Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[N:5]2[CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=[C:4]2[CH:3]=1.[CH2:21]([N:23]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)[S:24]([CH3:27])(=[O:26])=[O:25])[CH3:22].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Pd]>[CH2:21]([N:23]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=3)[N:5]3[CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=[C:4]3[CH:3]=2)[CH:33]=1)[S:24]([CH3:27])(=[O:25])=[O:26])[CH3:22]
Reactant: CCN(c1cccc(B(O)O)c1)S(C)(=O)=O
Reactant: Cc1cc(Nc2nc(Cl)cc3nc(C(C)C)cn23)n[nH]1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCN(c1cccc(-c2cc3nc(C(C)C)cn3c(Nc3cc(C)[nH]n3)n2)c1)S(C)(=O)=O
Temperature: 150 °C

Procedure:
7-chloro-2-isopropyl-N-(5-methyl-1H-pyrazol-3-yl)imidazo[1,2-c]pyrimidin-5-amine (0.17 mmol, 0.05 g), 3-(N-ethylmethylsulfonamido)phenylboronic acid (0.35 mmol) and (Ph3)4 Pd (O) (0.086 mmol, 0.1 g) were stirred in dioxane (3 mL) and sat. K2CO3 (1.5 mL). The reaction mixture was heated to 150° C. using a microwave reactor for 20 minutes. The mixture was then concentrated and purified by LC-MS to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (t, J=7.07 Hz, 3H) 1.35 (d, J=6.82 Hz, 6H) 2.29 (s, 3H) 3.04 (s, 3H) 3.76 (q, J=7.07 Hz, 2H) 6.70 (s, 1H) 7.57 (s, 1H) 7.59-7.67 (m, 2H) 8.11 (d, J=7.58 Hz, 1H) 8.17 (s, 1H) 8.45 (s, 1H) 10.80 (s, 1H) 12.35 (s, 1H); ESI-MS: m/z calc'd for C22H27N7O2S 453.56; found 454.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[CH2:26][N:25](CC5C=CC(OC)=CC=5)[C:24]4=[O:38])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH:27]([CH3:28])[CH2:26][NH:25][C:24]4=[O:38])=[CH:21][CH:22]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cc3)C2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NCC4C)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.9 %

Procedure:
3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (105 mg) described in Example 420 was dissolved in dichloromethane (1 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture, 5% aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform/methanol (10/1). The organic layer was dried over sodium sulfate, and the solvent was evaporated. The obtained residue was suspension washing with IPE to give the title compound (86 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C:5](=[O:7])[CH:6]=1>[Pd].CCOC(C)=O>[CH3:1][CH:2]1[CH2:6][C:5](=[O:7])[CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1CC(=O)C=C1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC(=O)CC1C
Reaction time: 48 h
Yield: 98.6 %

Procedure:
EtOAc (580 mL) was added to a round bottom flask charged with 10 wt % Pd/C (7.6 g, 7.1 mmol) at about 0° C., under a nitrogen atmosphere. The cooling bath was removed and ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate (60.0 g, 357 mmol) was added. Hydrogen gas was bubbled through the mixture for about 5 min and the mixture was then stirred under a hydrogen atmosphere (1 atmosphere) for about 48 h. The hydrogen source was removed and the mixture was bubbled with nitrogen for about 5 min and was filtered through a pad of Celite®. The filter cake was rinsed with EtOAc (500 mL). The filtrate was concd under reduced pressure to give ethyl 2-methyl-4-oxocyclopentanecarboxylate (59.9 g, 99%) as a yellow liquid: 1H NMR (CDCl3) δ 4.23-4.14 (m, 2H), 3.18 (ddd, J=5.6, 6.8, 8.1 Hz, 1H), 2.73-2.65 (m, 1H), 2.60 (ddd, J=1.7, 5.5, 18.7 Hz, 1H), 2.42-2.29 (m, 2H), 2.15 (ddd, J=1.7, 7.9, 18.3 Hz, 1H), 1.29 (t, J=7.1 Hz, 3H), 1.07 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12](B(O)O)=[C:11]([F:19])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].Br[C:21]1[S:22][C:23]([CH2:26][CH2:27][CH3:28])=[CH:24][CH:25]=1>>[F:19][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH:14]=[C:13]([F:15])[C:12]=1[C:21]1[S:22][C:23]([CH2:26][CH2:27][CH3:28])=[CH:24][CH:25]=1
Reactant: CCCc1ccc(Br)s1
Reactant: CCc1ccc(-c2cc(F)c(B(O)O)c(F)c2)cc1
Product: CCCc1ccc(-c2c(F)cc(-c3ccc(CC)cc3)cc2F)s1

