Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:16]=[C:15]([CH3:17])[N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2C1CCCCO1.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=1.Cl>C(O)C.C([O-])(O)=O.[Na+]>[CH3:32][O:31][C:28]1[N:29]=[CH:30][C:25]([NH:24][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][NH:12]3)=[CH:26][CH:27]=1
Reactant: COc1ccc(N)cn1
Reactant: Cc1nc(-c2cnccc2Cl)c2ncn(C3CCCCO3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Nc2ccncc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 160 °C
Yield: 57.8 %

Procedure:
A glass microwave reaction vessel was charged with 6-(4-chloropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (36 mg, 0.109 mmol) and 5-amino-2-methoxypyridine (27.1 mg, 0.218 mmol, Aldrich) in ethanol (1 mL) and a drop of 5N HCl. The reaction mixture was stirred and heated in a Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 160° C. for 30 min. The reaction mixture was diluted with NaHCO3 (5 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (3 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give a yellow solid. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column eluting with 10% MeOH/CH2Cl2 to provide 6-methoxy-N-(3-(2-methyl-9H-purin-6-yl)pyridin-4-yl)pyridin-3-amine (21 mg, 58% yield) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 9.98 (s, 1H); 8.42 (s, 1H); 8.07-8.24 (m, 2H); 7.72 (d, J=8.92 Hz, 1H); 6.85-7.00 (m, 2H); 3.96 (s, 3H); 2.83 (s, 3H). m/z (ESI, +ve ion) 334 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[S:9][C:8](S)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Fe]>[CH3:1][C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2nc(S)sc12
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1cccc2ncsc12

Procedure:
Following the same procedure as in step 2 of Example 337 using 7-methyl-1,3-benzothiazole-2-thiol (3.8 g, 20.96 mmol, 1.00 equiv) and iron powder (9.28 g, 171.85 mmol, 8.20 equiv) in acetic acid (24 mL) as a yellow oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Pd]>[C:1]([N:8]1[CH2:9][CH2:10][C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=2)([OH:14])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)C=Cc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 48 h

Procedure:
A solution of 10-4 (0.42 g, 1.16 mmoles) in MeOH (6 ml) was treated with 0.17 g 10% Pd/C and this was hydrogenated under 1 atm. of H2 pressure for 48 hours. Solvent removal and purification by flash chromatography on silica gel eluting with 50% EtOAc/hexanes gave pure 10-5. Rf 0.55 (silica, 50% EtOAc/hexanes).
Reaction SMILES: [CH3:1][O:2]/[C:3](=[CH:7]\[C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)/[C:4]([OH:6])=[O:5].[H][H]>>[CH3:1][O:2][C@@H:3]([CH2:7][C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O

Procedure:
In an analogous manner to Example 10, 2.5 g (5.74 mmol) of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid were asymmetrically hydrogenated in the presence of 3.22 mg of [Ru(OAc)2((S)-6-MeO-2-naphthyl)-MeOBIPHEP)] (S/C molar ratio 2000) at 40° C. under 15 bar of hydrogen for 24 h to reach 99.6% conversion. Rotary evaporation of the reaction mixture afforded quantitatively (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid of 75.8% ee with 98.5% purity (HPLC area).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([OH:23])[CH:22]=2)[O:19][C:18]([CH3:25])([CH3:24])[CH2:17][C:16]3([CH3:27])[CH3:26])=[CH:7][C:6]=1[F:28].[OH-].[K+]>CO.O1CCCC1>[F:28][C:6]1[CH:7]=[C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([OH:23])[CH:22]=2)[O:19][C:18]([CH3:25])([CH3:24])[CH2:17][C:16]3([CH3:26])[CH3:27])[CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:29])=[O:2]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(CC(=O)O)c(F)c3)cc(O)c2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 127.3 %

Procedure:
A solution of [2-fluoro-4-(8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 21, 0.037 g, 0.0493 mmol) in methanol (2 mL) and tetrahydrofuran (1 mL) was treated with a 2M solution of potassium hydroxide (2 mL, 4 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product (0.024 g, 69%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.OC1C=C2C(C(=O)C(C3C=CC=CC=3)=CO2)=CC=1>>[C:4]1([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: Oc1ccc2c(c1)OCC(c1cccc(F)c1)C2
Agent: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Product: Oc1ccc2c(c1)OCC(c1ccccc1)C2

