Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:2]=1.[H][H]>C(O)C.Cl.[Pd]>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2]1
Reactant: O=C(NCc1cccnc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(NCC1CCCNC1)c1ccccc1
Yield: 82.6 %

Procedure:
Ba) A solution of 42.5 g of N-(3-pyridinylmethyl)-benzamide in 220 ml of ethanol and 220 ml of 1N hydrochloric acid is treated with 4.2 g of palladium on charcoal and hydrogenated at room temperature for 24 hours over 100 bar of hydrogen. Then, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in methylene chloride and shaken with 11N sodium hydroxide solution. The organic phase is washed with water, dried and evaporated. There are obtained 36.1 g of (RS)-N-piperidin-3-ylmethyl-benzamide, MS (FAB): 218 M+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29]Cl)[CH2:24][CH2:23]3)=[O:21])[C:10]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=3[O:42][CH2:43][CH3:44])=[N:9]2)=[CH:4][CH:3]=1.[CH:45]([N:48](C(C)C)[CH2:49]C)(C)C.CNC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29][N:48]([CH3:49])[CH3:45])[CH2:24][CH2:23]3)=[O:21])[C:10]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:40])([F:39])[F:41])=[CH:34][C:33]=3[O:42][CH2:43][CH3:44])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)CCl)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: ClCCl
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)CN(C)C)CC1
Temperature: 60 °C
Yield: 92 %

Procedure:
To a solution of 1-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-2-chloro-ethanone (9.65 mg) and diisopropylethylamine (5 uL) was added dimethylamine (50 uL, 2.0M solution in tetrahydrofuran). The reaction mixture was capped and heated at 60° C. overnight. It was diluted with methylene chloride and washed with water. The organic layer was concentrated to dryness to give 1-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-2-dimethylamino-ethanone (9.17 mg, 92% yield). LR-MS: 677.3 [(M+H)+].
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:24][C:14]2=[C:15]3[C:20](=[CH:21][CH:22]=[C:13]2[O:12][CH2:11]1)[N:19]=[C:18]([CH3:23])[CH:17]=[CH:16]3)C1C=CC=CC=1>C(Cl)Cl>[CH3:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]3[O:12][CH2:11][C@@H:10]([CH2:9][OH:8])[O:24][C:14]3=2)[N:19]=1
Reactant: Cc1ccc2c3c(ccc2n1)OCC(COCc1ccccc1)O3
Solvent: ClCCl
Product: Cc1ccc2c3c(ccc2n1)OC[C@@H](CO)O3
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of (2R)-2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline (0.74 g, 2.3 mmol) in CH2Cl2 (16 mL) being cooled in an ice-bath, FeCl3 (1.9 g, 12 mmol) was added. After 1 h, the ice-bath was removed and the reaction mixture was stirred for another 17 h. CHCl3 (30 mL) and 1N NaOH (50 mL) were added to result in a suspension which was then filtered. The filtered solid was washed with CH3OH (50 mL). The combined organic layers were concentrated in vacuo. Purification on SiO2, eluted with (10:1) CHCl3:iPrOH gave 0.45 g (84%) of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[CH:4][C:3]=1[O:21][CH3:22].S(=O)(=O)(O)O.[N+:28]([O-])([OH:30])=[O:29]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[NH:11][C:10]2=[O:20])=[C:4]([N+:28]([O-:30])=[O:29])[C:3]=1[O:21][CH3:22]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Agent: O=S(=O)(O)O
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(4-Chloro-6-fluoro-3-methoxyphenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (10.0 g, 29.5 mmol) was slowly added to a stirred mixture of con. sulfuric acid (36 ml) and con. nitric acid (4 ml) with stirring at −15° C. The solution was then slowly warmed to room temperature and allowed to stir for 2 hr. Addition of the solution to ice-water resulted in a light yellow precipitate which was separated by filtration to afford the title compound (9.1 g). NMR data for the compound are listed in Table XVIII.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C=O)C>[N:31]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1)=[N+:32]=[N-:33]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cc(F)cc(-c4ccccc4Cl)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1CCc2cc(F)cc(-c3ccccc3Cl)c2O1
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
A solution ((R)-8-(2-chlorophenyl)-6-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (400 mg, 0.90 mmol) and sodium azide (0.29 g, 4.5 mmol) in anhydrous DMF (20 mL) was heated to 90° C. under nitrogen for 20 hours. The cooled reaction mixture was quenched by the addition of water (30 mL) and the resulting suspension stirred vigorously for 10 minutes. The mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase separated, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Chromatography with 0–30% ethyl acetate in hexanes afforded 240 mg (88%) of (R)-2-azidomethyl-8-(2-chloro-phenyl)-6-fluoro-chroman as a colorless oil. MS (APPI) m/z 288 ([M−N2+H]+).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18]>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:17]([C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)=[O:18])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(Cl)c1ccco1
Reactant: NCCCn1cncn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCn1cncn1)c1ccco1

