Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].COC(=O)CN(CC(OC)=O)[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:10][CH:9]=1.[C:34]([CH2:37][N:38](C1C=CC(CCCCCCCCCCCCCC)=CC=1)[CH2:39][C:40]([OH:42])=[O:41])([OH:36])=[O:35]>CO>[C:34]([CH2:37][N:38]([C:9]1[CH:8]=[CH:13][CH:12]=[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:10]=1)[CH2:39][C:40]([OH:42])=[O:41])([OH:36])=[O:35]
Reactant: CCCCCCCCCCCCCCc1ccc(N(CC(=O)OC)CC(=O)OC)cc1
Reactant: CCCCCCCCCCCCCCc1ccc(N(CC(=O)O)CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCc1cccc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 72 h

Procedure:
A mixture of 1.0 g (3.45 mmol) of 4-tetradecylphenyl aniline (Aldrich Chemical Company), 5.0 ml (0.052 mol) of methyl bromoacetate, 0.95 g (6.9 mmol) of potassium carbonate and 0.5 g (3.45 mmol) of sodium iodide in 15 ml of DMF was stirred and heated at 100° for 45 hours. The solvent was removed at reduced pressure and water was added to the residue. The product was extracted with ethyl acetate and the extract was washed with sodium bisulfite solution, dried and concentrated. The residue was purified by chromatography on silica gel using 25% ethyl acetate-hexane to give 0.7 g of N-(2-methoxy-2-oxoethyl)-N-(4-tetradecylphenyl)glycine methyl ester. This dimethyl ester was hydrolyzed by treatment with 1.5 ml of 6N NaOH in 50 ml of methanol. The mixture was warmed briefly to dissolve the ester and then was kept at room temperature for 3 days. The solvent was removed at reduced pressure and the residue was acidified to pH 2. The product was extracted with ethyl acetate and the dried extract was concentrated at reduced pressure to a solid which was recrystallized from methanol-water to give 0.26 g, mp 160°-165°, of N-(carboxymethyl)-N-(4-tetradecylphenyl)glycine.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:33])=[C:17]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4([C:30]#[N:31])[CH2:29][CH2:28]4)[CH:22]=3)[CH:18]=2)=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:33])=[C:17]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4([C:30]#[N:31])[CH2:28][CH2:29]4)[CH:22]=3)[CH:18]=1)[N:10]=2
Reactant: Cc1ccc(Oc2ccc(N)cn2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc(Oc2ccc3nc(N)sc3n2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Potassium thiocyanate (506 mg, 5.2 mmol) was suspended in acetic acid (10 mL), and the mixture was stirred at room temperature for 10 min. A solution of N-{5-[(5-aminopyridin-2-yl)oxy]-2-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (500 mg, 1.3 mmol) in acetic acid (10 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 15 min. A solution of bromine (230 mg, 1.43 mmol) in acetic acid (7.0 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 4 hr. The yielded yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and washing solution were combined, and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (200 mL), and the suspension was washed with 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (350 mg, 61%) as a pale-yellow amorphous substance. The amorphous substance was used for the next reaction without further purification.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].C(O)C(N)(CO)CO.[N-]=C=O>C(Cl)Cl>[C:33]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: O=C(Nc1ccc2c(c1)NCCC2)c1ccc(-c2ccccc2)cc1
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-(1,2,3,4-tetrahydroquinolin-7-yl)-1,1′-biphenyl-4-carboxamide (Example 24) (66 mg, 0.2 mmol) in DCM (1 ml) was added triethylamine (42 ul, 0.3 mmol) followed by acetyl chloride (20.5 ul, 0.3 mmol). The reaction was stirred at ambient temperature for 15 mins then treated with polymer supported trisamine resin (31 mg, 0.1 mmol) and polymer supported isocyanate resin (20 mg, 0.04 mmol). After 5 mins the resins were removed by filtration and the filtrate was washed with 2M hydrochloric acid, dried over MgSO4 and concentrated in vacuo to give the title compound as an off-white solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.94 (d, 2H), 7.84 (d, 1H), 7.78 (br, 1H), 7.72 (d, 2H), 7.64 (d, 2H), 7.45 (m, 4H), 7.15 (d, 1H), 3.80 (t, 2H), 2.74 (t, 2H), 2.33 (s, 3H), 1.98 (qn, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[CH:5][NH:4][N:3]=1.CN(/[CH:11]=[C:12](/[C:17]([F:20])([F:19])[F:18])\[CH:13]=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)(=O)C>C(O)C>[Br:7][C:6]1[CH:5]=[N:4][N:3]2[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=[N:1][C:2]=12
Reactant: CN(C)/C=C(\C=[N+](C)C)C(F)(F)F
Reactant: Nc1n[nH]cc1Br
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CC(=O)O
Product: FC(F)(F)c1cnc2c(Br)cnn2c1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
3-Amino-4-bromopyrazole (4.29, 26.5 mmol) and 2-(trifluoromethyl)-1,3-bis(dimethylamino)trimethinium hexafluorophosphate (9.00 g, 26.5 mmol) were dissolved in ethanol (52.9 mL) and acetic acid (35.3 mL) and the reaction heated to 70° C. for 16 h. The solution was cooled to room temperature and concentrated. The residue was filtered through a fritted funnel, the precipitate washed with water, and dried under reduced pressure to afford the title compound (6.22 g, 23.4 mmol). LRMS (APCI) calc'd for (C7H3BrF3N3) [M+H]+, 266.0; found 265.9. 1H NMR (CDCl3, 500 MHz) δ 8.96 (d, J=1.1, 2.1, 1H), 8.71 (d, J=2.1, 1H), 8.28 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[N:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.CO.O>[C:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10]2[CH:15]=[N:14][C:13]([O:16][C:17]3[CH:25]=[CH:24][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Oc3ccc(C(=O)O)cc3)nc2)cc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)Nc2ccc(Oc3ccc(CO)cc3)nc2)cc1
Temperature: 25 °C

