Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH3:13])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:6]([NH:5][C@H:4]([CH:3]=[O:2])[CH3:13])([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
Boc-L-alanine methyl ester (5.0 g, 24.6 mmol) was dissolved in dry toluene (150 ml) under an argon atmosphereand cooled in a dry ice-acetone bath. To this vigorously stirred solution was added a solution of diisobutylaluminumhydride (1.0M in hexanes, 61.5 ml, 61.5 mmol), pre-cooled in a dry ice-acetone bath, via a transfer needle. After 6 minutes, the reaction was carefully quenched with methanol (4 ml) and the mixture allowed to warm to room temperature. The reaction mixture was poured into a separatory funnel containing 250 ml ether and 200 ml of ice cold 0.25N hydrochloric acid. The layers were separated and the organic layer was washed with 0.25N hydrochloric acid (3×80 ml) and brine (50 ml). The organic layer was dried overmagnesium sulfate, filtered and concentrated using a rotary evaporator at ambient temperature. The residue was chromatographed using hexanes--30% ethylacetate to give Boc-L-alaninal. The compound may also be prepared by the technique described in Synthesis, 1983, pg. 676.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][NH:21][C:22]3[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]=[C:24]([N:30]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:23]=3[NH2:49])[O:17][N:16]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:30]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[C:24]2[C:23]([NH:49][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])=[C:22]([NH:21][CH2:20][C:18]3[O:17][N:16]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)[CH:19]=3)[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]=2)=[CH:46][CH:45]=1
Reactant: CCOCC(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c(NCc3cc(-c4ccc(F)cc4)no3)c2N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCC(=O)Nc1c(N(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)nc(C)c(C)c1NCc1cc(-c2ccc(F)cc2)no1
Reaction time: 0.7 h
Yield: 91.3 %

Procedure:
Under a nitrogen atmosphere, ethoxyacetyl chloride (1.4 g, 11 mmol) was added dropwise to a solution of N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-N2,N2-bis(4-methoxybenzyl)-5,6-dimethylpyridine-2,3,4-triamine (5.898 g, 10.39 mmol) and triethylamine (2.2 mL, 15 mmol) in dichloromethane (30 mL) at 0° C. After the reaction was stirred for 0.7 hours, an analysis by HPLC indicated the presence of starting material, and additional ethoxyacetyl chloride (0.54 g) was added. The stirring was continued, and after 1.5 hours, the reaction mixture was diluted with dichloromethane and washed sequentially with saturated aqueous potassium carbonate, water, and brine; dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 6.2 g of N-[2-[bis(4-methoxybenzyl)amino]-4-({[3-(4-fluorophenyl)isoxazol-5-yl]methyl}amino)-5,6-dimethylpyridin-3-yl]-2-ethoxyacetamide as a yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([SH:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].I[CH3:29].[OH-].[K+]>CO>[CH2:1]([C:5]1[N:6]=[C:7]([S:27][CH3:29])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CI
Reactant: CCCCc1nc(S)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc(SC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A mixture of 4′-[(4-butyl-2-mercapto-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.3 g), iodomethane (0.54 mL), potassium hydroxide (0.44 g) and methanol (20 mL) was stirred at room temperature for 3 hr. The obtained crystallized product was collected by filtration and washed with water and diethyl ether to give the title compound as colorless crystals (1.98 g, 83%).
Reaction SMILES: [OH-:1].[Na+:2].[O:3]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:11][C:10](=[O:12])[C:9]2([CH3:14])[CH3:13])=[CH:4]1>O1CCCC1>[Na+:2].[O:3]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]([CH3:14])([CH3:13])[C:10]([O-:1])=[O:12])[NH2:11])=[CH:4]1
Reactant: CC1(C)C(=O)NC1c1ccoc1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C(=O)[O-])C(N)c1ccoc1
Yield: 94.6 %

Procedure:
Sodium hydroxide (378 mg, 9.45 mmol) and tetrahydrofuran (10 ml) were added to 4-(3-furyl)-3,3-dimethyl-2-azetidinone (1.2 g, 7.21 mmol) and the mixture was refluxed for 8 hours. After the solvent was distilled off, the residue was washed with ethyl acetate to give a powder of β-(3-furyl)-α,α-dimethyl-β-alanine sodium salt (1.4 g, quant.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[N:14][CH:13]=[C:12](Br)[N:11]=2)=[O:9])=[CH:3][CH:2]=1.[O:18]1[CH2:22][CH2:21][O:20][CH:19]1[CH2:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1>>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[N:14][CH:13]=[C:12]([C:27]3[CH:26]=[N:25][N:24]([CH2:23][CH:19]4[O:20][CH2:21][CH2:22][O:18]4)[CH:28]=3)[N:11]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: CC1(C)OB(c2cnn(CC3OCCO3)c2)OC1(C)C
Reactant: Nc1ncc(Br)nc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2cnn(CC3OCCO3)c2)nc1C(=O)Nc1ccncc1

