Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([C:24]4[O:28][N:27]=[C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:25]=4[C:35]([OH:37])=O)[O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:38][C:39]([F:43])([F:42])[CH2:40][NH2:41].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(CC)CC>CN(C=O)C>[C:29]1([C:26]2[C:25]([C:35](=[O:37])[NH:41][CH2:40][C:39]([F:43])([F:42])[F:38])=[C:24]([C:22]3[O:21][N:20]=[C:19]([C:16]4[CH:17]=[CH:18][C:13]([CH2:12][N:10]5[CH2:11][CH:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]5)=[CH:14][CH:15]=4)[N:23]=3)[O:28][N:27]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(=O)O)n3)cc2)C1
Reactant: NCC(F)(F)F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(=O)NCC(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A mixture of 5-(3-(4-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-phenylisoxazole-4-carboxylic acid (30 mg, 0.060 mmol), 2,2,2-trifluoroethylamine (7.15 μL, 0.090 mmol), BOP-Cl (18.24 mg, 0.072 mmol) and Et3N (0.025 mL, 0.179 mmol) in DMF (0.5 mL) was stirred at rt over the weekend. The reaction mixture was partitioned between EtOAc (30 mL) and saturated sodium bicarbonate solution (30 mL). The organic layer was washed with water (2×30 mL) and brine (30 mL). After drying (MgSO4) and filtration, the organic layer was concentrated to a colorless solid that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-70% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford tert-butyl 1-(4-(5-(3-phenyl-4-(2,2,2-trifluoroethylcarbamoyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (18 mg, 0.031 mmol, 51.7% yield) as a white solid. This material was deemed suitable to use in the next step without further purification. HPLC retention time=1.71 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient. MS: (M+H)=584.10.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[CH:4][C:3]=1[CH3:11].[CH3:12]I.[H-].[Na+].O.C[N:18]([CH:20]=O)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:9])[C:20]#[N:18])=[CH:4][C:3]=1[CH3:11]
Reactant: CI
Reactant: CN(C)C=O
Reactant: Cc1cc(CC#N)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C(C)(C)C#N)ccc1Br
Temperature: 0 °C
Yield: 99 %

Procedure:
To a stirred solution of 2-(4-bromo-3-methylphenyl)acetonitrile (11.2 g, 53.3 mmol) in anhydrous DMF (125 mL) is added methyl iodide (13.2 mL, 213 mmol). The solution is cooled to 0° C. and sodium hydride (60% susp. in oil, 3.84 g, 160 mmol) is added in small portions over 20 min. The reaction mixture is then left stirring and slowly warmed up to room temperature for 18 h. At 0° C., water (500 mL) is then slowly added then extracted with ethyl acetate containing 10% of hexanes. The organic layer is separated, dried with MgSO4, filtered and concentrated under reduced pressure to provide the expected product 2-(4-bromo-3-methylphenyl)-2-methylpropanenitrile (12.6 g, 99%) as a clear yellow oil which is used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.71 (s, 6H) 2.43 (s, 3H) 7.14 (dd, J=8.40, 2.34 Hz, 1H) 7.34 (d, J=2.54 Hz, 1H) 7.53 (d, J=8.40 Hz, 1H)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10](C(OCC(Cl)(Cl)Cl)=O)[NH:11][C:12](OCC(Cl)(Cl)Cl)=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.CO.[C:30]([O-:33])(=O)[CH3:31].[NH4+].[C:35](OCC)(=O)CC(C)=O>C(O)C.[Zn]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:30](=[O:33])[CH2:31][C:12]([CH3:35])=[N:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(NN(C(=O)OCC(Cl)(Cl)Cl)c1ccc2c(c1)CCO2)OCC(Cl)(Cl)Cl
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: CO
Product: CC1=NN(c2ccc3c(c2)CCO3)C(=O)C1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
