Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[O:12]1[CH:18]2[CH:13]1[C:14]([CH3:31])([CH3:30])[O:15][C:16]1[CH:22]=[CH:21][C:20]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:19][C:17]=12>CS(C)=O>[CH3:1][O:2][C:3]1[C:4](=[O:9])[N:5]([C@@H:18]2[C:17]3[CH:19]=[C:20]([S:23]([C:26]([F:27])([F:29])[F:28])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][C:14]([CH3:30])([CH3:31])[C@H:13]2[OH:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc[nH]c1=O
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2C2OC21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccn([C@@H]2c3cc(S(=O)(=O)C(F)(F)F)ccc3OC(C)(C)[C@H]2O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
98 mg of 3-methoxy-2(1H)-pyridone were added to a suspension of 38 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in 3 ml of dimethyl sulfoxide, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, a solution of 200 mg of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-trifluoromethylsulfonyl-2H-1-benzopyran (prepared as described in Preparation 8) in 1.5 ml of dimethyl sulfoxide was added at the same temperature and under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 4 days, after which it was worked up in a similar manner to that described in Example 2. The product was then purified by column chromatography through silica gel, using a 1:2 by volume mixture of ethyl acetate and cyclohexane as the eluent, to give 16 mg of the title compound, melting at 223°-225° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([I:26])=[N:9]2)=[CH:5][CH:4]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]([C:43](O)=[O:44])=[CH:39][CH:38]=[N:37]2)=[CH:32][CH:31]=1.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C>CN(C=O)C>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:43]([C:40]2[C:41](=[O:42])[N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[N:37]=[CH:38][CH:39]=2)=[O:44])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[N:9]=[C:10]([I:26])[C:11]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(I)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (1.50 g, 3.06 mmol; prepared as in Example 7, Step B), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (1.43 g, 6.12 mmol; prepared as in Example 19, Step C), and HOBT-H2O (2.81 g, 18.4 mmol) dissolved in dry DMF (30 mL) was added EDCI (3.52 g, 18.4 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was then partitioned between ethyl acetate (60 mL) and aqueous NH4Cl (100 mL). The organic layer was separated, washed with saturated NaHCO3, dried over NaSO4, and evaporated to dryness. The crude material was triturated with MeOH and the solid removed by filtration, dried to afford the title compound as yellow solid. Yield: 1.93 g, 89%. LRMS (APCI pos) m/e 707.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH3:25])=[CH:20][CH:19]=1>>[Cl:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[N:1]=[C:24]([C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)[CH:25]=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(=O)c1ccc(F)cc1
Product: Fc1ccc(-c2cc(-c3ccccc3)c3cc(Cl)ccc3n2)cc1
Temperature: 165 °C

