Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[CH:28]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(N(CC)CC)C>[C:29]([NH:1][CH:2]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[CH:28]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2cc(OCC(N)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(COc1ccc2sc(C)nc2c1)CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-[2-amino-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazinecarboxylate (260 mg) and 4-dimethylaminopyridine (3 mg) in methylene chloride (6 ml) and triethylamine (178 μl) at 0° C. was added acetic anhydride (160 mg), and the mixture allowed to warm to room temperature. After stirring overnight, the mixture was partitioned between methylene chloride and water, and solvent removed from the organic layer under reduced pressure. The residue was chromatographed on a silica gel column, eluting with 25% ethyl acetate/hexanes followed by 10% methanol/methylene chloride, to provide crude tert-butyl 4-[2-(acetylamino)-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinecarboxylate, which was purified by preparative TLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[O-]S([O-])(=O)=O.[Mg+2].[CH3:15][C:16]([CH3:20])(O)[C:17]#[N:18]>>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16]([CH3:20])([CH3:15])[C:17]#[N:18])=[CH:3][CH:4]=1
Reactant: CC(C)(O)C#N
Reactant: Nc1ccc(O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CC(C)(C#N)Nc1ccc(O)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
A mixture of 4-aminophenol (1.09 g, 10 mmol), acetone cyanohydrin (10 ml) and MgSO4 (2 g) was heated to 80° C. and stirred for 4 h. After concentration of the medium under vacuum, compound 3a was crystallized from water (20 ml). The solid was filtered and dried to yield 2-(4-hydroxyphenylamino)-2-methylpropanenitrile, 3a (1.69 g, 9.6 mmol, 96%).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=3[Cl:32])=[CH:19][CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[Cl:32][C:26]1[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=1[CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[CH:22][CH:21]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3cc(Cl)ccc3Cl)cc2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2ccc(OCc3cc(Cl)ccc3Cl)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 71A. mp 158-160° C.; IR (KBr) cm−1: 3070, 2573, 1747, 1716, 1236, 1106; 400 MHz 1H NMR (DMSO-d6): δ 12.95 (br(s), 1H), 7.57-7.62 (m, 1H) 7.47-7.53 (m, 1H), 7.38-7.45 (m, 1H), 7.08-7.16 (m, 2H), 7.04 (d, 1H, J=8.5 Hz), 6.85-6.92 (m, 2H), 6.56 (d, 1H, J=8.5 Hz), 5.06 (s, 2H), 4.61 (s, 2H), 3.94 (s, 2H), 2.75 (t, 2H, J=7.3 Hz), 2.67 (t, 2H, J=7.3 Hz), 1.89 (pentet, 2H); MS m/z 487 (M−1). Anal. Calc'd for C25H22Cl2O4S: C, 61.35; H, 4.53. found: C, 61.24; H, 4.43.
Reaction SMILES: O=[C:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][C:3]1([C:12]([OH:14])=[O:13])[CH2:4]3)[CH2:8]2.[NH3:15]>C(O)C.[Pt]=O>[NH2:15][CH:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][C:3]1([C:12]([OH:14])=[O:13])[CH2:4]3)[CH2:8]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1=O)C2
Reactant: N
Agent: O=[Pt]
Solvent: CCO
Product: NC1C2CC3CC(C2)CC1(C(=O)O)C3

