Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][C@@H:5]2[O:6][C:7]3[C:12]([CH2:13][CH2:14][CH2:15][C:16](O)=O)=[CH:11][CH:10]=[CH:9][C:8]=3[C@@H:4]2[C@H:3]1/[CH:20]=[CH:21]/[C@@H:22]([OH:29])[CH:23]([CH3:28])[CH2:24][C:25]#[C:26][CH3:27].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.[Cl-].[NH4+]>CN(C)C=O>[OH:1][C@@H:2]1[CH2:19][C@@H:5]2[O:6][C:7]3[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[CH:11][CH:10]=[CH:9][C:8]=3[C@@H:4]2[C@H:3]1/[CH:20]=[CH:21]/[C@@H:22]([OH:29])[CH:23]([CH3:28])[CH2:24][C:25]#[C:26][CH3:27]
Reactant: C1COCCN1
Reactant: CC#CCC(C)[C@H](O)/C=C/[C@@H]1[C@H]2c3cccc(CCCC(=O)O)c3O[C@H]2C[C@H]1O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC#CCC(C)[C@H](O)/C=C/[C@@H]1[C@H]2c3cccc(CCCCN4CCOCC4)c3O[C@H]2C[C@H]1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
10 mg of (1R,2R,3aS,8bS)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(3S,1E)-3-hydroxy-4-methyl-1-octene-6-ynyl]-5-(3-carboxypropyl)-1H-cyclopenta[b]benzofuran was taken and was dissolved in 2 mL of dimethylformamide. After addition of 8.1 mg of 1,1′-carbonyldiimidazole, it was stirred at 50° C. for 1 hour. It was cooled to ambient temperature, and 50 mg morpholine was added. After stirring at 50° C. for 1 hour, an aqueous solution saturated with ammonium chloride was added and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, and dried with anhydrous sodium sulfate. After filtration and concentration, 2 mL of tetrahydrofurane was added. While stirring on ice, 9.5 mg of lithium aluminium hydride was added and stirring continued at 0° C. for 15 minutes, then at 50° C. for 1 hour. While stirring at ambient temperature, 100 μL of an aqueous solution saturated with sodium sulfate was added, then 400 mg of anhydrous sodium sulfate was added, and stirred for 1 hour. A filtration was performed over celite, and after washing the residue with ethyl acetate, the filtrate was concentrated and subjected to a silicagel column chromatography, to obtain 5.3 mg of the compound presented in the title (48% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:9]2[CH2:12][CH:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[H-].[Na+].IC.[C:35](OCC)(=O)C>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:9]2[CH2:10][CH:11]([N:13]([CH3:35])[S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)(=[O:15])=[O:16])[CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1ccc(F)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CN(C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)S(=O)(=O)c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 0.26 g of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-4-fluorophenylsulfonamide in 5 cm3 of tetrahydrofuran is added, at room temperature under an argon atmosphere, to a suspension of 20.5 mg of 80% sodium hydride in 10 cm3 of tetrahydrofuran. After stirring for 1 hour at around 20° C., 60 mm3 of iodomethane are added and then after stirring for an additional 16 hours, the suspension is supplemented with 30 cm3 of ethyl acetate and 20 cm3 of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography on silica gel [eluant: cyclohexane/ethyl acetate (90/10 by volume)]. 19 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-methyl-4-fluorophenylsulfonamide are thus obtained in the form of a white powder [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.69 (s: 3H); 3.02 (split t, J=7 and 2 Hz: 2H); 3.35 (split t, J=7 and 2 Hz: 2H); 3.91 (mt: 1H); 4.27 (s: 1H); from 7.15 to 7.35 (mt: 10H); 7.75 (dd, J=9 and 5 Hz: 2H)].
