Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[N:27][CH:28]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1.[N:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:33]=S.O1CCOC[CH2:41]1>>[NH2:30][C:25]1[C:26]([NH:29][C:33]([NH:32][C:35](=[O:36])[O:37][CH2:38][CH3:39])=[CH2:41])=[N:27][CH:28]=[C:23]([C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH2:14][CH2:13][N:12]([C:5]4[C:4]5[CH2:3][C:2]([CH3:31])([CH3:1])[CH2:11][CH2:10][C:9]=5[N:8]=[CH:7][N:6]=4)[CH2:18][C:17]=3[CH:19]=2)[CH:24]=1
Reactant: C1COCCO1
Reactant: CCOC(=O)N=C=S
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N)c(N)c5)cc4C3)c2C1
Product: C=C(NC(=O)OCC)Nc1ncc(-c2ccc3c(c2)CN(c2ncnc4c2CC(C)(C)CC4)CCO3)cc1N
Reaction time: 24 h

Procedure:
A solution of 5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridine-2,3-diamine (188 mg, 0.45 mmol, example 27, step 3) and ethyl isothiocyanatoformate (59 mg, 0.45 mmol) in dioxane (2 mL) was stirred at room temperature for 30 h. After 24 h and 48 h reaction time, additional ethyl isothiocyanatoformate (50 mg, 0.38 mmol) was added each time. The mixture was concentrated and the residue purified directly by column chromatography on silica (ethyl acetate) to give crude ethyl [1-({3-amino-5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridine-2-yl}amino)ethenyl]carbamate (82 mg) which was used in the next step without further purification. MS (EI) for C28H33N7O3S: 548 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:17][C:18]1[NH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>O>[CH3:17][C:18]1[N:22]([C:2]2[N:3]=[C:4]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Solvent: O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sccc2n1
Temperature: 135 °C
Yield: 28 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 (155 mg) and 2-methylbenzimidazole (161 mg) were heated together at 135° C. overnight. The mixture was then cooled, diluted with water and extracted with ethyl acetate. Combined extracts were dried (Na2SO4), filtered and concentrated. Flash chromatography followed by trituration gave 174 (28%). NMR: (CDCl3): 2.95 (s, 3H, CH3), 3.89-3.91 (m, 4H, 2×CH2), 4.07-4.09 (m, 4H, 2×CH2), 7.25-7.28 (m, 2H, 2× ArH), 7.50 (d, H, ArH, J=5.47 Hz), 7.71 (m, H, ArH), 7.85 (d, H, ArH, J=5.48 Hz), 8.09 (m, H, ArH). MS: (ESI+): MH+=352.13
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)C1C=CC=CC=1.C[OH:23]>C(O)(=O)C.[C].[Pd]>[C:18]([OH:17])(=[O:23])[CH3:21].[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N)CC1
Reaction time: 8 h
Yield: 57 %

Procedure:
In methanol (2 ml) and acetic acid (30 ml), 4-benzylamino-1-tert-butoxycarbonylpiperidine (4.04 g) was dissolved, followed by the addition of 10% palladium carbon (water content: about 50%, 3.06 g). The resulting mixture was subjected to catalytic hydrogenation overnight under medium pressure (3 atmospheric pressure). After the removal of the catalyst by filtration, the filtrate was distilled off under reduced pressure. The residue was solidified in ethyl acetate, whereby the title compound (2.23 g, 57%) was obtained.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>O1CCCC1>[OH:14][C@@H:7]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: COP([O-])OC
Agent: Cl
Solvent: C1CCOC1
Product: COP(=O)(OC)[C@H](O)c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
The solution of the Al--Li-(R)-binaphthol complex (hereinafter abbreviated as ALB) obtained in Example 1 in tetrahydrofuran (0.1 M, 0.36 ml) was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring for 30 minutes, the reaction vessel was cooled to -40° C. After it was maintained at this temperature for 15 minutes, benzaldehyde (0.48 mmol) was added thereto. After reacting for 90 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-hydroxyphenylmethylphosphonate as a final product in a yield of 95%. The chemical reaction in this Example is shown in chemical formula 26. ##STR20##
