Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([PH:5][O:6]CC)([CH2:3][CH3:4])[CH3:2].[CH2:9]([Mg]Br)[CH:10]([CH3:12])[CH3:11].OS(O)(=O)=O>O1CCCC1>[CH2:9]([PH:5](=[O:6])[CH:1]([CH2:3][CH3:4])[CH3:2])[CH:10]([CH3:12])[CH3:11]
Reactant: CCOPC(C)CC
Reactant: CC(C)C[Mg]Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CCC(C)[PH](=O)CC(C)C

Procedure:
A solution of ethyl sec-butylphosphinite (25g., 0.17 mole) in tetrahydrofuran (50 ml.) was added dropwise to a cooled solution of iso-butyl magnesium bromide (0.4 mole) in tetrahydrofuran (150 ml.). The mixture was then heated under reflux for 18 hours. The mixture was then cooled, hydrolysed with 2N H2SO4, and extracted with methylene dichloride. The combined extracts were washed with NaHCO3 solution and then dried (MgSO4). The solvent was removed by distillation and the residue was distilled under reduced pressure to give isobutyl sec-butyl-phosphine oxide bp. 81°-3°/0.03 0.03 mm as a colourless liquid (yield 20g., 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=1)[O:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([CH2:32][Cl:33])[CH2:26]1>>[ClH:33].[CH3:17][C:18]1[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=1)[O:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([CH2:32][N:9]2[C:8](=[O:12])[CH2:7][C:6]3[CH:13]=[C:14]([O:15][CH3:16])[C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH2:11][CH2:10]2)[CH2:26]1
Reactant: Cc1cccc(OCCCN2CCCCC(CCl)C2)c1
Reactant: COc1cc2c(cc1OC)CC(=O)NCC2
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCCN(CCCOc3cccc(C)c3)C1)CC2
Product: Cl

Procedure:
Prepared from 7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and N-[3-(3-methyl-phenoxy)-propyl]-3-chloromethylhexahydro-azepine analogously to Example 2.
Reaction SMILES: [N:1]1([C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:15])[CH3:14])[CH2:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([C:12]2[CH2:11][N:10]([C:13](=[O:15])[CH3:14])[CH2:9][CH2:8][C:7]=2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:29])=[CH:26][CH:25]=1
Reactant: CC(=O)N1CC=C(N2CCCCC2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(N2CCCCC2)=C(C(=O)c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of crude 1-(3,4,5,6,3′,6′-hexahydro-2H,2′H-[1,4′]bipyridinyl-1′-yl)-ethanone in CH2Cl2 (1.5 L) was treated with Et3N (108 mL, 0.78 mol) and then cooled to 0° C. A solution of 4-fluorobenzoyl chloride (107 g, 0.68 mol) in CH2Cl2 (150 mL) was added over 1 h. The reaction mixture was stirred at rt for 2 h, then was concentrated to give a crude material which was directly used on next reaction. HPLC: RT=7.52 min. MS (ESI): exact mass calcd. for C19H23FN2O2, 330.17; m/z found, 331.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18]C)=[O:17])[CH:14]=2)[C:9](=[O:20])[N:8]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:7]=1[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:2][CH2:3][CH3:4].CO.[OH-].[Na+].Cl>O1CCCC1.O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=2)[C:9](=[O:20])[N:8]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:7]=1[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(=O)OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of methyl 4-butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate (synthesized according to the method similar to that in Example 75 (1)) (1.61 g, 3.5 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) was added 1N sodium hydroxide (5 ml). The obtained mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diethyl ether to give 4-butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (1.54 g, 98.7%) as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH:20]=[CH:19][CH:18]=[N:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: c1cn[nH]c1
Product: CC(C)(C)OC(=O)N1CCC(Cn2cccn2)CC1