Procedure:
A mixture of about 3.78 g of 1H-1,2,4-triazole-1-propanamine, about 33 ml of 1N sodium hydroxide and about 100 ml of methylene chloride was stirred, then about 3.3 ml of 2-furoyl chloride was added. The mixture was stirred overnight, then about 15 ml of 1N sodium hydroxide and about 100 ml of methylene chloride were added. The mixture was shaken, the organic layer separated, washed with two approximately 50 ml portions of water, dried, filtered and evaporated to an oil. Ether was added to the oil which was then triturated and the crystals collected. These were recrystallized from ether giving about 2.0 g of the desired product as beige crystals, mp 63°-66° C. The fumarate salt melts at 65° C.-70° C.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH2:16]([NH:23][CH:24]1[CH2:30][CH2:29][CH2:28][C:27]2[CH:31]=[C:32]([OH:35])[CH:33]=[CH:34][C:26]=2[CH2:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([N:23]([CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:24]1[CH2:30][CH2:29][CH2:28][C:27]2[CH:31]=[C:32]([OH:35])[CH:33]=[CH:34][C:26]=2[CH2:25]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1ccc2c(c1)CCCC(NCc1ccccc1)C2
Reactant: O=c1[nH]c2cccc(OCC3CO3)c2[nH]1
Solvent: CCO
Product: O=c1[nH]c2cccc(OCC(O)CN(Cc3ccccc3)C3CCCc4cc(O)ccc4C3)c2[nH]1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
A mixture of 4-oxiranylmethoxy-1,3-dihydro-2-benzimidazolone (82.5 mg) and N-benzyl-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amine (107 mg) in ethanol (1.5 ml) was stirred under reflux for 13 hours, cooled to room temperature and evaporated in vacuo. The residue was chromatographed (dichloromethane-methanol)by silica gel (4.2 g) to afford 1-[N-benzyl-N-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amino]-3-(1,3-dihydro-2-benzoimidazolon-4-yloxy)-2-propanol (123 mg) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[N:7]=[C:8](O)[C:9]2[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=3[S:12][C:10]=2[N:11]=1.O=P(Cl)(Cl)[Cl:23]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[N:7]=[C:8]([Cl:23])[C:9]2[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=3[S:12][C:10]=2[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)CCc1nc(O)c2c3c(sc2n1)CCCC3
Product: COC(=O)CCc1nc(Cl)c2c3c(sc2n1)CCCC3
Yield: 47 %

Procedure:
A solution of 3-(4-hydroxy-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl)-propionic acid methyl ester (2 g, 0.0068 mol) in POCl3 (10 ml) was refluxed for 2 hrs. After consumption of starting material, excess of POCl3 was distilled off. The reaction mixture was quenched with ice and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4, concentrated and purified by chromatography on 60-120 silica using ethyl acetate (30%) in hexane as eluant to give 1 g (47%) of 3-(4-chloro-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl)-propionic acid methyl ester. 1H NMR (400 MHz, DMSO) δ ppm=1.83 (m, 4H), 2.8 (m, 4H), 2.98 (m, 2H), 3.2 (t, 2H), 3.57 (s, 3H). LC-MS: [M+H]=311.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)O1>>[CH:10]12[O:15][CH:13]([CH2:12][CH2:11]1)[CH2:14][N:8]([C:6]1[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=[C:2]([C:28]3[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=3)[N:7]=1)[CH2:9]2
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: FC(F)(F)c1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Product: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)cc(C(F)(F)F)n2)cc1
Yield: 86 %

Procedure:
The title compound was prepared in 86% yield from 3-(2-chloro-6-trifluoromethyl-pyrimidin-4-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (63) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, using the general procedure from scheme 2 for the preparation of 6. MS (ES+): 351.2 (M+H)+.
Reaction SMILES: CO[C:3](=[O:18])[CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[N:8][CH:7]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.O>O1CCCC1>[CH2:11]([N:10]1[C:6]([CH2:5][CH2:4][C:3]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)[OH:18])=[CH:7][N:8]=[CH:9]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: COC(=O)CCc1cncn1Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: OC(CCc1cncn1Cc1ccccc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
1-benzyl-5-imidazole propionic acid methyl ester (6,4 g) in tetrahydrofuran is heated at 60° C. and to this is then added dropwise p-chlorophenylmagnesium bromide prepared above. After the addition is complete, the reaction mixture is refluxed for an additional 3 hours, cooled and poured into cold water. Tetrahydrofuran is evaporated, toluene is added and the mixture is made acidic with hydrochloric acid. The precipitated product is filtered, washed with ether and dried. Yield 12,2 g; m.p. 210°-213° C. M.p. of nitrate 157°-160° C. (made in water-ether mixture). M.p. of hydrochloride (from ethylacetate) 178°-187° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[C:14]([C:19]2([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:21][CH2:20]2)[N:13]=3)[CH:7]=[C:6]([CH3:28])[C:3]=1[CH:4]=O.[NH:29]1[CH2:32][CH2:31][CH2:30]1>>[N:29]1([CH2:4][C:3]2[C:6]([CH3:28])=[CH:7][C:8]([C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([C:19]3([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:20][CH2:21]3)[N:13]=4)=[CH:9][C:2]=2[CH3:1])[CH2:32][CH2:31][CH2:30]1
Reactant: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1C=O
Reactant: C1CNC1
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1CN1CCC1

