Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[N:15]=[C:14]([C:16]([OH:18])=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[N:3]=[CH:2]1.Cl.[OH:20][C:21]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][NH:25][CH2:26]2>>[S:1]1[CH:5]=[C:4]([C:6]2[N:15]=[C:14]([C:16]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:21]=4[OH:20])[CH2:26]3)=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[N:3]=[CH:2]1
Reactant: O=C(O)c1nc(-c2cscn2)nc2ccccc12
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3cscn3)nc3ccccc13)C2
Yield: 9 %

Procedure:
Reaction of 2-(4-thiazolyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 79 (9% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.62 and 2.89 (2t, 2H), 3.47 and 4.02 (2t, 2H), 3.73 and 3.80 (2s, 3H), 4.37 and 4.91 (2s, 2H), 6.31 and 6.77 (2d, 1H), 6.70 and 6.91 (2d, 1H), 7.70-7.97 (m, 2H), 8.10-8.18 (m, 2H), 8.66-8.72 (m, 2H), 9.27-9.29 (m, 1H); MS (ESI) m/z 419 ([M+H]+).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[F:18][C:19]([F:33])([F:32])[CH2:20][C:21]1[N:22]=[C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[S:24][CH:25]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:29]1[CH2:30][CH2:31][N:26]([C:23]2[S:24][CH:25]=[C:21]([CH2:20][C:19]([F:33])([F:18])[F:32])[N:22]=2)[CH2:27][CH2:28]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: FC(F)(F)Cc1csc(N2CCNCC2)n1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc(CC(F)(F)F)cs2)CC1
Yield: 28 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[4-(2,2,2-trifluoro-ethyl)-thiazol-2-yl]-piperazine. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as a white crystalline solid (yield 28%). MS (m/e): 492.1 (M+H+, 100%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([N:15](C(OC(C)(C)C)=O)[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:13][CH:14]=1>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:13][CH:14]=1
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(Br)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CNc1ccc(Br)cn1
Reaction time: 0.75 h
Yield: 100.4 %

Procedure:
A 50% solution of TFA in CH2Cl2 (200 mL) was added to 5-bromo-[N-(tert-butoxycarbonyl)-N-(methoxycarbonylmethyl)amino]pyridine (16.5 g, 46 mmole). After stirring for 45 min the reaction was concentrated to dryness, and the residue was diluted with 1.0 N Na2CO3 (300 mL). The mixture was extracted with EtOAc (300 mL), and the organic layer was washed with brine, dried (Na2SO4), and concentrated to dryness under vacuum. The title compound (11.32 g, 100%) was obtained as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J=2.3 Hz, 1 H), 7.48 (dd, 1 H), 6.40 (d, J=8.8 Hz, 1 H), 4.95 (br s, 1H), 4.12 (d, J=5.5 Hz, 2 H), 3.78 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:50]=[CH:49][C:37]([C:38]([NH:40][CH:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[CH2:43][CH2:42]2)=[O:39])=[CH:36][C:35]=1[O:51][CH3:52]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:50]=[CH:49][C:37]([C:38]([NH:40][CH:41]5[CH2:42][CH2:43][N:44]([CH2:47][CH3:48])[CH2:45][CH2:46]5)=[O:39])=[CH:36][C:35]=4[O:51][CH3:52])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(OC)c2)CC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCC3)CC(F)(F)C(=O)N4C)c(OC)c2)CC1
Yield: 41.6 %

Procedure:
A mixture of 0.0605 g (0.20 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0571 g (0.30 mmole) of toluenesulfonic acid monohydrate, 0.0555 g (0.20 mmole) of 4-amino-N-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 25 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (90:10:1) and then recrystallization from acetonitrile to give 0.0452 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide (I-10) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=1)=[O:6].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:29]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=1)=[O:6])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1N
Reactant: O=C(Cl)c1ccccc1
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1NC(=O)c1ccccc1
Yield: 45.4 %

