Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([CH3:21])[CH2:8][NH:9][C:10]2[N:20]=[CH:19][CH:18]=[CH:17][C:11]=2[C:12]([O:14][CH2:15]C)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:30])C>>[C:1]1([CH:7]([CH3:21])[CH2:8][N:9]2[C:10]3[N:20]=[CH:19][CH:18]=[CH:17][C:11]=3[C:12](=[O:13])[O:14][C:15]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cccnc1NCC(C)c1ccccc1
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Product: CC(Cn1c(=O)oc(=O)c2cccnc21)c1ccccc1

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 149A for the product of Example 3A (0.44 g, 99%). MS (DCI+) m/z 283 (M+H)−; 1H NMR (300 MHz, DMSO-d6) δ 1.26 (d, J=6.99 Hz, 3H), 3.37 (m, 1H), 4.21 (dd, J=13.24, 6.25 Hz, 1H), 4.36 (m, 1H), 7.21 (m, 1H), 7.29 (m, 4H), 7.38 (dd, J=7.72, 4.78 Hz, 1H), 8.39 (dd, J=7.72, 1.84 Hz, 1H), 8.77 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[NH:7]2.ClC1C=CC=C(C(OO)=[O:25])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[OH:25][CH2:14][CH:13]1[O:1][C:2]2=[C:3]3[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]2[CH2:12]1)[NH:7][C:6](=[O:16])[CH:5]=[CH:4]3
Reactant: C=CCc1cc(C)c2[nH]c(=O)ccc2c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CO)C2
Temperature: 50 °C
Reaction time: 17 h
Yield: 37.9 %

Procedure:
Chloroform (1.5 ml) was added to a mixture of 5-hydroxy-6-allyl-8-methylcarbostyril (50.6 mg) and m-chloroperbenzoic acid (61.5 mg). The obtained mixture was stirred at 50° C. for 17 hours. Excessive aqueous sodium sulfite solution was added thereto, and stirring was continued at room temperature for 30 minutes, followed by extracting with a solvent mixture of chloroform and methanol (4:1). The organic phase was dried over sodium sulfate, and condensed. The resultant residue was purified by thin layer chromatography (solvent=chloroform:methanol=10:1), obtaining 20.6 mg of 2-hydroxymethyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (37.9%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([CH:10](Cl)Cl)[CH:3]=1.C(O)=[O:14]>[Cl-].[Zn+2].[Cl-].O>[Br:1][C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([CH:10]=[O:14])[CH:3]=1
Reactant: O=CO
Reactant: O=[N+]([O-])c1sc(Br)cc1C(Cl)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: O=Cc1cc(Br)sc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
5-Bromo-3-(dichloromethyl)-2-nitrothiophene (60.5 g, 208 mmol) and zinc chloride (113 g, 832 mmol) were stirred in refluxing formic acid (800 mL) overnight. After cooling to ambient temperature, water was added and the products extracted into EtOAc (4×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as an orange solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][CH:13]1[CH:18]=[C:17]([C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[N:16]2[C:27](=[O:39])[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:15]2[S:14]1>C(Cl)(Cl)Cl>[CH3:12][CH:13]1[CH:18]=[C:17]([C:19]([O:21][CH2:22][C:23]([Cl:24])([Cl:25])[Cl:26])=[O:20])[N:16]2[C:27](=[O:39])[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:15]2[S:14]1=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Solvent: ClC(Cl)Cl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Reaction time: 1.5 h

Procedure:
A solution of 3-chloroperbenzoic acid (0.44 g.) in chloroform (5 ml.) was dropwise added under ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate (0.92 g.) in chloroform (10 ml.) and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, the precipitating crystals were filtered off and the filtrate was washed in turn with a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, followed by drying over magnesium sulfate, and then the solvent was distilled off. The residue was crystallized using a small amount of ether to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate-1-oxide, mp 173° to 175° C.
Reaction SMILES: [CH:1]1[NH:2][C:3]2[N:9]=[C:8]([NH2:10])[N:7]=[C:6](Cl)[C:4]=2[N:5]=1.NC(N)=[Se:14]>C(O)C>[NH:7]1[C:6](=[Se:14])[C:4]2[NH:5][CH:1]=[N:2][C:3]=2[N:9]=[C:8]1[NH2:10]
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: NC(N)=[Se]
Solvent: CCO
Product: Nc1nc2nc[nH]c2c(=[Se])[nH]1
Yield: 70 %