Procedure:
3-Phenylchroman-7-ol was prepared as described for 3-(3-fluorophenyl)-chroman-7-ol in Example 81(d) using 0.5 g of 7-hydroxy-3-phenylchromen-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.18 (br s, 1H), 7.31-7.34 (m, 4H), 7.25-7.27 (m, 1H), 6.88 (d, 1H, J 8.2 Hz), 6.30 (dd, 1H, J 8.2, 2.4 Hz), 6.20 (d, 1H, J 2.4 Hz), 4.21 (dd, 1H, J 10.3, 3.6 Hz), 4.00 (t, 1H, 10.3 Hz), 3.13 (m, 1H), 2.84-2.87 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][CH2:7][CH:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH:15]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[CH2:14][CH2:13]2)[OH:9])[CH3:3].[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>C(OCC)C>[C:26]([O:9][CH:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH:15]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[CH2:14][CH2:13]2)[CH2:7][O:6][CH2:5][CH2:4][N:2]([CH3:1])[CH3:3])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCOCC(O)c1ccc2c(c1)CCC2OC1CCCCO1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OC(COCCN(C)C)c1ccc2c(c1)CCC2OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2.5 g of 2-[2-(N,N-dimethylamino)ethoxy]-1-[1-(tetrahydropyran-2-yloxy)indan-5-yl]ethanol, 8 ml of acetic anhydride and 0.64 ml of pyridine was stirred at room temperature for 1 hour. The reaction mixture was added to a mixture of 50 ml of ice water and 50 ml of diethyl ether. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/methanol=10/1) to obtain 1.9 g of oily 1-acetoxy-2-[2-(N,N-dimethylamino)ethoxy]-1-[1-(tetrahydropyran-2-yloxy) indan-5-yl]ethane (compound No. 295).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11](N3CCC4C=CNC=4C3C)=[O:12])[CH:10]=2)[CH:7]=1.[F:23][C:24]1[O:25][C:26]2[CH2:31][CH2:30][NH:29][CH:28]([CH3:32])[C:27]=2[N:33]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:29]3[CH2:30][CH2:31][C:26]4[O:25][C:24]([F:23])=[N:33][C:27]=4[CH:28]3[CH3:32])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2oc(F)nc21
Reactant: CC1c2[nH]ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Product: CC1c2nc(F)oc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridin-6-yl)-methanone is reacted with 2-fluoro-4-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>CC(C)=O>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: BrCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCCCCBr)cc1
Yield: 69.9 %

Procedure:
To a mixture of methyl 4-hydroxybenzoate (1.52 g) and potassium carbonate (0.76 g) in acetone (30 ml) was added dropwise a solution of 1,7-dibromoheptane (3.1 g) in acetone (10 ml) at room temperature with stirring. The mixture was stirred at room temperature for 2.5 hours, and then refluxed for overnight with stirring. The reaction mixture was filtered under reduced pressure and the filtrate was concentrated under reduced pressure to give an oily solid. The oily solid was subjected to column chromatography on silica gel (silica gel 60 F254, Merck: 200 g) and eluted with a mixture of ethyl acetate and n-hexane (1:3). The fractions containing the objective compound were combined and concentrated under reduced pressure to give methyl 4-(7-bromo-n-heptyloxy]benzoate (2.3 g).
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)[CH:7]=[CH:6][N:5]=1)=O.CCOC(C)=O.Cl.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[N+:25]([C:21]1[CH:20]=[C:19]([C:11]2[C:10]([C:8]3[CH:7]=[CH:6][N:5]=[C:4]([NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:9]=3)=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:24]=[CH:23][CH:22]=1)([O-:27])=[O:26]
Reactant: CS(=O)c1nccc(-c2c(-c3cccc([N+](=O)[O-])c3)nn3ccccc23)n1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Temperature: 100 °C
Yield: 52 %

