Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH2:12])[O:9][N:8]=1)([CH3:6])[CH2:4][F:5].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:14](=[O:15])[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][N:8]=1)([CH3:6])[CH2:4][F:5]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(CF)(CF)c1cc(N)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)on1
Yield: 99.7 %

Procedure:
Using the procedure described in Example 161C, 3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-amine (0.19 g, 1.08 mmol) was reacted with phenyl chloroformate (0.235 g, 1.5 mmol) in the presence of K2CO3 (0.276 g, 2 mmol) in THF (10 mL), and purified by silica gel chromatography with 10-25% EtOAc/hexane as eluants to afford phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate as solid (0.319 g, 100%). 1H NMR (300 MHz, CDCl3) δ 7.83 (s, 1H), 7.17-7.45 (m, 5H), 6.23 (s, 1H), 4.69 (dq, 2H), 4.50 (dq, 2H), 1.40 (s, 3H); LC-MS (ESI) m/z 297 (M+H)+.
Reaction SMILES: CC(C)(O)[C:3]#[N:4].[C-]#N.[K+].[CH3:10][C@:11]12[CH2:28][CH2:27][C@H:26]3[C@@H:16]([CH2:17][CH2:18][C:19]4[C@:24]3([CH3:25])[CH2:23][CH2:22][C:21](=[O:29])[CH:20]=4)[C@@H:15]1[CH2:14][CH2:13][C:12]2=[O:30]>CO.O>[C:3]([C@@:12]1([OH:30])[CH2:13][CH2:14][C@H:15]2[C@H:16]3[C@H:26]([CH2:27][CH2:28][C@:11]12[CH3:10])[C@:24]1([CH3:25])[C:19](=[CH:20][C:21](=[O:29])[CH2:22][CH2:23]1)[CH2:18][CH2:17]3)#[N:4]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(O)C#N
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C#N
Reaction time: 3 h

Procedure:
Acetone cyanohydrin (82 ml), potassium cyanide (1 gm) and water (2 ml) are added to a slurry of androst-4-en-3,17-dione (0.80 g) in methanol (400 ml) and water (40 ml) at 35°. The reaction becomes homogeneous and on continued stirring a heavy slurry develops. After 3 hours, 120 ml of water is added dropwise, and the slurry allowed to stir overnight at 20°-25°. The slurry is then cooled in an ice bath, filtered, and the solids washed with methanol/water (1/1). The solvents are dried under reduced pressure to give 70.4 g of the title compound. An additional 13.17 g of product is isolated from the mother liquor on partial evaporation, m.p.=159°-160.5°; [α]D (c=1, CHCl3)=+145.9°; MS=313, 298, 286, 245 and 124 m/e; NMR (CDCl3)=1.00, 1.20, 3.5 and 5.72 δ.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:34])=[O:33])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and benzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH2:15][C:16]#[C:17][C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:4])=[O:3].[H][H]>[Pt].C(OCC)(=O)C.C1CCCCC1>[CH3:1][S:2]([CH:5]([CH2:15][CH2:16][CH2:17][C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: CCCCC[C@H](O)C#CCC(CCCCCCC(=O)O)S(C)(=O)=O
Reactant: [H][H]
Agent: [Pt]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCC[C@H](O)CCCC(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
8-Methylsulfonyl-12(S)-hydroxy-10-heptadecynoic acid (36.0 g., 0.10 mole) and 5% platinum-on-charcoal catalyst (4.0 g.) are placed in a mixture of ethyl acetate (100 ml.) and cyclohexane (200 ml.) and hydrogenated in a Parr apparatus with an initial hydrogen pressure of 45 pounds per square inch. The uptake of the required 0.2 mole of hydrogen is complete in 20 minutes. The catalyst is removed by filtration and the solvents evaporated to leave the product as a residual oil weighing 33.5 g. It is purified by chromatography on silica gel with benzene-dioxane-acetic acid elution. The title compound is obtained as a nearly colorless viscous oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10]C(=O)[C:8]2=[O:13])[CH3:2].[OH-:14].[Na+].OO.Cl>>[NH2:10][C:11]1[C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:13])=[O:14]
Reactant: CCc1cccc2c1NC(=O)C2=O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Product: CCc1cccc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.0 g of crude 7-ethyl-1H-indole-2,3-dione and 3 ml of a 2N aqueous sodium hydroxide solution was added dropwise to 2 g of aqueous hydrogen peroxide (30%) at room temperature, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 4 by an addition of 2N hydrochloric acid, and a deposited precipitate was collected by filtration. The resulting filter cake was partitioned between ethyl acetate and a saturated sodium hydrogen carbonate solution. The aqueous layer was adjusted to pH 4 by an addition of 2N hydrochloric acid, and a deposited precipitate was collected by filtration to obtain 0.42 g of 2-amino-3-ethylbenzoic acid of the formula:
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[OH:8][CH2:9][C:10]([NH:12][CH2:13][C@H:14]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)[CH3:15])=[O:11]>>[OH:8][CH2:9][C:10]([NH:12][CH2:13][C@H:14]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[C:19]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:2][C:3]3[S:4][CH:5]=[CH:6][N:7]=3)=[C:30]([CH3:35])[CH:29]=1)=[N:20][CH:21]=[N:22]2)[CH3:15])=[O:11]
Reactant: ClCc1nccs1
Reactant: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CNC(=O)CO)c23)ccc1O
Product: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CNC(=O)CO)c23)ccc1OCc1nccs1
Yield: 31 %