Procedure:
A three-necked, 2 L round-bottomed flask equipped with a thermometer, a mechanical stirrer and a distillation unit fitted with a nitrogen inlet valve was charged with 2-amino-5-chlorobenzophenone (695.0 g, 3.00 mol), and 4'-fluoroacetophenone (456.0 g, 3.30 mol), p-tosic acid (47.62 g, 0.25 mol). The reaction mixture was heated under nitrogen at 165° C. (44 h). The yellow 4'-acetophenone that co-distilled with the water was separated and reintroduced to the reaction mixture throughout the heating period. The mixture was further heated, to 190° C. (2 h). The mixture was cooled to 120° C. and was poured into 95% ethanol (10 L) while vigorously stirring with a mechanical stirring rod set up. The mixture was filtered and the precipitate was washed with ethanol (1 L). The solid was dried in a vacuum oven at 80° C. (16 h). Yield 969 g, 97%; mp 141.0°-142.1° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[Br:35][C:36]1[C:37]([F:44])=[C:38]([CH2:42][NH2:43])[CH:39]=[CH:40][CH:41]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:35][C:36]1[C:37]([F:44])=[C:38]([CH2:42][NH:43][C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[CH:24]=2)=[O:27])[CH:39]=[CH:40][CH:41]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Reactant: NCc1cccc(Br)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(Br)c2F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (210 mg, 0.466 mmol), [(3-bromo-2-fluorophenyl)methyl]amine hydrochloride (123 mg, 0.513 mmol), HBTU (194 mg, 0.513 mmol) and diisopropyl ethyl amine (0.5 mL) in DCM (10 mL) was stirred at room temperature for about 5 h. It was concentrated, mixed with EtOAc (25 mL), washed with aqueous NaHCO3 (25 mL) and then NH4Cl (25 mL). The organic layer was collected, dried and concentrated to afford the desired product as a crude mixture (330 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[C:16]3[NH2:20])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][C:28](=[O:30])[CH3:29])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)Cl
Reactant: Nc1nccn1Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nccn1Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-[1-(3,4-dichloro-phenyl)-1H-imidazol-4-yl-methyl]-1H-imidazol-2-ylamine (1.0 g, 3.2 mmol) in THF (32 ml) was treated at rt with triethylamine (0.33 g, 3.2 mmol) and acetyl chloride (0.25 g, 3.2 mmol). The mixture was stirred at rt for 2 h, filtered and the organic phase was evaporated to dryness. After chromatography [silica, elution with gradient CH2Cl2 to 50% (CH2Cl2/MeOH/aq. NH4OH=90:10:1)] the title compound (0.19 g, 17%) was isolated as a light brown solid. Mp. >236° C. dec.(AcOEt), MS: m/e=350 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8].C(N(CC)CC)C>C1COCC1>[C:6]([O:10][C:1](=[O:4])[CH:2]=[CH2:3])(=[O:9])[CH:7]=[CH2:8]
Reactant: C=CC(=O)Cl
Reactant: C=CC(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC(=O)C=C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
Acrylic anhydride was synthesized in 70-80% yield as in the following example. Acryloyl chloride (2.7 g, 30 mmol) was added dropwise over 5 min to an ice-cooled solution of acrylic acid (2.0 g, 30 mmol) and triethylamine (2.8 g, 30 mmol) in THF (50 mL), and the solution was stirred at room temperature for 16 h. The NH4+Cl− precipitate was collected in a fritted glass filter, and the solvent was then removed from the filtrate by rotary evaporation. The residue was dissolved in CH2Cl2 (25 mL), washed twice with dilute aq. NaHCO3 (50 mL each) and once with satd. NaCl aq. soln. (50 mL), and dried over anhy. Na2SO4. After filtration and removing the solvent by rotary evaporation, 2.8 g (80%) of acrylic anhydride was obtained as a light yellow liquid. It was used without further purification. 1H NMR (CDCl3, 77.23 ppm): 6.04 (m, ═CH trans to CO2), 6.14 (m, ═CH gem to CO2), 6.50 (d, ═CH cis to CO2). 13C NMR (CDCl3/DMSO-d6): 127.4 (═CH), 134.7 (′CH2), 161.2 (C═O).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[Li]CCCC.CCCCCC.[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CCOCC.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:31])=[C:3]([C:9]([F:12])([F:11])[F:10])[CH:4]=1
Reactant: FC(F)(F)c1cc(Br)ccc1Br
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: OC(c1ccccc1)c1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 90 %

Procedure:
To a solution of 1,4-dibromo-2-(trifluoromethyl)benzene (300 mg, 0.987 mmol) in 2 mL of Et2O (C=0.5M) was added dropwise a 1.6M solution of BuLi in hexane (650 μL, 1.05 eq) at −78° C. After 25 min of stirring, benzaldehyde (120 μL, 1.2 eq) was slowly added. The mixture was stirred for 2 h at −78° C. and was allowed to warm to r.t. overnight. Then, the reaction mixture was hydrolyzed with water and with a 1M HCl solution to acidify. The layers were separated. The aqueous layer was extracted with DCM (3×10 mL). The combined organics were washed with brine, dried over MgSO4, filtered and solvents were removed in vacuo. The crude residue was purified by silica gel flash chromatography (cyclohexane/AcOEt 95:5) to afford the desired product in 90% yield (295 mg) as uncoloured oil. 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=2.1 Hz, 1H), 7.67 (dd, J=8.4, 2.1 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.39-7.27 (m, 5H), 6.24 (s, 1H), 2.44 (s, OH); 13C NMR (75 MHz, CDCl3) δ 142.3 (C), 141.4 (q, J=1.4 Hz, C), 135.5 (CH), 131.5 (CH), 129.3 (q, J=30.9 Hz, C), 128.8 (q, J=6.1 Hz, CH), 128.7 (CH), 128.0 (CH), 126.5 (CH), 123.5 (q, J=274.6 Hz, C), 121.7 (C), 70.6 (q, J=2.1 Hz, CH); MS (ESI) m/z: 375.0, 377.0 [M−H+HCO2H, 79Br, 81Br]−; 705.2, 707.2 [2M−2H+HCO2H, 79Br, 81Br]−.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[NH4+].[H][H]>[Pd].CO>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[OH:15])=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=2
Reactant: Cc1ccc2c(O)c([N+](=O)[O-])cnc2c1
Reactant: [H][H]
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2c(O)c(N)cnc2c1
Yield: 84.1 %

