Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15](NC(=O)OCC)[NH:16][C:17](=O)[O:18]CC)=[C:11]([F:28])[CH:10]=1)#[N:8]>C1(C)C=CC=CC=1>[Cl:2][CH:15]([N:16]=[C:17]=[O:18])[C:12]1[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][C:11]=1[F:28]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)NC(NC(=O)OCC)c1ccc(C#N)cc1F
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(Cl)N=C=O)c(F)c1

Procedure:
Phosphorous pentachloride (9.63 g, 46.2 mmol) is added to a mixture of diethyl (4-cyano-2-fluorophenyl)methylenedicarbamate (intermediate 26, 6.50 g, 21.0 mmol) in toluene (25.0 mL), and the mixture is heated at reflux for 3 h. The toluene is evaporated, and the mixture is then purified by distillation under reduced pressure. The first fraction (ca. 35° C., ca. 0.2 mbar) is discarded. The second fraction (ca. 112° C., ca. 0.1 mbar) is collected. Yield: 1.90 g.
Reaction SMILES: [CH2:1]([N:8]([CH3:30])[C@@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11][C@H:10]1[CH2:24]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:31]([CH2:24][C@H:10]1[C@H:9]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:30])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(Cc1ccccc1)[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1COS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CN=[N+]=[N-]
Temperature: 60 °C
Yield: 94.5 %

Procedure:
A mixture of crude methanesulfonic acid trans-4-(benzyl-methyl-amino)-1-[2-(4-fluorophenyl)-ethyl]-piperidin-3-ylmethyl ester (139 mg, 294 μmol) and sodium azide (58 mg, 882 μmol) in N,N-dimethylformamide (2 mL) was heated at 60° C. for 20 hours, then cooled to room temperature. The mixture was diluted with ethyl acetate, washed three times with water, dried over sodium sulfate, and concentrated under vacuum to provide a gum (106 mg, 95%) which was used without purification. 1H NMR (300 MHz, CDCl3) δ7.33 (m, 5H), 7.16 (m, 2H), 6.99 (t, J=9 Hz, 2H), 3.70 (m, 2H), 3.52 (d, J=13 Hz, 1H), 3.41 (m, 1H), 3.20 (m, 2H), 2.83 (m, 2H), 2.61 (m, 2H), 2.42 (m, 1H), 2.3-1.8 (m, 4H), 2.19 (s, 3H), 1.75 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]#[C:14][C:15]([OH:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:11]([CH:29]=[O:30])[CH:10]=[C:9]1[C:31]([O:33]C)=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[CH2:1]([N:8]1[C:12]([C:13]#[C:14][C:15]([OH:28])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:11]([CH:29]=[O:30])[CH:10]=[C:9]1[C:31]([OH:33])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C=O)c(C#CC(O)(c2ccccc2)c2ccccc2)n1Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=Cc1cc(C(=O)O)n(Cc2ccccc2)c1C#CC(O)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 6 (0.49 g, 1.1 mmol) in MeOH (20 mL) and water (6 mL) was added KOH (0.18 g, 3.3 mmol) and stirred at 60° C. for 2 hours. The solvent was removed in vacuo. The residue obtained was acidified with 2N HCl to pH 2-3 and extracted with EtOAc (3×15 mL). The combined organic layer was dried over MgSO4, filtered and then concentrated in vacuo to give 7 as a light brown solid. The crude product was subjected to the next reaction without further purification. 1H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 7.50-7.52 (m, 4H), 7.45 (s, 1H), 7.21-7.26 (m, 7H), 7.02-7.03 (m, 2H), and 5.64 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([O:6][C:7]2[CH:12]=[C:11](Cl)[CH:10]=[CH:9][N:8]=2)=[C:4]([I:17])[CH:3]=1.[CH2:18]([OH:21])[CH2:19][OH:20].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([O:6][C:7]2[CH:12]=[C:11]([O:20][CH2:19][CH2:18][OH:21])[CH:10]=[CH:9][N:8]=2)=[C:4]([I:17])[CH:3]=1
Reactant: Clc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: OCCOc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 33.3 %