Procedure:
By a similar manner to Reference Example 29, 1-tert-butoxycarbonyl-piperidin-4-methanol (1.08 g, 5.0 mmol) was reacted with pyrazole (1.02 g, 15 mmol) to give the titled compound as pale yellow oily substance (980 mg, 74%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[CH:10]2.[C:17](=O)(O)[O-:18].[Na+]>CN(C=O)C>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[CH:17]=[O:18]
Reactant: Cn1ccc2cc(Cl)ccc21
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1cc(C=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
While stirring DMF (70 ml) at 0° C., phosphoryl chloride (4.97 ml, 53.3 mmol) was added dropwise in portions. After completion of the dropwise addition, the reaction mixture was stirred further for 10 minutes at the same temperature. A solution of 5-chloro-1-methylindole (5.89 g, 35.6 mmol) in DMF (10 ml) was added. The resulting mixture was stirred for cyclohexanecarboxylic time at 60° C. for 6 hours. The reaction mixture was cooled to room temperature, and added to a saturated aqueous solution of sodium bicarbonate in portions, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby from ethyl acetate eluate fractions, 5-chloro-1-methylindole-3-carbaldehyde (5.51 g, 80%) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[N:10]=[C:9]([CH2:12][C:13](=O)[CH3:14])O[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1)[NH2:18].[Cl:29]C1C=CC2C(=CC=CC=2)N=1>>[Cl:29][C:1]1[C:2]2[C:11](=[C:6]([CH3:7])[CH:5]=[CH:4][CH:3]=2)[N:10]=[C:9]2[N:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[N:18]=[C:13]([CH3:14])[C:12]=12
Reactant: NNc1ccc2ccccc2n1
Reactant: CC(=O)Cc1nc2c(C)cccc2c(=O)o1
Reactant: Clc1ccc2ccccc2n1
Product: Cc1cccc2c(Cl)c3c(C)nn(-c4ccc5ccccc5n4)c3nc12

Procedure:
Following the procedure described in Reference Example 2-3 and Example 2-1, the title compound was prepared from 8-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and 2-hydrazinoquinoline which was previously prepared form 2-chloroquinoline following the method described in Reference Example 2-2 (42% yield).
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=O)=[CH:21][CH:20]=2)[C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:12]=[CH:11]1.[NH2:29][C:30]1[CH:31]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:34][CH:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[N:10]1([C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=3)=[O:28])=[CH:23][CH:24]=2)[C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:12]=[CH:11]1
Reactant: O=C(O)Cc1ccc(-n2cnc3cnccc32)cc1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(-n2cnc3cnccc32)cc1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DIEA (0.15 mL, 0.87 mmol, 4.0 equiv) is added dropwise to a cold (0° C.) mixture of crude (4-imidazo[4,5-c]pyridin-1-yl-phenyl)-acetic acid (55 mg, 0.22 mmol), 3-aminobenzotrifluoride (39 mg, 0.24 mmol, 1.1 equiv), and TBTU (77 mg, 0.24 mmol, 1.1 equiv) in DMF (0.5 mL). The reaction mixture is allowed to warm to rt, stirred for 2 h, diluted with EtOAc and washed with a saturated aqueous solution of NaHCO3, H2O, and brine. The organic phase is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography (CH2Cl2/MeOH, 94:6) to afford the title compound as a white solid: ES-MS: 397.0 [M+H]+; single peak at tR=3.52 min (System 1); Rf=0.18 (CH2Cl2/MeOH, 94:6).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:24][O:25][CH2:26][CH3:27])[N:14]([CH2:15][CH2:16][CH2:17][C:18]3[O:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:28]>CO>[CH2:26]([O:25][CH2:24][C:13]1[N:14]([CH2:15][CH2:16][CH2:17][C:18]2[O:22][N:21]=[C:20]([CH3:23])[CH:19]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:28])[C:11]=2[N:12]=1)[CH3:27]
Reactant: N
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCCc1cc(C)no1
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCc1cc(C)no1