Reaction SMILES: [CH:1]1([NH:6][C@H:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C@@H:9]([CH3:27])[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[CH:1]1([N:6]([C@H:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C@@H:9]([CH3:27])[CH2:8]2)[C:37](=[O:39])[CH3:38])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](NC3CCCC3)C[C@@H]2C)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)C3CCCC3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a solution (2S,4R)-N-cyclopentyl-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine (100 mg, 02.7 mmol) in methylene chloride (5 mL) was added diisopropylethylamine (120 uL, 0.70 mmol) followed by acetyl chloride (90 uL, 1.27 mmol). The mixture was stirred at r.t. for 4 h. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes-ethyl acetate system) to afford pure N-cyclopentyl-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (100 mg, 91%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][NH2:11])[CH3:8])([CH3:4])[CH3:3].Cl[C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][C:18]([F:25])=[C:19]([F:24])[CH:20]=2)[N:15]=1.C(N(CC)C(C)C)(C)C>C1(C)C(C)=CC=CC=1>[CH3:4][C:2]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][NH:11][C:23]1[CH:14]=[N:15][C:16]2[C:21](=[CH:20][C:19]([F:24])=[C:18]([F:25])[CH:17]=2)[N:22]=1)[CH3:8])([CH3:1])[CH3:3]
Reactant: Fc1cc2ncc(Cl)nc2cc1F
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Product: CN(CCNc1cnc2cc(F)c(F)cc2n1)C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of (2-amino-ethyl)-methyl-carbamic acid dimethyl-ethyl ester (1.01 g, 5.8 mmol), 2-chloro-6,7-difluoro-quinoxaline (1.00 g, 5.8 mmol) and N,N-diisopropylethylamine (3.02 ml, 17.4 mmol) in xylene (10 ml) was heated under argon at 80° C. for 18 h. The cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with diethyl ether/pentane to afford the title compound as a pale orange solid.
Reaction SMILES: [OH-:1].[Na+].[C:3]1([F:12])([C:8]([F:11])([F:10])[F:9])[O:5][C:4]1(F)F.[CH3:13][OH:14]>>[CH3:4][O:5][C:3]([F:12])([C:8]([F:11])([F:10])[F:9])[C:13]([OH:14])=[O:1]
Reactant: [OH-]
Reactant: CO
Reactant: FC(F)(F)C1(F)OC1(F)F
Agent: [Na+]
Product: COC(F)(C(=O)O)C(F)(F)F
Yield: 67.9 %

Procedure:
The synthesis of Example 9 was carried out under pressure as follows. A 100 ml stainless steel stirred reactor chilled to 0° was charged with 32.8 g of aqueous sodium hydroxide solution and 50.1 g of methanol. The reactor was cooled to -78° and 23.7 g (0.143 mol) of hexafluoropropene epoxide was condensed therein. The cooling bath was removed, and stirring was started. The reaction temperature rose to 50°, and the pressure to 185 psig. The reaction was completed in an hour, but stirring was continued for another hour. The reaction mixture was neutralized by 3 g of 50% aqueous sodium hydroxide solution. The low boilers were removed by evaporation, and the resulting white solid (40.6 g) was combined with 40.7 g of 99% phosphoric acid and distilled to afford 17.1 g (67.9%) of 2-methoxytetrafluoropropionic acid (1H NMR) b.p. 55°-60° (7 mm Hg).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:4].[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13]Br.[Na+].[Br-]>CN(C)C=O.C1C=CC=CC=1>[C:3]([CH:5]([CH2:13][CH:12]([O:15][CH3:16])[O:11][CH3:10])[C:6]([O:8][CH3:9])=[O:7])#[N:4]
Reactant: COC(CBr)OC
Reactant: COC(=O)CC#N
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C(C#N)CC(OC)OC