Procedure:
7-Methyl-3-nitro-4-quinolinol (11.8 g, 58 mmol), methanol (about 300 mL), ammonium hydroxide (50 mL), and palladium on carbon (1 g of 10%) were combined. The mixture was placed on a Parr apparatus under a 35-40 psi (2.4-2.8 Kg/cm2) hydrogen atmosphere for about 1 hour. The reaction mixture was filtered through a layer of Celite® filter agent and the filter cake was rinsed well with methanol. The filtrate was treated with charcoal and then concentrated under vacuum to provide a fluffy pale green solid. This material was triturated with acetonitrile to provide 8.5 g of 3-amino-7-methyl-4-quinolinol.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[C:23]([O:27][C:28](=[O:40])[NH:29][CH2:30][CH2:31][O:32][C:33]1[CH:34]=[N:35][CH:36]=[C:37](Br)[CH:38]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:40])[NH:29][CH2:30][CH2:31][O:32][C:33]1[CH:34]=[N:35][CH:36]=[C:37]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[F:1])[N:9]([CH3:12])[C:8](=[O:13])[CH2:7][CH2:6]3)[CH:38]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCOc1cncc(Br)c1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc21
Product: CN1C(=O)CCc2cc(-c3cncc(OCCNC(=O)OC(C)(C)C)c3)c(F)cc21

Procedure:
In analogy to the procedure described for the preparation of example 45, 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-22) has been coupled to [2-(5-bromo-pyridin-3-yloxy)-ethyl]-carbamic acid tert-butyl ester (intermediate A-7) to give the title compound as a yellow waxy solid. MS: 416.4 (M+H+).
Reaction SMILES: F[C:2](F)(F)[C:3](OC(=O)C(F)(F)F)=[O:4].[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[O:24][CH:25]=[CH:26][CH:27]=1)(=[O:16])[CH3:15].O>C(O)(=O)C>[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[O:24][C:25]([C:3](=[O:4])[CH3:2])=[CH:26][CH:27]=1)(=[O:16])[CH3:15]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(=O)OCCCCCc1ccco1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCCCCCc1ccc(C(C)=O)o1
Reaction time: 16 h

Procedure:
To a mixture of 100 ml of trifluoroacetic anhydride and 100 ml of glacial acetic acid was added 89 g of 5-(2-furanyl)pentanol acetate in 100 ml of acetic acid. The reaction mixture was allowed to stand at room temperature for about 16 hours, then poured into water and extracted with methylene dichloride. The extracts were concentrated and the residue distilled to give 60.6 g of 5-(5-acetyl-2-furanyl)pentanol acetate, b.p. 120°-123° C. (0.05 mm).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[N:5][C:6]([N+:9]([O-])=O)=[CH:7][CH:8]=1>C(O)C>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[N:5][CH:4]=1
Reactant: CN(C)c1ccc([N+](=O)[O-])nc1
Solvent: CCO
Product: CN(C)c1ccc(N)nc1

Procedure:
The N,N-dimethyl-6-nitropyridine-3-amine obtained above is taken up in 25 mL of ethanol. After addition of 4.8 g of stannous chloride, the reaction mixture is refluxed for 30 minutes and then concentrated to dryness. The residue is chromatographed on a column of silica, eluting with a 90/10 mixture of dichloromethane and ammoniacal methanol. The fractions containing the expected product are combined and concentrated to give 750 mg of 5-dimethylaminopyridine-2-amine in the form of a pasty yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6]O.S(Cl)([Cl:17])=O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Cl:17]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cc(CCl)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In 40 ml of benzene was dissolved 10 g of 3,4,5-trimethoxybenzyl alcohol. To the resulting solution was dropwise added under chilling with ice 10 ml of benzene solution containing 7.6 g of thionyl chloride. After the addition was complete, the mixture was stirred at room temperature for 15 min. The reaction solution was poured into a chilled aqueous potassium carbonate, and a separated benzene portion was collected. The benzene portion was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and placed under reduced pressure to distill off the solvent. The desired compound was obtained as a yellow solid (yield: 11.0 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14](Cl)=[CH:15][CH:16]=[C:11]2[N:10]=[N:9]1.FC1C=CC=CC=1N.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:31]>CS(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([OH:31])=[CH:15][CH:16]=[C:11]2[N:10]=[N:9]1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Fc1ccccc1-n1nnc2ccc(Cl)nc21
Agent: Nc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Oc1ccc2nnn(-c3ccccc3F)c2n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A solution of 3-(2-fluorophenyl)-5-chloro-1,2,3-triazolo[4,5-b]pyridine (1.01 g, 4.06 mmol; prepared following the procedure described in GB Patent No. 1268772 but using 2-fluoroaniline instead of aniline) and 2M sodium hydroxide (4 ml) in DMSO (15 ml) was stirred at 100° C. under nitrogen for 3 h. The mixture was cooled, diluted with water (250 ml) and neutralised with aqueous citric acid. After standing for 18 h, the brown precipitate was collected, dissolved in dichloromethane (100 ml), dried (Na2SO4), filtered and concentrated to give 3-(2-fluorophenyl)-5-hydroxy-1,2,3-triazolo[4,5-b]pyridine (0.80 g, 86%) as a brown solid. δH (360 MHz; d6-DMSO) 6.81 (1H, broad d, J=9), 7.50 (1H, dd, J=8 and 8), 7.60 (1H, dd, J=8 and 7), 7.68-7.72 (1H, m), 7.81 (1H, ddd, J=8, 8 and 2), 8.44 (1H, broad d, J=9) and 12.15 (1H, broad s); m/z (ES+) 231 (M+H+).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.[C:12](N1C=CN=C1)([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:8]1[CH:9]=[CH:10][N:11]=[C:7]1[NH:6][C:12]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:13]
Reactant: Nc1ncc[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncc[nH]1)n1ccnc1

