Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH:9]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:10]=[CH:11][CH:12]1[CH:16]([CH:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15](=[O:28])[CH:14]=[CH:13]1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].CN(C1C=CC=CN=1)C.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Si:2]([O:1][CH:9]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:10]=[CH:11][CH:12]1[C:16](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15](=[O:28])[CH:14]=[CH:13]1)([C:5]([CH3:6])([CH3:8])[CH3:7])([CH3:4])[CH3:3]
Reactant: CCCCCC(C=CC1C=CC(=O)C1C(O)CCCCCC(=O)OC)O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCCCCC(C=CC1C=CC(=O)C1=CCCCCCC(=O)OC)O[Si](C)(C)C(C)(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 24.6 %

Procedure:
480 mg (1.0 mmole) of 4-(3-t-butyldimethylsiloxy-1-octenyl)-5-(1-hydroxy-6-methoxycarbonylhexyl)-2-cyclopentenone was dissolved in 5 ml of dichloromethane, followed by addition of 730 mg (6 mmoles) of dimethylaminopyridine and 230 microliters (3.0 mmoles) of methanesulfonyl chloride in this order. The mixture was stirred at 40° C. for 2 hours. An aqueous solution of sodium bicarbonate was added, and the mixture was stirred with dichloromethane. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The dried product was filtered, concentrated and subjected to silica gel column chromatography (silica gel 20 g; eluent, hexane:ethyl acetate=10:1) to give 114 mg (yield 25%) of 4-(3-t-butyldimethylsilyloxy-1-octenyl)-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone. The resulting compound had the following spectral data.
Reaction SMILES: F.[K].[Br:3][C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[N:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(O)([C:17]([F:20])([F:19])[F:18])=O.FC([Si](C)(C)C)(F)F.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O.CCOC(C)=O.CCCCCC>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]([NH:9][CH:10]2[CH2:11][CH2:12]2)[C:17]([F:20])([F:19])[F:18])=[CH:13][CH:14]=1
Reactant: Brc1ccc(C=NC2CC2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C[Si](C)(C)C(F)(F)F
Agent: F
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Solvent: CC#N
Solvent: O
Product: FC(F)(F)C(NC1CC1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Potassium hydrogen fluoride (0.697 g, 8.92 mmol) and N-(4-bromobenzylidene)-cyclopropanamine (2 g, 8.92 mmol) were dissolved in acetonitrile (17.85 ml) and cooled to 0° C. TFA (1.031 ml, 13.39 mmol) was added and the reaction was stirred for 5 min. Then (trifluoromethyl)trimethylsilane (2.64 ml, 17.85 mmol) was added and the reaction was allowed to stir at rt overnight. Saturated Na2CO3 was added to the reaction mixture and the reaction stirred 5 min, then diluted with water and EtOAc/Hexane (1:1). The aqueous phase was extracted with EtOAc (×2), and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage™ 50 g column by eluting with 2% to 25% EtOAc:Hexane to give product. A second purification was performed on this product on a Biotage™ 100 g column by eluting with 2% to 25% EtOAc to provide the desired product. LC-MS: calculated for C11H11BrF3N 293.00 observed m/e: 294.15 (M+H)+ (Rt 1.23/2 min).