Bis(2,2,2-trichloroethyl) 1-(2,3-dihydrobenzofuran-5-yl)hydrazine-1,2-dicarboxylate 7b (2.9 g, 5.8 mmol) was dissolved in 50 mL of ethanol and 5 mL of methanol followed by addition of zinc powder (10.8 g, 166 mmol) and aqueous ammonium acetate (15 mL, 1 mol/L) and the mixture was reacted at room temperature for 1 hour. Then ethyl acetoacetate (0.75 mL, 5.9 mmol) was added dropwise. The reaction mixture was heated to reflux for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound 2-(2,3-dihydro-benzofuran-5-yl)-5-methyl-2,4-dihydro-pyrazol-3-one 7c (706 mg, yield 56.5%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:11])=[CH:3][CH2:4][CH2:5][C:6]([OH:10])([C:8]#[CH:9])[CH3:7].[H][H]>>[CH2:9]=[CH:8][C:6]([CH2:5][CH2:4][CH:3]=[C:2]([CH3:11])[CH3:1])([CH3:7])[OH:10]
Reactant: [H][H]
Reactant: C#CC(C)(O)CCC=C(C)C
Product: C=CC(C)(O)CCC=C(C)C

Procedure:
In a 300 ml pressure reactor, 10 g of the Ru catalyst as described in the catalyst production example were placed in a catalyst basket insert and 150 g (0.99 mol) of dehydrolinalool were added. The hydrogenation was carried out using pure hydrogen at a constant pressure of 40 bar and a temperature of 80° C. After a reaction time of 4 hours, the reactor was vented. The conversion of dehydrolinalool was 95% and linalool was obtained in a selectivity of 90%.
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(NC2C=C(C(O)=O)C(NC3C=CC(C)=CC=3)=CC=2C(O)=O)=CC=1>>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 125 °C

Procedure:
A stirred vessel is charged with 450 parts of polyphosphoric acid containing 83.0% P2O5. Then 37.5 parts of 2,5-dianilinoterephthalic acid and 112.5 parts of 2,5-di-(4-toluidino)terephthalic acid are introduced at 125° C. with stirring and the mixture is heated at 125° C. for 1 hour during which ring closure takes place to form the quinacridone. The reaction is then metered over the course of 5 minutes into a second stirred vessel containing 1431 parts of 70% strength phosphoric acid and is hydrolyzed at 30° C. with stirring. During hydrolysis, the temperature rises to 60° C.
Reaction SMILES: [C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH:15]=1)([OH:3])=[O:2].[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>C(O)C>[C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH:15]=1)([O:3][CH2:17][CH3:18])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CSCCCCCC1=CCCC1=O
Solvent: CCO
Product: CCOC(=O)CSCCCCCC1=CCCC1=O

Procedure:
A mixture of 74 g. (0.306 mols) of 2-(7-carboxy-6-thiaheptyl)-2-cyclopentenone, 1200 ml. of ethanol and 1 g. p-toluenesulfonic acid is stirred and refluxed for 18 hours. The resulting solution is concentrated and the residue is dissolved in ether. The organic phase is washed with water, sodium bicarbonate solution and saline, dried (MgSO4) and evaporated. The residue is distilled to give a light yellow oil, n.p. 147°-150° C. (0.07 Torr).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([NH:28][CH2:29][CH2:30][NH:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)(=[O:27])=[O:26].[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(N(CC)CC)C>ClCCl.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])=[O:13])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([NH:28][CH2:29][CH2:30][N:31]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)[S:41]([CH3:40])(=[O:43])=[O:42])(=[O:26])=[O:27]
Reactant: CCOC(=O)c1c(S(=O)(=O)NCCNc2ccc(OC)cc2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(S(=O)(=O)NCCN(c2ccc(OC)cc2)S(C)(=O)=O)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The material from Example 96, Step C was combined with methanesulfonyl chloride (1.1 equivalents) and triethylamine (3 equivalents) in dichloromethane, and stirred for for one hour at room temperature. The reaction was diluted with EtOAc, washed with sat NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo to obtain the titled compound. ESI+ MS: 714 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:29]([O:31]C)=[O:30])[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])[CH:17]=2)[CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2].[OH-].