Procedure:
To a solution of 100 ml of 2-hydroxyadamantane dissolved in 250 ml pyridine is added 137.9 g of trifluoroacetic anhydride dropwise, and the reaction mixture is stirred overnight. The reaction mixture is poured over ice then diluted to 1.0 liter with water and extracted three times with 500 ml of diethyl ether. The combined diethyl ether extracts are washed with 5% hydrochloric acid until the wash is acidic then washed once with 5% sodium bicarbonate solution and dried over magnesium sulfate. The solvent is removed under reduced pressure to give 2-adamantyl trifluoroacetate as an oil. 50 Grams of 2-adamantyl trifluoroacetate are dissoled in 500 ml of hexane and photolyzed (254 nm) for 4 days. The solvent is removed under reduced pressure and the oily residue is placed in a low pressure column and eluted with dichloroethane. The starting material is the first major component eluted. The second major component is the product, 1-trifluoroacetyl-2-hydroxyadamantane which is crystallized from pentane. To 100 ml of 10% sodium hydroxide solution is added 13.0 g of 1-trifluoroacetyl-2-hydroxyadamantane. The reaction mixture is heated for 15 minutes on a steam bath then diluted to 200 ml with water and washed two times with 150 ml of diethyl ether. The aqueous solution is acidified with concentrated hydrochloric acid. The precipitate is collected by filtration, washed with water and dried in a steam cabinet to give 2-hydroxy-1-adamantanecarboxylic acid. 6.7 Grams of 2-hydroxy-1-adamantanecarboxylic acid are dissolved in 50 ml of acetone and enough 8 N Jones Reagent (chromic anhydride in dilute sulfuric acid) is added to retain a red color for 1 minute. Isopropyl alconhol is added to destroy any excess Jones reagent and the solvent is removed under reduced pressure. The residue is diluted with water, collected by filtration and washed with water then suction dried to give 2-keto-1-adamantanecarboxylic acid. 4.7 Grams of 2-keto-1-adamantanecarboxylic acid is dissolved in 75 ml of ethanol and hydrogenated over platinum oxide in the presence of ammonia gas under 60 psi of pressure at room temperature. The solvent is removed under reduced pressure. 15 ml of water is added to the residue and removed under reduced pressure. This step is repeated with another 15 ml of water then the residue is dried at 100° C. under reduced pressure for 1 hour to give 2-amino-1-adamantanecarboxylic acid which is represented by the following structure ##STR45##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CC(C)([O-])C.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 86.5 %

Procedure:
A mixture of 4-bromobenzotrifluoride (3.0 g, 13.3 mmol), tert-butyl piperazine-1-carboxylate (2.9 g, 15.3 mmol), bis(dibenzylideneacetone)palladium (306 mg, 0.53 mmol), tri-o-tolylphosphine (162 mg, 0.53 mmol), and sodium tert-butoxide (2.2 g, 22.7 mmol) in toluene (60 ml) was refluxed under a nitrogen atmosphere for 4 hours. Ethyl acetate and water were added to the reaction mixture, which was stirred for a while, and the insoluble substances were removed by filtration through Celite, and the filtrate was then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/methylene chloride=2/1) to afford tert-butyl 4-(4-trifluoromethylphenyl)-piperazine-1-carboxylate (3.8 g, yield 87%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6](O)=[O:7].[BH4-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]/[CH2:6][OH:7]
Reactant: O=C(O)C=Cc1ccccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC/C=C/c1ccccc1Cl
Yield: 61.9 %

Procedure:
A solution of 2-chlorocinnamic acid (5.00 g, 27.4 mmol) in THF (50 mL) was slowly added to a suspension of NaBH4 (1.24 g, 32.9 mmol) in THF (50 mL) at room temperature. The mixture was stirred until evolution of gas ceased. A solution of 12 (3.47 g, 13.7 mmol) in THF (50 mL) was then added and the mixture was stirred at room temperature for 1 h. Aqueous 3 N HCl solution (10 mL) was added carefully and the mixture was extracted with Et2O. The combined organic layers were successively washed with aqueous 1 N NaOH solution and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2:(CH3)2CO, 95:5) to yield the title compound (2.86 g, 62% yield).
Reaction SMILES: CC1CC(O)CC=1C.[Si:9]([O:16][CH:17]1[CH2:21][C:20]([O:29]COC)([CH2:22][C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[Si:9]([O:16][CH:17]1[CH2:21][C:20]([OH:29])([CH2:22][C:23]#[C:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[CH:19]=[CH:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: COCOC1(CC#C[Si](C)(C)C)C=CC(O[Si](C)(C)C(C)(C)C)C1
Agent: CC1=C(C)CC(O)C1
Product: CC(C)(C)[Si](C)(C)OC1C=CC(O)(CC#C[Si](C)(C)C)C1
Yield: 65 %