Procedure:
The procedure described in Example 3 was repeated using 2-(chloromethyl)-1,3-thiazole and 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide (obtained as described in Example 82, preparation of starting materials) to give the title compound as a light brown solid in 31% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.25 (s, 3H), 3.42 (dt, 1H), 3.73 (m, 1H), 3.79 (d, 2H), 4.94 (m, 1H), 5.44 (s, 2H), 5.47 (t, 1H), 7.09 (d, 1H), 7.23 (d, 1H), 7.30 (d, 1H), 7.58 (d, 1H), 7.63 (dd, 1H), 7.69 (t, 1H), 7.77 (d, 1H), 7.84 (d, 1H), 8.16 (t, 1H), 8.43 (s, 1H), 9.96 (s, 1H); Mass spectrum MH+ 480.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35].C(O)(=O)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[N:12]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[O:34][CH3:35])[C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)c(OC)c1
Reactant: O=C1CC[C@@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)cn2)N1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)CC[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cn2)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6.72 g (20.92 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one (Example 121, Step F) in DMF (˜0.5M) at 0° C. was slowly added a dispersion of 60% sodium hydride in mineral oil (2.51 g, 62.8 mmol). The reaction was stirred 0° C. for 30 min, followed by addition of 1-(chloromethyl)-2,4-dimethoxybenzene (7.81 g, 41.8 mmol). Upon completion, the reaction was quenched at 0° C. with a small excess of acetic acid (4.79 mL, 84 mmol). It was neutralized with sat. aq. NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and the filtrate as concentrated under reduced pressure to yield a reddish oil. Purification by flash chromatography on silica gel (eluent: 0 to 30% ethyl acetate/DCM, gradient elution) provided the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](=O)[CH:6]([C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH:9]=1)[CH3:2].O.[NH2:19][NH2:20]>C(O)C>[CH2:1]([O:3][C:4]1[C:5]2[NH:20][N:19]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]=2[CH2:7][CH2:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)C1CCC=C(OCC)C1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1n[nH]c2c1CCC=C2OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.7 %

Procedure:
1.2 g (5 mmol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate were dissolved in 20 mL of ethanol and 25 mL (5.2 mmol) of hydrazine hydrate 98% were added dropwise. The solution was stirred at room temperature for 5 hours, then heated at 60° C. for further 5 hours. The solvent was removed in vacuo and the residue taken up with diethyl ether and the resulting precipitate collected by filtration giving 0.8 g of the title compound, that was employed in the next step without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C1COCC1>[C:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Oc1ccc(Br)cc1
Yield: 102.3 %

Procedure:
A solution of 20.02 g of 4-bromophenol (0.116 mol) in 100 mL of dry THF was treated with 15.0 mL of pivaloyl chloride (0.126 mol), followed by 35.5 mL of triethylamine (0.255 mol). A large amount of white solid precipitated so 50 mL of additional THF was added to the mixture to afford a free-flowing slurry. The reaction mixture was filtered and the precipitate was washed with 200 mL THF and then discarded. The filtrate was concentrated in vacuo to a liquid which solidified when dried under reduced pressure to yield 30.5 g (100%) of 4-bromophenyl pivalate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\[N+:22]#[C-:23])/[C:11](/[N+:20]#[C-:21])=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C>[CH2:30]([O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]=[C:11]([N+:20]#[C-:21])[C:10]([N+:22]#[C-:23])=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:14][CH:15]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: [C-]#[N+]C(=C\c1ccc(O)cc1)/C(=C/c1ccc(OC)cc1)[N+]#[C-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: [C-]#[N+]C(=Cc1ccc(OC)cc1)C(=Cc1ccc(OCc2ccccc2)cc1)[N+]#[C-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
16 mg of xanthocillin X monomethyl ether was dissolved in 3 ml of DMF and 48 mg of potassium carbonate was added thereto. Further, 48 μl of benzyl bromide was added thereto and the mixture thus formed was stirred at room temperature for 20 hours. Then the reaction mixture was poured into 50 ml of water and extracted with 30 ml portions of ethyl acetate thrice. The extracts were combined, successively washed with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The sodium sulfate was filtered off and the solvent was distilled from the filtrate. Thus 20 mg of 1-(4'-benzyloxy- (5H, m) and 7.80 (4H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]([CH:14]1[O:18][CH2:17][CH2:16][O:15]1)[CH3:13].C1(OC)C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Cu]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=1)[CH:6]=[C:5]2[CH2:11][CH:12]([CH:14]1[O:18][CH2:17][CH2:16][O:15]1)[CH3:13]
Reactant: Fc1ccc(I)cc1
Reactant: CC(Cc1c[nH]c2ccc(Cl)cc12)C1OCCO1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COc1ccccc1
Product: CC(Cc1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12)C1OCCO1