Procedure:
The reaction of 3-amino-6-bromo-pyrazine-2-carboxylic acid pyridin-4-ylamide (synthesis described for “A10”) with 1-[1,3]dioxolan-2-ylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole gives the compound “A12”
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([N:62]5[CH2:63][CH2:64][N:59]([CH3:58])[CH2:60][CH2:61]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1CCNCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and N-methylpiperazine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27-1.35 (m, 2 H) 1.54-1.67 (m, 3 H) 1.72-1.84 (m, 5 H) 2.83 (s, 3 H) 3.31 (d, J=3.2 Hz, 3 H) 3.91 (d, J=4.6 Hz, 3 H) 3.95-4.33 (m, 10 H) 4.39-4.54 (m, 1 H) 7.06 (dd, J=8.1, 2.0 Hz, 1 H) 7.13 (d, J=110 Hz, 1 H) 8.10-8.18 (m, 1 H) 8.22 (d, J=3.0 Hz, 1 H). [M+H] calc'd for C27H35F2N7O3 544; found 544.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][NH:16][C@H:17]1[CH2:22][N:21](C(OC(C)(C)C)=O)[C@H:20]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:19][CH2:18]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][NH:16][C@H:17]1[CH2:22][NH:21][C@H:20]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:19][CH2:18]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
TFA (600 mL) was added to a solution of (2S,5R)-1-tert-butyl 2-ethyl 5-((benzyloxy)amino)piperidine-1,2-dicarboxylate (263 g, 0.7 mol) in DCM (600 mL) at 20° C. The mixture was stirred at rt overnight and then concentrated in vacuum. The crude product was adjusted to pH 10 with sat. NaHCO3 solution, and then extracted with DCM three times. The combined organic layer was concentrated in vacuum and purified by silica gel column chromatography (20:1 DCM/MeOH) to afford (2S,5R)-ethyl 5-((benzyloxy)amino)piperidine-2-carboxylate (184.9 g, 95%) as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:9][OH:10])[CH2:8][CH2:7][S:6][CH2:5][S:4]1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>N1C=CC=CC=1>[C:17]1([CH3:18])[CH:19]=[CH:20][C:14]([S:11]([O:1][CH2:2][C:3]2([CH2:9][O:10][S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH2:8][CH2:7][S:6][CH2:5][S:4]2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1(CO)CCSCS1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2(COS(=O)(=O)c3ccc(C)cc3)CCSCS2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4,4-bis(hydroxymethyl)-[1,3]dithiane (405 mg, 2.25 mmol) and TsCl (1.29 g, 6.75 mmol) in anhydrous pyridine (4 mL) was stirred at rt for 48 h. Solvent was removed in vacuo and co-evaporated with toluene (3×3 mL). CH2Cl2 (40 mL) and sat aq NaHCO3 (40 mL) were added, the phases separated and the organic phase dried (Na2SO4), filtered and concentrated under reduced pressure. The residue obtained was flash chromatographed (35-55% EtOAc in light petroleum) to provide 4,4-bis(p-toluenesulphonyloxymethyl)-[1,3]dithiane (525) as a white solid material.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:46][CH2:47][CH:48]([OH:52])[CH:49]([CH3:51])[CH3:50]>ClCCl>[OH:52][CH:48]([CH:49]([CH3:51])[CH3:50])[CH2:47][NH:46][C:14]([CH2:13][CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16]
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CC(C)C(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(O)CNC(=O)CCNC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
46.00 g (206.07 mmol) 3-benzyloxycarbonylamino-propionic acid, 51.37 g (267.95 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 27.85 g (206.07 mmol) hydroxybenzotriazole (HOBT) and 37.14 ml (267.95 mmol) triethylamine are placed in 700 ml dichloromethane, the mixture is stirred for 0.5 hours at 0°, then 23.70 g (229.73 mmol) 1-amino-3-methyl-butan-2-ol are added. The reaction mixture is stirred for 16 hours at ambient temperature. Then it is extracted with potassium carbonate solution and dichloromethane. The organic phase is washed with 1 molar sodium hydroxide solution, dried and evaporated to dryness. The residue is extracted with diethyl ether, then recrystallised with acetonitrile.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[N:31]1([CH2:38][CH2:39][O:40][C:41]2[CH:42]=[CH:43][C:44]([C:47]([O-])=O)=[N:45][CH:46]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.[Na+]>>[N:31]1([CH2:38][CH2:39][O:40][C:41]2[CH:42]=[CH:43][C:44]([CH2:47][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[CH:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[N:45][CH:46]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: O=C([O-])c1ccc(OCCN2CCCCCC2)cn1
Reactant: CCNc1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: [Na+]
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cn1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 47.1 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and sodium 5-(2-azepan-1-ylethoxy)pyridine-2-carboxylate (60 mg) according to an analogous synthetic method to Example 152, the title compound (16 mg) was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([Mg]Br)[CH2:36][CH3:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:35][CH2:36][CH3:37])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(C=O)cc1OC
Reactant: CCC[Mg]Br
Product: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(CCCC)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 64A(i), but using N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(4-formyl-2-methoxyphenyl)octanamide (prepared as described in Preparation 63A) and propylmagnesium bromide, the title compound was obtained as a foam-like substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10](=[O:18])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:18])[CH2:9][CH:8]3[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C1CC(c2cccc(Cl)c2)c2ccccc2N1
Reactant: O=C(O)c1ccc(Cl)cc1
Product: O=C1CC(c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2N1
Temperature: 0 °C
Yield: 2.4 %