Procedure:
To a stirred suspension of 2-aminoimidazole sulfate (667 mg, 5.05 mmol) in CH2Cl2 (25 mL) was added 1,1′-carbonyldiimidazole followed by DIPEA (2.70 mL, 15.50 mmol). The resultant mixture was stirred at room temperature overnight then concentrated under reduced pressure and provided 1.53 g of imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([C:10](Cl)=[O:11])=[N:8][N:7]([CH3:13])[N:6]=1)=[O:4].C(N(C(C)C)C(C)C)C>C1COCC1.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH:10]=[O:11])=[N:8][N:7]([CH3:13])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nn(C)nc1C(=O)Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nn(C)nc1C=O

Procedure:
To a solution of freshly prepared 5-Chlorocarbonyl-2-methyl-2H-1,2,3-triazole-4-carboxylic acid methyl ester (2.7 g; ca. 13 mmol) in THF (270 ml) was added ethyl-diisopropyl-amine (1.88 g; 1.1 eq.). The mixture was hydrogenated in the presence of 2.7 g 10% Pd/C at 0-5° C. at normal pressure for 2½ hours and subsequently filtered from the catalyst. The clear solution was evaporated to give the crude as a solid which was dissolved again in ethyl acetate and stirred for a couple of minutes with silica gel. After filtration and evaporation 1.77 g (84%) of pure product as off-white crystals were obtained [m.p. 107-108° C.; 1H-NMR (300 MHz, CDCl3), δ (ppm): 10.43 (s, 1H), 4.33 (s, 3H), 4.01 (s, 3H)].
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[CH2:10]([O:17][C:18]1[CH:35]=[CH:34][C:21]([C:22]([NH:24][CH2:25][C:26](=[O:33])[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:23])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:10]([O:17][C:18]1[CH:35]=[CH:34][C:21]([C:22]([NH:24][CH2:25][C:26]([N:27]2[CH2:32][CH2:31][N:30]([C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[CH3:1])=[O:9])[CH2:29][CH2:28]2)=[O:33])=[O:23])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccsc1C(=O)O
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: Cc1ccsc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
3-Methyl-2-thiophene carboxylic acid (74 mg, 0.53 mmol) was added to 4-benzyloxy-N-(2-oxo-2-piperazin-1-yl-ethyl)-benzamide (155 mg, 0.44 mmol) in DMF (5 mL). EDCI.HCl (126 mg, 0.66 mmol), HOBT (71 mg, 0.53 mmol) and DIPEA (227 μL, 1.32 mmol) were then added and the resulting mixture was allowed to stir at room temperature overnight. Water was then added and the product was extracted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford a crude product. Column chromatography purification (using neutral alumina 90:10 EtOAc:MeOH as the eluent) afforded 4-benzyloxy-N-{2-[4-(3-methyl-thiophene-2-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide in 46% yield. LC-MS purity: 87%. 1H NMR (DMSO-D6): δ 8.4 (t, 1H), 7.8 (d, 2H), 7.6 (d, 1H), 7.4 (m, 5H), 7.1 (d, 2H), 6.9 (d, 1H), 5.2 (s, 2H), 4.2 (d, 2H), 3.5 (d, 8H), 2.3 (s, 3H).
Reaction SMILES: CC1C2C(=NC(C3C=CC(O)=CC=3)=CC=2CN2CC(C)(C)NCC2(C)C)NN=1.[CH3:29][C:30]1[C:38]2[C:37]([C:39](O)=O)=[CH:36][C:35]([C:42]3[CH:47]=[CH:46][C:45]([O:48]C4CCCCO4)=[CH:44][CH:43]=3)=[N:34][C:33]=2[N:32](C2CCCCO2)[N:31]=1.C([N:68]1[CH2:73][C:72]([CH2:76][CH3:77])([CH2:74][CH3:75])[NH:71][CH2:70][C:69]1([CH3:79])[CH3:78])C1C=CC=CC=1>>[CH2:76]([C:72]1([CH2:74][CH3:75])[CH2:73][NH:68][C:69]([CH3:79])([CH3:78])[CH2:70][N:71]1[CH2:39][C:37]1[CH:36]=[C:35]([C:42]2[CH:43]=[CH:44][C:45]([OH:48])=[CH:46][CH:47]=2)[N:34]=[C:33]2[NH:32][N:31]=[C:30]([CH3:29])[C:38]=12)[CH3:77]
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OC4CCCCO4)cc3)cc(C(=O)O)c12
Reactant: CCC1(CC)CN(Cc2ccccc2)C(C)(C)CN1
Agent: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(CN3CC(C)(C)NCC3(C)C)c12
Product: CCC1(CC)CNC(C)(C)CN1Cc1cc(-c2ccc(O)cc2)nc2[nH]nc(C)c12