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A vigorously stirred suspension of sodium hydride (36 g, 1.5 mole) in a mixture of 1400 ml of anhydrous N,N-dimethylformamide and 450 ml of anhydrous benzene was cooled to -10° C. under an argon atmosphere and methyl cyanoacetate (163.5 g, 1.65 mole) dissolved in 150 ml of anhydrous benzene was added dropwise over a period of 60 minutes. The temperature of this solution was allowed to slowly reach the room temperature and further stirred for 60 minutes until all the sodium hydride dissolved. A solution of bromoacetaldehyde dimethyl acetal (228.2 g, 1.35 mole) was added at once and the temperature of the reaction mixture was slowly rised to about 100° C. over a period of 60 minutes and further maintained for additional 120 minutes until the precipitation of all NaBr occurred. The solution was filtered, and the filtrate was concentrated to a small volume by evaporation under vacuum and then partitioned between ether and water. The ether portion was washed with water, dried over anhydrous Na2SO4 which was then removed by filtration, and evaporated to leave a liquid residue. This liquid was distilled at reduced pressure. The fraction distilling at 65°-68° C. and 0.15 Torr was collected yielding 83.2 g (32.9% theory).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.[C:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)#[N:14].Cl>O1CCOCC1>[O:9]=[C:7]1[NH:14][C:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[N:1][C:2]2[S:3][C:4]([CH3:12])=[CH:5][C:6]1=2
Reactant: CCOC(=O)c1cc(C)sc1N
Reactant: COC(=O)c1ccc(C#N)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2nc3sc(C)cc3c(=O)[nH]2)cc1
Yield: 119.2 %

Procedure:
5 g of 2-amino-5-methyl-3-ethoxycarbonyl-thiophene is dissolved with 2.7 g of methyl 4-cyanobenzoate in 40 ml of dioxane. Gaseous HCl is then passed through the solution for 5 hours. After customary working up, 6 g of methyl 4-(3,4-dihydro-4-oxo-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoate are obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9]>O1CCOCC1>[CH2:8]([NH:10][C:11]([NH:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5])=[O:12])[CH3:9]
Reactant: CCN=C=O
Reactant: CC(C)(CN)CO
Solvent: C1COCCO1
Product: CCNC(=O)NCC(C)(C)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 3-amino-2,2-dimethylpropan-1-ol (1.03 g, 10 mmol) in dry 1,4-dioxane (20 mL) was added dropwise ethyl isocyanate (0.71 g, 10 mmol) at room temperature under nitrogen. The reaction mixture was then stirred at room temperature under nitrogen overnight. The solvent was removed under reduced pressure to give the title compound as colorless oil (1.74 g, 100%). MS 175 (MH+).
Reaction SMILES: C(OC([C:6]1[N:7]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])C2[C:13]([CH:14]=1)=CC=CC=2)=O)C.[OH-:25].[Na+].[C:27]1([CH3:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[OH:25][CH2:13][CH2:14][C:6]1[N:7]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:32]2[C:27]([CH:33]=1)=[CH:28][CH:29]=[CH:30][CH:31]=2
Reactant: Cc1ccccc1
Reactant: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccc(C)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(CCO)cc3ccccc32)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To stirred solution of Red-A1 (sodium dihydro-bis(2-methoxyethoxy)aluminate≈70% in toluene) (30 mL) in dry THF (100 mL) cooled at 5° C. and under nitrogen was added dropwise and at this temperature a solution of compound of step 1 (26,8 g, 78 mmol) in dry THF (75 mL). After stirring one hour at 5° C. and then one hour at room temperature the mixture was cooled at 10° C. and treated dropwise with 2N NaOH, to effect hydrolysis of the intermediate complex. The organic phase was separated and the solvent in vacuo evaporated. The residue was solved in ethyl ether, the solution washed with water, dried over MgSO4 and evaporated to give the required alcohol (23.3 g, 98%) as a yellow oil; IR (film) 3500, 1597 cm-1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:2][C:3]2[CH:22]=[CH:21][CH:20]=[C:5]([O:6][CH2:7][C:8]3[N:9]=[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:11][C:12]=3[CH3:13])[CH:4]=2)=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH3:24]
