Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:23][Sn](C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10]([CH3:23])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2onc(-c3ccccc3)c2c1O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C)c2onc(-c3ccccc3)c2c1O
Temperature: 130 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A mixture of 7-bromo-4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (231 mg, 0.64 mmol), tetramethyltin (177 μl, 1.28 mmol), bis(triphenylphosphine)palladium(II) dichloride (45 mg, 0.06 mmol), and dimethylformamide (2.5 ml) was stirred at 130° C. for 1 h before it was cooled to room temperature, quenched with water, and filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (95 mg): MS: (+) m/z 299.49 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[N+:37]([O-:39])=[O:38])=[CH:22][C:18]=1[C:19](Cl)=[O:20])([O-:16])=[O:15]>C1(C)C=CC=CC=1>[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][C:28]=2[N+:37]([O-:39])=[O:38])=[CH:22][C:18]=1[C:19]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:20])([O-:16])=[O:15]
Reactant: OC1CCOC1
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCOC1)c1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])ccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and adtition funnel. A solution of 2-nitro-5-(2-nitro-4-trifluoromethylphenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-nitro-5-(2-nitro-4-trifluoromethylphenoxy)benzoate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Br[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1)[C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Reactant: COCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(CN(CCOC)c2cccc(-c3ccc(C(F)(F)F)cc3)c2C)cc1C
Yield: 60.2 %

Procedure:
To a solution of N-(2-methoxyethyl)-2-methyl-4′-(trifluoromethyl)-1,1′-biphenyl-3-amine (500 mg, 1.62 mmol) in acetonitrile (30 mL) was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (488 mg, 1.7 mmol) and N,N-diisopropylethylamine (295 μl, 1.7 mmol). The resultant mixture was heated for 4.5 h at 80° C. On cooling the solvents were removed in vacuo, the residue diluted with water and extracted with CH2Cl2. The organic solution was passed through a hydrophobic frit and the solvent removed in vacuo. Purification by Biotage™ chromatography (silica, 40 g) eluted with 5% EtOAc/cyclohexane afforded the title compound as a colourless oil (503 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([O:14][CH2:15][CH2:16][CH3:17])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([O:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30](Cl)=[CH:31][CH:32]=[N:33]2)=[CH:28][C:27]=1[O:37][CH3:38])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:18]([O:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30]([O:1][C:2]3[C:3]([C:12]([O:14][CH2:15][CH2:16][CH3:17])=[O:13])=[CH:4][C:5]4[C:10]([CH:11]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:31][CH:32]=[N:33]2)=[CH:28][C:27]=1[O:37][CH3:38])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: CCCOC(=O)c1cc2ccccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCc3ccccc3)c(OC)cc12
Temperature: 120 °C
Reaction time: 5 h
Yield: 50.1 %

Procedure:
Propyl 3-hydroxy-naphthalene-2-carboxylate (460 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (200 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (4 ml), and the mixture was stirred at 120° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give propyl 3-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-naphthalene-2-carboxylate (165 mg, yield 50%).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[O:4]C1C=CC([N+]([O-])=O)=CC=1.C(N(CC)C(C)C)(C)C.[CH3:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1>ClCCl>[CH3:1][NH:2][C:3]([NH:32][NH:31][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([CH3:24])=[CH:34][CH:33]=1)=[O:4]
Reactant: CNC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(C(=O)NN)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)NNC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
653 mg (3.33 mmol) of 4-nitrophenyl methylcarbamate and 473 mg (3.22 mmol) of N,N-diisopropylethylamine are added to 500 mg (3.33 mmol) of 4-methylbenzoic acid hydrazide in 15 ml dichloromethane and the mixture stirred overnight at room temperature. The precipitate formed is recovered by filtration, washed with diethyl ether and dried in vacuo. 602 mg (87% of theory) of the target compound are thus obtained.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH2:36][CH3:37])([C:21]3[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([CH2:33][CH3:34])([OH:32])[CH2:30][CH3:31])=[C:23]([CH3:35])[CH:22]=3)[CH2:19][CH3:20])=[CH:14][C:13]=2[CH3:38])=[CH:10][CH:11]=1)C.[OH-].[Na+].P([O-])(O)(O)=O.[Na+]>CO.O1CCCC1>[CH2:19]([C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]=[CH:7][C:6]([CH2:5][C:4]([OH:39])=[O:3])=[CH:11][CH:10]=2)=[C:13]([CH3:38])[CH:14]=1)([C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([CH2:30][CH3:31])([OH:32])[CH2:33][CH3:34])=[C:23]([CH3:35])[CH:22]=1)[CH2:36][CH3:37])[CH3:20]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(CC)CC)c(C)c3)cc2C)nc1
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)O)cn3)c(C)c2)cc1C)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
[6-(4-{1-Ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester (Example 81-(1); 24.6 mg, 0.047 mmol) was dissolved in methanol/tetrahydrofuran=1:1 (1 mL). A 1 N sodium hydroxide aqueous solution (0.1 mL) was added, and the mixture was stirred at room temperature for one hour. A 30% sodium dihydrogenphosphate aqueous solution (0.3 mL) was added to the reaction mixture, and then the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=1/1) to give the title compound (15 mg, 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.CC(C)=O.C(=O)=O.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1
Reactant: COc1ccc(C)c(-n2cccc2)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1ccc(O)cc1-n1cccc1