Procedure:
4-Chloro-2-(ethoxymethyl)-1-[3-(3-methylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinoline (1.87 g, 4.86 mmol) was treated with a solution of 7 M ammonia in methanol (20 mL) according to the procedure described in Part C of Example 5. The crude product was purified by flash chromatography (silica gel, gradient elution from 5% to 20% CMA in chloroform). The appropriate fractions were combined and concentrated to yield a solid that was triturated with 9:1 dichloromethane/methanol. The final material was dried under vacuum to yield 2-(ethoxymethyl)-1-[3-(3-methylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.29 mg) as a white powder, mp 163.0-164.0° C.
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][C:25]=1[Cl:37]>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=4)=[CH:26][C:25]=3[Cl:37])=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Product: O=C1CCC(c2ccc(OCCNCC(O)COc3ccc(CCOCC4CCC4)cc3)c(Cl)c2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[CH2:15]([NH:17][CH3:18])[CH3:16]>>[Cl:12][C:9]1[CH:10]=[CH:11][C:5]2[S:4](=[O:14])(=[O:13])[N:3]=[C:2]([N:17]([CH2:15][CH3:16])[CH3:18])[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)ccc21
Reactant: CCNC
Product: CCN(C)C1=NS(=O)(=O)c2ccc(Cl)cc2N1

Procedure:
Starting from 3,6-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (500 mg; 1.99 mmol) and N-ethyl-N-methylamine (500 mg; 8.47 mmol) and with the use of same procedure as in example 21 200 mg (36.7%) of the title compound was prepared; m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 10.35 (s, 1H, NH), 7.65 (d, 1H, H-8), 7.58 (dd, 1H, H-5), 7.3 (d, 1H, H-7), 3.5 (q, 2H, CH2), 3.11 (s, 3H, CH3), 1.14 (t, 3H, CH3). Analysis: C10H12ClN3O2S requires C, 43.88; H, 4.42; N, 15.35; (found C, 43.78; H, 4.51; N, 15.24).
Reaction SMILES: Cl[CH:2]1[NH:7][C:6]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:10][C:5]=2[C:4](=[O:17])[N:3]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.[CH3:25][NH:26][CH3:27].C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:3]2[C:4](=[O:17])[C:5]3[S:10][CH:9]=[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:6]=3[N:7]=[C:2]2[N:26]([CH3:27])[CH3:25])=[CH:19][CH:20]=1
Reactant: CNC
Reactant: O=C1c2scc(-c3ccccc3)c2NC(Cl)N1c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)c1nc2c(-c3ccccc3)csc2c(=O)n1-c1ccc(Cl)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
The thus synthesized compound 2-chloro-3-(4-chlorophenyl)-7-phenyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (22.7 mg, 0.06 mmol) was mixed with a solution of N,N-dimethylamine (3 ml) and diisopropylethylamine (0.01 ml, 0.06 mmol) in THF. The mixture was heated with stirring at 65° C. overnight. After the completion of the reaction was confirmed by TLC, the reaction mixture was cooled to room temperature and separated with water and dichloromethane. The extracted organic layer was washed with brine, dried over anhydrous MgSO4, and filtered. The filtrate was distilled under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc:Hex=1:5) to give 14.1 mg (0.037 mmol, 62% yield) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][C:4]#[CH:5].I[C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[CH:15]\[CH2:16][O:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:20]([CH3:30])[CH:19]=2)=[CH:10][CH:9]=1>O1CCCC1.C(N(CC)CC)C.[Cu]I.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>[CH3:1][N:2]([CH2:3][C:4]#[C:5][C:8]1[CH:9]=[CH:10][C:11](/[C:14](/[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=2)=[CH:15]\[CH2:16][O:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:20]([CH3:30])[CH:19]=2)=[CH:12][CH:13]=1)[CH3:6]
Reactant: C#CCN(C)C
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2cccc(C(F)(F)F)c2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)C)cc2)c2cccc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dimethyl(prop-2-ynyl)amine (114 mg, 1.374 mmol) was added to a solution of methyl (E)-[4-[3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.687 mmol; prepared as described in example 34) in a mixture of tetrahydrofuran (12 mL) and triethylamine (12 mL). The mixture was degassed and copper(I) iodide (20 mg, 0.109 mmol) and tetrakis(triphenylphosphine)palladium (63 mg, 0.054 mmol) were added. The reaction mixture was stirred at ambient temperature for 24 h. Further portions of dimethyl(prop-2-ynyl)amine (57 mg, 0.687 mmol), copper(I) iodide (10 mg, 0.0545 mmol) and tetrakis(triphenylphosphine)palladium (31.5 mg, 0.027 mmol) were added and the reaction mixture was stirred under argon for additional 20 h. The mixture was evaporated in vacuo; the residue was dissolved in ethyl acetate (30 mL) and was washed with water (2×15 mL) and brine (10 mL). The organic solution was dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 3:5) yielding methyl (E)-[4-[3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate as oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.B(F)(F)F.CC[O:18]CC>CC(C)=O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:18])[CH2:1]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CC(C)=O
Product: CC1(C)CC(=O)CC(C)(C)N1
Yield: 116 %