Procedure:
3-Amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (30 mg, 0.072 mmol) was reacted with benzoyl chloride (9 μl, 0.079 mmol) via procedure V to afford 17 mg of 3-benzamido-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide as a white solid. MS (Q1) 520 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=3)=[N:10][CH:11]=1)=[O:5])C.[OH-].[K+].CO.Cl>O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:13]2[C:14]3[C:19](=[CH:18][C:17]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:16][CH:15]=3)[CH:20]=[C:12]2[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH3:1])=[O:5])=[CH:11][N:10]=2)=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)nc1
Temperature: 22.5 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-(5-ethoxycarbonylpyridin-2-yl)-1-(4-fluorobenzyl)-5-methanesulfonylindole (0.68 g), potassium hydroxide (0.24 g) and methanol (45 ml) was stirred at 15 to 30° C. for 30 minutes under nitrogen atmosphere. To the reaction solution was added water and the mixture was neutralized with hydrochloric acid. The precipitated crystal was filtered off. The resulting crude crystal was recrystallized (methanol) to obtain 0.44 g of the desired. product.
Reaction SMILES: [Br:1][C@@H:2]1[C@H:8]2[CH2:9][C@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.[NH3:11].CO>C1COCC1>[Br:1][C@H:2]1[CH2:3][CH2:4][C@@H:5]([C:6]([NH2:11])=[O:10])[CH2:9][C@H:8]1[OH:7]
Reactant: N
Reactant: O=C1O[C@@H]2C[C@H]1CC[C@@H]2Br
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)[C@@H]1CC[C@H](Br)[C@H](O)C1

Procedure:
(1R,4S,5R)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one (351a) (2.13 g, 10.4 mmol) was taken up in THF (20 mL) and treated with 0.880 ammonia (5.3 mL) at 20° C. for 24 h with stirring. The solvent was then removed in vacuo to give a white solid in quantitative yield; [α]D=+40.6° (c=1, MeOH).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=O)[CH3:11])=[N:2]1.Cl.[NH2:14][OH:15].N1C=CC=CC=1>C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=[N:14][OH:15])[CH3:11])=[N:2]1
Reactant: NO
Reactant: CC(=O)c1noc2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=NO)c1noc2ccccc12
Temperature: 0 °C

Procedure:
A mixture of 1.4 g of 1-(1,2-benzisoxazol-3-yl)ethanone, 0.7 g of hydroxylamine hydrochloride and 10 ml of pyridine is refluxed for 1 h. The reaction mixture is then poured onto a mixture of ice/water and the precipitated product is isolated by filtration. The product is dissolved in ethyl acetate, the solution is washed once with water, then twice with a saturated solution of sodium chloride and finally dried over sodium sulfate. The solvent is stripped off under vacuum, to give pure 1-(1,2-benzisoxazol-3-yl)ethanone oxime having a melting point of 193°-195° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[CH:34]=[CH:33][C:22]([CH2:23][NH:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][N:24]([CH2:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:17][CH:16]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN(Cc1ccc(Br)cc1)C(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Prepared using General Procedure 6: To a stirred solution of 4-((tert-butoxycarbonyl)amino)benzoic acid (2.0 g, 8.43 mmol), tert-butyl 2-((4-bromobenzyl)amino)acetate INT-60 (2.53 g, 8.43 mmol) and TEA (1.76 mL, 12.6 mmol) in DMF (15 mL) was added HATU (3.53 g, 9.27 mmol) at room temperature. After stirring at room temperature for 2 h the reaction mixture was diluted with EA (150 mL) and washed with brine (200 mL). The organics were concentrated in vacuo and the residue was purified by chromatography (EA/hexanes) to afford 3.97 g (91%) of tert-butyl 2-(N-(4-bromobenzyl)-4-((tert-butoxycarbonyl)amino)benzamido)acetate INT-61 as a viscous oil. LCMS-ESI (m/z) calculated for C25H31BrN2O5: 519; found: 517/519 [M−H]−, tR=2.68 min (Method 10).
Reaction SMILES: C([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[CH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12](C(C)(C)C)=CC=3)[CH:6]=1)(C)(C)C.[C:23]1(=[O:30])[CH:28]=[CH:27][C:26](=[O:29])[CH:25]=[CH:24]1>>[C:23]1(=[O:30])[C:28]2[C:9]3[CH:8]=[C:7]4[C:16]([CH:17]=[CH:18][CH:5]=[CH:6]4)=[CH:15][C:14]=3[CH:13]=[CH:12][C:27]=2[C:26](=[O:29])[CH:25]=[CH:24]1
Reactant: CC(C)(C)c1ccc2cc3cc(C(C)(C)C)ccc3cc2c1
Reactant: O=C1C=CC(=O)C=C1
Product: O=C1C=CC(=O)c2c1ccc1cc3ccccc3cc21