[Li+].Cl>C1COCC1.CO.O>[CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:29]([OH:31])=[O:30])[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])[CH:17]=2)[CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCCNC(=O)Nc1cccc(-c2cccc(OC[C@H](NC(=O)OCC)C(=O)OC)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCNC(=O)Nc1cccc(-c2cccc(OC[C@H](NC(=O)OCC)C(=O)O)c2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound of Example 7 (100.0 mg, 0.23 mmol, 1 equiv) was dissolved in THF/MeOH/H2O (3:1:1 2.3 mL) and the solution was cooled to 0° C. followed by addition of solid lithium hydroxide (5.4 mg, 0.23 mmol, 1 equiv). The reaction mixture was allowed to reach rt and stirred for 1 hour. It was acidified with 0.1 M aqueous HCl solution to pH 3 and extracted three times with ethyl acetate. The combined organic extracts were dried over Na2SO4 and the solvents were removed under reduced pressure and the remaining crude product was purified by chromatography (SiO2; toluene/EtOH/AcOH 95:4:1). Yield 23.7 mg, 24.5%. 1H NMR (DMSO; 200 MHz) δ 13.05 (brs, 1H); 8.59 (s, 1H); 7.72 (s, 1H); 7.05 (d, 1H); 7.41-7.22 (m, 3H); 7.17-7.03 (m, 3H); 6.91 (d, 1H); 6.22 (dd, 1H); 4.49-4.81 (m, 1H); 4.30-4.19 (m, 2H); 4.0 (q, 2H); 3.04 (q, 2H); 1.49 (sextett, 2H); 1.19 (t, 3H); 0.94 (t, 3H). MS (EI) 430 (M+H), 345, 210.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]12[CH2:33][C:30]([CH2:34]O)([CH2:31][CH2:32]1)[CH2:29][CH2:28][CH2:27]2.C([Li])CCC.CCCCCC>O1CCCC1>[N:26]12[CH2:33][C:30]([CH2:34][O:7][C:6](=[O:8])[C:5]3[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[CH:3][C:4]=3[O:12][CH3:13])([CH2:31][CH2:32]1)[CH2:29][CH2:28][CH2:27]2
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: OCC12CCCN(CC1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(N)c(Cl)cc1C(=O)OCC12CCCN(CC1)C2
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A solution of 4-amino-5-chloro-2-methoxybenzoic acid (1.62 g, 8.0 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.38 g, 8.5 mmol), stirred one hour, and degassed under a stream of nitrogen over 10 minutes. Meanwhile, a cooled (-10° C.) solution of 1-azabicyclo[3.2.1]octane-5-methanol (1.20 g, 8.5 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.50N n-butyllithium/hexane (8.25 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The above degassed solution was transferred into this solution by syringe, and the mixture was stirred at room temperature for 65 hours and at 50° C. for one hour, then concentrated in vacuo. The residue was partitioned between toluene (100 mL) containing a little 2-propanol and saturated aqueous sodium carbonate (50 mL), and the organic layer was separated. The aqueous solution was extracted with toluene (2×50 mL) containing a little 2-propanol, and the combined organic solution was dried (Na2SO4) and concentrated in vacuo. The residue was filtered through alumina (eluted with 2% methanol/tetrahydrofuran, then with 35% methanol/tetrahydrofuran to collect product), and the filtrate was concentrated in vacuo and triturated from cold ether. Recrystallization from ethyl acetate/hexane afforded 1.23 g (47%) of a colorless solid; mp 131°-133° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]#[CH:13])[CH:10]=1)=[O:5])[CH3:2].I[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.CN(C=O)C>O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]#[C:13][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: Cc1ccc(I)cc1
Reactant: C#CCn1cc(C(=O)OCC)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1cnn(CC#Cc2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
A mixture of 1-prop-2-ynyl-1H-pyrazole-4-carboxylic acid ethyl ester obtained as given in example B1 (0.200 g, 1.1 mmol), 4-iodo toluene (0.254 g, 1.1 mol), copper iodide (0.021 g, 0.11 mmol), dichlorobis (triphenylphosphine)-palladium (II) (39 mg, 0.06 mmol), triethylamine (2 ml), DMF (2 ml) was degassed for 10 min. and stirred for 20 hrs at 25-25° C. Reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate. Organic layer was washed with brine solution and dried over Na2SO4. The solvent was evaporated and crude product was purified by column chromatography (Ethyl acetate:hexane-12:78) to obtain pure 1-(3-p-tolyl-prop-2-ynyl)-1H-pyrazole-4-carboxylic acid ethyl ester compound (0.226 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2CCN.[CH3:16][CH2:17]N=C=NCCCN(C)C.Cl.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH3:12])=[O:34])=[CH:31][CH:30]=1.[CH2:16]([C:37]1[CH:36]=[C:32]([CH:31]=[CH:30][C:29]=1[Cl:28])[C:33]([NH2:8])=[O:35])[CH3:17]
