Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[CH:4]([OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH:22]=O.[BH4-].[Na+].O>C(O)(=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:2]([NH:1][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[O:19][CH3:18])=[C:3]([CH:13]=1)[CH:4]([OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1ccc(Cl)cc1C(O)c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccc(Cl)cc2C(O)c2ccccc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of 2-amino-5-chloro-α-(2-chloro phenyl)benzyl alcohol (5.0 g) and 2,4-dimethoxy benzaldehyde (3.72 g) in acetic acid (50 ml) was added, under ice-cooling, sodium borohydride (0.94 g). The mixture was stirred for one hour at room temperature, which was poured into water (200 ml), followed by extraction with ethyl acetate (200 ml×2). The ethyl acetate layer was washed with 1N sodium hydroxide, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=5:1) to give 5-chloro-α-(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)aminobenzyl alcohol (7.5 g) as an oily product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2[C:29]([C:32](O)=[O:33])=[N:30][NH:31][C:25]=2[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH:10]1[CH2:11][CH2:12][N:13]([C:32]([C:29]2[C:26]3[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:24][C:25]=3[NH:31][N:30]=2)=[O:33])[CH2:14][CH2:15]1
Reactant: Fc1ccc(Cl)c(C2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)O)n[nH]c2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4cc(F)ccc4Cl)CC3)n[nH]c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a solution of 4-(2-chloro-5-fluorophenyl)piperidine hydrochloride (17, 70 mg, 0.28 mmol), 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (104 mg, 0.39 mmol), and diisopropylethylamine (0.15 mL, 0.84 mmol) in DMF (5.4 mL) was added EDCI (65 mg, 0.34 mmol) and HOBt (45 mg, 0.34 mmol). The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (4×20 mL). The combined organic extracts were washed with a saturated brine solution (9×20 mL), H2O (2×20 mL) and concentrated to dryness under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 100% EtOAc in hexanes) to provide tert-butyl 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (47) as a white solid (57 mg, 44%): 1H NMR (300 MHz, DMSO-d6) δ 13.16-12.78 (m, 1H), 7.48 (dd, J=9.0, 5.7 Hz, 1H), 7.28 (dd, J=10.5, 3.3 Hz, 1H), 7.17-7.05 (m, 1H), 4.90-4.59 (m, 2H), 4.53-4.40 (m, 2H), 3.62-3.48 (m, 2H), 3.28-3.07 (m, 2H), 2.92-2.73 (m, 1H), 2.64-2.50 (m, 2H, overlaps with solvent), 1.93-1.69 (m, 2H), 1.68-1.49 (m, 2H), 1.42 (S, 9H); ESI MS m/z 463 [M+H]+.
Reaction SMILES: F[C:2](F)([C:9](O)=O)[C:3](F)(F)[C:4](O)=O.F[C:14](F)(F)[C:15]1[CH:20]=[C:19](N=C=O)[CH:18]=[CH:17][C:16]=1[N:24]=C=O.C[N:30]1[C:34](=O)[CH2:33][CH2:32][CH2:31]1>>[C:16]1([C:15]2[CH2:14][CH2:19][CH2:20][CH2:15][CH2:16][CH2:17][CH2:17][CH2:18][CH2:19][CH:20]=2)[CH2:9][CH2:2][CH2:3][CH2:4][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][N:24]=1
Reactant: O=C=Nc1ccc(N=C=O)c(C(F)(F)F)c1
Reactant: O=C(O)C(F)(F)C(F)(F)C(=O)O
Reactant: CN1CCCC1=O
Product: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1