Procedure:
A mixture of 15g (0.067 mole) of 5-chloro-3-[2-(1,3-dioxolan-2-yl)propyl] indole, 225 ml of anisole, 30g (0.135 mole) of 4-fluoroiodobenzene, 30g of copper powder and 60g of dry sodium carbonate are heated to reflux for 96 hours.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[F:11].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([S:13]([Cl:12])(=[O:15])=[O:14])[C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[F:11]
Reactant: Fc1cc(F)c(Cl)c(F)c1Cl
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1c(F)c(Cl)c(F)c(Cl)c1F
Temperature: 80 °C
Yield: 65.4 %

Procedure:
1,3-Dichloro-2,4,6-trifluorobenzene (5.0 g, 25 mmol) and chlorosulfonic acid (10.0 mL, 150 mmol) were mixed at ambient temperature under a nitrogen atmosphere and the reaction was heated at 80° C. for 24 h. The mixture was then allowed to cool to ambient temperature and was poured onto 12 g of crushed ice. The product was extracted with diethyl ether, dried over MgSO4, and the solvent was evaporated to produce 4.9 g of the title compound, which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2].[CH3:31][C:32]1[O:36][C:35]([C:37]2[CH:38]=[C:39]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=2)[NH2:40])=[N:34][N:33]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:40][C:39]2[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=[C:37]([C:35]3[O:36][C:32]([CH3:31])=[N:33][N:34]=3)[CH:38]=2)=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)O)c(F)c1
Reactant: Cc1nnc(-c2cc(N)cc(C(F)(F)F)c2)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cc(-c3nnc(C)o3)cc(C(F)(F)F)c2)c(F)c1
Reaction time: 2 h
Yield: 12.9 %

Procedure:
To a mixture of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (300 mg, 0.729 mmol), 3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)aniline (195 mg, 0.802 mmol), and Et3N (0.203 ml, 1.458 mmol) in DCM (15 ml) was added HATU (333 mg, 0.875 mmol) at 25° C. Then the mixture was stirred for 2 h, the mixture was concentrated to give the residue which was extracted with DCM (30 mL×2). The organic extract was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (DCM:MeOH=30:1, Rf=0.7) to yield 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide (60 mg, 0.094 mmol, 13% yield): 1H NMR (400 MHz, MeOD-d4) δ 8.52 (br. s., 1H), 7.99 (br. s., 1H), 7.95 (br. s., 1H), 7.42-7.39 (m, 2H), 7.30 (d, J=8.4 Hz, 3H), 6.89 (d, J=8.6 Hz, 3H), 6.52-6.50 (m, 1H), 5.11 (br. s., 2H), 4.64-4.62 (m, 2H), 4.31 (d, J=7.1 Hz, 2H), 2.63 (br. s., 3H), 1.38 (t, J=7.1 Hz, 3H); ES-LCMS m/z 637 (M+H).
Reaction SMILES: C(O)(C)C.[CH2:5]([NH2:15])[C:6]1[CH:14]=[CH:13][C:12]2[O:11][CH2:10][O:9][C:8]=2[CH:7]=1.[Cl:16][C:17]1[N:26]=[C:25](Cl)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:28]#[N:29])[CH:23]=2)[N:18]=1>C(N(CC)CC)C>[Cl:16][C:17]1[N:26]=[C:25]([NH:15][CH2:5][C:6]2[CH:14]=[CH:13][C:12]3[O:11][CH2:10][O:9][C:8]=3[CH:7]=2)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:28]#[N:29])[CH:23]=2)[N:18]=1
Reactant: N#Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N#Cc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 79.4 %