Procedure:
6,14-di-tert-butyl-9,10-dihydro-9,10[1′,2′]benzenoanthracene-1,4-diol 45 is illustrated in FIG. 9F. 2,6-di-tert-butyl-anthracene (19.0 g, 0.0654 mol) and 1,4-benzoquinone (7.78 g, 0.072 mol) in xylenes (150 ml) was heated to reflux for 2 h. Solvent was removed in vacuo and the crude product was purified by flash chromatography (2:3, hexane:dichloromethane) to give benzenoanthracene-1,4-dione, which was dissolved in acetic acid (150 ml) and heated to reflux and a drop of aqueous HBr (48%). After 10 min, the reaction was cooled and water was added. Precipitates were collected and dried to give compound 45 as an off-white solid (12.73 g, 0.0319 mol, 49%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][CH2:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][N:16]=[CH:15][C:14]=1[O:21][CH3:22])C.O>C1COCC1>[CH3:20][O:19][C:18]1[CH:17]=[N:16][CH:15]=[C:14]([O:21][CH3:22])[C:13]=1[CH2:12][CH2:11][CH2:10][OH:9]
Reactant: CCOC(=O)CCc1c(OC)cncc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cncc(OC)c1CCCO
Yield: 98 %

Procedure:
Lithium aluminum hydride (1.1 g, 30 mmol) is suspended in THF (50 ml), and thereto is added with stirring 3-(3,5-dimethoxypyridin-4-yl)propionic acid ethyl ester (3.5 g, 15 mmol) obtained in Reference Example 22 at 50° C. over a period of time for 40 minutes. The mixture is further heated under reflux for 30 minutes, and thereto are added successively water (1.1 ml), a 15% aqueous sodium hydroxide solution (1.1 ml) and water (3.3 ml) in order to quench the reaction. The reaction solution is filtered, and the insoluble materials are removed, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol), and further recrystallized from isopropyl ether/hexane to give the title compound (2.9 g) as colorless crystals, m.p. 88-89° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.O.CN([CH:20]=[O:21])C>O=P(Cl)(Cl)Cl>[CH:20]([N:14]1[C:15]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]2[C:13]1=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:21]
Reactant: COc1cccc2c1[nH]c1ccccc12
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2c3ccccc3n(C=O)c12
Temperature: 0 °C
Yield: 96 %

Procedure:
In a 50 mL round bottomed flask was dissolved POCl3 (0.6 mL, 15.23 mM) in 20 mL of dry DMF. The reaction mixture was stirred at 0° C. in an ice bath. To this was added slowly, 1-methoxy-9H-carbazole (1 g, 5.07 mM) dissolved in 30 mL of dry DMF. The reaction mixture was stirred for 2 hrs. Water was added to the reaction mixture and the precipitated product was filtered off. The residue was dissolved in EtOAc and was washed with brine and dried over anh. Na2SO4. Ethyl acetate was then evaporated to obtain the desired product as a white fluffy solid with a yield of 96% (1.1 g); mp 161-163° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2Br)[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].[CH3:32][N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][C:34]1=[O:42].C(=O)([O-])[O-].[K+].[K+].ClCCl>C(#N)C>[C:1]([C:4]1[C@@H:5]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[C:36]2[CH:37]=[CH:38][N:33]([CH3:32])[C:34](=[O:42])[CH:35]=2)[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1Br
Reactant: Cn1ccc(B(O)O)cc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)[C@@H]1c1ccc(C#N)cc1-c1ccn(C)c(=O)c1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
4-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-3-bromo-benzonitrile (intermediate 4)(300 mg, 0.61 mmol) and (1-methyl-2-oxo-4-pyridyl)boronic acid (121 mg, 0.79 mmol) are suspended in acetonitrile (9 mL) and are degassed with a stream of argon. Potassium carbonate solution (2 mol/L, 914 μL, 1.83 mmol) and 1.1-bis(diphenylphosphino)-ferrocendichloropalladium(II), complex with dichloromethane (1:1) (9.95 mg, 0.012 mmol) are added and the reaction is shaken at 75° C. overnight. The reaction mixture is filtrated over a layer of silica gel and basic aluminum oxide 1:1 and purified by reversed phase HPLC. Yield: 142 mg; ESI mass spectrum [M+H]+=521; Retention time HPLC: 0.99 min (HPLC method Z018_S04).
Reaction SMILES: [C:1]1([S:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=2[N+:25]([O-:27])=[O:26])[O:18][CH2:19][CH2:20][OH:21])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=2[N+:25]([O-:27])=[O:26])[O:18][CH2:19][CH2:20][O:21][S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1CS(=O)(=O)c1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)cc1