Procedure:
A mixture of 2-(4,5-dichloro-2-iodophenoxy)-4-chloropyridine (0.45 g, 1.128 mmol), ethane-1,2-diol (4 mL, 71.89 mmol), K2CO3 (0.45 mg, 3.26 mmol) in acetone (6 mL) was stirred at 120° C. for 5 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed withed brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1 to 4:1) to afford the desired product (160 mg, 33% yield). ESI-MS m/z: 426.0[M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:21])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH2:16][CH3:17])[CH:12]=[C:11]([O:18][CH2:19][CH3:20])[C:8]=2[C:9]=1[CH3:10].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:19]([O:18][C:11]1[C:8]2[C:9]([CH3:10])=[C:4]([CH2:3][CH2:2][N:33]3[CH2:32][CH2:31][N:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])[CH2:35][CH2:34]3)[C:5](=[O:21])[O:6][C:7]=2[CH:14]=[C:13]([O:15][CH2:16][CH3:17])[CH:12]=1)[CH3:20]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOc1cc(OCC)c2c(C)c(CCCl)c(=O)oc2c1
Product: CCOc1cc(OCC)c2c(C)c(CCN3CCN(c4ccccc4OC)CC3)c(=O)oc2c1
Yield: 52 %

Procedure:
Process A; starting materials: 3-(2-chloroethyl)-5,7-diethoxy-4-methyl-2H-1-benzopyran-2-one (Example 37) and 1-(2-methoxyphenyl)piperazine; yield 52% of oily crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:13]#[N:14])[C:8](=[CH:11][CH:12]=1)[C:9]#[N:10].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:13]([C:7]1[CH:6]=[C:5]([CH:12]=[CH:11][C:8]=1[C:9]#[N:10])[O:4][C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[NH:1][C:19](=[O:21])[CH3:20])#[N:14]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(Oc2ccccc2N)cc1C#N
Product: CC(=O)Nc1ccccc1Oc1ccc(C#N)c(C#N)c1

Procedure:
4-(2-Aminophenoxy)phthalonitrile (0.54 g, 2.3 mmol) was stirred in acetic acid anhydride (20 ml) at room temperature for 1 hour. The reaction mixture was poured into crushed ice. The precipitate was filtered off and washed with water and dried in vacuo to give N-[2-(3,4-dicyanophenoxy)phenyl]acetamide as white crystals (yield: 0.57 g, (89%)). Mp: 152.2-153.7° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].S(Cl)([Cl:17])=O>>[N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([Cl:17])=[O:14])=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCc1ccc(CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: [N-]=[N+]=NCc1ccc(CC(=O)Cl)cc1

Procedure:
By stirring a mixture of the thus obtained p-azidomethylphenylacetic acid in thionyl chloride at room temperature for 20 hours the corresponding acid chloride is obtained after removal of the excess reagent under high vacuum at room temperature.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:11][C:12]2[C:13]3[CH2:21][NH:20][CH2:19][CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)[CH3:10])=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28](F)=[C:29]([CH:32]=1)[C:30]#[N:31].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N:20]2[CH2:19][CH2:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][C@@H:9]([C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][CH:5]=4)[CH3:10])[C:13]=3[CH2:21]2)=[C:29]([CH:32]=1)[C:30]#[N:31]
Reactant: N#Cc1cc(Cl)ccc1F
Reactant: C[C@@H](Nc1ncnc2c1CNCC2)c1ccc(C(F)(F)F)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](Nc1ncnc2c1CN(c1ccc(Cl)cc1C#N)CC2)c1ccc(C(F)(F)F)nc1
Yield: 52 %