Procedure:
A suspension of 4-[5-(4-cyanobenzoylamino)-pyridin-2-yloxy]benzoic acid (1.80 g, 5.01 mmol) in THF (20 mL) was cooled with ice-common salt, and to the solution was added triethylamine (0.77 mL, 5.51 mmol), and then ethyl chlorformate (0.53 mL, 5.51 mmol). The resulting solution was stirred at room temperature. Thirty minutes later, the reaction solution was filtered and insoluble matter was removed. The resulting filtrate was poured while stirring under ice cooling into an aqueous solution of sodium borohydride (0.95 g, 25.05 mmol) in 80% methanol (40 mL). After stirring for 30 minutes at room temperature, water (200 mL) was added to the reaction solution. The obtained mixture was extracted with ethyl acetate (200 mL). The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from a mixed solution of ethyl acetate-n-hexane, to thereby yield 1.26 g of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[CH:3][CH:2]=1.[N+:13]([CH:16]=[C:17](SC)SC)([O-:15])=[O:14]>CO>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][NH:12][C:17]2=[CH:16][N+:13]([O-:15])=[O:14])=[CH:3][CH:2]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCCNCc1ccncc1
Solvent: CO
Product: O=[N+]([O-])C=C1NCCCN1Cc1ccncc1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A mixture of N-(4-pyridylmethyl)trimethylenediamine (16.5 g), 1-nitro-2,2-bis(methylthio)ethylene (16.5 g) and methanol (100 ml) was refluxed for 2 hours with stirring. The generated gas was collected by an alkali trap. The reaction mixture was cooled to room temperature, and the resulting crystals were filtered to give 1-(4-pyridylmethyl)-2-(nitromethylene)tetrahydropyrimidine (16 g) of the following formulas as pale yellow crystals. Concentrating the filtrate further gave 3 g of this compound. mp. 226°-228° C. ##STR14##
Reaction SMILES: ClC1C(Cl)=C([OH:9])C(Cl)=C(Cl)N=1.[C:12]([O:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21])(=[O:15])[CH2:13][CH3:14].CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.CCCCCC>[O:15]=[C:12]([O:16][CH2:17][CH2:18][NH:19][C:20](=[O:9])[OH:21])[CH2:13][CH3:14]
Reactant: CCC(=O)OCCN=C=O
Reactant: Oc1c(Cl)c(Cl)nc(Cl)c1Cl
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CCC(=O)OCCNC(=O)O