Procedure:
3-[2-(Methylsulfinyl)-4-pyrimidinyl]-2-(3-nitrophenyl)pyrazolo[1,5-a]pyridine (1.5 g, 3.9 mmol) was dissolved in aniline (5 mL). The dark mixture was heated at 100° C. for 5 h. The mixture was cooled and EtOAc (20 mL) and 1N HCl (10 mL) was added. The aqueous layer was extracted with EtOAc (20 mL) and the organic extracts combined, washed with 1N HCl, (15 mL), brine (10 mL), dried over MgSO4 and filtered. The organic solvent was removed in vacuo. The crude material was purified by silica gel chromatography (30-50% EtOAc/hexanes) to give the titled product (830 mg, 52% yield). 1H NMR (400 MHz, d6-DMSO) δ 6.58 (d, 1H, J=5.3 Hz), 6.98 (m, 1H), 7.05 (m, 1H), 7.19 (brs, 1H), 7.28-7.36 (m, 3H), 7.57-7.63 (m, 3H), 8.00 (m, 1H), 8.25-8.31 (m, 3H), 8.54 (m, 1H), 8.69 (m, 1H); ES-LC/MS: m/z (M+H)=409.
Reaction SMILES: [CH2:1]1[CH:6]2[CH:7]([NH:10][C:11]([C@H:13]([NH2:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[C:8](=[O:9])[N:5]2[C:4]([C:21]([OH:23])=[O:22])=[C:3]([Cl:24])[CH2:2]1.O.Cl.OC1C=CC(C(OCC)=O)=CC=1>C(O)C>[CH:17]1[CH:16]=[CH:15][C:14]([C@@H:13]([NH2:20])[C:11]([NH:10][C@@H:7]2[C:8](=[O:9])[N:5]3[C@@H:6]2[CH2:1][CH2:2][C:3]([Cl:24])=[C:4]3[C:21]([OH:23])=[O:22])=[O:12])=[CH:19][CH:18]=1
Reactant: N[C@@H](C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CCC12)c1ccccc1
Agent: CCOC(=O)c1ccc(O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: N[C@@H](C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cl)CC[C@H]12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.2 %

Procedure:
The pH of aqueous loracarbef monohydrate mother liquor (1000 ml, having 9.23 mg/mil of loracarbef monohydrate) was adjusted to 3.6 with HCl. Ethyl p-hydroxybenzoate (ethyl paraben) (4.52 g) in ethanol (36 ml) was added dropwise over 15 minutes. After approximately 5 minutes, precipitation occurred, resulting in white crystals. The mixture was stirred overnight (15 hrs) at room temperature, filtered, washed with H2O, and dried under vacuum at 40° C. The yield was 11.72 g having a potency of 73.5% as loracarbef, and the theoretical yield was 8.78 g as loracarbef, resulting in a percent yield of 98.2%. The loracarbef:ethyl paraben exhibited the following X-ray powder diffraction pattern:
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:9](O)=[O:10])[CH:3]([CH3:5])[CH3:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:47]([C:51]1[CH:52]=[C:53]([CH:58]=[C:59]([CH3:61])[N:60]=1)[C:54]([NH:56][NH2:57])=O)[CH:48]([CH3:50])[CH3:49].N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>CN(C=O)C.CCOCC.C(Cl)Cl>[CH2:47]([C:51]1[CH:52]=[C:53]([C:54]2[O:10][C:9]([C:8]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:6]([CH2:2][CH:3]([CH3:5])[CH3:4])[CH:7]=3)=[N:57][N:56]=2)[CH:58]=[C:59]([CH3:61])[N:60]=1)[CH:48]([CH3:50])[CH3:49]
Reactant: Cc1cc(C(=O)NN)cc(CC(C)C)n1
Reactant: Cc1cc(C(=O)O)cc(CC(C)C)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cc(-c2nnc(-c3cc(C)nc(CC(C)C)c3)o2)cc(CC(C)C)n1
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To a solution of 2-isobutyl-6-methyl-isonicotinic acid hydrochloride (41 mg, 0.178 mmol) and DIPEA (69 mg, 0.535 mmol) in DMF (2 mL) is added TBTU (57 mg, 0.178 mmol) at 0° C. The mixture is stirred for 30 min at 0° C. before 2-isobutyl-6-methyl-isonicotinic hydrazide (37 mg, 0.179 mmol) is added. Stirring is continued for 2 h. The mixture is diluted with ether (200 mL) and washed with 10% aq. citric acid solution (3×10 mL), sat. aq. NaHCO3-solution (3×10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated to give crude 2-isobutyl-6-methyl-isonicotinic acid N′-(2-isobutyl-6-methyl-pyridine-4-carbonyl)-hydrazide (70 mg) as a yellow oil; LC-MS: tR=0.60 min, [M+1]+=383.25. A part of this material (45 mg, 0.119 mmol) is dissolved in DCM (7 mL) and pyridine (47 mg, 0.595 mmol) followed by trifluoromethanesulfonic anhydride (37 mg, 0.131 mmol) is added at 0° C. The mixture is stirred for 2 h at 0° C. and 15 h at rt before it is diluted with DCM, washed with water, dried over MgSO4, filtered and the solvent of the filtrate is evaporated. The crude product is purified by prep. TLC with heptane:EA 2:3 to give 2-isobutyl-4-[2-(2-isobutyl-6-methyl-4-pyridinyl)-[1,3,4]oxadiazol-5-yl]-6-methyl-pyridine (27 mg) as a colourless oil; LC-MS: tR=0.72 min, [M+1]+=365.54; 1H NMR (CDCl3): δ 0.99 (d, J=6.5 Hz, 12H), 2.19 (hept, J=7.0 Hz, 2H), 2.68 (s, 6H), 2.77 (d, J=7.3 Hz, 4H), 7.64 (s, 2H), 7.69 (s, 2H).
Reaction SMILES: [OH-].[Na+].CC(C)=O.O.Cl[C:9]1[CH:14]=[C:13]([Cl:15])[N:12]=[CH:11][N:10]=1.[OH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2>CCOC(C)=O.O>[Cl:15][C:13]1[N:12]=[CH:11][N:10]=[C:9]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH:14]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: Clc1cc(Cl)ncn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: Clc1cc(Oc2ccc3[nH]ccc3c2)ncn1
Temperature: 65 °C
Reaction time: 1.17 h