Procedure:
A mixture of (R)—N-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (500 mg, 1.55 mmol), 5-chloro-2-fluorobenzonitrile (360 mg, 2.3 mmol), N,N-diisopropylethylamine (540 mL, 3.1 mmol), and acetonitrile (3.0 mL) was subjected to microwave irradiation at 180° C. for 2 h. Then more 5-chloro-2-fluorobenzonitrile (360 mg) was added and the mixture was subjected to microwave irradiation at 180° C. for another 2 h. After that an additional 5-chloro-2-fluorobenzonitrile (360 mg) was added and the mixture was subjected to microwave irradiation at 180° C. for an additional 2 h. After cooling the mixture was concentrated in vacuo and the residue was purified by silica gel column (0-100% EtOAc/hexane) and the obtained solid was washed with ether to yield an off-white solid (370 mg, 51%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[N:12][C:13]3[C:20]4([CH3:23])[CH2:21][CH2:22][CH:17]([C:18]([CH3:25])([CH3:24])[O:19]4)[C:14]=3[N+:15]=2[O-])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)Cl.[OH-].[Na+]>ClCCCl>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[N:12][C:13]3[C:20]4([CH3:23])[CH2:21][CH2:22][CH:17]([C:18]([CH3:25])([CH3:24])[O:19]4)[C:14]=3[N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC12CCC(c3c1nnc(-c1cccc([N+](=O)[O-])c1)[n+]3[O-])C(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: ClP(Cl)Cl
Solvent: ClCCCl
Product: CC12CCC(c3nc(-c4cccc([N+](=O)[O-])c4)nnc31)C(C)(C)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask equipped with stirrer, reflux condenser and gas inlet there is added under nitrogen a mixture of 6.9 g. (0.020 mole) of (+)-3-(m-nitrophenyl)-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine-4-oxide, 20 ml. (0.23 mole) of phosphorous trichloride in 300 ml. of 1,2-dichloroethane. The resulting mixture is refluxed for 6.5 hours and then cooled to room temperature, and poured into a beaker containing 500 g. of ice. To this mixture there is added cautiously 60 ml. of 50% aqueous sodium hydroxide while maintaining stirring for 1 hour. The resulting mixture is then transferred to a separatory funnel and permitted to separate. The layers are partitioned and the aqueous phase extracted twice with 300 ml. of methylene chloride and the extracts combined with the organic phase. The resulting solution is washed once with brine, dried over anhydrous magnesium sulfate, and then concentrated to yield a residue which is then recrystallized from absolute ethanol to give (-)-3-(m-nitrophenyl)-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine; m.p. 184° to 185° C.; ORD-1.8°.
Reaction SMILES: [CH2:1]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][O:25]2)=[O:21])=[CH:23][CH:24]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C1=COCCC1
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)OC2CCCCO2)cc1

Procedure:
A mixture of 7 g. 4-(4-tetradecenylamino)benzoic acid, 2 g. dihydropyran and 100 mg. of anhydrous p-toluenesulfonic acid in 50 ml. toluene is stirred at room temperature for 20 hours. The solution is washed with saturated sodium bicarbonate, dried, and evaporated. The residue is collected and crystallized from methylcyclohexane to yield the product as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[N:5]2[N:16]=[C:17]([CH3:20])[C:18]([I:19])=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.[NH:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH2:35][OH:36]>C(#N)C>[F:15][C:10]1[CH:9]=[C:8]([C:6]2[N:5]3[N:16]=[C:17]([CH3:20])[C:18]([I:19])=[C:4]3[N:3]=[C:2]([N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[CH2:35][OH:36])[CH:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: OC[C@@H]1CCCN1
Reactant: Cc1nn2c(-c3ccc(F)c(F)c3)cc(Cl)nc2c1I
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn2c(-c3ccc(F)c(F)c3)cc(N3CCC[C@H]3CO)nc2c1I
Yield: 85 %

Procedure:
5-Chloro-7-(3,4-difluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine (401 mg), DIPEA (0.35 mL) and (S)-2-pyrrolidinemethanol (401 mg) are stirred for 2.5 hours in an acetonitrile (60 mL) solvent at 90° C. The reaction solvent is removed by distillation under reduced pressure. The remainder is purified by column chromatography to yield the target compound (395 mg). 1H NMR (CDCl3, 300 MHz) δ 7.82 (m, 1H), 7.67 (m, 1H), 7.29 (q, J=8.7 Hz, 1H), 6.11 (s, 1H), 4.45 (br, 1H), 3.85 (m, 1H), 3.77 (m, 1H), 3.57 (m, 2H), 2.38 (s, 3H), 2.08-2.01 (m, 3H), 1.70 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19](=[O:24])NCOC)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH2:25]([Mg]Br)[CH3:26]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:24])[CH2:25][CH3:26])=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: COCNC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.7 %

