Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH2:29][CH2:30][CH:31]=[CH2:32]>>[CH2:32]([O:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:15]=2)=[CH:5][C:4]=1[O:3][CH:2]([F:1])[F:27])[CH2:31][CH:30]=[CH2:29]
Reactant: C=CCCBr
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Product: C=CCCOc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 367 and 4-bromo-1-butene, white powdery N-[2-(4-but-3-enyloxy-3-difluoromethoxy phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 98.
Reaction SMILES: [I:1]I.[CH2:3]([C:5]1[NH:6][C:7]([CH2:12][CH3:13])=[CH:8][C:9](=[O:11])[CH:10]=1)[CH3:4].[OH-].[Na+]>O>[CH2:3]([C:5]1[NH:6][C:7]([CH2:12][CH3:13])=[CH:8][C:9](=[O:11])[C:10]=1[I:1])[CH3:4]
Reactant: CCc1cc(=O)cc(CC)[nH]1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(=O)c(I)c(CC)[nH]1
Reaction time: 1 h
Yield: 36.9 %

Procedure:
Iodine (720 mg) was added to a solution of compound F (430 mg) and sodium hydroxide (120 mg) in water (15 ml) and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and purified by flash chromatography, eluting with methanol/dichloromethane (1:19 v/v), to give 2,6-diethyl-3-iodo-4(1H)-pyridone (G) (290 mg), m.p. 225°-227° C.; NMR (d6 -DMSO): 1.15(t, 6H), 2.5(q, 2H), 2.8(q, 2H), 5.9(s, 1H), 11.4(br s, 1H).
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11]([CH2:14][C@H:15]([NH:19][CH:20]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:21]([F:24])([F:23])[F:22])[C:16]([OH:18])=O)(=[O:13])=[O:12].Cl.[NH2:34][C:35]1([C:38]#[N:39])[CH2:37][CH2:36]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>[C:38]([C:35]1([NH:34][C:16](=[O:18])[C@@H:15]([NH:19][C@@H:20]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:21]([F:23])([F:22])[F:24])[CH2:14][S:11]([CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH:2]([F:1])[F:32])(=[O:13])=[O:12])[CH2:37][CH2:36]1)#[N:39]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)[C@H](CS(=O)(=O)Cc1ccccc1OC(F)F)NC(c1ccc(F)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@H](CS(=O)(=O)Cc2ccccc2OC(F)F)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CC1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 3-(2-difluoromethoxyphenylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethylamino]propionic acid (157 mg, 0.325 mmol) in DMF (5 mL) was added 1-aminocyclopropanecarbonitrile hydrochloride (46.4 mg, 0.39 mmol), HATU (186.3 mg, 0.49 mmol) and DIPEA (63.2 mg, 0.49 mmol). After 1 h, the reaction mixture was extracted with ethyl acetate (100 mL) and washed with satured NaHCO3 and brine. After drying with MgSO4, the solvent was removed and the residue was purified by column chromatograph yield the title compound (125 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]([CH3:25])[CH3:24])=[C:16]([NH:26][C:27]2[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=2)[N:15]=1.O>CN(C=O)C>[CH:23]([N:20]1[CH:19]=[N:18][C:17]2[C:21]1=[N:22][C:14]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[N:15][C:16]=2[NH:26][C:27]1[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=1)([CH3:25])[CH3:24]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(Oc3cccc([N+](=O)[O-])c3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.4 %

Procedure:
To a solution of 3-nitro-phenol (143 mg, 1.03 mmol) in DMF (15 mL) was added sodium hydride (56 mg, 1.4 mmol) slowly and the mixture was stirred at rt for 30 min. 2-chloro-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (200 mg, 0.69 mmol), as prepared in step 1 of Example 2, was added slowly. After the addition, the mixture was stirred at 110° C. overnight. The cooled reaction mixture was poured into water (100 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried over Na2SO4, concentrated and the residue was purified by flash column chromatography (MeOH:EtOAc=1:10) to give the title compound (50 mg, 18% yield) as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:31]=[CH:30][C:5]2[N:6]=[C:7]([CH3:29])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:13][C:12]=3[O:27]C)[C:9](=[O:10])[C:4]=2[CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[N:31]=[CH:30][C:5]2[N:6]=[C:7]([CH3:29])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:13][C:12]=3[OH:27])[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: COc1cc(OCCCN2CCCCC2)ccc1-n1c(C)nc2cnc(Cl)cc2c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1nc2cnc(Cl)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.7 %