Reaction SMILES: O.Cl.Cl.N[C:5]1[CH:6]=[C:7]([C:11]2[N:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15](=[O:21])[NH:16]3)[CH:8]=[CH:9][CH:10]=1.S(=O)(=O)(O)[OH:23].N([O-])=O.[Na+].[OH-].[NH4+]>O>[OH:23][C:5]1[CH:6]=[C:7]([C:11]2[N:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15](=[O:21])[NH:16]3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1cccc(-c2nccc3[nH]c(=O)ccc23)c1
Agent: Cl
Agent: O=N[O-]
Agent: [NH4+]
Solvent: O
Product: O=c1ccc2c(-c3cccc(O)c3)nccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture containing 6.9 g of 5-(3-aminophenyl)-1,6-naphthyridin-2(1H)-one dihydrochloride monohydrate and 50 ml of water in an ice bath was slowly added 50 ml of concentrated sulfuric acid followed by 1.45 g of sodium nitrite. The reaction mixture was stirred in an ice bath for about 2 hours and then allowed to warm up to room temperature. It was next heated on a steam bath for about 2 hours and then allowed to stand at room temperature overnight. The reaction mixture was treated with ammonium hydroxide solution until it became weakly basic. The separated solid was collected, washed with water and dried in a vacuum oven at 90° C. The solid was recrystallized from boiling isopropyl alcohol using decolorizing charcoal, the mixture filtered and the filtrate concentrated until the solid separated. The solid was collected and washed with isopropyl alcohol. Additional solid was obtained by concentrating the filtrate. The solids were combined and recrystallized from dimethylformamide using decolorizing charcoal and dried in a vacuum oven at 90° C. to yield 1.3 g of 5-(3-hydroxyphenyl)-1,6-naphthyridin-2(1H)-one, m.p. 297°-299° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17](I)[CH:16]=[CH:15][C:3]=1[O:4][Si:5]([CH:12]([CH3:14])[CH3:13])([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7].[C:20]([C:24]1[CH:28]=[C:27]([NH2:29])[NH:26][N:25]=1)([CH3:23])([CH3:22])[CH3:21].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[C:20]([C:24]1[CH:28]=[C:27]([NH2:29])[N:26]([C:17]2[CH:16]=[CH:15][C:3]([O:4][Si:5]([CH:12]([CH3:14])[CH3:13])([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7])=[C:2]([Cl:1])[CH:18]=2)[N:25]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)[Si](Oc1ccc(I)cc1Cl)(C(C)C)C(C)C
Reactant: CC(C)(C)c1cc(N)[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2N)cc1Cl)(C(C)C)C(C)C
Temperature: 111 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
To a solution of aryl iodide of Example 1 (493.6 g, 1.202 moles) in toluene (1000 ml) under nitrogen, was added 3-tert-butyl-1H-pyrazol-5-amine (184.2 g, 1.322 moles) followed by trans-N,N′dimethylcyclohexane-1,2-diamine (16.2 g, 0.240 moles), potassium carbonate (348 g, 2.52 moles) and copper (I) iodide (11.6 g, 0.061 moles). The mixture was heated at 111° C. for 16 hours. After this time the reaction was cooled to 20° C., and partitioned with water (1500 ml) and ethyl acetate (1500 ml). The organic phase was sequentially washed with 10% w/v aqueous citric acid solution (1500 ml) and water (1500 ml). Solvent was distilled under reduced pressure and replaced by n-heptane (1500 ml). The solution was cooled to 5° C. granulated for 16 hours. The solid was collected by filtration to give the title compound as a brown solid (334 g, 65%).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[C:25]([O:27]C(C)(C)C)=[O:26])[C:5]1=[O:34])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>CCOCC>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([CH:24]([CH2:32][CH3:33])[C:25]([OH:27])=[O:26])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC(C)(C)C)C1=O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)C(=O)O)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 15-mL round-bottomed flask was added (S)-tert-butyl 2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate (420 mg, 0.813 mmol) (Example 1, Step F) and anisole (444 μL, 4.07 mmol), followed by TFA (4066 μL) which had been pre-cooled to 0° C. The reaction mixture was stirred at 0° C. for 1 h, diluted with 50 ml of ether, and the combined organics were washed with 20 ml water, NaHCO3/sat NaCl solution until neutral, then dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (eluent: 0 to 20% EtOAc/hexanes, gradient elution) provided the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[S:27][C:26]([CH2:28]O)=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:28][C:26]5[S:27][C:23]([F:22])=[CH:24][CH:25]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: OCc1ccc(F)s1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)s4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 5 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (127 mg), (5-fluorothiophen-2-yl)methanol (40 mg) and tributylphosphine (182 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (227 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine successively, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (MeOH/DCM) followed by preparative HPLC to afford the title compound (6 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH:15]1([NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH:15]1([NH:18][C:19]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([C:2]3[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]4[CH2:12][CH2:11]4)=[O:7])=[CH:4][N:3]=3)[CH:21]=2)=[O:36])[CH2:16][CH2:17]1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1)(25.5 mg, 0.10 mmol) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8)(30 mg, 0.110 mmol), aqueous sodium carbonate (2N, 0.5 ml) and tetralkis(triphenylphosphine)palladium (4 mg) were heated at 90° C. in DMF (1 ml) for 3 hours. The reaction was absorbed onto silica, applied to a bond-elut (5 g, silica) and eluted with an ethylacetate/cyclohexane (0 to 100%) and then acetone. The solvent was evaporated from the product fractions under vacuum and the residue triturated with ether to 6-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-N-cyclopropylmethyl-nicotinamide as a cream solid. LCMS: retention time 2.70 min, MH+ 350. NMR: δH [2H6]-DMSO 9.11,(1H, s), 8.84,(1H, t), 8.48,(1H, d), 8.31,(1H, dd), 7.88,(1H, s), 7.81,(1H, d), 7.70,(1H, d), 7.41,(1H, d), 3.20,(1H, t), 2.86,(1H, m), 2.37,(3H, s), 1.06,(1H, m), 0.69,(2H, m), 0.57,(2H, m), 0.46,(2H, m), 0.26, (2H, m).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]=[CH:10]2)#[N:2].[BH4-].[Na+]>C(O)C>[C:1]([CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2)#[N:2]
Reactant: N#CCOc1cccc2c1CCC=C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CCOc1cccc2c1CCCC2
Temperature: 25 °C
Yield: 79.8 %

Procedure:
The product from Example 14 (11.4 g) was refluxed for 2.5 hours in ethanol (250 ml) containing sodium borohydride (3.0 g). The reaction was cooled to room temperature and evaporated to dryness. Aqueous hydrochloric acid (50 ml) was carefully added followed by extraction with dichloromethane. The organic layer was separated, dried and evaporated affording the product (9.2 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[C:26]2[CH2:27][CH2:28][N:29]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:30][C:25]=2[C:5]2[C:6]([OH:24])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:40].[N:41]1([CH2:46][CH2:47][CH2:48][C:49](O)=[O:50])[CH2:45][CH2:44][CH2:43][CH2:42]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:40].[CH3:39][C:2]1([CH3:1])[C:26]2[CH2:27][CH2:28][N:29]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:30][C:25]=2[C:5]2[C:6]([O:24][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCCC1
Reactant: CCCCCCCCCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CCc2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCCCCCCCCC(C)c1cc(OC(=O)CCCN2CCCC2)c2c(c1)OC(C)(C)C1=C2CN(CCc2ccccc2)CC1

Procedure:
5,5-Dimethyl-10-hydroxy-2-phenethyl-8-(2-tetradecyl)-1,2,3,4-tetrahydro-5H-[ 1]benzopyrano[3,4-d]pyridine, γ-pyrrolidinobutyric acid hydrochloride and dicyclohexylcarbodiimide are reacted in equimolar amounts according to Example 1 to produce the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])[CH:7]=[CH:8][C:9]=1OS(C(F)(F)F)(=O)=O)[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>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.C(COC)OC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])[CH:7]=[CH:8][C:9]=1[C:29]1[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=1)[CH3:2]