Procedure:
From 8.9 g of (1RS,4RS)-4-hydroxy-4-(3-trimethylsilyl-2-propynyl)-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether was obtained by the same procedures as in (3) of the intermediate preparation example 1 (1RS,4RS)-4-methoxymethoxy-4-(3-trimethylsilyl-2-propynyl)-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether in an amount of 6.6 g. Yield 65%
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([CH:13]=[CH2:14])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:21].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OOC(C)(C)C)(C)(C)C.O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([CH:13]=[CH2:14])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:21])[CH:12]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: C=CC1(CCC(C)C)C(OC)=CCc2ccccc21
Agent: CC(C)(C)OOC(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: C=CC1(CCC(C)C)C(OC)=CC(=O)c2ccccc21
Yield: 34 %

Procedure:
To a solution of Example 181B (0.13 g, 0.5 mmol) in benzene (5 mL) was added celite (0.13 g), pyridinium dichromate (0.38 g, 1.0 mmol), and a solution of 70% t-butyl peroxide in water (0.13 mL, 1.0 mmol). The heterogenous solution was filtered through celite. The filtrate was diluted with ethyl acetate (10 mL), washed with 5% Na2S2O5 (10 mL), dried (Na2SO4), and concentrated in vacuo. Column Chromatography on silica (20% dichloromethane/hexane -15% ethyl acetate/hexane) afforded product as a light yellow oil (46 mg, 35%). 1H NMR (300 MHz, CDCl3) δ ppm 0.51 (m, 1H), 0.76 (m, 7H), 1.37 (m, 1 H), 2.01 (m, 1H), 2.33 (m, 1H), 3.81 (s, 3H), 5.12 (m, 2H), 5.94 (m, 2H), 7.37 (m, 2H), 7.54 (m, 1H), 8.18 (d, J=8.09 Hz, 1H); MS m/z 270.9 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][C:16]4[S:17][CH:18]=[CH:19][C:20]=4[C:13]=3[NH:12][N:11]=2)=[CH:6][CH:5]=1.[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>C1COCC1>[Br:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][C:16]4[S:17][CH:18]=[CH:19][C:20]=4[C:13]=3[N:12]([CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[N:11]=2)=[CH:6][CH:5]=1
Reactant: Brc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)nc2)c2c1-c1ccsc1C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
At 0° C., NaH (60 percent, 0.6 g, 12.0 mmol) was added to a THF solution (15 mL) containing 6-(6-Bromo-pyridin-3-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (3.1 g, 9.7 mmol). Then SEM-Cl (2.5 mL, 12 mmol) was added to the reaction mixture and the resulting mixture was stirred at 0° C. for 30 min, warmed up to 80° C. and stirred for 2 hr. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and washed with saturated aqueous NH4Cl, dried over MgSO4(s), and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% ETOAc in hexane) to give 6-(6-Bromo-pyridin-3-yl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (3.0 g, 6.7 mmol) as brown solid in 70% yield.
Reaction SMILES: [H-].[Li+].[CH3:3][C:4]([CH3:19])([CH3:18])[C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([NH:13][O:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)=[O:6].[CH3:20][C:21]([CH3:34])([CH3:33])[C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)=[O:23]>C1(C)C=CC=CC=1>[CH3:3][C:4]([CH3:19])([CH3:18])[C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([N:13]([O:14][CH3:15])[C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([C:22](=[O:23])[C:21]([CH3:20])([CH3:33])[CH3:34])=[CH:32][CH:31]=2)=[O:12])=[CH:9][CH:8]=1)=[O:6]
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)Cl)cc1
Reactant: CONC(=O)c1ccc(C(=O)C(C)(C)C)cc1
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CON(C(=O)c1ccc(C(=O)C(C)(C)C)cc1)C(=O)c1ccc(C(=O)C(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of 0.64 grams(80 mmol) of lithium hydride in 150 ml of toluene, 9.4 grams (40 mmol) of solid 4- (2,2-dimethyl-1-oxopropyl)-N-methoxybenzamide is added portion-wise at room temperature and stirred for 1 1/2 hours. To this suspension, 9.93 grams (44.2 mmol) of 4- (2,2-dimethyl-1-oxopropyl)-benzoyl chloride dissolved in 50 ml of toluene is added at room temperature. The reaction mixture is stirred for 60 hours and then heated at 65°-70° C. for 22 hours. The mixture is poured into 250 ml. of cold pH7 phosphate buffer under nitrogen and the aqueous phase is then separated and extracted twice with t-butyl methyl ether. The organic layers are washed with dilute sodium bicarbonate solution and after drying over magnesium sulfate, the organic phase is evaporated to dryness. The crude product is crystallized from t-butyl methyl ether/heptane and then recrystallized 3 times from toluene/heptane. After each recrystallization, the nugget-like crystals, enriched in the desired product, are physically separated from the powdery crystals to yield the title compound (m.p. 103°-105 ° C. ).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:13][C:14](=[O:34])[CH:15]([NH:27][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH2:16][C:17]1[O:21][N:20]=[C:19]([CH:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)[CH:18]=1)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH2:31]([O:30][C:28]([NH:27][CH:15]([CH2:16][C:17]1[O:21][N:20]=[C:19]([CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=1)[C:14]([OH:34])=[O:13])=[O:29])[CH:32]=[CH2:33]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2)no1)C(=O)OCC
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)c2ccccc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
Benzoyl chloride (21 μl, 0.18 mmol, 1.0 equivalents) was added in one portion to a solution of 2-allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionic acid ethyl ester hydrochloride (1C) (74 mg, 0.20 mmol, 1.1 equivalents) in pyridine (29 μl, 0.36 mmol, 2.0 equivalents) and dichloromethane (2 mL) at 0° C. The reaction was stirred at room temperature for 4 hours then diluted with ethyl acetate (30 mL). The reaction was extracted with 1N hydrochloric acid (30 mL) and brine (30 mL). The organic portion was dried over sodium sulfate and concentrated in vacuo to give the title compound (66 mg, 84%). MS (Cl) m/z 442.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([OH:14])=[O:13].[CH:16](NC(=NC(C)C)OC)(C)C>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:15])[C@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([O:14][CH3:16])=[O:13]
Reactant: CC1(C)[C@H](/C=C2\CCOC2=O)[C@H]1C(=O)O
Reactant: COC(=NC(C)C)NC(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1[C@@H](/C=C2\CCOC2=O)C1(C)C
Yield: 55.8 %