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:3](/[CH:11]=[CH:10]/[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1cccnc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ncccc1N

Procedure:
950 mg (4.94 mmol) of the bromide from Example 5A, 1900 mg (14.83 mmol) of tert-butyl acrylate, 330 mg (1.50 mmol) of palladium(II) acetate, 450 mg (1.50 mmol) of tri-ortho-tolylphospine are dissolved in 15 ml of acetonitrile, and 1000 mg (9.88 mmol) of triethylamine are added. The mixture is stirred under reflux for 16 h. The reaction mixture is concentrated, mixed with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate, filtered, concentrated and purified by column chromatography on silica gel with cyclohexane/ethyl acetate (7:3). 95 mg (6% of theory) of product are obtained.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[O:26]1[C:31]2([CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[CH2:30][NH:29][CH2:28][CH2:27]1.[CH3:44][C:45]1[S:49][CH:48]=[C:47]([C:50](O)=[O:51])[CH:46]=1.C(N(CC)CC)C>CN(C=O)C.[Cl-].[Na+].O>[CH3:44][C:45]1[S:49][CH:48]=[C:47]([C:50]([N:29]2[CH2:30][C:31]3([CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)[O:26][CH2:27][CH2:28]2)=[O:51])[CH:46]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: Cc1cc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Reaction time: 16 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.91 g) was added to a solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.5 g), 5-methyl-thiophene-3-carboxylic acid (0.243 g) and triethylamine (0.95 mL) in DMF (10 mL) and the resulting mixture stirred for 16 h. The reaction mixture was poured into brine (40 mL) and extracted with ethyl acetate (3×50 mL). The combined organic solutions were washed with water (150 mL), brine (150 mL), dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a clear oil. Yield 0.34 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([CH3:35])[CH:29]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:28]3[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([CH3:35])[CH:29]=3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2ccnc(Cl)c2)n1
Reactant: Cc1cc(Br)cc(C)n1
Product: Cc1cc(-c2cc(C)nc(C(=O)Nc3ccnc(Cl)c3)c2)cc(C)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (2-chloro-pyridin-4-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-2,6-dimethylpyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=353.2, 355.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]\[CH2:18][N:19]2[CH:23]=[CH:22][CH:21]=[C:20]2[C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:12][CH:11]=1)([CH3:7])[C:3]([O:5]C)=[O:4].CO.[OH-].[Li+]>C1COCC1.O>[CH3:7][C:2]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]\[CH2:18][N:19]2[CH:23]=[CH:22][CH:21]=[C:20]2[C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:12][CH:11]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)OCc1ccc(/C=C\Cn2cccc2C(=O)c2ccc(C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cccn2C/C=C\c2ccc(COC(C)(C)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To the compound of Example 1-1 (410 mg, 0.95 mmol) in THF (4 ml) were added methanol (4 ml) and 1N aqueous lithium hydroxide solution (4 ml), followed by stirring for 8 hours at room temperature. The reaction mixture was diluted with water and washed with diethyl ether. To the aqueous layer was added 5% aqueous potassium hydrogen sulfate solution and the solution was adjusted around pH3 and extracted with ethyl acetate. The organic layer was washed with water, saturated brine, dried over magnesium sulfate and filtered. The solvent was removed in vacuo to give the subject compound (262 mg, 66%).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=1)[NH:18][CH:17]=[CH:16]2.[Cl:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH:35](O)[CH:36]1[CH2:38][CH:37]1[C:39]#[N:40]>ClCCCl.ClCCl>[Cl:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH:35]([C:16]1[C:15]2[C:19](=[C:20]([CH2:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[C:13]([F:12])[CH:14]=2)[NH:18][CH:17]=1)[CH:36]1[CH2:38][CH:37]1[C:39]#[N:40]