Reactant: COc1ccc(OB(O)O)cc1
Reactant: CCOc1cc(/C=C/C(=O)OC)ccc1OS(=O)(=O)C(F)(F)F
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: [Na+]
Solvent: COCCOC
Product: CCOc1cc(/C=C/C(=O)OC)ccc1-c1ccc(OC)cc1
Reaction time: 15 h

Procedure:
A mixture of 1.0 g (2.82 mmol) of methyl 3(E)-(3-ethoxy-4-trifluoromethanesulfonyloxyphenyl)acrylate, 0.47 g (3.10 mmol) of 4-methoxyphenylboric acid, 0.71 g (8.46 mmol) of sodium bicarbonate and 20 ml of dimethoxyethane is flushed three times with argon, 163 mg (0.14 mmol) of tetrakis(triphenylphosphine)palladium(0) are then added and the reaction is then allowed to continue for 15 hours at 80° C. Thereafter, the reaction mixture is cooled and is partitioned between ethyl acetate and water and the organic phase is washed with water and dried over magnesium sulfate, filtered and evaporated down. The residue is chromatographed over 100 g of silica gel using toluene/ethyl acetate (3:1). This gives methyl 3(E)-(2-ethoxy-4′-methoxybiphenyl-4-yl)acrylate.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]2[NH:13][C:12](=[O:14])[C:11](=[C:15]([CH3:17])[CH3:16])[CH2:10][C@@H:9]2[OH:18])[CH2:6][CH2:5][CH2:4][CH2:3]C1>C(OCC)(=O)C.[Pd]>[CH:7]1([C@@H:8]2[NH:13][C:12](=[O:14])[C@H:11]([CH:15]([CH3:16])[CH3:17])[CH2:10][C@@H:9]2[OH:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:1]1
Reactant: CC(C)=C1C[C@H](O)[C@H](CC2CCCCC2)NC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1C[C@H](O)[C@H](C2CCCCC2)NC1=O

Procedure:
A solution of the product of Example 80e (24.7 g, 98.4 mmol) in 500 ml of ethyl acetate was treated with 2.5 g of dry Pd/C and hydrogenated at 4 atm for 4h at ambient temperature. The reaction mixture was filtered and concentrated to a white foamy solid which was taken on without further purification. mp 97°-99° C.; [α]D =-95.1° (c=1.075, CHCl3); IR (KBr, cm-1) 3605, 3400, 2925, 1642; 1H NMR (300 MHz, CDCl3) δ 6.3 (bs, 1H), 4.11 (m, J=4.5, 1H), 3.47 (m, 1H), 2.72 (bs, 1H), 2.5 (m, 1H), 2.3 (m, 1H), 1.9 (m, 1H), 1.8-1.5 (m, 8H), 1.43-1.12 (m, 6H), 0.97 (d, 3H), 0.87 (m, 3 H); 13C NMR (75.5 Hz, CDCl3) ppm 174.2, 67.1, 52.6, 44.3, 37.7, 34.5, 33.8, 32.4, 27.6, 26.4, 26.3, 26.2, 26.0, 20.2, 17.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[I:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH:7][S:18]([C:15]2[CH:16]=[CH:17][C:12]([I:11])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH:8]=1
Reactant: CSc1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(I)cc1

Procedure:
Following General Procedure B, the title compound was prepared from 5-chloro-2-(methylthio)aniline and 4-iodo-benzenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[S:13](=[O:16])(=[O:15])[NH2:14].N[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1.C(O)CCCC.O=C1C2C(=CC=CC=2)C(=O)N1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:7])[N:8]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=4)[CH2:20][CH2:19]3)[C:9]2=[O:10])=[CH:11][C:12]=1[S:13]([NH2:14])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Reactant: NC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: O=C1NC(=O)c2ccccc21
Solvent: CCCCCO
Product: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(C1CCN(Cc3ccc(Cl)cc3)CC1)C2=O

Procedure:
Reaction of 4-chloro-5sulfamoylphthalimide (5.57 g., 0.0214 mole) and 4-amino-1-(4-chlorobenzyl)piperidine (4.8 g., 0.0214 mole) in 85 ml. of n-pentanol according to the procedure of Example 1(a) with heating at 130°-138° for a 48 hr. period afforded 7.07 g. (71%) m.p. 248°-250° (dec.) of the 1,3-dioxoisoindole product. A sample crystallized from dimethylformamide-methanol provided analytically pure 6-chloro-2-[1-[(4-chlorophenyl)methyl]-4-piperidinyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-sulfonamide, m.p. 250°-251° (dec.).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](I)[CH:6]=1)(=[O:3])[CH3:2].[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:15]#[C:14][CH2:13][CH2:12][OH:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C#CCCO
Reactant: CC(=O)Oc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CC(=O)Oc1cccc(C#CCCO)c1
Temperature: 25 °C

Procedure:
