Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:13][C:12]2[C:3](=[C:4]([CH:9]=[CH:10][C:11]=2[O:14][CH3:15])[C:5]([O:7][CH3:8])=[O:6])[O:2]1.[Br:16]Br>C(Cl)(Cl)Cl>[CH2:1]1[O:13][C:12]2[C:3](=[C:4]([CH:9]=[C:10]([Br:16])[C:11]=2[O:14][CH3:15])[C:5]([O:7][CH3:8])=[O:6])[O:2]1
Reactant: BrBr
Reactant: COC(=O)c1ccc(OC)c2c1OCO2
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)c(OC)c2c1OCO2
Yield: 93.2 %

Procedure:
Compound 122 (5.56 g, 25.6 mmol) was dissolved in anhydrous chloroform. Bromine (4.5 g, 28.5 mmol) was added dropwise over 2 hours at 5°-8° C. Then the mixture was maintained for an additional 2 hours at the same temperature. After the usual workup, 6.9 g of white solid 123 was obtained (88% yield). m.p. 165°-6° C. (crystallized from ethyl acetate). IR cm-1 1710 (s, C=O), 1425, 1400 (s, C--O); MS m/z (%): 288 (M+, 100), 290 (M+2, 96); 1H NMR δ ppm 3.91 (s, 3H, OCH3), 4.14 (s, 3H, ArOCH3), 6.10 (s, 2H, OCH2O), 7.65 (s, 1H, 6-ArH); Anal. (C10H9O5Br) C, H, Br.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][O:9][C:10](=[O:40])[C@H:11]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:12][C:13](=[O:32])[C@H:14]([CH2:28][C:29](=[O:31])[OH:30])[NH:15][C:16](=[O:27])[C@@H:17]([CH3:26])[NH:18]C(OC(C)(C)C)=O>C(OCC)C>[ClH:1].[CH3:8][O:9][C:10](=[O:40])[C@H:11]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:12][C:13](=[O:32])[C@H:14]([CH2:28][C:29](=[O:30])[OH:31])[NH:15][C:16](=[O:27])[C@@H:17]([CH3:26])[NH2:18]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)N
Reaction time: 1 h

Procedure:
To 20 ml of 4N-HCl/dioxane was added 2.0 g of N-t-butoxycarbonyl-D-alanyl-α-L-aspartyl-L-phenylalanine methyl ester under ice cooling. The mixture was stirred for 1 hour. To the reaction mixture was added 150 ml of ethyl ether. Precipitated crystals were collected by filtration. Yield, 1.6 g; m.p., 205°-208° C. (decomposed).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])(=[O:3])[CH3:2].[CH3:13][CH2:14][C:15](=O)[CH2:16][CH3:17].N1CCCC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:14]([C:15]1([CH2:16][CH3:17])[CH2:2][C:1](=[O:3])[C:4]2[CH:5]=[C:6]([C:7]#[N:8])[CH:9]=[CH:10][C:11]=2[O:12]1)[CH3:13]
Reactant: CCC(=O)CC
Reactant: CC(=O)c1cc(C#N)ccc1O
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CCC1(CC)CC(=O)c2cc(C#N)ccc2O1
Reaction time: 3.5 h

Procedure:
To a suspension of 3-acetyl-4-hydroxybenzonitrile (10.48 g) and 3-pentanone (10.3 ml) in toluene (20 ml) was added pyrrolidine (2.7 ml) at ambient temperature. The reaction mixture was stirred overnight at the same temperature and for 3.5 hours under reflux, diluted with ethyl acetate, and then washed with water, 10% aqueous hydrochloric acid, saturated sodium bicarbonate solution and brine successively. The extract was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified with silica gel column chromatography using a mixture of methylene chloride and n-hexane (1:10→1:1) as an eluent. The fractions containing the object compound were concentrated in vacuo and the residue was triturated to give 2,2-diethyl-3,4-dihydro-4-oxo-2H-1-benzopyran-6-carbonitrile (2.51 g).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=O)=[CH:4][CH:3]=1.[C:17]1([CH2:23][C:24]([NH:26][NH2:27])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCO>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2/[CH:9]=[N:27]/[NH:26][C:24](=[O:25])[CH2:23][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)Cc1ccccc1
Reactant: Cc1ccc(Oc2ccccc2C=O)cc1
Solvent: CCO
Product: Cc1ccc(Oc2ccccc2/C=N/NC(=O)Cc2ccccc2)cc1
Temperature: 80 °C