Procedure:
1.7 g (10 mmol) of 6-chloroguanine and 1.2 g (10 mmol) of selenourea were put in 30 ml of absolute ethanol and boiled under reflux for 2 hours. After completion of the reaction, the resulting precipitate was separated by filtration, washed with water and dissolved in 200 ml of 2 wt% aqueous sodium carbonate solution by heating. The resulting solution was acidified with acetic acid to form crystals. The crystals were separated by filtration and dried to obtain 1.5 g (7 mmol) of 6-selenoguanine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl:12][O-].[Na+].Cl>O>[Cl:12][C:3]1[C:2]([OH:1])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1
Reactant: [O-]Cl
Reactant: COC(=O)c1cncc(O)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cnc(Cl)c(O)c1
Reaction time: 2 h

Procedure:
To a mixture of methyl 5-hydroxynicotinate (10.0 g) and water (2.0 mL) was added dropwise 5% aqueous sodium hypochlorite solution (69.2 mL) at 0° C., and the mixture was stirred for 2 hr. 2N Hydrochloric acid (50 mL) was added to the reaction mixture at 0° C., and the resulting white precipitate was collected by filtration. The crude crystals were washed with water, and the obtained solid was dissolved in acetonitrile. The solvent was evaporated under reduced pressure to give a crude product of the title compound (3.71 g) as a pale-yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:14]=[C:15]([S:18](=[O:21])(=[O:20])[NH2:19])[C:16]=1Cl)[C:9]([O:11]CC)=[O:10])[CH2:2][CH2:3][CH3:4].[C:22]1([SH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1([S-])C=CC=CC=1.[Na+]>C(O)C>[CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:14]=[C:15]([S:18](=[O:20])(=[O:21])[NH2:19])[C:16]=1[S:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Cl
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [S-]c1ccccc1
Solvent: CCO
Product: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccccc1