Reactant: CCOC(=O)CCc1cc(O)ccc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)cc1CCC(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.65 g), ethyl 3-(2-ethoxy-5-hydroxyphenyl)propionate (0.46 g), anhydrous potassium carbonate (0.30 g) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 5 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over, anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give an oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to acidify the residue. The precipitated solid was collected by filtration and dried with air to give crystals (0.89 g, 95%) of 3-[2-ethoxy-5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 136-137° 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.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][OH:30])=[CH:27][CH:26]=1>CCCCCC.C(OCC)(=O)C>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:30][C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=3[Cl:16])[C:6]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:5][N:4]=2)=[CH:27][CH:26]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Clc1ccc(COc2ncc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)cc1

Procedure:
2-Methylthio-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (from Reference Example 3) was reacted with 4-chlorobenzyl alcohol according to the procedures described in Example 1 to afford 2-(4-chlorobenzyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine as the higher Rf product (95/5 hexane/ethyl acetate TLC). HPLC/MS: m/e=477 (M+1); Rt=4.91 min; 1H-NMR 500 MHz (CDCl3): δ 5.50 (s, 2H), 7.02 (d, J=9 Hz, 2H), 7.22 (d, J=9 Hz, 1H), 7.22-7.30 (m, 4H), 7.40 (d, J=9 Hz, 2H), 7.50 (d, J=9 Hz, 2H), 8.62 (s, 1H). 2-(4-Chlorobenzyloxy)-4-(2-chloro-4-thiomethyl phenyl)-5-(4-chlorophenyl)pyrimidine was obtained as the lower Rf 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=4.81 min; 1H-NMR 500 MHz (CDCl3): δ 2.52 (s, 3H), 5.50 (s, 2H), 7.03 (m, 2H), 7.10-7.20 (m, 2H), 7.24-7.30 (m, 3H), 7.38 (d, J=9 Hz, 2H), 7.50 (d, J=9 Hz, 2H), 8.60 (s,1H).
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[CH3:29])=O)(=O)OC.O.[NH2:31][NH2:32]>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:31]=[N:32][C:3]3[C@:2]4([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]([C:4]=3[CH:19]=2)[CH2:6][CH2:7]4)=[C:23]([CH3:29])[CH:24]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: NN
Reactant: COP(=O)(CC(=O)c1ccc(F)cc1C)OC
Solvent: O
Product: Cc1cc(F)ccc1-c1cc2c(nn1)[C@@]1(C)CC[C@@H]2C1(C)C

Procedure:
yellow solid. MS (ESI): 297.3 (MH+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo [2.2.1]heptane-2,3-dione, [2-(4-Fluoro-2-methyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[H][H].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][N:20]=1>CN(C)C=O.CO>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:6]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[N:7]2)=[CH:21][N:20]=1
Reactant: [H][H]
Reactant: BrCc1ccc(Br)nc1
Reactant: CCCCc1n[nH]c(CCCC)n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCc1nc(CCCC)n(Cc2ccc(Br)nc2)n1
Temperature: 0 °C
Yield: 47 %

Procedure:
Under nitrogen, 3.15 g (17 mmol) of solid 3,5-dibutyl-1H-1,2,4-triazole from step 3 of Example 1 was added in small portions to 33 mmol of sodium hydride in 31 ml of dimethylformamide (DMF); stirring was continued until hydrogen evolution had ceased. The anion solution was cooled to 0° C. and treated with a solution of 7.9 g (19 mmol) of crude 2-bromo-5-bromomethylpyridine from step 1 in 10 ml of dry DMF. The reaction was allowed to warm to ambient temperature and stir overnight. Methanol (10 ml) was added to destroy any unreacted sodium hydride and the DMF was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, and dried (MgSO4). Silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (60:40) gave 4.8 g (47%) of 2-bromo-5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]pyridine as an oil: NMR (CDCl3) δ0.88 (t, J=7 Hz, 1H), 0.92 (t, J=7 Hz, 1H), 1.27-1.44 (m, 4H), 1.59-1.76 (m, 4H), 2.60-2.71 (m, 4H), 5.18 (s, 2H), 7.35 (dd, J=8 and 3 Hz), 7.46 (d, J=8 Hz, 1H), 8.23 (d, J=3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17](=[O:18])[C:16]3[C@@H:15]4[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]4)[C:11]=3[NH:10]2)=[CH:5][CH:4]=1.I[CH3:24]>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:17](=[O:18])[C:16]3[C@@H:15]4[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]4)[C:11]=3[N:10]2[CH3:24])=[CH:7][CH:8]=1