Procedure:
To a solution of 2-(4-methylphenoxy)-benzaldehyde (500 mg, 2.36 mmol) in EtOH (10 mL) is added phenyl acetic hydrazide (336 mg, 2.36 mmol) and the reaction is heated to 80° C. for 1 h. While cooling a white precipitate forms, and this solid is isolated by filtration and washed with portions of EtOH and Et2O. This solid is dried under vacuum to provide N′-{(1E)-[2-(4-methylphenoxy)phenyl]methylene)}2-phenylacetohydrazide (432 mg, 22%). 1H-NMR (400 MHz, DMSO-d6) 11.70–11.55 (m, 1H), 8.51–8.33 (m, 1H), 8.00–7.92 (m, 1H), 7.42–7.19 (m, 9H), 6.91–6.85 (m, 3H), 3.98–3.43 (m, 2H), 2.29 (s, 3H). ESI+ for C22H20N2O2: m/z=345 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.[F:12][C:13]([F:42])([F:41])[C:14]1[CH:15]=[C:16]([NH:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([O:32][C:33]4[CH:38]=[C:37]([CH:39]=[O:40])[N:36]=[CH:35][N:34]=4)=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[O:22])[CH:17]=[CH:18][CH:19]=1>C1COCC1>[F:41][C:13]([F:12])([F:42])[C:14]1[CH:15]=[C:16]([NH:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([O:32][C:33]4[CH:38]=[C:37]([CH:39]([OH:40])[C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=5)[N:36]=[CH:35][N:34]=4)=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Reactant: Cn1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ccnc1C(O)c1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-methyl-1H-imidazole (77 mg, 0.94 mmol) in 5 mL THF at −78° C. is added n-butyllithium (1.6 M in hexane, 0.44 mL). The solution is stirred at −78° C. for 1 h. Then, a solution of 5-(6-formyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (200 mg, 0.47 mmol) in THF (5 mL) is added. The reaction is allowed to warm up to rt and stir overnight. At that time the reaction is quenched with water and then extracted with EtOAc (3×25 mL). The combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue is then purified with semi-prep HPLC (C18; 30-100% I/H2O with 0.1% TFA) to give the title compound. The fractions are pololed and the pH is adjusted to 9 with sodium bicarbonate. The product is extracted with EtOAc. The organic layer is washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated to give the title compound. MS (ESI) m/z 509.0 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.59 (d, J=1.01 Hz, 1H), 8.36 (d, J=9.09 Hz, 1H), 8.06 (s, 1H), 7.94 (d, J=3.79 Hz, 1H), 7.90 (d, J=7.83 Hz, 1H), 7.57 (m, 2H), 7.46 (d, J=2.02 Hz, 1H), 7.29 (s, 1H), 7.16 (dd, J=8.97, 2.40 Hz, 1H), 7.05 (d, J=1.26 Hz, 1H), 6.85 (d, J=1.26 Hz, 1H), 6.75 (d, J=3.54 Hz, 1H), 5.91 (s, 1H), 3.72 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si]([C:11]#[C:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)(C)C>CO>[C:12]([C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[CH:26][CH:27]=1)#[CH:11]
Reactant: C[Si](C)(C)C#Cc1ccc(OCCN2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(OCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Potassium carbonate (4.15 g, 30.0 mmol) was added to a solution of the 4-[2-(4-trimethylsilanylethynyl-phenoxy)-ethyl]-morpholine 101b in methanol (25 mL). The mixture stirred at room temperature for 2.5 h and was then filtered through a pad of Celite along with dichloromethane. The filtrate was concentrated and partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford an orange oil. This oil was purified via column chromatography (eluting with 50-100% ethyl acetate-hexane) to afford 4-[2-(4-ethynyl-phenoxy)-ethyl]-morpholine 102b as an orange solid. MS (MH+) 232.2; Calculated 231 for C14H17NO2.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][C@H:6]([CH3:8])[CH2:5][C:4]([C:12]([O-:14])=[O:13])([C:9]([O-:11])=O)[CH2:3]1.[H-].[CH2:16]([Al+]CC(C)C)C(C)C>C(OCC)C>[CH3:16][O:14][C:12]([C:4]1([CH:9]=[O:11])[CH2:5][C@H:6]([CH3:8])[CH2:7][C@H:2]([CH3:1])[CH2:3]1)=[O:13]
Reactant: CC(C)C[Al+]CC(C)C
Reactant: C[C@@H]1C[C@H](C)CC(C(=O)[O-])(C(=O)[O-])C1
Agent: [H-]
Solvent: CCOCC
Product: COC(=O)C1(C=O)C[C@H](C)C[C@H](C)C1
Reaction time: 2.5 h