Procedure:
6-chloro-3-[2-methoxy-4-(3-piperidin-1-ylpropoxy)phenyl]-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one synthesized in Example 184 (143 mg, 0.32 mmol) was dissolved in methylene chloride (3 mL), boron tribromide (1M methylene chloride solution, 3.2 mmol) was added on an ice bath, stirred at room temperature for 15 hours, and stirred at 40° C. for 3 hours. Saturated carbonated water was added to stop the reaction, the mixture was extracted with ethyl acetate, and dried with anhydrous sodium sulfate. The product was purified by silica gel column chromatography (chloroform/methanol=20/1), and the target compound (49 mg, 35%) was obtained as a light yellow solid.
Reaction SMILES: [NH2:1]/[C:2](=[N:14]\[OH:15])/[CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.[CH3:16][CH2:17]N(C(C)C)C(C)C.C(Cl)(=O)C>C(#N)C>[CH3:16][C:17]1[O:15][N:14]=[C:2]([CH:3]2[CH2:4][N:5]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:6]2)[N:1]=1
Reactant: CC(C)(C)OC(=O)N1CC(/C(N)=N/O)C1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC(=O)Cl
Solvent: CC#N
Product: Cc1nc(C2CN(C(=O)OC(C)(C)C)C2)no1
Temperature: 0 °C
Yield: 54.8 %

Procedure:
In a 16 mL vial, tert-butyl 3-[(Z)-amino(hydroxyimino)methyl]azetidine-1-carboxylate (170 mg, 0.74 mmol; which may be prepared as described in Step 3) was dissolved in acetonitrile (7.4 mL) and cooled to 0° C. under nitrogen. DIPEA (387 μL, 2.22 mmol) and acetyl chloride (105 μL, 1.48 mmol) were added dropwise and the reaction mixture was allowed to warm to room temperature then heated to 80° C. overnight, cooled and concentrated. The residue was taken up in EtOAc and water, the aqueous layer extracted with EtOAc, dried over Na2SO4 and concentrated. The residue was taken up in o-xylene (8.4 mL) and heated to 150° C. for 2 h and concentrated. The crude mixture was purified on column chromatography (eluent: Pentane/EtOAc 7/3) to give the title compound (97 mg, 55%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O[CH:13]=[C:14]([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C1(C)C=CC=CC=1.CCCCCC>[C:20]([C:14](=[CH:13][NH:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:21]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CCc1cccnc1N
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CNc1ncccc1CC

Procedure:
A solution of 2-amino-3-ethylpyridine (13.0 g., 0.1063 mole) and ethyl ethoxymethylenecyanoacetate (18.0 g., 0.1063 mole) in toluene (50 ml.) was heated on a steam bath for 20 minutes. The solution was cooled and the resulting mixture diluted with Skellysolve B. The title compound (19.0 g.), m.p. 122°-125° C., was collected by filtration. From the mother liquors, after recrystallization from cyclohexane, was obtained a further crop (7.0 g.) of product, m.p. 122°-125° C. Total yield of title compound, 26.0 g. (99.6%). The material from cyclohexane was recrystallized twice from methanol to give analytical material, m.p. 123°-125° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[S:6][C:5](=[N:7][CH2:8][CH3:9])[S:4][C:3]1=[N:10][OH:11].[CH3:13][N:14]([S:18][C:19]([Cl:22])([Cl:21])[Cl:20])[C:15](F)=[O:16]>O1CCOCC1.O>[CH3:12][C:2]1([CH3:1])[S:6][C:5](=[N:7][CH2:8][CH3:9])[S:4][C:3]1=[N:10][O:11][C:15](=[O:16])[N:14]([CH3:13])[S:18][C:19]([Cl:22])([Cl:21])[Cl:20]
Reactant: CN(SC(Cl)(Cl)Cl)C(=O)F
Reactant: CCN=C1SC(=NO)C(C)(C)S1
Solvent: C1COCCO1
Solvent: O
Product: CCN=C1SC(=NOC(=O)N(C)SC(Cl)(Cl)Cl)C(C)(C)S1
Reaction time: 16 h
Yield: 57.4 %