Reactant: N#CC1CC1C(O)c1ccc(F)cc1Cl
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(F)cc3Cl)C3CC3C#N)c[nH]c12

Procedure:
1.62 g (7.31 mmol) of indium(III) chloride and 0.92 ml (12.0 mmol) of trifluoroacetic acid were added to 1.89 g (6.65 mmol) of the compound from Example 87A with a purity of 80% and 1.50 g (6.65 mmol) of the compound from Example 161A under argon in 75 ml of 1,2-dichloroethane, and the mixture was heated under reflux overnight. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative SFC HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 1.65 g (57% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[N:21]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH:27]1([NH:26][C:22]2[N:21]=[C:20]([C:8]3[N:4]4[CH:5]=[CH:6][CH:7]=[C:2]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[C:3]4=[N:10][C:9]=3[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[CH:25]=[CH:24][N:23]=2)[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: O=[N+]([O-])c1cccc(-c2nc3c(Cl)cccn3c2-c2ccnc(NC3CCCC3)n2)c1
Reactant: C1COCCN1
Product: O=[N+]([O-])c1cccc(-c2nc3c(N4CCOCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 150 °C
Yield: 6 %

Procedure:
A thick walled glass tube was charged with N-{4-[8-chloro-2-(3-nitrophenyl)imidazo[1,2-α]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine (44 mg, 0.10 mmol) and morpholine (4 mL). The vessel was sealed and heated to 150° C. for 4 days. The mixture was concentrated in vacuo and purified via flash chromatography on silica gel (2:1 to 1:1 hexanes:ethyl acetate) to provide N-cyclopentyl-4-[8-(4-morpholinyl)-2-(3-nitrophenyl)imidazo[1,2-α]pyridin-3-yl]-2-pyrimidinamine (3 mg, 6%) as a yellow solid. 1H NMR (CDCl3): δ 8.92 (m, 1H), 8.67 (s, 1H), 8.21 (d, 1H), 8.13 (m, 1H), 8.01 (d, 1H), 7.53 (t, 1H), 6.83 (t, 1H), 6.61 (d, 1H), 6.40 (d, 1H), 5.33 (m, 1H), 4.33 (m, 1H), 4.00 (m, 4H), 3.58 (m, 4H), 2.14–2.06 (m, 2H), 1.83–1.54 (m, 6H); MS m/z 486 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][N:16]=1.O1CCCC1.C(O)C.[BH4-].[Na+]>O>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:21][CH:22]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(C=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a mixture of 6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]nicotinaldehyde (4.20 g), tetrahydrofuran (50 ml) and ethanol (50 mL) was added sodium borohydride (0.51 g) at room temperature and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (4.10 g, 97%) of [6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-3-pyridyl]methanol. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 70-71° C.
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][CH:3](Cl)[CH2:4][CH2:5][CH2:6][CH3:7].[C:17]([NH:20][C:21]1[C:22]([I:37])=[C:23]([N:32]([C:34](=[O:36])[CH3:35])[CH3:33])[C:24]([I:31])=[C:25]([C:28]([O-:30])=[O:29])[C:26]=1[I:27])(=[O:19])[CH3:18].[K+].[I-].[Na+]>CN(C=O)C>[C:17]([NH:20][C:21]1[C:22]([I:37])=[C:23]([N:32]([C:34](=[O:36])[CH3:35])[CH3:33])[C:24]([I:31])=[C:25]([C:28]([O:30][CH:3]([O:2][C:1]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:29])[C:26]=1[I:27])(=[O:19])[CH3:18]
Reactant: CCCCC(Cl)OC(=O)Oc1ccccc1
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(OC(=O)Oc1ccccc1)OC(=O)c1c(I)c(NC(C)=O)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 48 h

Procedure:
1-Chloropentyl phenyl carbonate (0.14 g, 0.58 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (0.35 g, 0.53 mmol) and sodium iodide (0,008 g, 0.053 mmol) in dry DMF (3 ml). After stirring at 50° C. for 5 hours and at room temperature for 2 days the solvent was removed at reduced pressure. The residue was suspended in chloroform (15 ml) and washed four times with a saturated sodium hydrogen carbonate solution and finally twice with water. After drying with magnesium sulfate the solution was evaporated to dryness. Yield: 0.04 g. Purity by HPLC: 94.8% 1H-NMR (DMSO-d6): delta=0.92(CH3CH2); 1.31-1.55 (CH3CH2CH2); 1.68 (NCH3COCH3); 2.04 (CH2CH); 2.05 (NHCOCH3); 2.97 (NCH3); 6.95 (CH); 7.27-7.49 (phenyl); 10.13 ppm (NH). FAB/MS: 835 ((M+H)+).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:26]Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:26][C:9]1[C:10]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=2)=[N:11][N:12]([CH3:13])[C:8]=1[C:7]([CH3:25])([CH3:24])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1C(C)(C)O[SiH2]C(C)(C)C