Procedure:
11.7 Grams of 2,3,5,6-tetrachloro-4-pyridinol, 7.2 grams of isocyanatoethyl propionate, and a few drops of dibutyltin dilaurate (as activating agent) were added to 200 ml of acetone and stirred at reflux temperature for eight hours and then allowed to stand. The mixture was again stirred at reflux temperature for an additional seven hours before the addition of 6.0 grams of potassium carbonate. The reactants were then stirred for another hour after which the insoluble components were filtered off and the solvent removed under reduced pressure, leaving a residue. The resulting residue was slurried in n-hexane, cooled, and filtered to yield about 15 grams of soft, white solid as the desired 2,3,5,6-tetrachloro-4-pyridinyl ester of (2-(1-oxopropoxy)ethyl)carbamic acid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].CS(O)(=O)=O.[OH-].[Na+].[Cl-].[NH4+]>C(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17][C:18]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccccc2c1C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
To a solution of 4,4'-difluorobenzhydrol (12.8 g, 58.1 mmol) and ethyl indole-2-carboxylate (10.0 g, 52.9 mmol) in 100 ml of methylene chloride was added methanesulfonic acid (3.4 ml, 52.9 mmol), followed by stirring at room temperature for one hour. Then, 4,4'-difluorobenzhydrol (1.0 g, 4.54 mmol) was further added to the reaction mixture followed by stirring for 1.5 hours to complete the reaction. A 2N aqueous sodium hydroxide solution was added to the reaction solution, and a saturated aqueous solution of ammonium chloride was further added thereto for neutralization followed by extraction with chloroform. The resulting organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give a crude product. The obtained crude product was recrystallized from ethanol to give 8.4 g (yield: 40%) of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][N:22]1[CH2:26][CH2:25][CH:24](Br)[C:23]1=[O:28].C(N(CC)CC)C.[CH3:36][C:37]([C:40]1[C:45]([OH:46])=[C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])[N:43]=[C:42]([CH:51]=O)[N:41]=1)([CH3:39])[CH3:38]>C1COCC1.C(O)C>[CH3:39][C:37]([C:40]1[C:45]([OH:46])=[C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])[N:43]=[C:42]([CH:51]=[C:24]2[CH2:25][CH2:26][N:22]([O:21][CH3:20])[C:23]2=[O:28])[N:41]=1)([CH3:36])[CH3:38]
Reactant: CON1CCC(Br)C1=O
Reactant: CC(C)(C)c1nc(C=O)nc(C(C)(C)C)c1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CON1CCC(=Cc2nc(C(C)(C)C)c(O)c(C(C)(C)C)n2)C1=O
Temperature: 25 °C

Procedure:
Triphenylphosphine (1.5 g, 5.7 mmol) is added to a solution of N-methoxy-3-bromopyrrolidin-2-one (Ikuta, et al. J. Med. Chem. 1984, 30, 1995) (1.0 g, 5.2 mmol) in THF (10 mL) and the mixture is warmed to reflux under an argon atmosphere for 12 hours. The reaction mixture is cooled in an ice bath and the solvent is decanted away from the resulting solid. The solid is added to a solution of triethylamine (0.93 g, 9.3 mmol) and 4,6-bis-(1,1-dimethylethyl)-5-hydroxypyrimidine-2-carboxaldehyde (0.97 g, 4.1 mmol) in ethanol (10 mL). The resulting mixture is warmed to reflux for 3 hours under an argon atmosphere. The mixture is cooled to room temperature, the EtOH is evaporated and the residue is partitioned between 50 mL EtOAc and 50 mL H2O. The organic extract is dried over MgSO4. The solvent is evaporated and the solid is recrystallized from Et2O/hexane. Yield of 3-[[4,6-bis-(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]methylene]-N-methoxypyrrolidin-2-one=0.34 g (20%), mp 184°-186° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CN(C=O)C>CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][S:26]([C:23]4[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=4)(=[O:28])=[O:27])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)Nc2cccc(-n3ncc4c(N)ncnc43)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.3 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (36 mg, 1.1 eq, 0.16 mmol), 4-methoxybenzenesulphonylchloride (30 mg, 1.0 eq, 0.15 mmol) and diisopropylethylamine (25 μl, 1.0 eq, 0.15 mmol) were added to DMF (1 ml) and the mixture was stirred for 15 hours at room temperature under an inert atmosphere. Methanol was then added (1 ml) and the solvents were removed in vacuo. The resultant solid was purified by semi-preparative HPLC to yield the title compound as a white solid (30 mg, 0.08 mmol, 52%). LCMS: [M+H]+=397, Rt=1.68 min, 100% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:39]=[C:38]([CH3:40])[C:33]3[NH:34][C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:39]=[C:38]([CH3:40])[C:33]6[NH:34][C:35](=[O:37])[O:36][C:32]=6[CH:31]=5)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2