Procedure:
To a mixture of NaOH (720 mg, 18 mmol) and acetone/water 1:1 (72 ml), 4,6-dichloropyrimidine (2.4 g, 18 mmol) and 5-hydroxy-indole (2.68 g, 18 mmol) are added. After stirring for 70 min at 65° C., the brownish solution is cooled to rt and diluted with AcOEt and water. The aqueous layer is separated off and extracted twice with AcOEt. The organic layers are washed with water, saturated Na2CO3 solution, water and brine, dried (Na2SO4) and concentrated. The crude product can be used without further purification: m.p.: 137-138° C.; MS: [M+1]+=246.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6]1[C:7]([N+]([O-])=O)=[CH:8][C:9]([CH3:13])=[N+:10]([O-:12])[CH:11]=1.S(=O)(=O)(O)O>CO>[CH3:1][O:2][C:7]1[C:6]([O:5][CH3:4])=[CH:11][N+:10]([O-:12])=[C:9]([CH3:13])[CH:8]=1
Reactant: C[O-]
Reactant: COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)[n+]([O-])cc1OC
Temperature: 20 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
20 ml of a 30% strength sodium methylate solution are added dropwise to a suspension of 16.9 g of 5-methoxy-2-methyl-4-nitropyridine 1-oxide in 170 ml of dry methanol and the mixture is stirred at 20° C. for 15 hours and then at 50° C. for 4 hours. The pH is brought to 7 by careful addition of concentrated sulphuric acid, while cooling with ice, the mixture is concentrated, the residue is extracted by stirring with 200 ml of methylene chloride, the insoluble constituents are filtered off, 10 ml of toluene are added and the mixture is concentrated to dryness again. 15.2 g (98% of theory) of 4,5-dimethoxy-2-methylpyridine 1-oxide are obtained as colourless crystals of m.p. 118°-121° C.
Reaction SMILES: [H-].[Na+].[CH:3](/[C:6]1[C:10]2=[CH:11][CH:12]=[C:13]3[C:22]([NH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])=[C:9]2[NH:8][C:7]=1[CH:24]=C)=[CH:4]/[CH3:5].Cl[C:27]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]=[C:29]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:28]=1>ClCCl>[C:39]1([C:29]2[N:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:32]=[C:27]([N:21]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:14](=[O:23])[C:13]4[CH:12]=[CH:11][C:10]5[C:6]6[CH:3]=[CH:4][CH:5]=[CH:24][C:7]=6[N:8]([C:27]6[N:32]=[C:31]([C:33]7[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=7)[N:30]=[C:29]([C:39]7[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=7)[N:28]=6)[C:9]=5[C:22]3=4)[N:28]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: C=Cc1[nH]c2c(ccc3c(=O)c4ccccc4[nH]c32)c1/C=C\C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c2ccccc2n(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c2c1ccc1c3ccccc3n(-c3nc(-c4ccccc4)nc(-c4ccccc4)n3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3 g (75 mmol) of NaH (60% in oil) are initially introduced in 150 ml of dichloromethane. A solution of 8.4 g (28 mmol) of 3-((Z)-propenyl)-2-vinyl-1H,11H-1,11-diazacyclopenta[a]anthracen-6-one in dichloromethane is added dropwise at RT. After 1 h, 17 g (62 mmol) of 2-chloro-4,6-diphenyl-1,3,5-triazine are added dropwise, and the mixture is stirred at room temperature for 8 h. The solid which has precipitated out is recrystallised from toluene. The crystals which have deposited are filtered off with suction, washed with a little MeOH and dried in vacuo; yield: 14.6 g; 70% of theory; purity: 99.9% according to HPLC.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:27]([C:31]([O:33]C)=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1
Reactant: COCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 82.5 %