Procedure:
The compound 2-(3,5-difluoro-4′-ethylbiphenyl-4-yl)-5-propylthiophene (PUS-2-3) is prepared analogously to Example 2 from 4′-ethyl-3,5-difluoro-4-biphenylboronic acid and 2-bromo-5-propylthiophene.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]5[CH:29]=O)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[NH2:32][OH:33]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:26])[CH3:27])=[C:19]5/[CH:29]=[N:32]\[OH:33])=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NO
Reactant: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1C=O
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1/C=N\O
Reaction time: 48 h
Yield: 77.2 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-formyl-1H-indol-5-yl)cyclopropanecarboxamide (100 mg, 0.25 mmol) in dichloromethane (5 mL) was added hydroxylamine hydrochloride (21 mg, 0.30 mmol). After stirring for 48 h, the mixture was evaporated to dryness and purified by column chromatography (0-100% ethyl acetate/hexanes) to yield (Z)-1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-((hydroxyimino)methyl)-1H-indol-5-yl)cyclopropanecarboxamide (81 mg, 77%). ESI-MS m/z calc. 419.5, found 420.5 (M+1)+; retention time 3.42 minutes. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 0.5H), 10.55 (s, 0.5H), 8.56-8.50 (m, 2H), 8.02 (m, 1H), 7.24-7.22 (m, 1H), 7.12-7.10 (m, 1H), 7.03 (m, 1H), 6.96-6.90 (m, 2H), 6.03 (s, 2H), 1.43 (s, 9H), 1.40-1.38 (m, 2H), 1.04-1.01 (m, 2H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C1C[O:12][CH2:11]C1>>[N:7]1[C:11](=[O:12])[N:8]=[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=12
Reactant: C1CCOC1
Reactant: Nc1ccccc1N
Product: O=C1N=c2ccccc2=N1
Reaction time: 16 h

Procedure:
A solution of phenylene diamine 6.48 g in dry THF (150 ml) was cooled to 5° C. A suspension of 1,1-carbonyldiimidazole (10.7 g) in THF (100 ml) was added to this solution over 15 minutes keeping the temperature below 10° C. The mixture was stirred for 16 hours and the resultant solid was collected and dried to give the title compound (4.5 g); NMR: 6.9 (s, 4H), 10.5 (s, 2H); MS (ESP−): 135 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.Cl.[CH3:29][O:30][C:31](=[O:35])[C@H:32]([CH3:34])[NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCN(C(C)C)C(C)C>[CH3:29][O:30][C:31](=[O:35])[C@@H:32]([NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:34]
Reactant: COC(=O)[C@H](C)N
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C
Yield: 94.6 %

Procedure:
(S)-2-{[1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid methyl ester (863 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (750 mg), L-alanine methyl ester hydrochloride (293 mg), HBTU (870 mg), and DIEA (500 uL).
Reaction SMILES: C=O.[NH2:3][N:4]([CH2:9][CH2:10][OH:11])[C:5](=[O:8])[O:6][CH3:7].[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[O:11]1[CH2:10][CH2:9][N:4]([C:5]([O:6][CH3:7])=[O:8])[NH:3][CH2:12]1
Reactant: COC(=O)N(N)CCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COC(=O)N1CCOCN1
Temperature: 42 °C
Reaction time: 21 h
Yield: 85.8 %