Procedure:
35 ml of isopropyl alcohol, 900 mg of triethylamine and 1.35 g of piperonylamine were added to 2 g of 2,4-dichloro-6-cyanoquinazoline. The obtained mixture was heated under reflux for 1.5 hours and hot-filtered to recover a precipitate. Thus, 2.4 g of the title compound was obtained.
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]([C@H:21]([C@H:29]1[CH2:33]OS(=O)(=O)[O:30]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[N+:19]=[N-:20].S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1.CO>[N:18]([C@@H:21]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:29]([OH:30])[CH2:33][N:9]1[C@H:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=N[C@@H](Cc1ccccc1)[C@H]1COS(=O)(=O)O1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)N=[N+]=[N-]
Temperature: 25 °C
Yield: 13.3 %

Procedure:
A solution of 237 mg (1 mmol) of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 300 mg (1.1 mmol) of 4(S)-[1(S)-azido-2-phenylethyl]-1,3,2-dioxathiolane 2,2-dioxide in 10 ml of tetrahydrofuran was stirred at room temperature under an argon atmosphere for 2 days, during which time some white solid deposits formed. The mixture was evaporated to give a white powder which was taken up in a 10% solution of sulphuric acid in 70% aqueous methanol and heated under reflux for 30 minutes. After cooling to room temperature the solution was adjusted to pH 10 with 10% aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The ethyl acetate extracts were combined, washed with sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. Purification of the crude product by flash chromatography on silica gel using n-hexane/ethyl acetate (4:1) for the elution gave 57 mg of 2-[3(S)-azido-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide; MS: m/e 428 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2].[CH:30](C1N=C(C(O)=O)C(N)=C(C)N=1)(C)C>>[CH:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)([CH3:30])[CH3:2]
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1
Reactant: Cc1nc(C(C)C)nc(C(=O)O)c1N
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)nc(NC(C)C)n1

Procedure:
rac-3-{4-[5-(2-Isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol is prepared in analogy to rac-3-{4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol using 2-isopropyl-amino-6-methyl-pyrimidine-4-carboxylic acid; LC-MS: tR=0.85 min*; [M+H]+=414.12.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:8]1[C:12]2[N:13]=[N:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:11]=2[N:10]=[CH:9]1)[CH3:7].[I:24]N1C(C)(C)C(=O)N(I)C1=O.[OH-].[Na+]>C(Cl)Cl>[CH2:6]([N:8]1[C:12]2[N:13]=[N:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([I:24])[CH:18]=3)[C:11]=2[N:10]=[CH:9]1)[CH3:7]
Reactant: CCn1cnc2c(-c3ccc(F)cc3)cnnc21
Reactant: CC1(C)C(=O)N(I)C(=O)N1I
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCn1cnc2c(-c3ccc(F)c(I)c3)cnnc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95 %

Procedure:
Concentrated sulphuric acid (10 mL) was carefully added to 7-ethyl-4-(4-fluorophenyl)-7H-imidazo[4,5-c]pyridazine (Preparation 9, 825 mg, 2.4 mmol) surrounded by an ice bath, and the resultant reaction mixture was gently stirred at room temperature until a homogeneous solution was observed. To this was added 1,3-diiodo-5,5-dimethylhydantoin (1.36 g, 3.58 mmol) portion-wise, and stirring was continued for 5 minutes. The viscous mixture was then slowly poured into an aqueous sodium hydroxide solution (1M, 10 mL) at 0° C. with stirring. The black suspension slowly dissolved to give a blue solution. CH2Cl2 (20 mL) was added and the layers were separated. The organic layer was washed with saturated aqueous sodium bisulfite solution (20 mL) then concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with heptane:EtOAc 1:1 to 0:100 to afford the title compound as a white solid in 95% yield, 1.19 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH:13][C:14]([OH:16])=[O:15])([O-:3])=[O:2]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 93.3 %

Procedure:
A mixture of 151 g of m-nitrobenzaldehyde, 200 g of pyridine, and 120 g of malonic acid was heated for 3 hours with stirring. The mixture was poured into ice water. The resulting crystalline deposit was collected by filtration, washed with water, and dried, yielding 180 g of m-nitrocinnamic acid having a melting point of 156° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.[CH3:19][N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:21]>>[CH3:19][N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:21][C:9](=[O:11])[C:8]1[CH:12]=[C:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CC2)c1
Reactant: CN(N)c1ccccc1
Product: CN(NC(=O)c1cnc(OCC(F)(F)F)c(C2CC2)c1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to the procedure described in Example 34 c), using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (example 34b) and N-methyl-N-phenyl-hydrazine (CAN 618-40-6); MS (ESI) 366.2 (M+H)+.