Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:3])[CH3:2]>C(O)C.CCCCCC>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccc(OC)cc2)c(NC(C)=O)c2ccc(Cl)cc21
Solvent: CCO
Solvent: CCCCCC
Product: COc1ccc(C(=O)c2[nH]c3cc(Cl)ccc3c2NC(C)=O)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-acetylamino-6-chloro-1-ethoxycarbonyl-2-(4-methoxybenzoyl)indole (step 2). m.p.: 137-139° C. (ethanol/hexane)
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=3[NH2:24])=[N:9][C:8]=2[N:7]([CH2:25]CC)[C:5]1=[O:6])CC.[OH-].[K+].[NH4+]=S>>[NH2:24][C:16]1[CH:17]=[C:18]([NH2:21])[CH:19]=[CH:20][C:15]=1[C:10]1[NH:11][C:12]2[C:13](=[O:14])[N:4]([CH3:1])[C:5](=[O:6])[N:7]([CH3:25])[C:8]=2[N:9]=1
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc([N+](=O)[O-])cc3N)nc2n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Product: Cn1c(=O)c2[nH]c(-c3ccc(N)cc3N)nc2n(C)c1=O

Procedure:
1,3-dipropyl-8-(2-amino-4-nitrophenyl)xanthine (0.007 mol) was dissolved in 20 ml boiling 2.5N KOH. Five ml of 22% ammonium sulfide was added, and the solution was removed from heat after 1 minute. HCl was added to pH 8 in a hood, and the product was collected by filtration and washed with water. About 25% of the product was a sulfur-containing impurity. Since this impurity appeared to protect the xanthine from oxidation, no attempt was made to further purify the xanthine. 8-(2,4-diaminophenyl)theophylline was synthesized in the same way.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[CH:16]=[CH:15]1)[C:6]([O:8]C)=[O:7].CO.C1COCC1.O.[OH-].[Li+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[CH:16]=[CH:15]1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(Cn2ccc3ccc([N+](=O)[O-])cc32)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1Cn1ccc2ccc([N+](=O)[O-])cc21
Reaction time: 72 h
Yield: 91 %

Procedure:
Nitrogen was passed through a solution containing 1.39 g. methyl 3-methoxy-4-(6-nitroindol-1-ylmethyl)benzoate in 1:1 v/v methanol and THF together with 0.86 g. lithium hydroxide monohydrate in 25 ml. water. After 1 minute the reaction mixture was sealed and stirred for 3 days. Solvent was then evaporated. The residue was diluted with water, acidified (1 M hydrochloric acid) and extracted with ethyl acetate. The extracts were washed with water, then with brine and were dried (MgSO4) Evaporation of solvent gave a 3-methoxy-4-[6-nitroindol-1-ylmethyl]benzoic acid in 91% yield as a solid m.p. 243°-245.5° C. which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:22][N:21](C(OC(C)(C)C)=O)[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]2)[CH2:14][CH2:13]1)=[O:10]>Cl.O1CCOCC1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([CH:18]2[CH2:22][NH:21][C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]2)[CH2:16][CH2:17]1)=[O:10]
Reactant: COC(=O)[C@@H]1CC(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CC(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)CN1
Yield: 101.4 %

Procedure:
1-tert-Butyl 2-methyl (2S)-4-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)pyrrolidine-1,2-dicarboxylate (Example 51, 0.16 g, 0.32 mM) was stirred in 4 N hydrogen chloride in dioxane (4.0 ml) at room temperature for twenty minutes. The orange mixture was concentrated then dissolved in a small amount of MeOH/DCM, diluted with DCM, and washed with sodium bicarbonate. The organic layer was dried over MgSO4, filtered and concentrated to give an orange solid (0.130 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24]Cl)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:26]#[N:27])=[C:4]([F:28])[CH:3]=1.[I-].[Na+].[CH3:31][NH:32][CH3:33]>O1CCCC1>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][N:32]([CH3:33])[CH3:31])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:26]#[N:27])=[C:4]([F:28])[CH:3]=1
Reactant: CNC
Reactant: COc1cc2c(Nc3cc(O)c(Cl)cc3F)c(C#N)cnc2cc1OCCCl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)c(C#N)cnc2cc1OCCN(C)C
Temperature: 135 °C