Procedure:
In a four-necked flask provided with a condenser and a nitrogen gas inlet, 1.0 mol of tetrafluorosuccinic acid and 1.0 mol of 2-trifluoromethyl-p-phenylene diisocyanate were mixed with NMP to give a solid content concentration of 20% by weight, and 0.01 mol of diazabicycloundecene was added as a catalyst to the mixture. The mixture was stirred in the flask and allowed to react at 120° C. for about four hours.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]2[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][N:24]2[C:36]([O:38][C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=[O:37])[CH:16]=1>CO>[ClH:1].[ClH:1].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]2[CH2:28][NH:27][CH2:26][CH2:25][N:24]2[C:36]([O:38][C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)=[O:37])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc(F)cc2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C(Oc1ccc(F)cc1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 97 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of 4-tert-butyl 1-(4-fluorophenyl) 2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate TFA salt (88.9 mg, 0.163 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 63.7 mg (97%) of the desired product as a yellow solid. LC-MS: RT=4.07 min, [M+H]+=332.1.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)=[O:19]
Reactant: CN1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CC1
Reaction time: 2 h
Yield: 100.4 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-N-[(1-methylpiperidin-4-yl)oxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 51 (0.065 g, 0.167 mmol) and Pd/C (0.060 g) in methanol (30 mL) was hydrogenated at 35 psi at room temperature for 2 h. The mixture was filtered through a Celite pad and concentrated to provide 52 (0.050 g, quantitative) as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[C:11]1([S:17]([CH2:20][C:21]#[N:22])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(O)C>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:20](/[S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:18])=[O:19])\[C:21]#[N:22])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: N#CCS(=O)(=O)c1ccccc1
Solvent: CCO
Solvent: O
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 50 %

Procedure:
2-Nitrothiophen-5-carboxaldehyde (0.157 g) and phenylsulfonyl acetonitrile (0.199 g) were stirred in 2 mL of ethanol containing 0.01 mL piperidine for four hours at 100° C. The mixture was cooled to room temperature and water was added for crystallization. The crude product was filtered and recrystallized from ethanol and water to give 0.16 g of (E)-3-(2-nitrothien-5-yl)-2-(phenylsulfonyl) acrylonitrile. Alternatively, the crude product was purified on a silica gel column with a mixture of ethylacetate and hexane as eluent.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[CH3:19]C(OC(C)=O)=O>C(OC(OCC)OCC)C>[Br:8][C:5]1[N:4]=[C:3]2[C:2](=[N:7][CH:6]=1)[N:1]=[CH:19][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:9]2=[O:10]
Reactant: Nc1ncc(Br)nc1C(=O)Nc1cccc(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: O=c1c2nc(Br)cnc2ncn1-c1cccc(F)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of 3-amino-6-bromo-N-(3-fluorophenyl)pyrazine-2-carboxamide (100 mg, 0.29 mmol) in triethoxymethane (5 mL) was added Ac2O (1 mL). The mixture was stirred at 130° C. for 1 h and 90° C. for 3 h. After being cooled and extracted with EtOAc, the combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by prep-TLC (PE:EtOAc=1:1) to give the pure product of 6-bromo-3-(3-fluorophenyl)pteridin-4(3H)-one (60 mg, yield: 60%). 1H-NMR (CDCl3, 400 MHz) δ 8.98 (s, 1H), 8.35 (s, 1H), 7.49˜7.55 (m, 1H), 7.15˜7.24 (m, 3H). MS (M+H)+: 321/323.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:17]([OH:29])[C:18](=[O:28])[NH:19][C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])=O)C1C=CC=CC=1.[H][H]>[Pd].O.C(O)C>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:17]([OH:29])[C:18](=[O:28])[NH:19][C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21]
Reactant: [H][H]
Reactant: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: C[C@@H](NC(=O)C(O)[C@H](CCCCN)NC(=O)OC(C)(C)C)c1ccccc1
Yield: 93.3 %