Procedure:
Intermnediate (1-a) (58.6 g), 4-chlorobenzoic acid (71.2 g) and polyphosphoric acid (580 g) were stirred at 140° C. for 48 hours. The mixture was poured into ice water and filtered off. The precipitate was washed with water, then with a diluted NH4OH solution and taken up in DCM. The organic layer was dried, filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent:CH2Cl2/CH3OH/NH4OH 99/1/0.1). The pure fractions were collected and evaporated, and recrystallized from CH2Cl2/CH3OH/DIPE, yielding 2.2 g of (±)-6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-3,4-dihydro-2(1H)-quinolinone (interm. 1-b, mp. 194.8° C.).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH3:15].[F:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]>C1COCC1>[F:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH:19]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH3:15])[OH:20]
Reactant: COc1ccc(Br)c(C)c1
Reactant: COc1ccc(C=O)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc(OC)cc2F)c(C)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
n-Butyllithium (2.5 M, 44.0 mL) was added dropwise into a cold (−78° C.) solution of 1-bromo-4-methoxy-2-methylbenzene (22.0 g, 109.4 mmol), and THF (150 mL). The reaction mixture was stirred at −78° C. for 3 h, and then 2-fluoro-4-methoxybenzaldehyde (16.8 g, 109.4 mmol) in THF (10 mL) was added. The mixture was allowed to warm up to 0° C. stirred for 10 min, and then quenched with aqueous ammonium chloride. The mixture was poured into water, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/EtOAc 3/1) gave (2-fluoro-4-methoxyphenyl)(4-methoxy-2-methylphenyl)methanol as a yellow oil (23.6 g, 78% yield). The product was dissolved in acetone (150 mL), cooled to 10° C. and Jones Reagent (79.7 mL) was added dropwise. The reaction stirred for poured into water and extracted with ethyl ether. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/EtOAc 3/1) gave a yellow oil (23.6 g, 78% yield, m.p. 88-90° C.); MS m/e 275 (M+H)+.
Reaction SMILES: C[O:2][C:3]1([O:9][CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:11][C:12]([O:15]O)([CH3:14])[CH3:13]>C1(C)C=CC(S(O)(=O)=O)=CC=1.CS(C)=O>[CH3:10][O:9][C:3]1([O:2][O:15][C:12]([CH3:14])([CH3:13])[CH3:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC1(OC)CCCCC1
Reactant: CC(C)(C)OO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Product: COC1(OOC(C)(C)C)CCCCC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
A mixed solution consisting of 16.4 g of dimethyl sulfoxide and 1.2 g of p-toluenesulfonic acid was kept at 20° C., and another mixed solution consisting of 28.9 g of cyclohexanone-dimethylacetal and 18.5 g of 1,1-dimethylethyl hydroperoxide was dropwise added to the former mixed solution. The resulting solution has an acid concentration of 0.1 mol/kg of the solution. The solution was stirred at 20° C. for 3 hours to complete the reaction. Then, 20 ml of petroleum ether was added to the solution, and the resulting solution was washed with 10 ml of water, then with 50 ml of a 5% NaOH aqueous solution, and further with 20 ml of water 3 times, and then dried by means of anhydrous sodium sulfate. The solvent was distilled off from the dried solution under vacuum to obtain 26.1 g (yield: 57%) of crude 1-methoxy-1-(1,1-dimethylethylperoxy)cyclohexane having a purity of 89%. The resulting crude peroxyketal was distilled at 40°-45° C. under a vacuum of 1 mmHg to obtain a purified peroxyketal having a purity of 99%.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)(=[O:5])[CH3:4].[CH3:18][S:19]([C:22]1[CH:34]=[CH:33][C:25]([CH2:26]P(=O)(OC)OC)=[CH:24][CH:23]=1)(=[O:21])=[O:20]>COCCOC>[C:3]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH:26][C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:34][CH:33]=2)=[CH:12][CH:11]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCCOc1ccc(C=O)cc1
Reactant: COP(=O)(Cc1ccc(S(C)(=O)=O)cc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)OCCOc1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 0 °C
Yield: 98.2 %