A solution of 3-iodophenyl acetate (5.6 g) (J. Org. Chem. 1983, 48,1542-4) in acetonitrile (100 mL) was treated with (Ph3P)2PdCl2 (673 mg) and Cul (368 mg) and stirred at room temperature. 3-Butyn-1-ol (1.78 g) was added and the reaction mixture stirred for a further 20 h and concentrated in vacuo. The residue was purified by chromatography (SPE, gradient from cyclohexane to DCM) to give the title compound. LCMS RT=2.54 min
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[N:25]=[CH:24][C:23]3[CH:26]=[C:27]([C:33]4[CH:34]=[N:35][N:36](C(OC(C)(C)C)=O)[CH:37]=4)[N:28](S(C)(=O)=O)[C:22]=3[CH:21]=2)=[N:17][CH:18]=1>CN(C=O)C.O>[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[N:25]=[CH:24][C:23]3[CH:26]=[C:27]([C:33]4[CH:37]=[N:36][NH:35][CH:34]=4)[NH:28][C:22]=3[CH:21]=2)=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccc(F)cn4)cc3n2S(C)(=O)=O)cn1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Fc1ccc(Nc2cc3[nH]c(-c4cn[nH]c4)cc3cn2)nc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
DBU (10.8 μL, 0.072 mmol) was added to a solution of tert-butyl 4-(6-(5-fluoropyridin-2-ylamino)-1-(methylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)-1H-pyrazole-1-carboxylate (Preparation 54, 17 mg, 0.036 mmol) in DMF (240 μL). The reaction mixture was stirred for 1 hour at 50° C. and for 1 hour at 100° C. The reaction mixture was diluted with water and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was then purified using preparative TLC eluting with 5% MeOH/aq NH3 10/1 in DCM to afford the title compound as a white solid (7 mg, 24%). 1H NMR (500 MHz, CD3OD): δ 6.66 (d, J=0.9 Hz, 1H), 7.18-7.21 (m, 1H), 7.46-7.50 (m, 1H), 7.71 (s, 1H), 8.03 (br s, 2H), 8.07-8.09 (m, 1H), 8.42 (d, J=0.9 Hz, 1H). ESI-HRMS Found 295.1103, calculated for C15H12FN6 [M+H]+: 295.1102. MPS1 IC50 (uM): 0.1586
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1([CH2:14][C:15]2[CH:29]=[CH:28][C:18]3[O:19][CH:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[N:11]1[CH2:10][CH2:9][N:8]([CH2:14][C:15]2[CH:29]=[CH:28][C:18]3[O:19][CH:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[CH2:13][CH2:12]1
Reactant: Clc1ncccn1
Reactant: c1ccc(C2Oc3ccc(CN4CCNCC4)cc3O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(C2Oc3ccc(CN4CCN(c5ncccn5)CC4)cc3O2)cc1
Yield: 81.2 %

Procedure:
A solution of 5.7 g (0.05 mole) of 2-chloropyrimidine and 14.7 g (0.05 mole) of 5-(1-piperazinyl methyl)-2-phenyl benzo [d]-1,3-dioxole in 200 ml of dimethylformamide was refluxed for 9 hours in the presence of 13.8 g of dry potassium carbonate. The so-obtained salt was suction-filtered off and the solvent was evaporated off under reduced pressure. The crystallised residue was washed with water, and was then recrystallised from 110 ml of cyclohexane. There was obtained 15.2 g of 5-[4-(2-pyrimidinyl)-1 piperazinyl] methyl-2-phenyl benzo [d]-1,3-dioxole, cream-coloured crystals melting at (K) 106° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:15]([CH2:16][C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])[CH:14]=[N:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:35][C:36]([CH3:38])=[O:37]>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:15]([CH:16]([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])[C:36]([OH:37])([CH3:38])[CH3:35])[CH:14]=[N:13][CH:12]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cncn1Cc1ccccc1C#N
Reactant: CC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)C(c1ccccc1C#N)n1cncc1CCO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
2-{5-[2-(tert-Butyldimethylsilanyloxy)-ethyl]-imidazol-1-ylmethyl}-benzonitrile (1.14 g, 3.34 mmol) is dissolved in THF (20 mL) and cooled to −78° C. LHMDS (1M in THF, 5 mL, 5 mmol) is added dropwise. Ten min after the end of addition, acetone (0.295 g, 5.01 mmol) is added. The reaction mixture is stirred at −78° C. for 40 min. It is then quenched with saturated aqueous sodium bicarbonate (10 mL). The mixture is allowed to warm to room temperature, then poured into water. After extraction with ethyl acetate the organic phase is dried over Na2SO4 and concentrated in vacuo to give 2-(1-{5-[2-(tert-butyldimethylsilanyloxy)-ethyl]-imidazol-1-yl}-2-hydroxy-2-methyl-propyl)-benzonitrile; MS (ESI) m/z 400.3 (M+H)