Procedure:
A slurry of 1.5 g of 10 wt % palladium on carbon in 3 mL of water was added to a solution of 15.28 g (29.70 mmol) of tert-butyl (1S)-5-{[(benzyloxy)carbonyl]amino}-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate in 200 mL of ethanol. The resulting slurry was stirred vigorously under 45 psi of hydrogen gas at 50° C. for 18 h. The catalyst was then filtered off, rinsing with 400 mL of ethanol. Concentration of the filtrate under vacuum afforded 10.52 g (93%) of tert-butyl (1S)-5-amino-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate as a colorless oil that crystallized upon standing under vacuum. 1H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J=8 Hz) and 8.08 (d, J=8 Hz) total 1H; 7.90-7.87 (m, ca 1H); 7.87-7.28 (m, 4H); 7.25-7.20 (m, 1H); 6.51 (d, J=9 Hz) and 6.17 (d, J=9 Hz) total 1H; 4.99-4.92 (m, 1H); 3.96 (d, J=4 Hz) and 3.90 (d, J=3 Hz) total 1H; 3.80-3.69 (m, 1H); 2.68-2.64 (m) and 2.53-2.57 (m) total 1H; 1.53-1.23 (m, 18H). ES-LCMS m/z 380 (M+H).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:40][CH3:41])[CH:9]=[C:10]([C:13]([N:15]4[CH2:20][CH2:19][C:18]5([CH2:29][C:28](=[O:30])[C:27]6[C:22](=[CH:23][CH:24]=[C:25]([C:31]7[CH:32]=[N:33][CH:34]=[C:35]([CH:39]=7)[C:36]([OH:38])=[O:37])[CH:26]=6)[O:21]5)[CH2:17][CH2:16]4)=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+:43]>O>[Na+:43].[CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:40][CH3:41])[CH:9]=[C:10]([C:13]([N:15]4[CH2:16][CH2:17][C:18]5([CH2:29][C:28](=[O:30])[C:27]6[C:22](=[CH:23][CH:24]=[C:25]([C:31]7[CH:32]=[N:33][CH:34]=[C:35]([CH:39]=7)[C:36]([O-:38])=[O:37])[CH:26]=6)[O:21]5)[CH2:19][CH2:20]4)=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)cc2c1ccn2C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)[O-])c4)ccc2O3)cc2c1ccn2C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-{1′-[(1-Cyclopropyl-4-methoxy-1H-indol-6-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic acid (434 mg) was suspended in water (5 mL), and aqueous 1 N sodium hydroxide solution (0.865 mL) was added thereto and stirred at room temperature for 1 hour. The solution was purified by ODS reversed-phase column chromatography (water/methanol, gradient) to obtain the intended compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.90 (1H, d, J=1.7 Hz), 8.74 (1H, d, J=2.4 Hz), 8.29-8.27 (1H, m), 7.99-7.94 (2H, m), 7.29 (1H, d, J=3.2 Hz), 7.25-7.22 (2H, m), 6.59 (1H, s), 6.40 (1H, d, J=3.2 Hz), 4.49-4.04 (1H, br m), 3.87 (3H, s), 3.82-3.58 (1H, br m), 3.51-3.28 (3H, m), 2.95 (2H, s), 2.13-1.90 (2H, br m), 1.88-1.75 (2H, br m), 1.09-1.02 (2H, m), 0.95-0.90 (2H, m); MS [M+Na]+=574.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[H-].[Na+].[CH3:19]N(C=O)C.IC>O>[CH3:19][NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:11])([F:12])([F:13])([F:10])[F:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: CN(C)C=O
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CNc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture 4-amino-3-nitro-phenyl sulfur pentafluoride (2.0 g), 60% sodium hydride (oil) (310 mg) and DMF (15 ml) was added dropwise iodomethane (447 μL) while ice-cooling. After that, the mixture was stirred at room temperature for 3 hours. To the reaction mixture was poured water, and the precipitated solid was collected by filtration. The solid was washed with water and dried to give methyl-(2-nitro-4-pentafluorosulfanyl-phenyl)-amine (2.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[NH:11][C:12]2[C:17]\1=[C:16]([C:18]#[C:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:15]=[CH:14][CH:13]=2.[OH-].[Na+:27]>O1CCCC1>[Na+:27].[CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[NH:11][C:12]2[C:17]\1=[C:16]([C:18]#[C:19][CH2:20][CH2:21][C:22]([O-:24])=[O:23])[CH:15]=[CH:14][CH:13]=2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCC(=O)O)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCC(=O)[O-])c21

