen for 10 minutes, treated with Pd(Ph3P)4 (0.043 g, 0.038 mmol), then sparged for 15 min. The reaction tube was sealed and heated (90° C., heating block) for 90 min. The reaction was cooled, diluted with water (5 mL) and extracted with Et2O. The ether layer was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was adsorbed onto silica gel, then purified by biotage column chromatography (5%-55% EtOAc in hexanes). The product fractions were pooled and concentrated under reduced pressure to afford (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(2′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate. 1H NMR (500 MHz, CDCl3) δ 7.94 (t, J=1.5 Hz, 1H), 7.86 (dt, J=7.7, 1.4 Hz, 1H), 7.47-7.52 (m, 1H), 7.39-7.45 (m, 1H), 7.25 (s, 1H), 6.95-7.02 (m, 5H), 6.88-6.92 (m, 1H), 5.96-6.10 (m, 1H), 5.51 (br. s., 1H), 5.29-5.37 (m, 1H), 5.24 (dd, J=10.3, 1.5 Hz, 1H), 5.04-5.09 (m, 1H), 4.24 (t, J=4.4 Hz, 2H), 3.67-3.76 (m, 1H), 3.65 (s, 2H), 3.58 (dd, J=15.2, 6.1 Hz, 1H), 3.16-3.23 (m, 2H), 2.84 (s, 3H), 1.95 (s, 1H), 1.17 (s, 9H). LCMS (M+H)=653.4.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].O.C1COCC1.Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH2:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22]>>[OH:22][CH2:21][CH:20]([NH:19][C:14](=[O:15])[O:16][CH2:17][CH3:18])[CH2:23][OH:24]
Reactant: NC(CO)CO
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)NC(CO)CO
Reaction time: 4 h
Yield: 54.5 %

Procedure:
In a 1 liter round bottom flask with magnetic stir bar, serinol (10.0 g) and Na2CO3 (25.0 g) were dissolved in the mixture of DI water (250 mL) and THF (150 mL). The reaction mixture was allowed to cool in ice. Ethyl chloroformate (10.5 mL) was added drop-wise and the reaction was allowed to proceed in ice for 4 hours, followed by about 16 hours at room temperature. Another 100 mL of DI water was added to the reaction mixture and the product was extracted into ethyl acetate (20×100 mL). The crude product (11.6 g) was further purified by flash column chromatography, using silica as the packing material and CH3OH:CHCl3 (1:9) mixture as the eluent. The final product was a transparent viscous oil that was crystallized in the presence of trace ethyl acetate (1 to 2 mL) along with vigorous scratching using a spatula. The crystallized product was washed with cold ethyl acetate:hexanes (1:1) mixture (1×100 mL), and dried under vacuum to result in white crystalline solid (8.9 g, 54.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1.Cl[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:10]=[N:11][N:12]=1
Reactant: COC(=O)CCl
Reactant: Cc1ccccc1-c1nnn[nH]1
Product: COC(=O)Cn1nnnc1-c1ccccc1C

Procedure:
Feed materials: 5-(2-methylphenyl)tetrazole and methyl chloroacetate.
Reaction SMILES: CS([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH3:23])=[O:21])[CH:15]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1)=O.[N:24]1([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CC(N(C)C)=O>[CH3:23][NH:22][C:20]([C:16]1[CH:15]=[C:14]([O:13][C:11]2[CH:10]=[CH:9][C:7]3[N:8]=[C:4]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([CH2:31][CH2:30][N:24]5[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]5)[CH:33]=4)[O:5][C:6]=3[CH:12]=2)[CH:19]=[CH:18][N:17]=1)=[O:21]
Reactant: Nc1cccc(CCN2CCCCC2)c1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)oc3c2)ccn1
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cc(Oc2ccc3nc(Nc4cccc(CCN5CCCCC5)c4)oc3c2)ccn1
Temperature: 120 °C