Procedure:
At 22° C., 22.4 g (0.746 mol) of paraformaldehyde were added with stirring, over a period of 2 min to a mixture of 100 g (0.746 mol) of methyl N-amino-N-2-hydroxyethylcarbamate in 1500 ml of methylene chloride. After addition of 8.5 g (0.045 mol) of p-toluenesulfonic acid, the mixture was stirred at 42° C. for 21 h, until the precipitate had dissolved, and was then cooled to 20° C., and magnesium sulfate was added. The mixture was filtered and the filtrate was concentrated under reduced pressure. This gave 111.8 g of the title compound as a colorless resin with a GC purity of 85%, corresponding to a yield of 85.8% of theory.
Reaction SMILES: [F:1][C:2]1[C:3]([C:40]([F:43])([F:42])[F:41])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]4[CH2:24][N:23]([C:25]([N:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[O:26])[CH2:22][C:19]=4[NH:20][N:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:3]([C:40]([F:43])([F:41])[F:42])=[C:4]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:18]4[CH2:24][N:23]([C:25]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[O:26])[CH2:22][C:19]=4[NH:20][N:21]=3)=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)N2Cc3[nH]nc(C(=O)N4CCC(c5ccc(F)c(F)c5C(F)(F)F)CC4)c3C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1n[nH]c2c1CN(C(=O)N1CCNCC1)C2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
A solution of tert-butyl 4-(3-(4-(3,4-difluoro-2-(trifluoro-methyl)phenyl)piperidine-1-carbonyl)-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole-5-carbonyl)piperazine-1-carboxylate (47 mg, 0.077 mmol) in anhydrous CH2Cl2 (1.5 mL) was cooled to 0° C. under an atmosphere of N2 and treated with TFA (1.5 mL). When the addition was complete, the cooling bath was removed and the reaction stirred at room temperature for 1 h. After this time, the mixture was concentrated to dryness under reduced pressure, diluted in CH2Cl2 (100 mL) and washed with 2 M aqueous NaOH (2×50 mL). The organic layer was dried over Na2SO4 and the drying agent removed by filtration. The filtrate was concentrated to dryness under reduced pressure and the resulting residue chromatographed over silica gel (Isco CombiFlash Rf unit, 120 g Redisep column, 0% to 40% CH3OH in CH2Cl2). The combined column fractions were concentrated to dryness under reduced pressure and found to contain residual TFA (˜17%). The resulting residue (21 mg) was diluted in a mixture of CH2Cl2 (5 mL) and CH3OH (1 mL), treated with MP-carbonate and stirred at room temperature for 2 h. After this time the mixture was filtered and the filtrate concentrated to dryness under reduced pressure to provide (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(piperazine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone as a white solid (13 mg, 33%): mp 153-155° C.; 1H NMR (500 MHz, DMSO-d6) δ 13.20 (br s, 1H), 7.75 (dd, J=18.0, 9.0 Hz, 1H), 7.55-7.52 (m, 1H), 4.65-4.51 (m, 6H), 3.24-3.22 (m, 2H), 3.14 (t, J=5.0 Hz, 4H), 2.96-2.80 (m, 1H), 2.70-2.68 (m, 3H), 2.32-2.22 (m, 1H), 1.79-1.70 (m, 4H), 1 proton not readily observed; ESI MS m/z 513 [M+H].
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C=O)C.[C:10]1([S:16]([N:19]2[C:31]3[CH:30]=[C:29]([CH:32](O)[CH3:33])[CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[C:10]1([S:16]([N:19]2[C:31]3[CH:30]=[C:29]([CH:32]([Cl:3])[CH3:33])[CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(O)c1ccc2c3ccccc3n(S(=O)(=O)c3ccccc3)c2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(Cl)c1ccc2c3ccccc3n(S(=O)(=O)c3ccccc3)c2c1

Procedure:
Thionyl chloride (0.26 ml, 3.54 mmol) and catalytically effective amount of DMF were added at room temperature to a solution of 9-benzenesulfonyl-2-(1-hydroxyethyl)carbazole (0.621 g, 1.77 mmol) in methylene chloride, and the mixture was heated under reflux for 1.5 hours. After evaporation of the solvent under reduced pressure, the thus obtained residue was mixed with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in that order, the organic layer was dried over magnesium sulfate and then the solvent was evaporated under reduced pressure to obtain 9-benzenesulfonyl-2-(1-chloroethyl)carbazole.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:23][C:12]2=[C:13]3[N:18]([N:19]=[C:11]2[CH2:10]1)[C:17]([CH3:20])=[C:16]([Cl:21])[C:15]([CH3:22])=[N:14]3)=O)(C)(C)C.CC(OC)(C)C>CC(O)=O>[ClH:21].[Cl:21][C:16]1[C:15]([CH3:22])=[N:14][C:13]2[N:18]([N:19]=[C:11]3[CH2:10][NH:9][CH2:23][C:12]3=2)[C:17]=1[CH3:20]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: Cc1nc2c3c(nn2c(C)c1Cl)CNC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 199.4 %