Procedure:
To a solution of (3R,5S)-3,5-dimethyl-cyclohexane-1,1-dicarboxylate (7.38 g, 32.4 mmol) in diethyl ether (250 mL) at −78° C. under a nitrogen atmosphere was added diisobutylaluminum hydride (1.5M in toluene, 43 mL, 64.8 mmol) dropwise. After 2.5 h, the reaction mixture was quenched with saturated aqueous NH4Cl solution (100 mL) then with 1N HCl solution (100 mL). The aqueous phase was extracted with diethyl ether (100 mL×5), was dried (MgSO4) and was evaporated in vacuo to yield the title compound as a clear, colorless oil (5.5 g, 85%) which was used without further purification. MH+199.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([S:17]([N:20]2[CH2:24][CH2:23][CH2:22][CH:21]2[CH:25]=O)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:11]1([S:17]([N:20]2[CH2:24][CH2:23][CH2:22][CH:21]2[CH:25]=[CH2:1])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CC1CCCN1S(=O)(=O)c1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CC1CCCN1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a suspension of methyl triphenylphosphonium bromide (357 mg, 1 mmol) in THF (10 mL) at −78° C. is added dropwise KHMDS (1 mmol, 2 mL of 0.5M solution). To this yellow solution is added dropwise a solution of 1-benzenesulfonylpyrrolidine-2-carbaldehyde (235 mg, 1 mmol) in THF (1 mL). The mixture is stirred at −78° C. for 2 h then is allowed to warm to RT. The mixture is poured into 1N HCl and extracted with EtOAc. The organic phase is washed with brine and dried over magnesium sulfate then the solvent removed under reduced pressure. The resulting oil is purified by flash chromatography using a gradient of 0-20% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:21])OC(C)=C)[CH:10]=2)=[CH:6][CH:5]=[C:4]([NH:22][C:23]([NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:24])[N:3]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CN1CCCC1>O1CCOCC1>[CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:21])[CH:10]=2)=[CH:6][CH:5]=[C:4]([NH:22][C:23]([NH:25][C:26](=[O:31])[C:27]([CH3:29])([CH3:30])[CH3:28])=[O:24])[N:3]=1
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2C)ccn1
Reactant: C1COCCN1
Agent: CN1CCCC1
Solvent: C1COCCO1
Product: Cc1nc(NC(=O)NC(=O)C(C)(C)C)ccc1Oc1ccnc(NC(=O)N2CCOCC2)c1
Temperature: 80 °C
Yield: 12 %

Procedure:
A mixture of prop-1-en-2-yl (4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)carbamate (0.164 g, 0.384 mmol), morpholine (0.067 g, 0.767 mmol) and N-methylpyrrolidine (3.27 mg, 0.038 mmol) in dioxane (4 mL) was heated at 80° C. overnight. The mixture was cooled to RT, concentrated to dryness and purified twice via silica gel chromatography (MeOH/DCM, then MeOH/EtOAc). The material was treated with satd. NaHCO3, extracted with DCM (4×) and the combined organics were dried over Na2SO4, concentrated to dryness and further purified via silica gel chromatography (MeOH/DCM) to afford N-(4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)morpholine-4-carboxamide (21 mg, 12%). 1H NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 10.39 (s, 1H), 9.27 (s, 1H), 8.11 (d, J=5.7 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.27 (d, J=2.3 Hz, 1H), 6.57 (dd, J=5.7, 2.4 Hz, 1H), 3.53 (m, 4H), 3.38 (m, 4H), 2.23 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 457.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(=O)C.C(O)C.O.C(O)(=O)C>[C:17]1([NH:23][N:24]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:9][CH:10]=2)[CH3:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNc1ccccc1
Reactant: CCCCCCNc1ccc(C(C)=O)cc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCNc1ccc(C(C)=NNc2ccccc2)cc1