Reactant: COc1ccc2[nH]c(C)c(CCN)c2c1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCc1cc(C(N)=O)ccc1Cl
Product: COc1ccc2c(c1)cc(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A reaction mixture containing Compound 7 oxalate salt (520 mg, 2.55 mmol), EDCl (489 mg, 2.55 mmol), DMAP (31 mg, 0.255 mmol), and 4-chlorobenzoic acid (354 mg, 2.26 mmol) in anhydrous methylene chloride (15 mL) was stirred at rt for 3 hours. The reaction mixture was diluted with water and extracted with CH2Cl2 (2×15 mL). The combined CH2Cl2 extracts were washed with water, dried (MgSO4), filtered, and the solvent concentrated in vacuo. The crude amide was chromatographed on silica gel (EtOAc:hexanes; 25:75 then 60:40) to afford the precursor amide Compound 8e as a yellow oil (390 mg, 45%), which was used in the next step without any further characterization owing to its unstable nature.
Reaction SMILES: [N:1]([C@@H:4]1[C@:8](C(=O)C)([OH:9])[C@@H:7]([CH:13](C(=O)C)[OH:14])[O:6][C@H:5]1[N:18]1[CH:25]=[CH:24][C:22](=O)[NH:21][C:19]1=[O:20])=[N+:2]=[N-:3].C(O)C.S(Cl)(Cl)=O.C[N:34](C)C=O>>[N:1]([C@@H:4]1[C@H:8]([OH:9])[C@@H:7]([CH2:13][OH:14])[O:6][C@H:5]1[N:18]1[CH:25]=[CH:24][C:22]([NH2:34])=[N:21][C:19]1=[O:20])=[N+:2]=[N-:3]
Reactant: CC(=O)C(O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](N=[N+]=[N-])[C@@]1(O)C(C)=O
Reactant: CN(C)C=O
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1 g. 2'-Azido-2'-desoxy-3',5'-diacetyl-uridine (see J. Hobbs, H. Sternbach, M. Sprinzl and F. Eckstein, Biochemistry, 12, 5138/1973) was mixed with 14 ml. ethanol-free chloroform and 0.14 ml. dimethyl formamide and then mixed with 2 ml. thionyl chloride. The reaction mixture was boiled under reflux, with the exclusion of moisture, for 6 hours. After cooling, the reaction mixture was evaporated in a vacuum and the residue treated with ammoniacal methanol (30 ml. dry methanol plus 30 ml. methanol saturated with ammonia). The solution was stirred for 2 days at ambient temperature and then left to stand for 2 days at 37° C. Thin layer chromatography (methanol/chloroform mixture (4/6 v/v) on silica gel plates, Herck 60 F 254) shows mainly a product with an Rf value of 0.62. The solution was evaporated, the residue applied to two plates coated with silica gel for preparative thin layer chromatography (Merck 60 F 254, 2 mm. layer thickness, 20×40 cm.) and developed with a chloroform/methanol mixture (6/4 v/v). The main bands were scraped off, the material was eluted with methanol and applied to an ion exchanger column (Dowex 1×2, OH, 1.7×21.5 cm.). After washing with water, the product was eluted with 30% aqueous methanol. The solution obtained was evaporated and the residue recrystallized from ethanol. 2'-Azido-2'-desoxycytidine was obtained in a yield of 12310 A270 units (1.32 mMol; 47% of theory). The product melts at 215° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:30]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[F:41])[C:35]([OH:37])=O)#[N:31]>>[C:30]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[F:41])[C:35]([N:14]([CH:13]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][N:11]([C:16]([CH:18]2[CH2:19][CH2:20][N:21]([C:24]([C:26]3([CH3:29])[CH2:28][CH2:27]3)=[O:25])[CH2:22][CH2:23]2)=[O:17])[CH2:12]1)[CH3:15])=[O:37])#[N:31]
Reactant: N#Cc1cc(C(=O)O)ccc1F
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)c1ccc(F)c(C#N)c1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 3-cyano-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-benzamide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 3-cyano-4-fluorobenzoic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 585.2 [M]+.