Procedure:
To a solution of 3.5 grams (0.017m) of 5,5-dimethyl-2-ethylimino-4-oximino-1,3-dithiolane (XXIII) and 3.84 grams (0.017m) of N-methyl-N-trichloromethanesulfenyl carbamoyl fluoride in 75 ml of dioxane, was added dropwise with stirring 1.71 grams (0.017m) of triethylamine. After allowing the reaction mixture to stand at room temperature for 16 hours it was diluted with 250 ml of cold water and was extracted in ethylacetate. The organic extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to a residual oil which crystallized on the addition of isopropyl ether and hexane, to afford 4.0 grams of a white solid. m.p. 69°-71° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A mixture of 4-(trifluoromethoxy)phenol (2.50 g, 14.036 mmol), 4-fluoro-1-nitrobenzene (1.98 g, 14.036 mmol), potassium carbonate (2.90 g, 20.982 mmol) and N,N-dimethylacetamide (15 ml) was stirred at 160° for 2 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (4.18 g, 100%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([OH:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][C:11](=[O:22])[CH:10]=1.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.ClCCCCCCOC1C(OC)=CC=C2C=1NC(=O)C=C2NC1C(Cl)=CN=CC=1Cl>>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11](=[O:22])[CH:10]=[C:9]2[NH:8][C:7]1[C:6]([Cl:23])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Reactant: BrCCCCCCBr
Agent: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCBr

Procedure:
8-(6-Bromohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one was prepared from 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one (Intermediate 3) and 1,6-dibromohexane following the procedure outlined for Intermediate 4 (modifications: 1.3 equiv NaH and 2.5 equiv of dibromide used; reaction run at room temperature). MS (ESI): 514.0.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-phenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 69% overall yield. FDMS m/e=366 (M+ of free base). α[D]589 =-10.45 (c=0.61, methanol).
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C@H:11]1[NH:16][C:15](=[O:17])[C@@H:14]([C@@H:18]([CH3:21])[CH2:19][CH3:20])[N:13]([CH:22]([C:26]2[C:27]([CH3:33])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[C:23](O)=[O:24])[C:12]1=[O:34].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>ClCCl>[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C@H:11]1[NH:16][C:15](=[O:17])[C@@H:14]([C@@H:18]([CH3:21])[CH2:19][CH3:20])[N:13]([C@H:22]([C:26]2[C:27]([CH3:33])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[C:23]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:24])[C:12]1=[O:34]
Reactant: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)O)c1ccc(C)nc1C
Reactant: C1COCCN1
Agent: Cl
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N1CCOCC1)c1ccc(C)nc1C
Reaction time: 18 h
Yield: 44.9 %