Procedure:
A solution of methyl 2-methoxymethyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.2 g) in methanol (10 ml) and 1N-NaOH (1.5 ml) was heated at 80° C. for 20 hours. The solution was concentrated to dryness to give a residue. The residue was dissolved in H2O and made acidic to give a crystalline product. Recrystallization from DMF-MeOH-H2O gave colorless prisms (0.16 g, 80%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-])=O)=[C:12]2[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C2C(C(NCCOC3C=CC=CC=3)=C([N+]([O-])=O)C=N2)=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([NH2:19])=[C:12]2[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28][CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSCCCCCNc1c([N+](=O)[O-])cnc2ccc(OCc3ccccc3)cc12
Agent: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1NCCOc1ccccc1
Product: CSCCCCCNc1c(N)cnc2ccc(OCc3ccccc3)cc12

Procedure:
A modification of the general method described in Part B of Example 46 was followed using 6-benzyloxy-N-[5-(methylthio)pentyl]-3-nitroquinolin-4-amine (5.1 g, 12 mmol) in lieu of (7-benzyloxy-3-nitro-quinolin-4-yl)-(2-phenoxyethyl)amine. The reaction was maintained under hydrogen pressure (49 psi, 3.4×105 Pa) for three hours. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with methanol (100 mL) and chloroform (50 mL). The filtrate was concentrated under reduced pressure to provide 6-benzyloxy-N4-[5-(methylthio)pentyl]quinoline-3,4-diamine as a yellow oil, which was used without purification.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=1)=[C:2]=[S:3].[H-].[Na+].[NH2:18][C:19]1[C:24]([C:25](OC)=[O:26])=[CH:23][CH:22]=[C:21]([Cl:29])[N:20]=1.Cl>CN(C)C=O.C(OCC)C>[Cl:29][C:21]1[CH:22]=[CH:23][C:24]2[C:25](=[O:26])[N:1]([C:4]3[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([F:13])([F:15])[F:14])=[CH:8][CH:9]=3)[C:2](=[S:3])[NH:18][C:19]=2[N:20]=1
Reactant: FC(F)(F)COc1ccc(N=C=S)cc1
Reactant: COC(=O)c1ccc(Cl)nc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=c1c2ccc(Cl)nc2[nH]c(=S)n1-c1ccc(OCC(F)(F)F)cc1
Reaction time: 0.33 h
Yield: 17.9 %

Procedure:
1-Isothiocyanato-4-(2,2,2-trifluoroethoxy)benzene (4.06 g) was dissolved in N,N-dimethylformamide (50 ml), and sodium hydride (60% in oil, 1.39 g) was added thereto under ice-cooling. Methyl 2-amino-6-chloropyridine-3-carboxylate (2.95 g) was dissolved in N,N-dimethylformamide (25 ml), the solution was added dropwise to the reaction mixture under ice-cooling, and the mixture was stirred for 20 min, and then at room temperature for 1 hr and 30 min. The reaction mixture was poured into 0.5M hydrochloric acid (80 ml), and the white precipitate was collected by filtration. The precipitate was dissolved in tetrahydrofuran (100 ml), and the solution was diluted with ethyl acetate (200 ml), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a white residue. The residue was suspended in diethyl ether (100 ml), and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane), and washed with diethyl ether to give the white title compound (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[N:14]=[CH:13][N:12]([CH2:15][C:16]([OH:18])=O)[N:11]=2)=[O:8])=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]2=[O:32])=[CH:22][C:21]=1[F:33]>>[F:33][C:21]1[CH:22]=[C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]2=[O:32])[CH:24]=[CH:25][C:20]=1[NH:19][C:16]([CH2:15][N:12]1[CH:13]=[N:14][C:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])=[N:11]1)=[O:18]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: O=C(O)Cn1cnc(NC(=O)c2ccc(Cl)s2)n1
Product: O=C(Cn1cnc(NC(=O)c2ccc(Cl)s2)n1)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
61.4 According to general method B, {3-[(5-chloro-thiophene-2-carbonyl)-amino]-[1,2,4]triazol-1-yl}-acetic acid was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) to give 5-chloro-thiophene-2-carboxylic acid (1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-1H-[1,2,4]triazol-3-yl)-amide. Off-white solid. MS 473.4 ([M+H]+)