Procedure:
Aq. 32% HCl (1.14 mL; 11.62 mmol; 3 eq.) was added to a suspension of 6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carboxylic acid tert-butyl ester (1.25 g; 3.87 mmol; 1 eq.) in AcOH (6.25 mL) and the resulting mixture was stirred at room temperature for 2 hours then poured into MTBE (40 mL). The precipitate was filtered off, washed with MTBE (3×) and dried to afford the title compound (1 g, 100%) as an off-white solid. 1H NMR (DMSO-d6) δ 10.55 (s, 2H), 4.57-4.52 (m, 4H), 2.83 (s, 3H), 2.61 (s, 3H). HPLC (max plot) 100.0%; Rt 1.38 min. UPLC/MS: (MS+) 222.9 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C([Li])CCC.C[Si](Cl)(C)C.[S:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1.Cl>O1CCCC1.C(OCC)C>[NH2:5][C:4]1[CH:3]=[C:2]([F:1])[C:8]([C:23]2([OH:26])[CH2:24][CH2:25][S:20][CH2:21][CH2:22]2)=[C:7]([F:9])[CH:6]=1
Reactant: O=C1CCSCC1
Reactant: Nc1cc(F)cc(F)c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1cc(F)c(C2(O)CCSCC2)c(F)c1
Reaction time: 0.5 h

Procedure:
3,5-Difluoroaniline (12.9 g, 0.1 M) in dry tetrahydrofuran (400 ml) was stirred and cooled under nitrogen to −78°. n-Butyllithium (1.6M in hexanes, 131 ml, 0.21 M) was run in slowly over 15 minutes, maintaining the temperature below −65°. Stirring was continued at the same temperature for 30 minutes, then trimethylsilyl chloride (22.8 g, 0.21 M) in tetrahydrofuran (100 ml) was added dropwise over 15 minutes. The temperature was then allowed to rise to ambient, and the mixture stirred overnight. After recooling to −78°, further n-butyllithium (1.6M in hexanes, 68.8 ml, 0.11 M) was added dropwise below −70°, and stirring continued for 5 hours to form anion. A solution of tetrahydrothiopyran-4-one (12.5 g, 0.107 M) in tetrahydrofuran (80 ml) was added dropwise, keeping the temperature below −70°, and the temperature allowed to warm to ambient overnight. The mixture was cooled in an ice-bath and acidified to pH<1 by slow addition of hydrochloric acid (1M, ˜500 ml). After stirring 15 minutes, diethyl ether (1 L) was added, and the phases separated. The organic layer was washed with hydrochloric acid (1M, 200 ml), and the combined aqueous layers made basic with concentrated ammonia solution, then extracted with diethyl ether (600 ml). The extract was washed with water (100 ml), brine (100 ml), dried (magnesium sulfate) and evaporated. After dissolving the residue in dichloromethane, the desired product was precipitated by the addition of isohexane (17.4 g). MS (Negative ES): 244 (M—H—) for C11H13F2NOS
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:14][C:13](=O)[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][NH:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1(C)CCC(c2ccc(F)c(F)c2)NC1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)CCC(c2ccc(F)c(F)c2)NC1

Procedure:
To a stirred solution of 6-(3,4-difluorophenyl)-3,3-dimethylpiperidin-2-one (50.0 mg, 0.209 mmol, prepared according to Intermediate 14, Step A) in THF (1 mL) at 0° C. was added diisobutylaluminum hydride (1.05 mL of a 1 M solution in toluene, 1.05 mmol). The reaction mixture was stirred for 4 days, with additional diisobutylaluminum hydride (1.05 mL of a 1 M solution in toluene, 1.05 mmol) added on the 2nd and 3rd days. The reaction was quenched with saturated potassium sodium tartrate (5 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of MeOH:CH2Cl2-0:100 to 5:95, to give the title compound. MS: m/z=226 (M+1).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[F:9][C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([OH:16])[CH:15]=1.O>ClCCCl>[F:9][C:10]1[CH:15]=[C:14]([OH:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[C:5](=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: COc1ccc(F)cc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: COc1cc(C(C)=O)c(F)cc1O
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
To a suspension of AlCl3 (1.17 g; 8.79 mmol) in 1,2-dichloroethane (2 mL) was added acetyl chloride (0.55 g; 7.03 mmol). After 10 min stirring was added dropwise a solution of 5-fluoro-2-methoxyphenol (0.50 g; 3.52 mmol) in 1,2-dichloroethane (2 mL). The reaction mixture was stirred overnight at 40° C. The mixture was then poured on iced water and extracted with diethylether. The organic phases were combined, washed with brine, dried (Na2SO4) and concentrated to afford 582 mg (90%) of the title compound as an off-white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([CH:7]=[CH:8][C:9]3[O:10][C:11](=[O:18])[C:12]([CH3:17])([CH3:16])[C:13]=32)=[CH:5][C:4]=1[C:19]#[N:20].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.[Na].O>CN(C)C=O>[CH3:16][C:12]1([CH3:17])[C:11](=[O:18])[O:10][C:9]2[CH:8]=[CH:7][C:6]3[C:14]([C:13]1=2)=[CH:15][C:3]([CH2:2][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)=[C:4]([C:19]#[N:20])[CH:5]=3
Reactant: CC1(C)C(=O)Oc2ccc3cc(C#N)c(CBr)cc3c21
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(=O)Oc2ccc3cc(C#N)c(Cn4cncn4)cc3c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 8-bromomethyl-1,2-dihydro-1,1-dimethyl-2-oxonaphtho[2,1-b]furan-7-carbonitrile in N,N-dimethylformamide (3 ml) was treated with sodium 1,2,4-triazole (0.18 g) and the mixture was stirred at room temperature for 4 h, then treated with water (20 ml). The mixture was extracted twice with ethyl acetate and the combined extracts were dried and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography using methanol:ethyl acetate, 1:99 v/v, as eluant to give 1,2-dihydro-1,1-dimethyl-2-oxo-8-(1H-1,2,4-triazol-1-ylmethyl)naphtho(2,1-b)-furan-7-carbonitrile, m.p. 198°-198° after recrystallisation from a mixture of ethyl acetate and cyclohexane.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:1][CH2:2][C:3]([C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:20][CH:21]=1)([CH3:5])[CH3:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(CN)c1ccc(Oc2ccc(C(N)=O)cn2)cc1
Reactant: O=Cc1ccccc1
Product: CC(C)(CNCc1ccccc1)c1ccc(Oc2ccc(C(N)=O)cn2)cc1