Procedure:
A solution of 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-ethanol (14.3 g, 36.9 mmol), p-toluenesulfonylchloride (14.9 g, 78.2 mmol) and triethylamine (23 mL, 170 mmol) in methylene chloride (400 mL) was stirred under nitrogen at ambient temperature for 2 hours, 45 minutes. The reaction mixture was then concentrated and partitioned in methylene chloride and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 25-75% ethyl acetate in hexane and 100% ethyl acetate. Drying for 25 minutes in vacuo at 80° C. yielded toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-ethyl ester as a rust-colored solid (15.7 g, 78.5%). Mass Spectrum (+EI, [M+H]+) m/z 542. 1HNMR (500 MHz, DMSO-d6): 88.53 (dd, 1H, J=8.18 Hz and 1.10 Hz), 8.31 (d, 1H, J=8.30 Hz), 8.09-8.11 (m, 1H), 7.94-7.99 (m, 2H), 7.62-7.75 (m, 5H), 7.42 (d, 2H, J=7.93 Hz), 6.98 (dd, 1H, J=9.15 Hz and 2.93 Hz), 6.80 (d, 1H, J=2.81 Hz), 5.20 (s, 2H), 4.28-4.30 (m, 2H), 4.10-4.12 (m, 2H), 2.37 ppm (s, 3H).
Reaction SMILES: Br[CH2:2][C@@H:3]([OH:22])[C@@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1.C(OCC)(=O)C.[OH-].[K+]>C(O)C>[F:13][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:3]2[CH2:2][O:22]2)[CH:11]=[C:10]([F:12])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reaction time: 0.5 h

Procedure:
tert-Butyl (1S, 2S)-3-bromo-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate (IV, PREPARATION 2) is dissolved in absolute alcohol (150 mL) and ethyl acetate (100 mL) and potassium hydroxide (2.3 g, 34.9 mmole, 1.1 eq.) in ethyl alcohol (85%, 5 mL) is added at −20°. The cold bath is then removed and the mixture stirred for 30 minutes. The reaction is monitored by TLC (ethyl acetate/hexane, 20/80). When the reaction is complete, it is diluted with dichloromethane and extracted, washed with water, saline, dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The crude material is purified by flash chromatography on silica gel to give the title compound, TLC (ethyl acetate/hexane, 20/80) Rf=0.3; MS (MH+)=300.4.
Reaction SMILES: [CH2:1]([O:5]/[N:6]=[N+:7](/[N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][OH:15])\[O-:8])[CH2:2][CH2:3][CH3:4].Cl[C:17]([O:19][CH:20]([Cl:22])[CH3:21])=[O:18].N1C=CC=CC=1>C(Cl)Cl>[C:17](=[O:18])([O:19][CH:20]([Cl:22])[CH3:21])[O:15][CH2:14][C@@H:10]1[CH2:11][CH2:12][CH2:13][N:9]1/[N+:7](/[O-:8])=[N:6]/[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCCCO/N=[N+](\[O-])N1CCC[C@H]1CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCO/N=[N+](\[O-])N1CCC[C@H]1COC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {(2S)-1-[(2)-butoxy-NNO-azoxy]pyrrolidin-2-yl}methanol (Example 1, Step A) (856 mg, 3.94 mmol) in CH2Cl2 (15 mL) at rt was added 1-chloroethyl chloroformate (676 mg, 4.73 mmol) and followed by pyridine (935 mg, 11.8 mmol). After stirring at rt for 3 h, the mixture was purified by flash chromatography (Biotage 25+M) using 10-30% EtOAc/hexane gradient, affording the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH:7]([CH2:17][CH2:18][CH2:19][N:20](C)[CH3:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1.ClC(OCC)=O>C1C=CC=CC=1>[CH3:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH:7]([CH2:17][CH2:18][CH2:19][NH:20][CH3:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1CCc1ccccc1C2CCCN(C)C
Agent: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CNCCCC1c2ccccc2CCc2c(C)cccc21