Procedure:
A mixture of 0.8 g (1.83 mmol) of 4-(4-chloro-2-fluoro-5-hydroxy-phenylamino)-7-(2-chloro-ethoxy)-6-methoxy-quinoline-3-carbonitrile and 0.11 g of sodium iodide in 16.1 ml of 2M dimethylamine in tetrahydrofuran was placed in a sealed tube and heated to 135° C. for 14 hr. The solvent was removed and the residue was mixed with warm ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. Solvent was removed and the residue was chromatographed on silica gel eluting with ethyl acetate-methanol-triethylamine 60:40:3 giving 0.41 g of the title compound as a tan solid: mass spectrum (electrospray, m/e) M+H 430.9; (M+2H)+2 216.0.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([O:14]C)=[O:13])[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1
Reactant: COC(=O)c1cc(-c2ccnn2C)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nccc1-c1csc(C(=O)O)c1
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (3 g, 13.50 mmol) in 6N sodium hydroxide (22.50 ml, 135 mmol) and tetrahydrofuran (27.0 ml) was stirred in a sealed tube at 70° C. After 1 h, the solution was partitioned between H2O-DCM and the pH of the aqueous layer was adjusted to ˜3. The aqueous layer was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated affording 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (2.8 g, 13.45 mmol, 100% yield) as a yellow solid which was used directly without further purification: LCMS (ES) m/e 209 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:7][C:6]([C:5]2[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:9])=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)CSc2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
A mixture of 10.0 g (47 mmol) 4-methylphenacyl bromide, 6.8 g (47 mmol) 4-chlorothiophenol, and 6.5 g (47 mmol) anhydrous potassium carbonate in 100 ml dry DMF was stirred for 3 h at 80° C. It was filtered and the filtrate was concentrated under reduced pressure. The concentrate was stirred in water, and the resulting solid was filtered off, washed with water, and recrystallized from ethanol to give 10.7 g (82%) of the crude title compound.
Reaction SMILES: C(O[C:5]1[C:6](OC(=O)C)=[C:7]([I:11])[CH:8]=[CH:9][CH:10]=1)(=O)C.[OH-].[K+].[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:23][CH:24]=1>CO>[C:19]1([CH3:18])[CH:20]=[CH:21][C:22]([S:25]([N:28]=[C:7]2[CH2:6][CH2:5][CH2:10][CH2:9][I:11]2[C:7]2[CH:6]=[CH:5][CH:10]=[CH:9][CH:8]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N=C2CCCCI2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 113.3 %

Procedure:
Diacetoxyiodobenzene (12.88 g, 40 mmol) was added to a solution of KOH (5.61 g, 100 mmol) and p-toluenesulfonamide (6.85 g, 40 mmol) in methanol (160 mL) at 8° C. A yellow color developed within 1 minute. The cooling bath was removed, and the solution was allowed to warm to RT with stirring for 3 hours. Water (180 mL) was added and the reaction was refrigerated overnight. The precipitate was collected by filtration and dried overnight in a vacuum dessicator to yield 10 g (66%) of a light yellow solid which was used with out further purification or characterization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=O)[NH:13][CH:12]=2)[CH:6]=[CH:5][N:4]=1.P(Cl)(Cl)([Cl:24])=O.Cl.O.N>O1CCOCC1.CCOC(C)=O>[Cl:24][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([CH2:10][CH2:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)=[CH:12][N:13]=1
Reactant: COc1cc(CCc2c[nH]c(=O)c3ccccc23)ccn1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(CCc2cnc(Cl)c3ccccc23)ccn1
Temperature: 65 °C
Reaction time: 7 h