Procedure:
Reaction of 2,6-dimethyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (29.3 mg, 76 μmol) and azetidine (18 μL, 267 μmol) according to Reference R and the general procedure for reductive amination gave 2-(4-(azetidin-1-ylmethyl)-3,5-dimethylphenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine as a light yellow solid. MS (ESI) m/z: Calculated: 425.2; Observed: 426.1 (M++1). 3-(Azetidin-1-yl)-N-(2,6-dimethyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)propan-1-amine was also obtained from this reaction as a light yellow solid. MS (ESI) m/z: Calculated: 482.3; Observed: 483.2 (M++1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:13]([O:15]CC)=O.[C:18]([O:21][CH2:22][C:23]1[C:28]([Br:29])=[CH:27][CH:26]=[CH:25][C:24]=1Br)(=[O:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I.O1CCOCC1>[Br:29][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([N:1]2[CH2:2][CH2:3][N:4]3[C:12]4[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=4[CH:6]=[C:5]3[C:13]2=[O:15])[C:23]=1[CH2:22][O:21][C:18](=[O:20])[CH3:19]
Reactant: CCOC(=O)c1cc2c(n1CCN)CCCC2
Reactant: CC(=O)OCc1c(Br)cccc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(=O)OCc1c(Br)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
A 350-mL sealed tube equipped with a magnetic stirring bar was charged with 3,4,6,7,8,9-hexahydro-2H-pyrazino[1,2-a]indol-1-one 101k (5.0 g, 0.026 mol), 2,6-dibromobenzyl acetate 104g (16.2 g, 0.052 mol) N,N′-dimethylethylenediamine (2.6 mL, 0.026 mol), Cs2CO3 (17.0 g, 0.052 mol), and 1,4-dioxane (80 mL). After a stream of nitrogen was passed through the resulting suspension for 30 min., CuI (2.5 g, 0.013 mol) was added and the resulting reaction mixture was stirred at 95° C. for 16 h. Then the mixture was cooled to room temperature, partitioned between EtOAc (50 mL) and water (50 mL), and the organic phase was extracted with EtOAc (30 mL×3). The combined organic phases were washed with water (20 mL×2) and brine (20 mL×1), dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography (dichloromethane:MeOH, 97:3) to give 35% yield (4.5 g) of 113a as white solids.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[O:24]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:14][S:13][C:9]2=[C:10]([C:34]2[CH:35]=[CH:36][C:31]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:32][CH:33]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3F)c2c1O
Product: CCOC(=O)c1nc(-c2ccc(Oc3ccccc3)cc2)c2snc(-c3ccccc3F)c2c1O

Procedure:
The title compound was synthesized in analogy Example 1 from 7-bromo-3-(2-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 4-phenoxyphenylboronic acid: MS (m/z) 487.1 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][CH3:25])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]([CH3:25])[C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN(c1ccc([N+](=O)[O-])cc1)C1CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Yield: 95.4 %