Procedure:
2-[(Methoxymethylcarbamoyl)methoxy]pyrimidine-5-carboxylic acid (4-fluorophenyl)amide (prepared as in Example 4, 60 mg, 0.18 mmol) was suspended in 1.8 mL THF and cooled to 0° C. Ethyl magnesium bromide (1 M in THF, 0.45 mL, 0.45 mmol) was added dropwise while maintaining internal reaction temperature between 0° C. and 5° C. The reaction mixture was warmed to ambient temperature and held for 1 h. The reaction mixture was cooled back to 0° C. and a second addition (0.45 mL, 0.45 mmol) of Grignard reagent was performed. The reaction was warmed to ambient temperature and held for 2.5 hours. The reaction was quenched with 0.1 M HCl and diluted with ethyl acetate. The organic layer was separated, dried using Na2SO4 and concentrated to 36 mg of yellow oil. The crude material was purified by SiO2 chromatography to deliver 8 mg (15% yield) of the titled compound. ESI-MS m/z 304 (MH+), 302 (M−H−).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12]C1C=CC(S(O)(=O)=O)=CC=1.O>CO>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(Br)cc1C
Yield: 1135 %

Procedure:
To a solution of 4-bromo-2-methylbenzoic acid (2.0 g, 9.3 mmol) in methanol (20 mL) was added p-TsOH.H2O (90 mg, 0.50 mmol). The mixture was heated at reflux overnight. Methanol was evaporated and the residue was purified by chromatography on silica gel (3% ethyl acetate in petroleum ether) to afford 4-bromo-2-methyl-benzoic acid methyl ester (1.3 g, 61%). 1H NMR (CDCl3, 300 MHz) δ 7.78 (d, J=8.4 Hz, 1H), 7.41-7.36 (m, 2H), 3.89 (s, 3H), 2.57 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:30])[C@@H:3]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)[N:9]=[CH:8]2.C(N(CC)CC)C.[O:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[C:43](Cl)=[O:44]>ClCCl>[O:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[C:43]([NH:1][C@@H:2]([CH3:30])[C@@H:3]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)[N:9]=[CH:8]2)=[O:44]
Reactant: O=C(Cl)c1ccco1
Reactant: COC(=O)c1ccc(-n2ncc3cc(O[C@H](c4ccccc4)[C@H](C)N)ccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2ncc3cc(O[C@H](c4ccccc4)[C@H](C)NC(=O)c4ccco4)ccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
Methyl 4-{5-[(1R,2S)-2-amino-1-phenylpropoxy]-1H-indazole-1-yl}benzoate (64.3 mg, 0.16 mmol) is dissolved in 6.1 mL of dichloromethane. Triethylamine (0.053 mL, 0.38 mmol) and 2-furoylchloride (20.9 mg, 0.16 mmol) are added. After 4 h stirring at r.t. the reaction mixture is diluted with dichloromethane, washed with water and brine and dried over Na2SO4. The reaction mixture is filtered, the solvent evaporated and the residue purified by chromatography (silicagel, eluents: ethyl acetate/hexane). 38.2 mg (48.1%) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][CH:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1>C(O)CCC>[CH3:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:2]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])[CH2:20]1
Reactant: C[Si](C)(C)CCOCn1ncc([N+](=O)[O-])c1Cl
Reactant: CC1CCCNC1
Solvent: CCCCO
Product: CC1CCCN(c2c([N+](=O)[O-])cnn2COCC[Si](C)(C)C)C1
Yield: 113.9 %