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)c(Br)c1C(C)(C)O[SiH2]C(C)(C)C
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
A solution of 5-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole (162 mg, 437 μmol) in dichloromethane (1.7 ml) was added within 10 min to a mixture of bromine (20 μl, 480 μmol) and sodium carbonate (93 mg, 880 μmol) in dichloromethane (4.3 ml) at 0° C. under an argon atmosphere. After stirring at 0 to 5° C. for 1 h and then at ambient temperature for 1 h, the mixture was quenched with water (5 ml) and extracted two times with dichloromethane. The combined extracts were washed with aqueous saturated NaHSO3 solution and brine/ice water 1/1 and dried over sodium sulfate. Removal of the solvent under reduced pressure left off-white crystals which were purified by column chromatography (silica gel, heptane/AcOEt) to give 90 mg (0.2 mmol, 46%) of the title compound as colorless crystals.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:20])[C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)([CH3:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:22][CH3:23].[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[CH:1]1([NH:7][C:8](=[O:20])[C:9]([S:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:22][CH3:23])=[CH:17][CH:18]=2)([CH3:11])[CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(Sc1ccc(O)cc1)C(=O)NC1CCCCC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ccc(SC(C)(C)C(=O)NC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N-Cyclohexyl-2-[(4-hydroxyphenyl)thio]-2-methylpropanamide (prepared as example 67) was dissolved in DMF and to the solution was added iodoethane. The solution was cooled in an ice-water bath and treated with NaH (60% in mineral oil). After stirring in the ice-water bath for half an hour and at rt for 2 h, water was added followed by EtOAc. After stirring for 10 min., the layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica, hexanes:EtOAc, 6:1) to provide the desired product as a white solid. LCMS: (M+H)+=322.2.
Reaction SMILES: [S:1]1[C:5]([C:6]2[N:10]3[CH2:11][CH2:12][NH:13][CH2:14][C:9]3=[N:8][N:7]=2)=[N:4][CH:3]=[N:2]1.C(N(CC)CC)C.[Cl:22][C:23]1[C:24]([CH3:33])=[C:25]([CH:29]=[CH:30][C:31]=1[F:32])[C:26](Cl)=[O:27].C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(OCC)(=O)C>[Cl:22][C:23]1[C:24]([CH3:33])=[C:25]([C:26]([N:13]2[CH2:12][CH2:11][N:10]3[C:6]([C:5]4[S:1][N:2]=[CH:3][N:4]=4)=[N:7][N:8]=[C:9]3[CH2:14]2)=[O:27])[CH:29]=[CH:30][C:31]=1[F:32]
Reactant: c1nsc(-c2nnc3n2CCNC3)n1
Reactant: Cc1c(C(=O)Cl)ccc(F)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1c(C(=O)N2CCn3c(nnc3-c3ncns3)C2)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (I115) (50 mg, 0.240 mmol) and triethylamine (0.050 mL, 0.360 mmol) in DCM (1.5 ml) was treated with 3-chloro-4-fluoro-2-methylbenzoyl chloride (I58) (54.7 mg, 0.264 mmol) in DCM (0.5 ml) and stirred at room temp for 1 h. After 1 h, 2 drops of methanol and then NaHCO3 solution (5 ml) and ethyl acetate (30 ml) were added. The product was extracted into the ethyl acetate which was dried (Na2SO4) and concentrated. Purification by high pH MDAP gave desired product as a white solid in 44 mg.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cc(F)cc3c(C)c4n(c23)CCNC4=O)cc1

Procedure:
The title compound, off-white solid (66 mg, 86%), MS (ISP) m/z=309.5 [(M+H)+], mp 226° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available p-tolylboronic acid (44.2 mg, 0.325 mmol).