Procedure:
(Z)-5-[2,3-Dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid (100 mg, 3 mmol) (from Example 10 above) was dissolved in tetrahydrofuran (1 mL), and 1N sodium hydroxide (3 mL) was added. The resulting product, (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid sodium salt, was purified via reverse-phase HPLC (acetonitrile—water over 15 minutes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11]C(=O)/C=C\C(O)=O)=[O:10])[CH:6]=[CH:5][N:4]=1.O=P(Cl)(Cl)Cl.[NH2:24][NH:25][C:26]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[CH:37][N:36]=1)=[N:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34]>C1(C)C=CC=CC=1>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[N:27]1[C:6](/[CH:7]=[CH:8]/[C:3]2[O:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=3)=[N:11][N:4]=2)=[N:24][N:25]=[C:26]1[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[CH:37][N:36]=1
Reactant: COc1cc(C(=O)NC(=O)/C=C\C(=O)O)ccn1
Reactant: CCOc1ccc(C(=Nc2ccccc2Cl)NN)nc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2nnc(/C=C/c3nnc(-c4ccnc(OC)c4)o3)n2-c2ccccc2Cl)nc1

Procedure:
To a suspension of (Z)-4-(2-methoxypyridine-4-carboamido)-4-oxobut-2-enoic acid 9 (0.30 g, mmol) in 20 mL of PhMe was added 0.5 mL of POCl3. The mixture was stirred at reflux for 2 h. After removal of solvent, the residue was dissolved in 20 mL of dichloromethane and added to 240 mg (0.68 mmol) of N-amino-N′-(2-chlorophenyl)-5-ethoxy-pyridine-2-carboxamidine 5. The mixture was stirred at ambient temperature for 2 h. After removal of solvent, the residue was suspended in 20 mL of PhMe and refluxed for 3 h. After removal of solvent, the residue was purified by column (0-5% of methanol in dichloromethane) to give 2-(4-(2-chlorophenyl)-5-((E)-2-(5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl)vinyl)-4H-1,2,4-triazol-3-yl)-5-ethoxypyridine as a solid. Yield: 20 mg, 3.5%.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[NH2:34][C:35]1[CH:36]=[CH:37][C:38](OC)=[C:39]([OH:41])[CH:40]=1.[CH2:44]1COCC1>>[OH:41][C:39]1[CH:40]=[C:35]([NH:34][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:33])[CH:36]=[CH:37][C:38]=1[CH3:44]
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C(C)(C)C)n1
Reactant: C1CCOC1
Reactant: COc1ccc(N)cc1O
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(C)c(O)c3)c2)n(C(C)(C)C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
A small screw cap test tube was charged with 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 50, 70 mg, 0.157 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methoxyphenol (26 mg, 0.1868 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 71% yield (0.063 g, 0.111 mmol).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:11]=O)[S:9][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+:13]([CH2:16][CH3:17])([O-:15])=[O:14].NCCC(O)=O>C(O)CCC>[N+:13]([C:16]([CH3:17])=[CH:11][C:8]1[S:9][CH:10]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:7]=1)([O-:15])=[O:14]
Reactant: O=Cc1cc(-n2ccnc2)cs1
Reactant: CC[N+](=O)[O-]
Agent: NCCC(=O)O
Solvent: CCCCO
Product: CC(=Cc1cc(-n2ccnc2)cs1)[N+](=O)[O-]
Reaction time: 9 h

Procedure:
A mixture of 94 g 4-(1-imidazolyl)-thiophene-2-aldehyde (EPA 112 987), 47.7 g nitroethane, 4.9 g β-alanine and 327 ml n-butanol is stirred for 9 hours at reflux temperature. Subsequently, it is evaporated and the residue is purified by column chromatography (silica gel//dichloromethane/methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][NH:11][C:12]([CH3:14])=[O:13].[N:22]([O-])=O.[Na+]>S(=O)(=O)(O)O.O>[NH:11]([CH2:10][CH2:9][N:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:3][C:2]=2[N:1]=[N:22]1)[C:12]([CH3:14])=[O:13]
Reactant: CC(=O)NCCNc1ccc(C2=NNC(=O)CC2)cc1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)NCCn1nnc2cc(C3=NNC(=O)CC3)ccc21