Procedure:
p-Hexylaminoacetophenone dissolved in ethanol acetic acid is treated with a solution of phenylhydrazine in water-acetic acid. After a short time the phenylhydrazone separates out, and is collected and washed with water.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([Br:26])[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[O:3]>CO.Cl.O1CCOCC1>[Br:26][C:6]1[CH:7]=[C:8]2[C:12](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=1)[NH:11][CH:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(=O)c1cc(Br)cc2c(C3CCNCC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indol-3-yl]-1-piperidinecarboxylate (1.56 g, 3.7 mmol) in methanol (10 mL), HCl in dioxane (4M, 35.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the resulting residue was partitioned between ethyl acetate (50 mL) and 5% of aqueous NaOH (50 mL). The aqueous layer was washed with ethyl acetate (2×50 mL) and the combined organic phases were dried with MgSO4 and concentrated under reduced pressure to give the desired product (685 mg, 58%), which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]2[N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[CH:12][C:8]=2[S:7][CH:6]=1)=[O:4].CO.O.[Li+].[OH-]>C1COCC1.CC(O)=O>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:10]2[CH:11]=[CH:12][C:8]3[S:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:9]2=3)=[CH:15][CH:16]=1
Reactant: COC(=O)c1csc2ccn(Cc3ccc(C(F)(F)F)cc3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1csc2ccn(Cc3ccc(C(F)(F)F)cc3)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.9 %

Procedure:
A mixture of 1.0 g of the product of Step 6 was dissolved in 45 ml THF, 30 ml of MeOH and 15 ml of water, followed by 15 ml of 1N aqueous LiOH solution. After stirring for 5 h at room temperature, 2 ml of AcOH was added and the mixture was extracted with 150 ml of EtOAc. The organic layer was washed with 50 ml of brine and dried over Na2SO4, filtered, and concentrated to give 0.9 g of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>O1CCCC1>[NH:14]1[CH2:15][CH2:16][CH:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH2:1])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc3cc(N)ccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Nc1ccc2c(ccn2C2CCNCC2)c1
Yield: 38.6 %

Procedure:
tert-Butyl 4-(5-amino-1H-indol-1-yl)piperidine-1-carboxylate (7.95 mmol, 2.506 g) was stirred in tetrahydrofuran (10 mL)/trifluoroacetic acid (10 mL) at room temperature for 1 hour. The solvent was removed at reduced pressure. The resulting residue was passed down an SCX column to afford the title compound (660 mg).
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH:29]([CH3:31])[CH3:30]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)Br
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Product: Cc1cccnc1C(=O)CCc1coc(-c2ccc(OC(C)C)c(OC(F)F)c2)n1