Procedure:
A solution of 15.4 g. of acetonine in 60 g. of acetone was added dropwise with 6.5 g. of boron trifluoride etherate at room temperature. After completion of the addition, the mixture was heated at 48°-50°C. for 3 hours to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 1 to obtain triacetonamine in a yield of 116%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9]2=[O:25])[CH:3]=1.C(N(CC)CC)C>CCO.[Pd]>[O:25]=[C:9]1[N:10]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]1[C:4]1[CH:3]=[CH:2][N:7]=[CH:6][N:5]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(-c2cc(Cl)ncn2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Cn1c(=O)n(-c2ccncn2)c2ccccc21
Reaction time: 2 h

Procedure:
A mixture of tert-butyl [3-(6-chloropyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate from Step A (260 mg, 0.720 mmol), 10% Pd/C (23 mg) and triethylamine (0.150 mL, 1.08 mmol) in EtOH (5 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm) for 2 h. The mixture was filtered through a pad of Celite, washing with EtOH, and the filtrate was concentrated to give the title compound. MS: m/z=327 (M+1).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][N:8]([CH2:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)[CH3:9].[OH2:21]>CO>[CH3:7][N:8]([CH2:10][CH2:11][CH2:12][S:13]([C:14]1[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][CH:19]=1)(=[O:1])=[O:21])[CH3:9]
Reactant: O
Reactant: O=S([O-])OO
Reactant: CN(C)CCCSc1ccc(Br)cc1
Agent: [K+]
Solvent: CO
Product: CN(C)CCCS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
Oxone (14 g, 23 mmol) was added to a solution of 1-[3-(N,N-dimethylamino) propylthio]-4-bromobenzene (Method 62; 5.24 g, 19.1 mmol) in MeOH (150 ml) and water (30 ml) and the mixture was stirred at ambient temperature for 90 minutes. The reaction mixture was poured onto an Isolute SCX-2 column, washed MeOH (6×40 ml) and the product eluted with 2% methanolic ammonia (10×40 ml). The solvent was evaporated and residue purified by flash chromatography on silica gel eluting with DCM/2% methanolic ammonia (100:0 increasing in polarity to 94:6) to yield the title compound (4.68 g, 80%) as a pale yellow oil. NMR 1.62 (m, 2H), 2.03 (s, 6H), 2.19 (t, 2H), 3.32 (m, 2H), 7.81 (m, 4H); m/z 306.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:5][N:4]=1.[CH3:24][CH:25]([OH:33])[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[CH3:24][CH:25]([O:33][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:5][N:4]=1)[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1
Reactant: CC(O)c1ccc(F)cc1
Reactant: CSc1ncc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1
Product: CC(Oc1ncc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1)c1ccc(F)cc1