Procedure:
A mixture of ethyl 3-butylthio-4-chloro-5-sulfamylbenzoate (0.85 g), thiophenol (0.6 ml), and dry ethanol (25 ml) containing 5 millimoles of sodium thiophenolate is refluxed for 6 hours. After evaporation in vacuo 1 N sodium hydroxide (20 ml) and ethanol (10 ml) are added, and the mixture is refluxed for 15 minutes. After cooling and extraction with diethyl ether, 3-butylthio-4-phenylthio-5-sulfamylbenzoic acid is precipitated from the aqueous layer by addition of 4 N hydrochloric acid. The precipitate is collected by filtration and recrystallized from aqueous ethanol to yield the desired acid having a melting point of 192° - 193°C.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[N:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:43][CH:42]=4)=[CH:37][N:36]=3)=[CH:31][CH:30]=2)[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]([O:23]C(C)(C)C)=[O:22])=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[N:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:43][CH:42]=4)=[CH:37][N:36]=3)=[CH:31][CH:30]=2)[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]([OH:23])=[O:22])=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)cc3)nc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N4CCC[C@H]4C(=O)O)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
Prepared using General Procedure 8. To a stirred solution of (S)-tert-butyl 1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate (350 mg, 0.465 mmol) in DCM (5 mL) was added TFA (5 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with toluene (10 mL) and solvent removed. The residue was dissolved in EA (50 mL), THF (5 mL) and acetone (10 mL) and washed with a mixture of saturated aqueous NaHCO3 (10 mL) and brine (40 mL). The aqueous layer was removed and acetic acid (5 mL) was added. The organic layer was washed with brine (50 mL) and dried over MgSO4. The solvent was removed and residual acetic acid was removed under high vacuum overnight. The material was dissolved in DCM (5 mL) and ACN (5 mL) was added. The material was stirred under a flow of air for 1 hour and the suspension was filtered and the solid washed with additional ACN (5 mL) and iso-hexanes (20 mL) to give 134 mg (41%) of (S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylic acid Compound 328 as a yellow powder. LCMS-ESI (m/z) calculated for C40H48N4O5S: 696.3. found 697.3 [M+H]+, tR=10.59 min (Method 10). The chiral purity was calculated at >93% e.e. (Chiral Method). 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.17 (s, 2H), 8.74 (d, J=8.3 Hz, 1H), 8.38-8.27 (m, 2H), 7.86-7.76 (m, 2H), 7.71 (d, J=3.9 Hz, 1H), 7.57-7.48 (m, 2H), 7.14-7.02 (m, 2H), 6.92 (d, J=3.9 Hz, 1H), 4.94-4.86 (m, 1H), 4.33-4.27 (m, 1H), 4.04 (t, J=6.5 Hz, 2H), 3.86-3.74 (m, 1H), 3.69-3.59 (m, 1H), 3.19-3.01 (m, 2H), 2.24-2.13 (m, 1H), 2.01-1.84 (m, 3H), 1.80-1.68 (m, 2H), 1.52-1.23 (m, 17H), 0.93-0.85 (m, 3H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:47][O:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:52]2[CH2:53][CH2:54][CH:49]([O:48][CH3:47])[CH2:50][CH2:51]2)=[O:23])=[CH:15]3)=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: COC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-methoxy piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][O:17][CH3:18])=[CH:11][CH:10]=1.Cl.[CH3:32][O:33][NH2:34].C([O-])(=O)C.[Na+].O>CO>[CH3:32][O:33][N:34]=[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:23][C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])=[CH:21][C:20]=2[Cl:30])=[CH:10][CH:11]=1)[CH2:16][O:17][CH3:18]
Reactant: COCC(=O)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCC(=NOC)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
296 mg of 1-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-2-methoxy-ethanone, 56 mg of O-methylhydroxylamine hydrochloride and 55 mg of sodium acetate are stirred in 4 ml of methanol at room temperature for 24 hours. The reaction mixture is poured into water and extracted with ethyl acetate. After concentration of the organic phases and purification over silica gel, the title compound is obtained in the form of an E/Z mixture. 1H-NMR (CDCl3) 300 MHz: 2.30 (m, 2H), 3.32+3.46 (s+s, 3H), 3.93+3.99 (s+s, 3H), 4.18 (t, 2H), 4.29 (m, 2H), 4.53-4.61 (m, 4H), 6.11 (t, 1H), 6.83 (s, 2H), 6.91 (d, 2H), 7.62 (d, 2H)
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)[CH3:8])[CH:6]=[CH:5][CH:4]=CC=1.C1C2C(=CC=CC=2)C=CC=1O.C=CC1C=CC=CC=1.S(=O)(=O)(O)O>>[CH:7]1([C:9]2[CH:18]=[C:17]3[C:12](=[CH:11][CH:10]=2)[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16]3)[CH2:8][CH2:4][CH2:5][CH2:6][CH2:1]1
Reactant: CC(c1ccccc1)c1ccc2cc(O)ccc2c1
Agent: O=S(=O)(O)O
Agent: Oc1ccc2ccccc2c1
Solvent: C=Cc1ccccc1
Product: Oc1ccc2cc(C3CCCCC3)ccc2c1

Procedure:
It is known that as a rule the alkylation of 2-naphthol with an olefin or alcohol in the presence of an inorganic acid or organic sulfonic acid principally gives a 6-alkylated 2-naphthol. J. Org. Che., 17 (1952), 243- 248 describes the preparation of 6-(α-phenylethyl)-2-naphthol by reacting 2-naphthol with styrene in the presence of sulfuric acid, the yield being 92 percent. J. Org. Chem., 16 (1951), 185-191 discloses that 6-cyclohexyl-2-naphthol is formed by reacting 2-naphthol with cyclohexanol in the presence of phosphoric acid.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1)(=[O:15])=[O:14].[CH3:25][S-:26].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:1][N:2]([CH3:24])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][C:17]1[N:18]=[N:19][C:20]([S:26][CH3:25])=[CH:21][CH:22]=1)(=[O:15])=[O:14]
Reactant: C[S-]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc(Cl)nn3)cccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)nn1
Temperature: 100 °C
Yield: 37.7 %