Procedure:
Using the compound obtained in Example 356 and 2-bromopropane, white powdery 3-[2-(3-difluoromethoxy-4-isopropoxy phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH:14]1[CH:19]=[C:18]2[C:20]([C:22]3[C:27]([C:28](=[O:29])[C:17]2=[CH:16][CH:15]=1)=[C:26]([NH2:30])[C:25]([S:31]([O-:34])(=[O:33])=[O:32])=[CH:24][C:23]=3Br)=[O:21].[Na+:36].[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Na+:36].[NH2:30][C:26]1[C:27]2[C:28](=[O:29])[C:17]3[C:18](=[CH:19][CH:14]=[CH:15][CH:16]=3)[C:20](=[O:21])[C:22]=2[C:23]([NH:46][S:43]([C:40]2[CH:41]=[CH:42][C:37]([CH3:47])=[CH:38][CH:39]=2)(=[O:44])=[O:45])=[CH:24][C:25]=1[S:31]([O-:34])(=[O:32])=[O:33]
Reactant: Nc1c(S(=O)(=O)[O-])cc(Br)c2c1C(=O)c1ccccc1C2=O
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [Cu+2]
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2cc(S(=O)(=O)[O-])c(N)c3c2C(=O)c2ccccc2C3=O)cc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
Copper (II) sulphate pentahydrate (0.122 g, 0.0005 mol) and glucose monohydrate (1.6 g, 0.008 mol) are added to a mixture of bromaminic acid sodium salt (38.2 g, 0.1 mol) and p-toluenesulphonamide (18.8 g, 0.11 mol) in water (250 ml) containing sodium carbonate (3.8 g) and sodium bicarbonate (19.0 g). The mixture which has a pH of 8.5-9, is heated to 70° C. and stirred at this temperature for 5 hours. The resulting mixture is diluted with water to a volume of 750 ml and cooled to 40° C. The solid product is filtered off and washed with a solution of sodium chloride (12 g) in water (1300 ml) to give a 99% yield of 1-amino-4-(4'-methylphenylsulphonamido)-anthraquinone-2-sulphonic acid sodium salt - a product of formula I where M denotes sodium and R denotes a group of formula IV. Analysis shows that the filtrate and washing liquid contain only 0.0025 mol of copper per mol of bromaminic salt starting material. Part of the solid product (25.5 g, 0.054 mol) is added to a solution of sodium hydroxide (62 g, 1.55 mol) in methanol (200 ml). The mixture is heated under reflux for 10 hours, then diluted with water to a volume of 900 ml at 70° C. 98% sulphuric acid is added to reduce the pH of the mixture to 6.0-7.0 and the mixture is heated at 70° C.-75° C. for 30 minutes. The solid product obtained is filtered off and washed with water at 40° C. (1000 ml) to give a substantially quantitative yield of 1-amino-4-(4'-methylphenylsulphonamido)-2-methoxyanthraquinone (C.I. Disperse Red 86). Analysis shows that the filtrate and washings contain only 0.0015 mol of copper per mol of bromaminic salt, while the product contains only 0.001 mol of copper per mol of bromaminic salt.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].N1C=CC=CC=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22]>ClCCl.C(OCC)(=O)C>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:22]
Reactant: Nc1ccc2cccnc2n1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2cccnc2n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[1,8]-Naphthyridin-2-ylamine (85 mg, 0.59 mmol) was dissolved in dichloromethane (2 mL) and pyridine (0.10 mL, 1.2 mmol). 2,6-Difluorobenzoyl chloride (0.068 mL, 0.76 mmol) was then added and the reaction mixture was stirred at room temperature for 30 minutes. Next, the reaction mixture was diluted with ethyl acetate and washed with water followed by brine. The resulting organic solution was purified by column chromatography (EtOAc/hexanes) to give 2,6-difluoro-N-[1,8]naphthyridin-2-ylbenzamide. Yield 35 mg (21%). LCMS (ESI): calc. C15H9F2N3O=285; obs. M+H=286.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C@@H:21]1[CH2:23][C@H:22]1[CH:24]([NH:26][O:27][CH3:28])[CH3:25].C1N2CCN(CC2)C1>C(#N)C>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C@@H:21]1[CH2:23][C@H:22]1[CH:24]([N:26]([O:27][CH3:28])[C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9])[CH3:25]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(C)[C@@H]1C[C@H]1c1ccc(Cl)cc1Cl
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)[C@@H]1C[C@H]1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (80 mg; 0.41 mmol) in acetonitrile (1 ml) was added dropwise to a stirred mixture of trans-N-{1-[2-(2,4-dichlorophenyl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine diastereomere B (88 mg; 0.34 mmol), prepared as described in example P13 and DABCO (54 mg; 0.48 mmol) in acetonitrile (1 ml) at ambient temperature. The reaction mixture was stirred for 16 hours at ambient temperature. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (10 g) (eluent: n-hexane/ethyl acetate 1:1).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28]>>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]([NH:28][CH2:27][C:23]4[O:22][CH:26]=[CH:25][CH:24]=4)=[O:19])=[CH:20][CH:21]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: NCc1ccco1
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)NCc1ccco1
Yield: 91 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.3 g, 1.04 mmol) and furan-2-ylmethaneamine (0.101 g, 1.04 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-N-(furan-2-ylmethyl)acetamide as a white solid (0.346 g, 90.8% yield).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc2c(c1C)OCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1CBr)OCO2
Temperature: 0 °C
Yield: 21.5 %

Procedure:
A mixture of methyl 4-methyl-1,3-benzodioxole-5-carboxylate (9.9 g), N-bromosuccinimide (9.6 g) in carbon tetrachloride was irradiated with a 500 W medium pressure ultraviolet lamp for six hours at reflux. The mixture was cooled to 0° C., filtered and the filtrate evaporated to give an oil which was crystallised from toluene/hexane and recrystallised from cyclohexane to give methyl 4-bromomethyl-1,3-benzodioxole-5-carboxylate (3.0 g) as a beige solid, m.p. 95°.varies.98° C.