Procedure:
Under a N2 atmosphere, 160 mg (0.57 mmol) of 4-[2-(2-methoxy-pyridin-4-yl)-ethyl]-2H-isoquinolin-1-one in 3.7 ml of acetontrile are mixed with 131 μl (1.43 mmol) of phosphorus oxychloride and 0.28 ml of 4 N HCl In dioxane and stirred for 7 h at 65° C. After cooling to RT, water/NH3 conc. 10:1 and EtOAc are added, the water phase is separated and extraction effected twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation to form 1-chloro-4-[2-(2-methoxy-pyridin-4-yl)-ethyl]-isoquinoline; 1H NMR (DMSO-d6) δ 8.30 (d, 1H), 8.27 (d, 1H), 8.13 (s, 1H), 8.03 (d, 1H), 7.94 (t, 1H), 7.85 (t, 1H), 6.90 (d, 1H), 6.73 (s, 1H), 3.80 (s, H3C), 3.32 (t, H2C), 2.95 (t, H2C).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@@:6]([CH3:16])([S:12]([CH3:15])(=[O:14])=[O:13])[C:7]([O:9]CC)=[O:8])=[N+:2]=[N-:3].[Li+].[OH-]>O>[N:1]([CH2:4][CH2:5][C@@:6]([CH3:16])([S:12]([CH3:15])(=[O:14])=[O:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3]
Reactant: CCOC(=O)[C@@](C)(CCN=[N+]=[N-])S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C[C@@](CCN=[N+]=[N-])(C(=O)O)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 34.8 %

Procedure:
To a solution of ethyl (2R)-4-azido-2-methyl-2-(methylsulfonyl)butanoate (3.9 g, 15.6 mmol, 1 eq) in water (7.5 mL) was added LiOH (16 mmol). The mixture was allowed to stir at 80° C. for 16 h. The crude product was then purified by reverse phase chromatography on a 100 g C18 column eluting with a 0-20% MeOH/water gradient (containing 0.5% TFA) to give the desired product (2R)-4-azido-2-methyl-2-(methylsulfonyl)butanoic acid (1.2 g, 35% yield). LC-MS: M+H+222.1.
Reaction SMILES: S(Cl)(Cl)=O.Cl.[NH2:6][C:7]1([C:18]([OH:20])=[O:19])[CH2:12][CH2:11][C:10]([O:16][CH3:17])([CH2:13][O:14][CH3:15])[CH2:9][CH2:8]1.[CH3:21]O>>[NH2:6][C:7]1([C:18]([O:20][CH3:21])=[O:19])[CH2:12][CH2:11][C:10]([O:16][CH3:17])([CH2:13][O:14][CH3:15])[CH2:9][CH2:8]1
Reactant: COCC1(OC)CCC(N)(C(=O)O)CC1
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COCC1(OC)CCC(N)(C(=O)OC)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
At 0° C., 4.1 ml (55.60 mmol) of thionyl chloride were added dropwise to 4.70 g of the compound from Example 20A in 50 ml of methanol. The mixture was stirred at 0° C. for 0.5 hours and at 40° C. overnight. After cooling, the mixture was concentrated, the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted repeatedly with ethyl acetate and the combined organic phases were dried over sodium sulphate, filtered and concentrated. This gave 392 mg (61% of theory from Example 16A) of the title compound as a diastereomer mixture which was reacted without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1Br)([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:40]1[CH:49]=[CH:48][CH:47]=[CH:46][C:41]=1[C:42]([O:44][CH3:45])=[O:43].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[CH3:45][O:44][C:42]([C:41]1[C:40]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:43]
Reactant: CC(C)(C)OC(=O)Cc1ccccc1Br
Reactant: COC(=O)c1ccccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1-c1ccccc1CC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 22 %