Procedure:
A suspension of {(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}(2,6-dimethyl-3-pyridinyl)acetic acid hydrochloride (5.0 g, 10.3 mmol) (intermediate 5) in dry dichloromethane (50 ml) was treated with 1,1-carbonyldiimidazole (2.6 g, 16 mmol) and the reaction mixture was stirred under nitrogen for 18 hours. Morpholine (4.8 ml, 55 mmol) was added and the resultant solution was left to stand under nitrogen for 18 hours. The solvent was removed in vacuo and the residue was separated between ethyl acetate and water. The organic phase was washed with brine and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was dissolved in dichloromethane. This was applied to a basic alumina cartridge (240 g) and eluted using a gradient of 0-7.5% methanol in diethyl ether (9CV), 7.5-10% methanol in diethyl ether (1CV) and 10% methanol in diethyl ether (1CV). The required fractions were combined and evaporated in vacuo to give (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione as a white solid (2.4 g, 45%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[C:23](O)(=[O:25])[CH3:24]>C(OC(=O)C)(=O)C>[C:23]([NH:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)O
Reactant: COc1ccc(-c2ccc3nc(N)[nH]c(=O)c3n2)cc1OC
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-c2ccc3nc(NC(C)=O)[nH]c(=O)c3n2)cc1OC
Yield: 77 %

Procedure:
2-amino-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidin-4(3H)-one (2.0 g, 6.70 mmol) was suspended in acetic anhydride (180 ml) and acetic acid (20 ml) and the mixture was refluxed for 16 hours. The hot suspension was filtered and the filtrate was concentrated under reduced pressure until crystallization started. The precipitate was filtered off to give the pure title compound (1.76 g, yield 77%) which was characterized by its mass spectrum as follows: MS (m/z): 341 ([M+H]+, 100).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([CH3:14])([CH3:13])/[C:4](/O)=[CH:5]/[C:6](=[O:11])/[CH:7]=[CH:8]/[O:9]C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[F:16][C:2]([F:1])([F:15])[C:3]([C:4]1[O:9][CH:8]=[CH:7][C:6](=[O:11])[CH:5]=1)([CH3:13])[CH3:14]
Reactant: CO/C=C/C(=O)/C=C(\O)C(C)(C)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(c1cc(=O)cco1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
To a mixture of (1E,4Z)-7,7,7-trifluoro-5-hydroxy-1-methoxy-6,6-dimethylhepta-1,4-dien-3-one (1 g, 4.20 mmol) in toluene (5 mL) was added TFA (0.647 mL, 8.40 mmol). The mixture was stirred at 25° C. for 16 h. Then the mixture was concentrated to afford 2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4H-pyran-4-one (800 mg, 3.10 mmol, 73.9% yield). TLC (PE/EA=1:1, Rf=0.2): 1H NMR (400 MHz, CD3OD): δ 8.12 (d, J=6.0 Hz, 1H), 6.53 (d, J=2.4 Hz, 1H), 6.39 (dd, J=2.4, 6.0 Hz, 1H), 1.53 (s, 6H). ES-LCMS m/z 207.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]#[N:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.S(=O)(=O)(O)[OH:23]>>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:19])=[O:23])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Product: NC(=O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Temperature: 0 °C

Procedure:
A mixture of 3.0 g of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (prepared as described in U.S. Pat. No. 4,236,005) and 150 ml of concentrated sulfuric acid was stirred at room temperature for 4 hours. The solution was then carefully poured into ice water with stirring. The white precipitate formed was collected, washed with water and then with saturated sodium bicarbonate until it was neutral. The solid was heated with one liter of isopropyl alcohol and filtered. The white solid was dried in vacuo and gave the product of the example as a colorless solid, mp 256°-258° C.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5]C=CC=1.[H-].[Na+].[S:10]1[CH2:15][CH2:14][CH2:13][S:12][CH:11]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].BrCC1CC1>CN(C=O)C>[CH2:19]([O:18][C:16]([C:11]1([CH2:7][CH:1]2[CH2:6][CH2:5]2)[S:12][CH2:13][CH2:14][CH2:15][S:10]1)=[O:17])[CH3:20]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C1SCCCS1
Agent: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CC2CC2)SCCCS1
Reaction time: 18 h