Procedure:
A mixture of 4.2 g of (1R,trans) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-furanylidene)-methyl]-cyclopropane-1-carboxylic acid, 3.5 g of methyl N,N'-diisopropyl-carbamimidate and about 20 ml of ethyl acetate was refluxed for 2 hours and was cooled and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 6-4 cyclohexane-ethyl acetate mixture to obtain 2.5 g of methyl (1R,trans) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-furanylidene)-methyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+65°±2.5° (c=0.6% in ethanol).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C(O)C.O>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1

Procedure:
To a solution of ethyl 6-[(4,6-diphenyl-2-pyridyl)oxy]hexanoate (3.7 g) in ethanol (100 cc) are added sodium hydroxide pellets (0.6 g). The reaction mixture is refluxed for 1 hour and then concentrated to dryness under reduced pressure. The residue obtained is dissolved in distilled water (150 cc). The pH of the aqueous phase is brought to about 5 by addition of a 2N aqueous solution of hydrochloric acid. It is then extracted with methylene chloride (3×50 cc). The organic phases are combined, washed with distilled water (3×50 cc), dried over sodium sulphate and concentrated to dryness at 40° C. under reduced pressure. The solid residue obtained is purified by recrystallization in an n-hexane-ethyl acetate (10-1) mixture (55 cc). (white crystals; m.p.=87°-88° C.)
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:7]=2[NH2:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18].C(OCC)C>ClC1C=CC=CC=1Cl>[F:16][C:13]([F:14])([F:15])[C:10]1[CH:9]=[C:7]2[C:6](=[CH:12][CH:11]=1)[N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:17](=[O:18])[NH:8]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(C(F)(F)F)ccc1-n1ccnc1
Solvent: Clc1ccccc1Cl
Solvent: CCOCC
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n2ccnc12
Yield: 75.4 %