Procedure:
The 4-(2-methanesulfinyl-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide from step 3 of Example 2 and 3-(2-piperidin-1-yl-ethyl)-phenylamine were dissolved in DMAC and heated in a CEM microwave reactor at 120° C. for 10 to 20 minutes. The crude reaction mixture was purified by preparatory reverse phase HPLC. MH+=472.2.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([CH2:34][O:35][CH3:36])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].[C:37](Cl)(=[O:39])[CH3:38].C(N(CC)C(C)C)(C)C.C(N(S(CCCI)(=O)=O)CC(COC)COCCCCCCCCCCCCCCCC)(=O)C>>[C:37]([N:8]([S:5]([CH2:4][CH2:3][CH2:2][I:1])(=[O:7])=[O:6])[CH2:9][CH:10]([CH2:34][O:35][CH3:36])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:39])[CH3:38]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)COC
Reactant: CC(=O)Cl
Agent: CCCCCCCCCCCCCCCCOCC(COC)CN(C(C)=O)S(=O)(=O)CCCI
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COC)CN(C(C)=O)S(=O)(=O)CCCI
Yield: 85 %

Procedure:
A mixture of 0.72 g (1.1 mM) of 3-(3-iodopropylsulfonylamino)-2-methoxymethyl-1-octadecylcarbamoyloxypropane IIk2, 88 μl (1.2 mM) of acetyl chloride and 0.25 ml (1.4 mM) of N,N-diisopropylethylamine is allowed to react by the same procedure as described in (110) and 0.65 g (85% yield) of the title compound IIk2' is obtained. m.p. 71°-72° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([CH3:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C([Li])CCC.C(OP(Cl)(OCC)=O)C.[N+:26]([C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1)([O-:28])=[O:27]>O1CCCC1.CCCCCC.O>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7](/[CH:10]=[CH:33]/[C:32]2[CH:35]=[CH:36][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)/C=C/c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To 15 g (85.47 mmol) of methyl p-tolyl sulfone dissolved in 450 cm3 of tetrahydrofuran are added, at a temperature in the region of 0° C. under an argon atmosphere, 117.5 cm3 (188 mmol) of a 1.06 M solution of n-butyl-lithium in hexane. After stirring for 30 minutes at a temperature in the region of 0° C. are added, under an argon atmosphere, 13 cm3 (85.47 mmol) of diethylchlorophosphate dissolved in 70 cm3 of tetrahydrofuran. After stirring for 30 minutes at a temperature in the region of 0° C., the reaction mixture is cooled to a temperature in the region of −78° C., followed by addition, under an argon atmosphere, of 13.05 g (85.47 mmol) of 4-nitrobenzaldehyde dissolved in 130 cm3 of tetrahydrofuran. After stirring for 1 hour at a temperature in the region of −78° C., the temperature of the reaction mixture is allowed to rise to a temperature in the region of 20° C., 100 cm3 of water are added and the mixture is concentrated under reduced pressure (2.7 kPa) to give a beige-coloured solid. The solid is stirred in 250 cm3 of water for 20 minutes, filtered, washed with three times 40 cm3 of water and oven-dried under reduced pressure (2.7 kPa) at 35° C. for 5 hours to give 25.43 g of 1-[(E)-2-(4-methylphenyl)sulfonylvinyl]-4-nitrobenzene in the form of a beige-coloured solid melting at 176° C.; M.W.=303, IE: m/z=303 M+, m/z=239 [M-SO2]+, m/z=139 [CH3-Ph-SO]+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5](N)=[C:4]([CH2:11][CH3:12])[CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:22].[K+]>O>[Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([I:22])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)cc(CC)c1N
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CCc1cc(Br)cc(CC)c1I
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a stirred mixture of 4-bromo-2,6-diethylaniline (13.6 g, 0.06 mol) in distilled water (14 ml) is added concentrated sulphuric acid (14 ml), followed by brief heating to 60° C. for 1 hour until dissolution is complete. The mixture is allowed to cool to room temperature then further cooled to approximately 0° C. in an ice/salt bath. To this slurry is added an aqueous solution of sodium nitrite (4.1 g, 0.059 mol) in distilled water (20 ml) dropwise over 15 minutes, maintaining the temperature below 5° C., followed by additional stirring for 30 minutes. The reaction mixture is allowed to come to room temperature and then a solution of aqueous potassium iodide (29.8 g, 0.18 mol) in distilled water (30 ml) is added dropwise at room temperature. After the addition is complete the solution is briefly heated to 80° C. then allowed to cool to room temperature again. The reaction mixture is extracted with ethyl acetate (150 ml×3) and the organic phase is washed with 1M aqueous hydrochloric acid (75 ml) and aqueous sodium thiosulfate (2×75 ml). The organic phase is dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2,6-diethyl-1-iodobenzene (19 g) as an orange liquid.