Procedure:
4-[4-(2,2-diethyl-5,5-dimethyl-piperazin-1-ylmethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol was synthesized in analogy to Example 49 (4-[3-Methyl-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol) starting from 3-methyl-1-(tetrahydro-pyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid and 1-benzyl-5,5-diethyl-2,2-dimethyl-piperazine.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2>>[ClH:1].[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][CH:18]=[CH:17]4)=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Fc1ccc2c(Cl)ncnc2c1
Product: Cl
Product: Fc1ccc2c(Nc3ccc4[nH]ccc4c3)ncnc2c1
Yield: 65 %

Procedure:
Using an analogous procedure to that described in Example 5, 4-chloro-7-fluoroquinazoline was reacted with 5-aminoindole to give 7-fluoro-4-(5-indolylamino)quinazoline hydrochloride in 65% yield;
Reaction SMILES: C([O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:18](\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)/[CH2:19][CH2:20][Cl:21])=[CH:13][CH:12]=1)(=O)C(C)(C)C.CO.O.[OH-].[Na+]>C1COCC1>[CH:25]1[CH:26]=[CH:27][C:22](/[C:18](/[CH2:19][CH2:20][Cl:21])=[C:17](\[C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][OH:7])=[CH:12][CH:13]=2)/[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)C(=O)OCCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: OCCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.4 %

Procedure:
(Z)-2-(4-(4-Chloro-1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl pivalate (1 g, 2.16 mmol) was dissolved in THF (8 ml) followed by addition of MeOH (1 ml) and water (1 ml). Sodium hydroxide (0.1 g, 2.5 mmol) was added in one portion and the reaction was stirred at room temperature for 12 h. After completion of the reaction the mixture was partitioned between water (20 ml) and EtOAc (20 ml). Organic phase was washed with water (20 ml) and brine (20 ml), dried (Na2SO4), filtered and concentrated. The residue was crystallized from i-PrOH yielding ospemifene (0.29 g, 35%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.37 (2H, t, J=8 Hz, ArH), 7.29 (3H, t, J=7.2 Hz, ArH), 7.20 (2H, t, J=7.6 Hz, ArH), 7.16-7.13 (3H, m, ArH), 6.80 (2H, d, J=8.8 Hz, ArH), 6.57 (2H, d, J=8.8 Hz, ArH), 3.94 (2H, t, J=4.4 Hz, ArOCH2CH2OH), 3.87 (2H, m, ArOCH2CH2OH), 3.42 (2H, t, J=7.2 Hz, ClCH2CH2), 2.92 (2H, t, J=7.2 Hz, ClCH2CH2), 1.95 (1H, t, J=6.4 Hz, OH). 13C-NMR (100 MHz, CDCl3) δ (ppm): 157.2, 143.2, 142.1, 141.3, 2×135.7, 132.2, 130.0, 129.8, 128.8, 128.7, 127.4, 127.0, 113.9, 69.3, 61.8, 43.3, 39.0.