Procedure:
5-Dimethylamino-N-(6-chloro-3-pyridazinyl)-1-naphthalenesulphonamide (0.72 g) was dissolved in N,N-dimethylformamide and sodium thiomethoxide (0.42 g) added. The mixture was heated to 100° C. for 6 hours, then cooled and 7% aqueous citric acid solution (15 ml) was added with stirring. The solid formed was collected by filtration and washed with water (10 ml). The solid was then purified by chromatography on silica gel (20 g) under reduced pressure, eluting with an ethyl acetate/toluene gradient, to give 5-dimethylamino-N-(6-methylthio-3-pyridazinyl)-1-naphthalenesulphonamide (0.28 g), m.p. 188-190° C.; mass spectrum (+ve CI): 375 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=1)=[CH:6]2.[CH:28]([N:31](C(C)C)[CH2:32]C)(C)C.CNC.O>CS(C)=O>[CH3:28][N:31]([CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=1)=[CH:6]2)[CH3:32]
Reactant: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(CCl)cc([N+](=O)[O-])c3[nH]2)=N1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: O
Solvent: CS(C)=O
Product: CN(C)Cc1cc([N+](=O)[O-])c2[nH]c(C3=N[C@H](COC(=O)C(C)(C)C)CS3)cc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.7 %

Procedure:
2,2-Dimethyl-propionic acid [(R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]methyl ester (1.0 g, 2.4 mmol) prepared in Preparation 41 was dissolved in dimethylsulfoxide (15 mL). Diisopropylethylamine (0.6 g, 4.9 mmol) and dimethylamine (0.2 g, 4.9 mmol) were added thereto, and the mixture was stirred for 6 h at room temperature. After completion of the reaction, water was added. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (0.7 g, Yield 71%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:10]=1[CH:11](OCC)OCC)=O)C.O.[NH2:26][NH2:27].Cl>C(O)(=O)C.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([N:9]2[C:10]3=[CH:11][N:26]=[N:27][C:4]([OH:3])=[C:6]3[CH:7]=[N:8]2)=[CH:19][CH:20]=1
Reactant: NN
Reactant: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1C(OCC)OCC
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Oc1nncc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-diethoxymethyl-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (5.70 g, 16.9 mmol) in acetic acid (100 mL) is added hydrazine monohydrate (5.0 mL, 6.1 mmol) and 12 N aqueous hydrochloric acid (200 μL). The reaction mixture is warmed at reflux. After 2 hours, the mixture is cooled to room temperature and diluted with water. The solid is collected by filtration, washed with water and air dried to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyridazin-4-ol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=4)[N:21]=3)[CH2:16][CH:15]2[C:41](O)=[O:42])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].Cl.[CH2:45]([NH:51][CH3:52])[CH2:46][CH2:47][CH2:48][CH:49]=[CH2:50]>>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:34]=[C:35]([F:40])[CH:36]=[C:37]([F:39])[CH:38]=4)[N:21]=3)[CH2:16][CH:15]2[C:41](=[O:42])[N:51]([CH2:45][CH2:46][CH2:47][CH2:48][CH:49]=[CH2:50])[CH3:52])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CCCCCNC
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3cc(F)cc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)O)C(=O)OCC
Agent: Cl
Product: C=CCCCCN(C)C(=O)C1CC(Oc2nc(-c3cc(F)cc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Yield: 81 %

Procedure:
The acid 167 was reacted with hex-5-enyl-methyl-amine hydrochloride as according to the same procedure described in example 157, which gave the title compound (0.838 g, 81%), LRMS (M+H) 691.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])[CH3:3].[OH-].[Na+].[CH3:20]I.O>CN(C)C=O>[CH3:14][C:13]([C:7]1[CH:8]=[C:9]([S:11][CH3:12])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[O:17][CH3:20])([CH3:16])[CH3:15]
Reactant: CI
Reactant: CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C(C)(C)C)cc(SC)cc1C(C)(C)C