Procedure:
275 mg (1.00 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 289 mg (1.00 mmol) 6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.348 mL (2.00 mmol) DIPEA were stirred overnight in 10 mL DMF at RT. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined, the organic solvent was eliminated i. vac. and the aqueous phase remaining was neutralised with 4N aqueous NaOH solution. The precipitate was suction filtered, washed with water and dried in the CAD.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[H-].[Na+].[F:7][C:8]1[CH:9]=[C:10]([Br:15])[CH:11]=[C:12](F)[CH:13]=1>CC(N(C)C)=O>[CH2:1]([O:4][C:12]1[CH:13]=[C:8]([F:7])[CH:9]=[C:10]([Br:15])[CH:11]=1)[CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: Fc1cc(F)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C=CCOc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.1 %

Procedure:
To a DMA (400 ml) solution of allyl alcohol (8.9 g, 0.154 mol), at room temperature (r.t.) is added NaH (60% oil dispersion) (6.4 g, 0.160 mol) in portions. The mixture is stirred at r.t. for 1.5 h followed by the slow addition of 3,5-difluoro bromobenzene (17.9 ml, 30 g, 0.155 mol). The reaction mixture is stirred at r.t. overnight. The reaction is quenched by the addition of 1500 ml of water and extracted with ether (4×300 ml). The organic layer is dried over MgSO4 and concentrated at reduced pressure to yield 24.6 g (69%) of a colorless oil after flash chromatography (pentane, rf.=0.3). Anal. Calc. for C9H8BrFO: C, 46.78; H, 3.49. Found: C. 46.18, H, 3.45. Calculated mass for C9H8OFBr: 229.97. Mass found for C9H8OFBr: (OAMS) ES−: 189.0 (M-allyl)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[N:21]1([CH2:26][CH:27]2[O:32][CH2:31][CH2:30][NH:29][CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:29]4[CH2:30][CH2:31][O:32][CH:27]([CH2:26][N:21]5[CH2:22][CH2:23][CH2:24][CH2:25]5)[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1CCN(CC2CNCCO2)C1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCOC(CN4CCCC4)C3)c(F)cc2c1=O

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(1-pyrrolidinylmethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-[2-(1-pyrrolidinylmethyl)morpholino]quinoline-3-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](F)=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:23][S-:24].[Na+].Cl>CN(C)C=O>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:24][CH3:23])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(SC)c(C(F)(F)F)c1
Temperature: 105 °C
Yield: 32.7 %