Procedure:
To a solution of 5-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (348.3 mg, 1.254 mmol) in 1 mL n-butanol was added 3-methyl-piperidine (0.20 mL, 1.7 mmol). The reaction mixture was subjected to microwave irradiation at a temperature of 120° C. for 30 minutes. The solvent was evaporated in vacuo and the crude product purified via flash chromatography on silica gel (0 to 40% ethyl acetate in heptanes) to yield 486.5 mg of 3-methyl-1-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidine. LCMS (ESI) m+H=341.4; 1H NMR (400 MHz, DMSO-d6) δ: 8.04 (s, 1H), 5.36 (s, 2H), 3.71-3.62 (m, 2H), 3.20 (m, 3H), 2.96-2.85 (m, 1H), 1.84-1.76 (m, 4H), 1.15 (m, 1H), 0.97-0.87 (m, 5H), 0.00 (s, 9H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]([Cl:21])([Cl:20])[C@@H:11]1[N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13](=[O:19])[O:12]1.[CH2:22]([O:29][CH2:30]Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([O:29][CH2:30][C@@:14]12[CH2:18][CH2:17][CH2:16][N:15]1[C@@H:11]([C:10]([Cl:9])([Cl:20])[Cl:21])[O:12][C:13]2=[O:19])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCOCc1ccccc1
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12COCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
To a solution of LDA (531 mL, 0.109M, 58.1 mmol) at −78° C. was added a solution of Intermediate 85a (10.0 g, 41.2 mmol) in THF (200 mL) over 30 min maintaining the temperature below −70° C. The mixture was stirred at −78° C. for 2 h, then a solution of benzyloxymethyl chloride (11.6 g, 74.1 mmol) in THF (50 mL) added, maintaining the temperature below −70° C. The mixture was allowed to warm to −30° C. over 3 h before being quenched with dropwise addition of water (300 mL). The aqueous was extracted with EtOAc (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC, using 0-60% diethyl ether in cyclohexane, to give the title compound as a clear oil (6.39 g, 42%). 1H NMR (400 MHz, CDCl3): 1.63-1.77 (1H, m), 1.94-2.04 (1H, m), 2.08-2.17 (1H, m), 2.26-2.36 (1H, m), 3.22-3.29 (1H, m), 3.30-3.38 (1H, m), 3.74, (2H, s), 4.62 (2H, s), 4.99 (1H, s), 7.26-7.37 (5H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[S:18]([NH2:28])(=[O:27])([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)=[O:19]>CN1C(=O)CCC1>[S:18]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:2]2[N:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:5]([Cl:17])=[CH:4][N:3]=2)=[CH:22][CH:21]=1)(=[O:19])(=[O:27])[NH2:28]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(Oc2nc(Cl)ncc2Cl)cc1
Solvent: CN1CCCC1=O
Product: COc1ccc(Oc2nc(Nc3ccc(S(N)(=O)=O)cc3)ncc2Cl)cc1
Yield: 19 %

Procedure:
A solution of 2,5 dichloro-4-(4-methoxyphenoxy)pyrimidine (Method 25; 0.65 g, 2.4 mmol) and sulphanilamide (0.38 g, 2.2 mmol) in NMP(1.5 ml) was heated to 100° C. for 4 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic solution was evaporated and the residue purified by column chromatography eluting with 0.1% formic acid, 4% methanol in dichloromethane to afford a solid product (0.17 g, 19%). NMR: 3.81 (s, 3H), 7.05 (d, 2H), 7.10 (s, 2H), 7.22 (d, 2H), 7.50 (d, 4H), 8.50 (s, 1H), 10.6 (br s, 1H); MS [M−H]−: 405, 407.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.Cl.[NH2:14][OH:15]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])/[CH:5]=[N:14]/[OH:15]
Reactant: NO
Reactant: Cc1cc(C=O)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Product: Cc1cc(/C=N/O)ccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a warm solution of 3-methyl-4-nitrobenzaldehyde (1.0 equiv.) in methanol was added hydroxylamine hydrochloride (2.0 equiv.) and the mixture was stirred at 65° C. for 2 hours. Methanol was evaporated and the residue was diluted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then recrystallized from ethyl acetate and petroleum ether 60-80, to provide the title compound as a creamish solid (81%); 1H NMR (300 MHz, CDCl3) δ: 2.62 (s, 3H), 7.54-7.56 (m, 2H), 7.89 (s, 1H), 7.98-8.01 (d, J=9.0 Hz, 1H), 8.14 (s, 1H); IR (KBr) 3375, 3207, 3087, 2994, 1607, 1585, 1506, 1384, 1319, 1161, 986, 841, 755 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[O:23][C:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:24])[C:17]=2[CH:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[O:23][C:15]([CH3:14])=[CH:16][C:17]=4[CH:18]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1cc2c(o1)CCNC2C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1cc2c(o1)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C
Yield: 12 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,4-Dimethyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=1O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:32]2[C:33]([F:40])=[C:34]([F:39])[C:35]([F:38])=[C:36]([F:37])[C:31]=2[F:30])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3c(F)c(F)c(F)c(F)c3F)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4- fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2,3,4,5,6-pentafluorophenol: ESMS m/e: 564.7 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=1>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=2)=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: COc1ccc(Br)cc1F
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2ccc(OC)c(F)c2)c(N)n1

Procedure:
The same procedure as described in Example 47 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (Example 1) and 4-bromo-2-fluoroanisole (Aldrich), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(3-fluoro-4-methoxy-phenyl)-methanone as a white solid. MS (M+H)+, 308.