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-(methylthio)phenol (1.16 g, 4.6 mmole) in dimethylformamide (15 ml) was added sodium hydroxide (0.37 g, 9.2 mmole). After the solution was warmed for one hour, methyl iodide (0.72 g, 5.1 mmole) was added, and the mixture was warmed for an additional three hours. The reaction mixture was poured into water (150 ml) and extracted with diethyl ether (180 ml in three positions). The ether extract was washed with saturated aqueous sodium carbonate, dried over sodium sulfate, filtered, and concentrated in vacuo to an oil. Upon standing the oil crystallized. Recrystallization from hexane gave the title compound, m.p. 50°-52°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:32])[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](/[CH:23]=[CH:24]/[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:33])=O)(C)(C)C>Cl.O1CCOCC1>[Cl:31][C:27]1[CH:26]=[C:25](/[CH:24]=[CH:23]/[C:19]2[N:18]=[C:17]([C:15]3[N:14]([CH3:32])[C:11]4[CH2:12][CH2:13][NH:8][C:9](=[O:33])[C:10]=4[CH:16]=3)[CH:22]=[CH:21][N:20]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Cn1c(-c2ccnc(/C=C/c3cccc(Cl)c3)n2)cc2c1CCN(C(=O)OC(C)(C)C)C2=O
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(-c2ccnc(/C=C/c3cccc(Cl)c3)n2)cc2c1CCNC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
A suspension of 2-{2-[(E)-2-(3-Chloro-phenyl)-vinyl]-pyrimidin-4-yl}-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.050 g, 0.107 mmol) in 4M HCl/dioxane (2.0 ml) was stirred at room temperature for 1 h. The solvent was removed under vacuum and the product was purified by crystallisation from methanol, yielding 2-{2-[(E)-2-(3-Chloro-phenyl)-vinyl]-pyrimidin-4-yl}-1-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one as a yellow solid (0.015 g, 0.041 mmol, 38%).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].CCCCCC.C([Li])CCC.[Br:23]C(Cl)(Cl)C(Br)(Cl)Cl.O>O1CCCC1>[Br:23][C:10]1[N:5]2[N:4]=[C:3]([CH2:1][CH3:2])[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: CCc1cc2ccccn2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
After dissolving 2-ethylpyrazolo[1,5-a]pyridine (80 mg) in tetrahydrofuran (1 mL), an n-butyllithiumhexane solution (1.6 M; 0.58 mL) was added dropwise at −78° C. under a nitrogen stream, and the mixture was stirred for 30 minutes. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (196 mg) in tetrahydrofuran (0.5 mL) was added to the reaction mixture, and stirring was continued for 30 minutes. The temperature was increased to room temperature, water was added, extraction was performed with ethyl acetate and the organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (90 mg) was obtained from the n-hexane:ethyl acetate (20:1) fraction as a light brown oil.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)=[O:4].[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[C:23]([N+:33]([O-:35])=[O:34])[CH:22]=1>C(#N)C>[Cl:12][C:10]1[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:37])([F:19])[F:36])=[CH:22][C:23]=3[N+:33]([O-:35])=[O:34])[CH2:28][CH2:29]2)[CH:11]=1
Reactant: O=C(CBr)Nc1cc(Cl)nc(-c2ccccc2)n1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCNCC1
Solvent: CC#N
Product: O=C(CN1CCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1)Nc1cc(Cl)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide (100 mg) was dissolved in acetonitrile (5 ml) and (4-trifluromethyl-2-nitrophenyl)piperazine (253 mg) added. The solution was stirred overnight at room temperature. After this time the solvent was removed in vacuo. Purification by flash chromatography on silica gel eluting with a mixture of dichloromethane and methanol (98:2, then 93:7 v/v) afforded the title compound. m/z (ES+) 521 (MH)+