Procedure:
To a solution of (2-bromo-phenyl)-acetic acid tert-butyl ester (678 mg, 2.5 mmol), bis(pinacolato)diboron (698 mg, 2.75 mmol), potassium acetate (736 mg, 7.5 mmol) and DMF (15 mL) was added PdCl2(dppf) (61 mg, 0.75 mmol). After evacuating and refilling with nitrogen three times, the reaction was heated to 80° C. for 2 h. After cooling to room temperature, methyl 2-bromo-benzoate (1.08 g, 5.0 mmol), 2M Na2CO3 aqueous (6.25 mL) and PdCl2(dppf) (61 mg, 0.75 mmol) was added to the reaction.). After evacuating and refilling with nitrogen three times again, the reaction was heated to 80° C. for 14 h. After cooling to room temperature, the mixture was poured into water (15 mL) and extracted with ether (3×25 mL). The combined organic layers were washed with water (3×25 mL), brine, dried (magnesium sulfate), and concentrated. The title compound was isolated in 22% yield as an oil following chromatography on silica gel utilizing ethyl acetate/hexane as solvent.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH2:29]=O>C(O)=O>[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][N:20]([CH3:29])[CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: C=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCNC1
Agent: Cl
Solvent: O=CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C)C1
Temperature: 85 °C
Yield: 59 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-[(3R)-pyrrolidin-3-yloxy]-7-methoxyquinazoline hydrochloride (0.24 g, 0.56 mmole; prepared as described in Example 29-preparation of starting materials) was dissolved in formic acid (4 ml) and formaldehyde (37% w/v in water) (2 ml) was added. The mixture was heated to 85° C. for one hour and then evaporated under vacuum and azeotroped with toluene. The residue was partitioned between ethyl acetate and saturated aqueous NaFfCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (94/6). The fractions containing the expected product were combined, evaporated and the residue triturated with isohexane/diethylether, filtered and dried under vacuum to give the title product as a white solid (0.13 g; 59%); 1H NMR Spectrum: (DMSO d6) 1.70-1.9 (m, 1H); 2.27 (s, 3H); 2.30-2.50 (m, 2H); 2.55-2.75 (na, 2H); 2.91-3.00 (m, 1H); 3.91 (s, 3H); 4.90-5.10 (m, 1H); 7.18 (s, 1H); 7.20-7.35 (m, 1H); 7.40-7.58 (m, 2H); 7.64 (s, 1H); 8.35 (s, 1H); 9.57 (s, 1H); Mass Spectrum: (M−H)− 401.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[S:27][CH:28]=[C:29]([CH:31]=O)[N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:31][C:29]3[N:30]=[C:26]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[S:27][CH:28]=3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: O=Cc1csc(-c2ccccc2)n1
Reactant: COC(=O)CCCC(N)c1c(OC)ccnc1OC
Product: COc1ccnc(OC)c1C1CCCC(=O)N1Cc1csc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,4-dimethoxypyridin-3-yl)pentanoate with commercially available 2-phenylthiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.74 min.; [M+H]+: 409.83 g/mol.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)[C:16]([F:28])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:25]1([C:23]2[NH:22][N:21]=[C:20]([NH:19][C:17]3[C:16]([F:28])=[CH:15][N:14]=[C:13]([NH:11][C@H:9]([C:6]4[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=4)[CH3:10])[N:18]=3)[CH:24]=2)[CH2:27][CH2:26]1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: Fc1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncc(F)c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Temperature: 180 °C
Yield: 242.5 %

Procedure:
A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 93 mg), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoropyrimidin-4-amine (Method 16, 127 mg) and DIPEA (0.22 ml) in n-BuOH (2.5 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 180° C. for 6 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound as solid (435 mg). NMR 11.28 (s, 1H), 8.92 (s, 3H), 8.24 (s, 1H), 6.04 (s, 1H), 4.92-5.54 (m, 1H), 1.82-1.98 (m, 1H), 1.56 (d, 3H), 0.94-1.06 (m, 2H), 0.64-0.80 (m, 2H). m/z 395.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[NH:19][N:18]=[N:17][N:16]=2)[CH:5]=[CH:4][C:3]=1[C:20](=[O:22])[CH3:21].Br.Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[N:19]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[N:18]=[N:17][N:16]=2)[CH:5]=[CH:4][C:3]=1[C:20](=[O:22])[CH3:21]
Reactant: BrCCCCc1cccnc1
Reactant: CCCc1c(OCCCc2nnn[nH]2)ccc(C(C)=O)c1O
Agent: Br
Product: CCCc1c(OCCCc2nnnn2CCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
1-[2-Hydroxy-3-propyl-4-[3-(1H-tetrazol-5-yl)propoxy]phenyl]ethanone was allowed to react with 3-(4-bromobutyl)pyridine hydrobromide according to procedure B and the product was purified by high pressure liquid chromatography to give 1-[2-hydroxy-3-propyl-4-[3-[1-[4-(3-pyridinyl)butyl]-1H-tetrazol-5-yl]propoxy]phenyl]ethanone, which is the N-1 isomer, and 1-[2-hydroxy-3-propyl-4-[3-[2-[4-(3-pyridinyl)butyl]-2H-tetrazol-5-yl]propoxy]phenyl]ethanone, which is the N-2 isomer.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1.CC(C)=O>CCOCC.[I-].[K+]>[CH:21]([C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:18][CH:19]=1)=[CH2:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: C=Cc1ccc(OCC(=O)OC(C)(C)C)cc1
Yield: 98.5 %