Procedure:
A solution of 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid methyl ester (7.0 g, 21.9 mmol) in N,N-dimethylformamide (50 mL) was treated with sodium methanethiolate (2.61 g, 33.0 mmol). The reaction mixture was then heated at 100-110° C. for 24 h. At this time, the reaction was poured onto a mixture of ice and a 2N aqueous hydrochloric acid solution (100 mL). This mixture was extracted into ethyl acetate (3×75 mL) and diethyl ether (1×50 mL). The combined organic layers were then washed with water (1×75 mL) and a saturated aqueous sodium chloride solution (3×100 mL). The organic layer was dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid methyl ester (2.48 g, 35.5%) as a pale yellow oil: EI-HRMS m/e calcd for C17H21F3O2S (M+) 346.1214, found 346.1212.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH2:7][CH2:8][N:9]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:18][CH:17]=3)[CH2:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:4].[OH-].[Na+]>CO>[C:25]([NH:24][C@H:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:9]2[CH2:8][CH2:7][C:6]3[C:5]([C:3]([OH:4])=[O:2])=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10]2)=[CH:17][CH:18]=1)[CH3:23])(=[O:27])[CH3:26]
Reactant: COC(=O)c1cccc2c1CCN(Cc1ccc([C@H](C)NC(C)=O)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N[C@@H](C)c1ccc(CN2CCc3c(cccc3C(=O)O)C2)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To 560 mg (1.53 mmol) 2-[4-((S)-1-acetylamino-ethyl)-benzyl]-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid methyl ester (example XXXVI) in 5 mL MeOH are added 1.68 mL (1.68 mmol) aq. NaOH solution (c=1 mol/L). The reaction mixture is stirred for 1 h at 70° C. After that time, the solvent is partially removed in vacuo and the residue is extracted with DCM. The aq. layer is separated, alkalized with aq. HCl solution (c=1 mol/L) and extracted with EtOAc. The aq. layer was separated and the solvent was removed by lyophilization.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:13]([NH:15][C:16]2[C:17]3[N:18]=[CH:19][N:20]([C:29]=3[N:30]=[CH:31][N:32]=2)[C@@H:21]2[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[CH2:22]2)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([N+:46]([O-:48])=[O:47])[C:41]=1[CH2:49][CH2:50][O:51][C:52](Cl)=[O:53].CC(O)C.N#N>C(Cl)Cl>[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([N+:46]([O-:48])=[O:47])[C:41]=1[CH2:49][CH2:50][O:51][C:52]([O:27][CH2:26][C@H:25]1[O:28][C@@H:21]([N:20]2[C:29]3[N:30]=[CH:31][N:32]=[C:16]([NH:15][C:13]([O:12][CH2:11][CH2:10][C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)=[O:14])[C:17]=3[N:18]=[CH:19]2)[CH2:22][C@@H:23]1[OH:24])=[O:53]
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)OCCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)OCCc1c(Cl)cccc1[N+](=O)[O-]
Agent: N#N
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COC(=O)OCCc2c(Cl)cccc2[N+](=O)[O-])O1)OCCc1ccc([N+](=O)[O-])cc1
Temperature: -60 °C
Yield: 83.2 %

Procedure:
N6 -(2-(4-nitrophenyl)ethoxycarbonyl)-2'-deoxyadenosine (5 g, 11.3 mmol) was co-evaporated with pyridine (2×60 ml, pro analysi quality, additionally dried over molecular sieve 4 Å), dissolved in pyridine (60 ml, see above) and cooled to -60° C. (i-PrOH/N2). A solution of 2-(2-chloro-6-nitrophenyl)ethoxycarbonyl chloride (4.17 g, 15.8 mmol) in CH2Cl2 (60 ml, dist. over CaH2) was added dropwise for 2 h. After it had been stirred another 2 h in conditions of i-PrOH/N2 cooling (-40° to -25° C.), the mixture was diluted with CH2Cl2 (150 ml) and washed with H2O (100 ml). The aqueous phases were post-extracted with CH2Cl2 (100 ml). Drying the organic phases over Na2SO4, filtering, evaporating the solvent under reduced pressure and co-evaporating with toluene (3×50 ml) yielded the crude product (8.73 g) which was purified by column chromatography (400 g SiO2, 28×5.7 cm, solvent: CH2Cl2 /MeOH 100:3). 5'-O-(2-(2-chloro-6-nitrophenyl)ethoxycarbonyl)-N6 -(2-(4-nitrophenyl)ethoxycarbonyl)-2'-deoxyadenosine (6.318 g, 83%) was obtained as a colourless foam.