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (12.24 mmol, 1.726 g), 1-benzyl-N-methylpiperidin-4-amine (12.24 mmol, 2.5 g) and potassium carbonate (12.24 mmol, 1.691 g) was heated at 100° C. using an oil bath for 48 hours. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane and filtered. The filtrate was concentrated under vacuum to give the intermediate 1-benzyl-N-methyl-N-(4-nitrophenyl)piperidin-4-amine (3.8 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[N:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:14]=[N:15][C:10]([N:4]4[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]4(=[O:8])=[O:7])=[CH:11][CH:12]=3)=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)nc3)CC2)c(C)c1
Yield: 39.6 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (203 mg) described in Preparation Example 4 and (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (375 mg) described in Preparation Example 127 and by the reaction and treatment in the same manner as in Example 1, the title compound (170 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]3[CH2:15][CH2:16][CH:17]([NH2:18])[CH:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26].OC1C2N=NNC=2C=CC=1.CN(C)CCCN=C=NCC>ClCCl>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:18][C@H:17]1[C@@H:11]2[CH2:10][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:19])[F:20])[N:8]=3)[CH2:14][CH2:13][N:12]2[CH2:15][CH2:16]1)=[O:26]
Reactant: O=C(O)c1cccc(F)c1
Reactant: NC1CCN2CCN(c3cccc(C(F)(F)F)n3)CC12
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: O=C(N[C@@H]1CCN2CCN(c3cccc(C(F)(F)F)n3)C[C@@H]12)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 96B (100 mg, 0.349 mmol), 3-fluorobenzoic acid (58.7 mg, 0.419 mmol) and hydroxybenzotriazole (58.8 mg, 0.384 mmol) in dichloromethane (1.5 mL), was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.067 mL, 0.384 mmol). The mixture was stirred at room temperature overnight. The mixture was then purified via HPLC (Gilson®, XBridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=250 nm) to give the title compound as the first eluting diastereomer. 1H NMR (500 MHz, methanol-d4) δ ppm 1.74-1.81 (m, 1 H), 2.19-2.25 (m, 1 H), 2.34 (td, 1H, J=11, 3 Hz), 2.38-2.44 (m, 1 H), 2.49 (m, 1H), 2.83 (dd, 1H, J=12, 10 Hz), 2.98-3.06 (m, 1 H), 3.08-3.18 (m, 2 H), 4.31-4.40 (m, 2 H), 4.51-4.57 (m, 1 H), 6.96 (d, 1H, J=7 Hz), 6.99 (d, 1H, J=8 Hz), 7.29 (td, 1H, J=8, 1 Hz), 7.49 (td, 1H, J=8, 6 Hz), 7.59 (dt, 1H, J=9, 2 Hz), 7.63-7.70 (m, 2 H); MS (DCI) m/z 409 (M+H)+.
Reaction SMILES: C([CH:3]([C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][N:21]([S:32]([C:35]4[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=4)(=[O:34])=[O:33])[C:18]3=[N:19][CH:20]=2)[N:12]=[CH:11][N:10]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])#N.C(OO)(=[O:44])C.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]1[C:17]2[C:18](=[N:19][CH:20]=[C:15]([C:13]3[N:12]=[CH:11][N:10]=[C:9]([C:3](=[O:44])[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])[CH:14]=3)[CH:16]=2)[N:21]([S:32]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH:22]=1
Reactant: CC(=O)OO
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(C(C#N)C(=O)N(C)C)ncn3)cc12
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(C(=O)C(=O)N(C)C)ncn3)cc12
Temperature: 0 °C
Yield: 64.4 %

Procedure:
2-Cyano-2-{6-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrimidin-4-yl}-N,N-dimethyl-acetamide (500 mg, 0.88 mmole) was suspended in tetrahydrofuran (11 mL) and cooled to 0° C. in an ice bath. Peroxy acetic acid (32% in acetic acid, 174 mg, 2.29 mmole) was added and after 10 min, the heterogeneous solution was removed from the ice bath and maintained at ambient temperature for 6 h. Sodium bisulfite (918 mg, 8.83 mmole) in water (10 mL) was added, followed by saturated aqueous sodium bicarbonate (20 mL) and the mixture extracted with ethyl acetate (3×30 mL). The combined organic portions were dried over magnesium sulfate, filtered, and concentrated to dryness. Silica gel chromatography of the crude residue afforded 2-{6-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrimidin-4-yl}-N,N-dimethyl-2-oxo-acetamide (315 mg, 89% yield) as a clear residue. MS: m/z 402.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1C=CC=CC=1.C(=O)(O)[O-].[NH4+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:9]1[C:10]([NH2:17])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(N)=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A reactor was charged with (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-proline (130 g, 1 wt, 1 eq.), dichloromethane (520 mL, 4 vol), pyridine (55 mL, 0.4 vol, 1.2 eq), and Boc-anhydride (145 g, 1.1 wt, 1.2 eq.). The reaction solution was stirred at approximately 20° C. for 2 hours. The reactor was charged with ammonium bicarbonate (62 g, 0.5 wt, 1.44 eq), and was stirred at approximately 20° C. overnight. The reaction was filtered over a bed of celite (130 g, 1 wt), and the filter cake was washed with dichloromethane (260 mL, 2 vol). The filtrate was concentrated to a volume of 3 volumes, heptane (520 mL, 4 vol) was added, and again concentrated to a final volume of 3 volumes. Heptane (390 mL, 3 vol) was added, and the reaction was cooled to approx. 5° C. for 30 min.