Procedure:
2-Methylthio-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with α-methyl-4-fluorobenzyl alcohol according to the procedure described in Example 59 to afford 2-(α-methyl-4-fluorobenzyloxy-)-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrimidine. (HRf): HPLC/MS: m/e=473 (M++1); Rt=4.91 min; 1H-NMR 400 MHz (CDCl3): δ 1.78 (d, J=9 Hz, 3H), 6.22-6.30 (dd, J=6 Hz, J=9 Hz, 1H), 7.02 (m, 3H), 7.20-7.25 (m, 5H), 7.50-7.59 (m, 3H), 8.40 (m, 1H).
Reaction SMILES: P([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12]P(O)(O)=O)[O:9][C@@H:8]([N:17]2[CH:24]=[C:23]([OH:25])[C:21]([NH2:22])=[N:20][C:18]2=[O:19])[CH2:7]1)(O)(O)=O.BrBr.[C@@H]1(N2C=CC(N)=NC2=O)O[C@H](CO)[C@@H](O)C1>O>[OH:25][C:23]1[C:21]([NH2:22])=[N:20][C:18](=[O:19])[N:17]([CH:24]=1)[C@@H:8]1[O:9][C@H:10]([CH2:11][OH:12])[C@@H:6]([OH:5])[CH2:7]1
Reactant: Nc1nc(=O)n([C@H]2C[C@H](OP(=O)(O)O)[C@@H](COP(=O)(O)O)O2)cc1O
Agent: BrBr
Agent: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Solvent: O
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1O
Reaction time: 2 h

Procedure:
5-Hydroxydeoxycytidine is synthesized in a similar manner to the published procedure of Eaton et al. (Biochem. Biophys. Acta 319:281-287, 1973) for 5-hydroxydeoxycytidine-3',5'-diphosphate. Bromine is added to a cooled (0° C.) solution of 2'-deoxycytidine (available from Sigma Chemical Company) in water until the yellow color persists. The excess bromine is quenched with cyclohexene and 2,4,6-collidine is added. After 2 hours, the reaction mixture is washed with ether and evaporated to dryness under vacuum. The crude 5-hydroxydeoxycytidine is then purified by reversed-phase HPLC on an ULTRASPHERE C18 column (Phenomenex) using a linear gradient of 0%-20% B in A (solvent A: 0.1 M NH4OAc, solvent B: 50% CH3CN in 0.1 M NH4OAc).
Reaction SMILES: [C:1]([N:8]([CH3:41])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH2:36][CH3:37])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:43]1[CH:48]=[CH:47][C:46]([C:49](=[O:51])[CH3:50])=[CH:45][CH:44]=1>>[C:49]([C:46]1[CH:47]=[CH:48][C:43]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH2:36][CH3:37])=[C:29]([CH2:28][N:15]([C:16]([C:18]3[S:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[C:19]=3[Cl:27])=[O:17])[CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:41])[C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][CH2:11]3)[CH:30]=2)=[CH:44][CH:45]=1)(=[O:51])[CH3:50]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CCOc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CCOc1ccc(-c2ccc(C(C)=O)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 12 (200 mg, 0.33 mmol) is coupled to 4′-bromoacetophenone (79 mg, 0.39 mmol) using Method B to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cccc(C(=O)N2CCCC2)c1
Yield: 126.2 %

Procedure:
A solution of 3-methoxybenzoic acid (13.5 g, 88.8 mmol), pyrrolidine (9 mL, 133 mmol), HATU (33 g, 88.8 mmol) and DIEA (30 mL, 172 mmol) in DMF (100 mL) was stirred at room temperature for 2 h. The solution was added water and extracted with ethyl acetate (200 mL×3). The organic layer was dried and concentrated. The residue was purified by silica gel chromatography (eluted with petroleum ether:ethyl acetate=2:1 to 1:1) to give (3-methoxyphenyl)(pyrrolidin-1-yl)methanone (23 g, 100%) as a yellow oil.