Reactant: CI
Reactant: COc1ccc(-n2[nH]c3c(c2=O)[C@H]2CC[C@]3(C)C2(C)C)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-n2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)cc1
Temperature: 100 °C
Yield: 75.2 %

Procedure:
A mixture of (4S,7R)-2-(4-methoxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 40; 300 mg, 1.0 mmol) and iodomethane (315 μL, 5.1 mmol) in dimethylformamide (9 mL) was heated in a sealed tube at ˜100° C. for 1 h 40 min. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane (100 mL), transferred to a round-bottomed flask and evaporated. Ethyl acetate (100 mL) and dichloromethane (50 mL) were added and the solution was washed with water, concentrated aqueous sodium thiosulfate (50 mL; 50% w/v), saturated aqueous sodium hydrogen carbonate (50 mL) and brine (50 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified using a Biotage 40S system, eluting with 3% methanol/dichloromethane. Fractions homogeneous for the product were evaporated, co-evaporated with ethanol and dried under high vacuum to give (4S,7R)-2-(4-methoxy-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (235 mg, 75%) as an off-white solid. APCI(+)-MS (M+H) 313.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.C([Li])CCC.[F:25][C:26]1[CH:27]=[C:28]([CH:37]=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41])/[CH:29]=[N:30]/[S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32]>C1COCC1>[F:25][C:26]1[CH:27]=[C:28]([C@@H:29]([C:6]2[N:7]=[CH:8][CH:9]=[CH:10][N:11]=2)[NH:30][S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH:37]=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ccc(C(F)(F)F)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(C(F)(F)F)c(F)c1)c1ncccn1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(tributylstannyl)pyrimidine (425 mg, 1.151 mmol) in THF (3 mL) at −78° C. was added n-butyllithium (0.720 mL, 1.151 mmol) (1.6 M in hexanes). The reaction was stirred at −78° C. for 1.5 h and then (S,E)-N-(3-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (408 mg, 1.382 mmol) in THF (1 mL) was added. The cooling bath was then removed as the reaction was allowed to warm to rt and stirred for 1 h. LCMS showed 2 products with a ratio of 10:1. The reaction was quenched with saturated aqueous NH4Cl (5 mL) and H2O (5 mL). The reaction mixture was extracted with EtOAc (2×5 mL). The organic layers were combined, dried (MgSO4), and concentrated to give the product. Purification by ISCO (12 g SiO2, 20-80% EtOAc/hexanes) gave the major product, (S)—N—((S)-(3-fluoro-4-(trifluoromethyl)phenyl)-(pyrimidin-2-yl)methyl)-2-methylpropane-2-sulfinamide.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si]([CH2:15][C:16]([O:18][CH3:19])=[O:17])(C)C.[O:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)=[CH:29][CH:28]=1)=O>C1COCC1>[O:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)=[CH:31][CH:32]=1)=[CH:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ncco1
Reactant: COC(=O)C[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C=C(c1ccc(OC2CCCCO2)cc1)c1ncco1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Lithium bis(trimethylsilyl)amide (3.46 mmol, 1M in THF) was added dropwise to a solution of methyl trimethylsilylacetate (3.46 mmol) in THF (5 mL) at −78° C. After 20 minutes at −78° C., a solution of 10.2 (2.16 mmol) in THF (9 mL) was added dropwise and the reaction was maintained at −78° C. for 1.5 hours. The reaction was quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed (silica gel, 1:1 EtOAc/hexane) to afford compound 10.3. MS ESI (pos.) m/e 330.1 (M+1).