Procedure:
Using a method similar to example 35, using 6-[4-(2-amino-1,1-dimethyl-ethyl)-phenoxy]-nicotinamide (example 193), and benzaldehyde affords the title compound: HPLC (5/95 to 95/5 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 6.01 minutes, Purity: 95.6%; mass spectrum (ion spray): m/z=376.1 (M+1).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>>[CH2:1]([O:8][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][Br:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCCCBr
Reactant: OCc1ccccc1
Product: BrCCCCCCOCc1ccccc1
Yield: 36 %

Procedure:
6-Benzyloxyhexyl bromide was prepared from benzyl alcohol (4.75 g, 44 mmol) and 1,6-dibromohexane (9.76 g, 40 mmol) using the general procedure given above. Yield: 36%, bp 100-105° C./torr: 1H-NMR: 1.2-1.9 (m, 8 H), 3.37 (t, 4 H), 4.46 (s, 2 H), 7.28 (m, 5 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[N:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)[CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:31]4[CH2:30][CH2:29][N:28]([C:26]5[CH:25]=[CH:24][CH:23]=[C:22]6[C:27]=5[N:18]=[CH:19][CH:20]=[CH:21]6)[CH2:33][CH2:32]4)[CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Fc1cc(N2CCNCC2)c2ncccc2c1
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Fc1cc(N2CCN(C3CCN(c4cccc5cccnc45)CC3)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a solution of 0.247 g of 6-fluoro-8-piperazino-quinoline (Step 3) in 10 mL of dichloroethane, was added 0.226 g of 1-quinolin-8-yl-piperidin-4-one (Example A, Step 6, above) followed by 0.274 g of sodium triacetoxyborohydride and 0.1 mL acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was washed with water and dried over magnesium sulfate. The product crystallized and filtered to give 0.200 g of the desired product. Mp: 211° C.; MS (ES) m/z (relative intensity): 442 (M++−H, 100).
Reaction SMILES: Cl[C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:8].[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[OH:29][C@@H:26]1[CH2:27][CH2:28][N:24]([C:3]2[C:2]([C:34]3[CH:35]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:23][C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([S:16]([C:19]([F:21])([F:20])[F:22])(=[O:18])=[O:17])=[CH:14][CH:15]=3)=[O:8])=[CH:5][N:4]=2)[CH2:25]1
Reactant: O=C(Nc1ccc(S(=O)(=O)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Cl)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(S(=O)(=O)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-chloro-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)sulfonyl)phenyl)nicotinamide (Stage 214.1) and pyrimidin-5-ylboronic acid to afford a solid. UPLC-MS (Condition 3), tR=0.92 min, m/z=−492.3; 1H-NMR (400 MHz, DMSO-d6), δ ppm 1.74 (br. s, 1H) 1.85 (br. s, 1H) 2.91 (d, J=10.95 Hz, 1H) 3.18-3.26 (m, 2H) 3.32-3.45 (m, 1H) 4.22 (br. s, 1H) 4.90 (d, J=3.52 Hz, 1H) 8.05-8.16 (m, 3H) 8.16-8.25 (m, 2H) 8.81-8.86 (m, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.65 (s, 1H).