Procedure:
15.98 g (55.3 mmol) of 6-(3-amino-4-acetaminoethylamino-phenyl)-4,5-dihydro-3(2H)-pyridazinone are dissolved in 300 ml of 2N sulphuric acid, then cooled to 2°-5° C. and a solution of 4.2 g (61 mmol) of sodium nitrite in 70 ml of water is slowly added dropwise with stirring. After about one hour the cooling bath is removed and the mixture is stirred for a further hour at ambient temperature. The solids precipitated are suction filtered, stirred into 100 ml of a 5% sodium bicarbonate solution and suction filtered again after 10 minutes.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21](=[O:36])[N:22]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][C:27]=2[Cl:35])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C1COCC1.[Pd]>[NH2:32][C:29]1[CH:30]=[CH:31][C:26]([N:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:21]2=[O:36])=[C:27]([Cl:35])[CH:28]=1
Reactant: [H][H]
Reactant: CC(C)(C)[Si](OCc1cccn(-c2ccc([N+](=O)[O-])cc2Cl)c1=O)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCc1cccn(-c2ccc(N)cc2Cl)c1=O)(c1ccccc1)c1ccccc1

Procedure:
800 mg (1.54 mmol) of the compound from Example 4A are dissolved in 48 ml of THF. 50 mg (0.05 mmol) of palladium on carbon are then added, and the mixture is hydrogenated at RT in a hydrogen atmosphere under atmospheric pressure. The mixture is then filtered, the filter cake is washed with THF and the filtrate is freed from the solvent. The reaction product (purity: 95%) is reacted further without further purification.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:39][CH2:38][CH:37]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH2:36][CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:35][CH2:36][CH:37]([NH:40][S:41]([CH3:44])(=[O:42])=[O:43])[CH2:38][CH2:39]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CS(=O)(=O)NC1CCNCC1
Product: CS(=O)(=O)NC1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
N—(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-methanesulfonamide was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and N-piperidin-4-yl-methanesulfonamide following General Procedure B.
Reaction SMILES: [Na].C([O:4][C:5](=[O:21])[CH2:6][S:7][C:8]1[N:13]=[C:12](Cl)[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1)C.[CH3:22][OH:23]>>[CH3:22][O:23][C:12]1[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=[C:8]([S:7][CH2:6][C:5]([OH:4])=[O:21])[N:13]=1
Reactant: CCOC(=O)CSc1nc(Cl)cc(-c2ccccc2)n1
Reactant: CO
Agent: [Na]
Product: COc1cc(-c2ccccc2)nc(SCC(=O)O)n1
Reaction time: 1.5 h

Procedure:
To a solution of 0.46 g of sodium metal in 50 ml. of absolute methanol was added 3.2 g of (4-chloro-6-phenyl-2-pyrimidinylthio)acetic acid ethyl ester as prepared in the preceding Example. The reaction mixture was heated under reflux for 3 hr. then filtered. The filtrate was taken to dryness in a rotary evaporator. The residue was dissolved in 30 ml. of 50% sodium hydroxide and the solution was diluted to 200 ml. The reaction mixture was allowed to stand at room temperature for 1.5 hr, cooled in ice and acidified with concentrated hydrochloric acid. The resulting precipitate was recrystallized from aqueous ethanol affording 1.4 g of product, mp. 157°-159°C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH3:13]I>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:10]([CH3:13])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CI
Reactant: Clc1ncnc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a stirred solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (27) (J. Org. Chem., 2001, 66, 17, 5723-5730) (643 mg, 4.15 mmol) in DMF (41 mL) was added NaH (60% in mineral oil, 330 mg, 8.3 mmol) in one portion at 0° C. and the mixture was stirred for 1 h followed by addition of methyl iodide (0.28 mL, 4.5 mmol). The reaction mixture was allowed to warm up to the room temperature, stirred for an additional hour and quenched with AcOH (1 mL) to form a suspension which was stirred for 10 min and concentrated under reduced pressure to give a solid. This material was dissolved in AcOEt, the solution was washed with cold saturated NaHCO3 solution and water, dried over Na2SO4, and concentrated to produce the title compound 28 as a pale yellow solid (640 mg, 93% yield). 1H NMR (400 MHz, CD3OD) δ(ppm): 8.51 (s, 1H), 7.75 (d, J=3.3 Hz, 1H), 6.62 (d, J=3.3 Hz, 2H), 4.15 (s, 1H). LRMS (M+1) 168.1 (100%), 170.1 (34%).