Reaction SMILES: [OH-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH:9]1([C:12](=[O:22])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH2:11][CH2:10]1>CS(C)=O>[CH:9]1([C:12]([CH:13]2[CH2:4][CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[O:22])[CH2:11][CH2:10]1
Reactant: O=C(C=Cc1cccc(O)c1)C1CC1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(C1CC1)C1CC1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 500 ml round bottom flask equipped with magnetic stirrer, nitrogen inlet, thermometer and addition funnel was charged 20 g (0.5 moles) of powdered sodium hydroxide, 110 (0.5 moles) of trimethyl sulfoxonium iodide, and 200 mls of anhydrous DMSO. The mixture was then stirred at ambient temperature for 30 minutes. The mixture was then cooled to 15° C., and a solution of 1-cyclopropyl-3-(3-hydroxyphenyl)-2-propene-1-one (47 g, 0.25 moles) was added dropwise in 50 mls of DMSO. The reaction was stirred for 2 hours at 10-15° C., then allowed to warm to ambient temperature, and stirred for an additional 16 hours. The reaction mixture was the quenched with 200 mls of 0.1 N HCl, and extracted with 3×100 mls of ethyl ether. The combined ether extracts were washed successively with 2×100 mls of water, and 100 mls of saturated aqueous sodium chloride solution. The ether extract was then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure with a rotary evaporator at 45° C. to afford 32 g of the title compound, 2-(3-hydroxyphenyl)cyclopropyl cyclopropyl ketone, as a thick amber oil that crystallized upon standing in a 64% isolated yield.
Reaction SMILES: COP([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(OC)=O.[H-].[Na+].[CH3:17][C:18]1[CH:27]=[C:26]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH2:40][CH:39]([CH:41]=O)[O:38][N:37]=3)=[CH:32][CH:31]=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>CN(C=O)C>[C:11]([O:10][C:8](=[O:9])[CH:7]=[CH:41][CH:39]1[O:38][N:37]=[C:36]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH2:28][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[C:18]([CH3:17])[CH:27]=3)=[CH:31][CH:32]=2)[CH2:40]1)([CH3:12])([CH3:13])[CH3:14]
Reactant: Cc1cc(COc2ccc(C3=NOC(C=O)C3)cc2)c2ccccc2n1
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(C3=NOC(C=CC(=O)OC(C)(C)C)C3)cc2)c2ccccc2n1
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
t-Butyl dimethylphosphonoacetate (0.31 g, 1.38 mmol) was added to a suspension of sodium hydride (washed with hexanes) (0.061 g @60%, 1.5 mmol) in DMF (3 mL) cooled in an ice bath, under a nitrogen atmosphere. The reaction was stirred for 0.5 h and the product from step 10b (0.31 g, 1.38 mmol) in DMF (3 mL) was added. The reaction was stirred for 2 h at 0° C. and was complete. This was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give an oil. The product was purified by FCC on silica gel eluting methylene chloride:ethyl acetate (70:30) to give 3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-acrylic acid tert-butyl ester (0.38 g, 61%) as an oil. MS found: (M+H)+=445.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]2[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C:32]3([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[CH3:10][C:6]1[N:5]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([C:26]3[CH:27]=[CH:28][C:29]([C:32]4([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:33][CH2:34][CH2:35]4)=[CH:30][CH:31]=3)[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: Cc1cccc2nc(Br)c(-c3ccccc3)n12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n12
Temperature: 120 °C
Yield: 83.1 %

Procedure:
A mixture of 2-bromo-5-methyl-3-phenylimidazo[1,2-a]pyridine (38 mg, 0.13 mmol), tert-butyl {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamate (see step 4, 64 mg, 0.17 mmol) and potassium phosphate (84.3 mg, 0.40 mmol) in 1.2 ml toluene/ethanol/water (1/2/1) was heated to 120° C. in a single mode microwave reactor (Biotage). This experiment was repeated employing the same protocol. Both reaction mixtures were combined and partitioned between dichloromethane and water. The mixture was filtered through a phase separator and concentrated in vacuo. The crude material was purified by column chromatography (Snap cartridge, hexane/ethyl acetate 95/5->hexane/ethyl acetate 1/1) to give 49 mg of the title compound (34% overall yield).