Procedure:
12.2 g. of 1-methyl-10,11-dihydro-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene, dissolved in 180 ml. of dry benzene, are added dropwise to a mixture of 13.6 g. of ethyl chloroformate and 50 ml. of dry benzene. The mixture is boiled and stirred under reflux for 20 hours. After cooling, the benzene solution is washed with dilute hydrochloric acid and water and evaporated. The residual 1-methyl-10,11-dihydro-5-(3-methylcarbethoxyaminopropyl)-5H-dibenzo[a,d]cycloheptene distils at 180° C./0.01 mmHg. 10.6 g. of 1-methyl-10,11-dihydro-5-(3-methylcarbethoxyaminopropyl)5H-dibenzo[a,d]cycloheptene, 12.6 g. of potassium hydroxide and 110 ml. of n-butanol are boiled at reflux for 20 hours under an atmosphere of nitrogen with strong stirring. The butanol is removed by distillation under reduced pressure. The residue is taken up in ether and the ethereal solution shaken with dilute hydrochloric acid. By treatment of the aqueous acidic phase with excess potassium carbonate, 1-methyl-10,11-dihydro-5-(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene separates out as an oil which distils at 150° C. under 0.01 mmHg. After recrystallization from ethanol-ether, the hydrochloride has a melting point of 173°-175° C.
Reaction SMILES: [OH:1][CH:2]([CH3:10])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:19]([Si:16]([CH3:18])([CH3:17])[O:1][CH:2]([CH3:10])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)C(=O)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)C(=O)N1CCCC1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 2-hydroxy-1-pyrrolidin-1-yl-propan-1-one (47.0 mmol, 6.72 g) in DMF (25 mL) was added imidazole (70.5 mmol, 4.8 g), N,N-dimethyl-4-aminopyridine (4.7 mmol, 0.57 g) at room temperature. Tert-butyl-dimethylsilyl chloride (48.5 mmol, 7.31 g) was then added while stirring. Some exotherm was observed. The initial pale yellow solution turned brwn-red in color and some precipitate was observed after 30 min. The reaction mixture was allowed to stir overnight and then filtered through a sintered glass funnel. The solid was washed with some Et2O. The filtrate was diluted with water (150 mL) and it was extracted with Et2O (2×100 mL). The organic extrats were combined and washed successively with water (100 mL), sat. NH4Cl solution and the organic layer was separated. It was dried over Na2SO4, filtered and the solvent was removed in vacuo to obtain 2-(tert-butyl-dimethyl-silanyloxy)-1-pyrrolidin-1-yl-propan-1-one as a golden yellow oil (10.4 g, 86% yield). The product was judged to be >95% pure by NMR and was used in next step without any purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[CH:23]=[CH:24][N:25]=[C:11]2[CH:10]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:14]1[C:9]([CH2:8][NH2:7])=[CH:10][C:11]2[N:12]([CH:23]=[CH:24][N:25]=2)[CH:13]=1
Reactant: CC(C)(C)OC(=O)NCc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Yield: 52.9 %

Procedure:
A solution of [6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-ylmethyl]-carbamic acid tert-butyl ester (30 mg, 0.07 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at RT for 30 min, then concentrated to dryness. The remaining residue was purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 19 mg, 0.037 mmol, 52%) as a white solid. MS: 293 [M+1]+; HPLC: AtRet=0.84.