Reaction SMILES: [C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>CCOCC.O>[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([N:9]1[CH2:10][CH:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([CH2:12]2)[CH2:8]1)=[O:30]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: c1ccc(C23CNCC2C3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: O=C(c1cccc(F)c1)N1CC2CC2(c2ccccc2)C1

Procedure:
A 6.4 g. portion of 1-phenyl-3-azabicyclo[3.1.0]-hexane is added to 60 ml. of benzene. A 4.2 g. portion of sodium carbonate in 40 ml. of water is added with stirring. A 6.3 g. portion of m-fluorobenzoyl chloride is added and the mixture is stirred overnight. The oil present in the aqueous layer is extracted with chloroform, washed successively with water, dilute hydrochloric acid and water, dried over magnesium sulfate, filtered and evaporated giving an oil. This oil is dissolved in ether. A small amount of petroleum ether is added and the product is recovered as a white solid, mp 68°-69.5° C.
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].ClCP(CCl)(=O)O.[C:12](N)([CH3:15])([CH3:14])[CH3:13].[C:17]([NH:21][CH2:22]P(CNC(C)(C)C)(=O)O)(C)(C)C>O>[C:12]([O:4][P:1]([CH2:17][NH:21][CH3:22])(=[O:3])[OH:2])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: O=[PH](O)O
Reactant: CC(C)(C)NCP(=O)(O)CNC(C)(C)C
Agent: O=P(O)(CCl)CCl
Solvent: O
Product: CNCP(=O)(O)OC(C)(C)C
Yield: 3.2 %

Procedure:
It must be presumed that, in the reaction mechanism of this surprising reaction, a four-membered ring intermediate is formed, which is hydrolyzed into the phosphonic acid by water, and that consequently the reaction proceeds in accordance with the following scheme: ##STR6## This reaction mechanism also seems to play a minor part in the reaction of aliphatic primary amines with bis(chloromethyl)phosphinic acid, where it occurs as a troublesome secondary reaction. It has been observed by the applicant for example that, in the reaction of bis (chloromethyl)-phosphinic acid with tert-butylamine in accordance with M. K. Il'ina and I. M. Shermergorn, Bull. Acad. Sci. USSR, 1968, page 1759 (English edition), not only is the desired bis(tert-butylaminomethyl)phosphinic acid described in this reference obtained in 30.4% yield, but also small amounts (3.2%) of tert-butyl-methylaminomethylphosphonic acid of the formula ##STR7## simultaneously result. Likewise, in the reaction of bis(chloromethyl)phosphinic acid with methylamine, a small amount of dimethylaminomethylphosphonic acid
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Br[CH2:22][C:23](=[O:26])[CH2:24][CH3:25]>>[CH2:22]([N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])[C:23](=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)CBr
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: CCC(=O)Cn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Yield: 49 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 1-bromo-2-butanone were reacted by the same way with the example 1 to obtain the titled compound (179 mg, yield: 49%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[N:9]=[C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[O:11][C:7]=2[CH:6]=1)=[O:4].[Br-].[Al+3].[Br-].[Br-].O.Cl>CSC.ClCCl>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]2[O:11][C:7]3[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:25]=[CH:24][C:8]=3[N:9]=2)=[CH:15][CH:16]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1ccc2nc(COc3ccc(C(C)(C)C)cc3)oc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(OCc2nc3ccc(C(=O)O)cc3o2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.6 %

Procedure:
To a solution of 2-(4-tert-butyl-phenoxymethyl)-benzoxazole-6-carboxylic acid methyl ester (67.8 mg, 0.20 mmol) in dimethyl sulfide (3 ml) and dichloromethane (3 ml) was added aluminum bromide (533.4 g, 2.0 mmol). The reaction mixture was stirred at room temperature for 2.5 h, after which water and 10% HCl were added. After stirring at room temperature for 1 h, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:EtoAc:MeOH=6:3:1) to give 2-(4-tert-butyl-phenoxymethyl)-benzoxazole-6-carboxylic acid as a white solid (50.5 mg, 77.7% yield).