Procedure:
To a stirred suspension of 3.0 g (0.075 mol) of 60% sodium hydride dispersion, 11.0 g (0.05 mol) of 4-(2-acetoxyethoxy)benzaldehyde (Example 1) and 125 mL of dry 1,2-dimethoxyethane were added, under nitrogen, 13.9 g (0.05 mol) of dimethyl 4-methylsulfonylbenzylphosphonate. The mixture was heated at reflux for 2 hr, after which time it was cooled and poured over ca. 200 g of crushed ice under nitrogen. The crude product was filtered, washed with water and air-dried to give 17.7 g (98%) of the white solid, which was used without further purification. m.p.=175°-177° C.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28][OH:29]>CCCCCC.C(OCC)(=O)C>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28][O:29][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: OCc1ccc(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Fc1ccc(COc2ncc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)cc1F

Procedure:
2-Methylthio-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (from Reference Example 3) was reacted with 3,4-difluorobenzyl alcohol according to the procedures described in Example 1 to afford 2-(3,4-difluorobenzyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine as the higher Rf product (95/5 hexane/ethyl acetate TLC. HPLC/MS: m/e=478 (M+); Rt=4.69 min; 1H-NMR 500 (CDCl3): δ 5.47 (s, 2H), 7.07 (d, J=9 Hz, 1H), 7.18-7.22 (m, 3H), 7.22-7.30 (m, 5H), 7.40 (d, J=2 Hz, 1H), 8.62 (s, 1H). 2-(3,4-Difluorobenzyloxy)-4-(2-chloro-4-thiomethylphenyl)-5-(4-chlorophenyl)pyrimidine was obtained as the lower Rf product which was the by-product of the thiomethyl anion displacement of the 4-chloro substituent on the 4-(2,4-dichlorophenyl) ring. HPLC/MS: m/e=489 (M+1); Rt=4.59 min; 1H-NMR 500 MHz (CDCl3): δ 2.52 (s, 3H), 5.47 (s, 2H), 7.0-7.10 (m, 2H), 7.15-7.21 (m, 3H), 7.24-7.30 (m, 3H), 7.40 (m, 2H), 8.60 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](C#N)[C:7](=[O:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]>Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Agent: Cl
Product: CC(=O)c1ccc(=O)[nH]c1C
Temperature: 25 °C

Procedure:
5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile (2.32 g, 0.013 mole) and concentrated HCl (50 ml) were heated and stirred at reflux under an argon atmosphere for 5 hours. Upon cooling to room temperature a solid precipitated. The solid was collected by filtration and allowed to air dry. The dry solid (1.25 g) was heated to 280°-290° C. and maintained at this temperature for 7 minutes. The residue was allowed to cool to room temperature then extracted into methylene chloride. Concentration of the methylene chloride solution followed by flash chromatography (50% methylene chloride-ethyl acetate) gave 0.46 g m.pt. 201°-202° C. (1:t 196°-198° C.).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[CH2:36]O>C(Cl)Cl>[Br:5][CH2:1][CH2:36][C:27]1[CH:28]=[C:29]([C:32]([F:33])([F:35])[F:34])[CH:30]=[CH:31][C:26]=1[I:25]
Reactant: OCc1cc(C(F)(F)F)ccc1I
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(I)c(CCBr)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Carbon tetrabromide (1.86 g; 5.6 mmol) and triphenylphosphine (1.47 g; 5.6 mmol) were added successively to a stirred solution of [2-iodo-5-(trifluoromethyl)phenyl]methanol (1.13 g; 3.74 mmol) in CH2Cl2 (25 mL) at 0° C. under N2. The reaction was stirred at room temperature for 48 h. A second equivalent of carbon tetrabromide (1.2 g; 3.74 mmol) and triphenylphosphine (0.98 g; 3.74 mmol) was added and the reaction was stirred an additional 14 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (0-25% EtOAc/hexanes gradient) to afford 2-(bromoethyl)-1-iodo-4-(trifluoromethyl)benzene as a clear oil. 1H NMR (CDCl3, 500 MHz): δ 8.02 (d, J=8.2 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.26 (dd, J=8.3, 1.8 Hz, 1H), 4.64 (s, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:30]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:30][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][N:21]2[C:23]([C:26]([OH:29])([CH3:27])[CH3:28])=[CH:24][N:25]=[C:20]12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(C)(C)O)cnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2N
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL, 26.9 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-(1-hydroxy-1-methylethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (100 mg, 0.24 mmol) in dichloromethane (3 mL). After 1 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 322.2 (M+1).