Procedure:
To a solution of 2-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (17.00 g; 74.8 mmol; 1 eq) in anhydrous 1,2-dichlorobenzene (375 mL), commercially available carbonyldiimidazole (24.72 g; 149.7 mmol; 2 eq) is added under an argon atmosphere. This reaction mixture is allowed to stir under reflux for 2 hours. The expected quinoxalinone precipitates as a grey powder during the reflux. The initial crystal clear solution quickly turns black after heating and becomes non homogeneous. This crude reaction mixture is allowed to precipitate at 4° C. during 48 hours. The grey powder formed is then filtered off on a fritted glass. This solid is transferred in a 1 L flask, diluted in fresh ethyl acetate (500 mL) and heated to gentle reflux for two hours. Hot filtration and then several washings of the solid with diethyl ether afforded the title compound (14.28 g; 56.4 mmol; 75%) as a grey powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@:13]([F:15])([CH3:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:28](O)=[O:29])=[N:22][N:23]([CH:25]([F:27])[F:26])[CH:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C@@:13]([F:15])([CH3:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:21]3[C:20]([Cl:19])=[CH:24][N:23]([CH:25]([F:27])[F:26])[N:22]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1nn(C(F)F)cc1Cl
Reactant: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(N)ccc1F
Product: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(NC(=O)c2nn(C(F)F)cc2Cl)ccc1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.3) and 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=434.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH:3]([OH:6])([CH3:5])[CH3:4].[Cl:7][C:8]1[CH:13]=[C:12](Cl)[N:11]=[CH:10][N:9]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:7][C:8]1[CH:13]=[C:12]([O:6][CH:3]([CH3:5])[CH3:4])[N:11]=[CH:10][N:9]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Cl)ncn1
Reaction time: 0.17 h

Procedure:
In 3.5 ml of tetrahydrofuran was suspended 0.11 g of sodium hydride (60% in oil), to which 0.5 ml of tetrahydrofuran containing 0.12 g of isopropyl alcohol dissolved therein was added dropwise at 0° C., followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of tetrahydrofuran containing 0.3 g of 4,6-dichloropyrimidine dissolved therein, followed by stirring at 0° C. for 2 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.26 g of 4-chloro-6-isopropyloxypyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:16])=[CH:4][C:3]=1[CH2:17][C:18](OCC)=[O:19].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[C:7]([CH:8]([OH:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:16])=[CH:4][C:3]=1[CH2:17][CH2:18][OH:19]
Reactant: CCOC(=O)Cc1cc(Cl)cc(C(=O)c2ccccc2)c1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(CCO)cc(Cl)cc1C(O)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of 15.85 g (0.05 mole) of 2-amino-3-benzoyl-5-chlorobenzeneacetic acid, ethyl ester dissolved in 100 ml of dry tetrahydrofuran was added dropwise to a suspension of 4.0 g (0.105 mole) of lithium aluminum hydride in 50 ml of dry tetrahydrofuran. Gentle reflux was maintained during the addition. Reflux was continued for 2 hours after completion of the addition. The mixture was cooled and carefully treated with 4 ml of water, 4 ml of 15% sodium hydroxide and 12 ml of water. The resulting mixture was filtered, the filtrate stripped and the resulting residue recrystallized from toluene. The titled compound, 10.5 g (70%) having a m.p. of 130°-132° C. was obtained.
Reaction SMILES: [CH3:1][CH:2]([O:4][P:5]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)(=[O:10])[O:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[H][H]>[Pd].CC(O)C>[CH3:9][CH:7]([O:6][P:5]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)(=[O:10])[O:4][CH:2]([CH3:1])[CH3:3])[CH3:8]
Reactant: [H][H]
Reactant: CC(C)OP(=O)(OC(C)C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)OP(=O)(OC(C)C)c1ccc(N)cc1
Yield: 92.5 %

Procedure:
A mixture of dipropan-2-yl(4-nitrophenyl)phosphonate (287 mg, 1.0 mmol), i-PrOH (30 ml) and 10% Pd/C (30 mg) was hydrogenated under 50 psi of hydrogen pressure at 40° C. for 6 h. The reaction mixture was then filtered and the filtrate concentrated in vacuo to afford 238 mg of desired dipropan-2-yl(4-aminophenyl)phosphonate (yield: 92%), which used directly in further chemistries without purification. 1H-NMR (DMSO-d6, 400 MHz): δ=1.11 (d, J=6.0 Hz, 6H), 1.21 (d, J=6.4 Hz, 6H), 4.38-4.43 (m, 2H), 5.74 (s, br, 2H), 6.56-6.59 (m, 2H), 7.27-7.32 (m, 2H). MS: m/z 257.90 [MH+].