Procedure:
To a flamed dried flask is added dry toluene (80 mL) and sodium hydride (60%, 33.5 mmol, 1.34 g). The reaction is cooled in a ice bath and a solution of ethyl 1,3 dithiane carboxylate (52 mmol, 10 g) and bromomethyl cyclopropane (62.4 mmol, 8.42 g) in DMF (24 mL) are added dropwise over 10 min. The ice bath is removed and the reaction is stirred for 18 h. Water is added (50 mL) and the organic layer is separated. The organic layer is washed with brine, dried (Na2SO4), and concentrated to a yellow oil (12 g, 92%). LC-MS: 247.0 (M+1).
Reaction SMILES: [CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[Br-:17].[Br-].[Br-].CN(C)C1C=C[NH+]=CC=1.CN(C1C=C[NH+]=CC=1)C.CN(C1C=C[NH+]=CC=1)C>C(Cl)(Cl)Cl>[Br:17][CH:1]=[C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: C=C1c2ccccc2CCc2ccccc21
Reactant: [Br-]
Agent: CN(C)c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: BrC=C1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.1 %

Procedure:
Dissolve 5-methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (10.00 g, 48.48 mmol) in CHCl3 (125 mL) and add 4-(dimethylamino)pyridinium tribromide (19.35 g, 53.32 mmol). Stir at room temperature for 2.5 h and quench with saturated aqueous Na2SO3. Separate layers, wash organics with saturated aqueous NaHCO3, then H2O. The dried organics (MgSO4) and concentrated to a yellow oil. Purify crude product by loading onto a 20 g plug of silica gel and eluting with hexanes until eluent shows no UV activity. Combine and concentrate hexane washes to afford 13.01 g (94%) of the title compound as a white solid, mp 73.6° C. HPLC shows 99% purity.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:15](O)[CH3:16]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH2:15][CH3:16])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc([N+](=O)[O-])c1
Reaction time: 18 h
Yield: 82 %

Procedure:
To a solution of 10 g (60 mmol) of 3-nitrophenylacetic acid in 120 ml of ethanol were added 20 ml of a saturated solution of hydrogen chloride in ethyl acetate and the mixture was heated at reflux for 4 hours, cooled and left to stand at room temperature for 18 hours. The mixture was evaporated and the residue was partitioned between 120 ml of diethyl ether and 100 ml of saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 10.3 g (82%) of ethyl 3-nitrophenylacetate as a pale yellow oil. [NMR spectrum (250 MHz) δ1.25(t) (3H), δ3.68(s) (2H), δ4.6(q) (2H), δ6.5-δ6.7(m) (3H), δ7.09(dd) (1H)].
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:37][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[Cl:36]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.3 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(3,4-dichloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.084 g) in dichloromethane (2 mL) was added TFA (2 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (2.5 mL) and MeOH (2.5 mL) were added. The mixture was stirred at room temperature for 30 min, the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (dichloromethane/heptane/MeOH) to yield the title compound as an off-white solid (0.054 g, 10%). MS (ISP) 514.2 [(M+H)+]; mp 239° C.
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][CH2:13][C@@H:14]([OH:26])[CH2:15][C:16](=[O:25])[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:11])([CH3:10])[CH3:9].[H][H]>C(O)C>[C:8]([O:12][CH2:13][C@@H:14]([OH:26])[CH2:15][C@@H:16]([OH:25])[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC[C@@H](O)CC(=O)CC(=O)OC(C)(C)C
Reactant: [H][H]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Yield: 62 %

Procedure:
In the same manner as in Example 5, 15 mg (0.009 mmole) of Ru2Cl4 ((R)-BINAP)2 (NEt3) was weighed, and 500 mg (1.75 mmole) of t-butyl (5S)-6-t-butoxy-5-hydroxy-3-oxohexanoate as synthesized in Example 4 and 50 ml of ethanol were added thereto to form a solution. The solution was transferred to a 100 ml-volume autoclave whose atmosphere had been displaced with nitrogen, and the solution was stirred at 30° C. for 16 hours at a hydrogen pressure of 50 kg/cm2 to conduct hydrogenation. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (diethyl ether/hexane: 5/1 by volume) to obtain 300 mg (yield: 60%) of t-butyl (3R,5S)-6-t-butoxy-3,5-dihydroxyhexanoate.