Procedure:
59.3 g (430 mmol) of potassium carbonate, 0.64 g of potassium iodide, 50.7 g (260 mmol) of tert-butyl bromoacetate and 31.2 g (260 mmol) of 4-hydroxystyrene are mixed with 145 ml of acetone in a 750 ml sulfonation flask. The resultant suspension is refluxed for 100 minutes, cooled, filtered and evaporated. The residue obtained is taken up in 750 ml of ether and washed twice with 100 ml of 1N NaOH solution in each case and then twice with 200 ml of water in each case. The organic phase is separated off, dried over magnesium sulfate and evaporated, leaving 60.02 g (256 mmol) of the desired product as a clear oil, which corresponds to a yield of 98.5% of theory. 1H-NMR (CDCl3, 300 MHz): δ ppm] 7.33/d/2H of the resultant product 6,84/d/2H 6,64/dd/1H 5,60/d/1H 5,12/d/1H 4,49/s/2H 1,47/s/9H
Reaction SMILES: Cl.Cl.[CH2:3]([N:5]([C:8]([O:10][CH2:11][CH:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1)=[O:9])[CH2:6][CH3:7])[CH3:4].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31]>C(Cl)Cl.C(Cl)Cl.CO.[NH4+].[OH-]>[CH3:39][O:38][C:34]1[CH:33]=[C:29]([CH:28]=[C:27]([O:26][CH3:25])[C:35]=1[O:36][CH3:37])[C:30]([N:16]1[CH2:15][CH2:14][NH:13][CH:12]([CH2:11][O:10][C:8]([N:5]([CH2:6][CH3:7])[CH2:3][CH3:4])=[O:9])[CH2:17]1)=[O:31]
Reactant: CCN(CC)C(=O)OCC1CNCCN1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)OCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Yield: 53.2 %

Procedure:
19.86 g (86 mmol) of 2-(N,N-diethylaminocarbonyloxymethyl)piperazine dihydrochloride prepared in accordance with step 2.2 of Example 2 are dissolved in 400 ml of CH2Cl2 and 42 ml (3.5 equivalents) of triethylamine in a 1 liter ground-necked conical flask on which is fitted an addition funnel, and which is immersed in an ice bath. A solution containing 19.83 g (86 mmol) of 3,4,5-trimethoxybenzoyl chloride in 200 ml of CH2Cl2 is added dropwise to the solution thus obtained. The reaction is monitored by thin-layer chromatography, using a CH2Cl2/MeOH/NH4OH mixture (80/20/0.5 v/v/v) as eluent, until the starting amine has disappeared. The solution is then washed with saturated NaHCO3 solution and then with water until a neutral pH is obtained. The organic phase is then dried (MgSO4), filtered and evaporated and the residue obtained is chromatographed on a column of silica gel with an MeOH/CH2Cl2 mixture (1/99 v/v) as eluent. 18.75 g of 4-(3′,4′,5′-trimethoxybenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine are thus obtained in the form of a viscous oil. Yield: 53.33%.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[S:21](Cl)(=[O:23])=[O:22]>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:21]([C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[CH3:11])(=[O:22])=[O:23])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cc([N+](=O)[O-])ccc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Orcinol monohydrate (2.84 g, 20.0 mmol) and 2-methyl-5-nitrobenzenesulfonyl chloride (4.71 g, 20.0 mmol) were mixed in saturated aqueous NaHCO3 (60 mL) and diethyl ether (60 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (100 mL) and extracted into ethyl acetate (3×60 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a pale yellow solid (4.20 g, 72%). 1H-NMR (300 MHz, CDCl3) δ 8.71 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 6.56 (s, 1H), 6.44 (s, 1H), 6.33 (s, 1H), 5.42 (s, 1H), 2.91 (s, 3H), 2.23 (s, 3H).