Procedure:
A solution of 86.6 g (0.46 mole) of 4-methyl-3-(pyrrol-1-yl)-anisole in 1.5 liters of absolute methylene chloride is cooled to -78° with acetone/dry ice. At this temperature, 231.7 g (0.92 mole) of boron tribromide are added dropwise. Subsequently, the cooling bath is removed and the reaction mixture is heated to from 0° to 5°, then poured into 2 liters of ice/water, and the methylene chloride phase is removed and washed with saturated sodium chloride solution. The aqueous phases are then extracted a further twice with methylene chloride. The organic phases are combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. Distillation of the residue in a high vacuum yields 4-methyl-3-(pyrrol-1-yl)-phenol, b.p. 105°-107°/0.03 torr, Rf (toluene/ethyl acetate=10:1):0.38.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[C:24](Br)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:24]([N:1]([C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1)[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1ccco1
Reactant: O=C(Br)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: N#Cc1c(SCCc2ccccn2)nc(N(C(=O)c2ccccc2)C(=O)c2ccccc2)nc1-c1ccco1
Temperature: 50 °C
Reaction time: 3 h
Yield: 30.3 %

Procedure:
To a stirred solution of 200 mg (0.62 mmol) 2-amino-4-furan-2-yl-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile and 8 mg (0.06 mmol) 4-dimethylaminopyridine in 2 ml pyridine was added dropwise 0.73 ml (6.18 mmol) benzoyl bromide and the reaction mixture stirred at 50° C. for 3 hours. The reaction mixture was then cooled to room temperature and partitioned between water and ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. Chromatography (1/2 ethyl acetate/hexane then 1/1 ethyl acetate/hexane then ethyl acetate) followed by trituration in ether afforded 100 mg (30%) N-benzoyl-N-[5-cyano-4-furan-2-yl-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidin-2-yl]-benzamide as a white crystalline solid. ES-MS m/e (%): 532 (M+H+, 68).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClCCl>[C:1]1([CH2:7][CH2:8][NH:9][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)c1ccccc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)c1ccccc1Br

Procedure:
A mixture of 62.7 ml (500 mmol) of phenylethylamine, 70.4 ml (506 mmol) of triethylamine and 150 ml of dichloromethane was admixed dropwise at 0° C. with a solution of 109.2 g of 2-bromobenzoyl chloride in 50 ml of dichloromethane with good stirring at such a rate that the temperature did not exceed 30° C. Subsequently, the mixture was stirred at room temperature for a further 1 h. The colorless solid thus obtained was filtered off with suction, washed three times with 200 ml of dichloromethane and dried under reduced pressure. The yield at a purity of approx. 99.0% was 138.2 g (453 mmol), 90.7% of theory.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[O:6]1)=[C:2]=[O:3].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[O:23]=[C:15]1[C:14](=[C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]([CH2:4][NH:1][C:2]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:3])[O:6]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1
Reactant: C1CCNCC1
Reactant: O=C=NCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=C1OC(CNC(=O)N2CCCCC2)c2ccccc21
Yield: 24.8 %

Procedure:
A solution of 3-(3-isocyanatomethyl-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (95 mg, 0.31 mmol) and piperidine (92.8 μl, 0.94 mmol) in THF (2.0 ml) was stirred at room temperature for 4 hours. The reaction was partitioned between EtOAc and water. The organic layer was washed with dilute HCl aqueous solution, water, saturated NaHCO3 aqueous solution, water, brine, dried with anhydrous Na2SO4, and rotary evaporated to a brown film. The brown film was chromatographed through silica gel column (CHCl3 to 4% MeOH/CHCl3 gradient) to produce piperidine-1-carboxylic acid [3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-ylmethyl]-amide as a yellow solid (30 mg, 25%).
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29](OC(N1CCN(CC2C=CC(OCCCN3CCCCC3)=CC=2)CC1)=O)(C)([CH3:31])[CH3:30]>CC(C)=O>[CH:29]([N:26]1[CH2:27][CH2:28][CH:23]([O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:12]3[CH2:11][CH2:10][N:9]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:8])[CH2:14][CH2:13]3)=[CH:17][CH:18]=2)[CH2:24][CH2:25]1)([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Reactant: O=C(c1ccccc1)N1CCN(Cc2ccc(OC3CCNCC3)cc2)CC1
Solvent: CC(C)=O
Product: CC(C)N1CCC(Oc2ccc(CN3CCN(C(=O)c4ccccc4)CC3)cc2)CC1

Procedure:
The title compound (E33) was prepared from 1-phenyl-1-{4-[4-(piperidin-4-yloxy)-benzyl]-piperazin-1-yl}-methanone (E32) and acetone using the method described in Description 1 (D1). MS(ES+) m/e 422 [M+H]+.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[Cl:12][C:13]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:15](=[O:16])[C:14]3[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:13]=3[Cl:12])[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc(Cl)c1Cl

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 2,3-dichlorobenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.91-1.99 (m, 6H), 2.07 (d, 1H), 2.26 (d, J=13 Hz, 2H), 2.35 (s, 2H), 3.44-3.52 (m, 2H), 3.77-3.89 (m, 1H), 4.43 (s, 1H), 7.36-7.42 (m, 2H), 7.63 (dd, J=6, 4 Hz, 1H); MS (APCI/NH3) m/z 325 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2(O)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[CH3:15][S:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2.FC(F)(F)C(O)=O.[Cl-].[NH4+]>ClCCl>[CH:1]1([C:4]2([C:23]3[C:22]4[C:26](=[C:18]([CH2:17][S:16][CH3:15])[CH:19]=[CH:20][CH:21]=4)[NH:25][CH:24]=3)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: OC1(C2CC2)CCc2cc(F)ccc21
Reactant: CSCc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C3(C4CC4)CCc4cc(F)ccc43)c[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
200 mg (0.78 mmol) of the compound from Example 76A with a purity of 75% and 152 mg (0.86 mmol) of the compound from Example 8A were introduced into 3.8 ml of dichloromethane at 0° C., 0.07 ml (0.94 mmol) of trifluoroacetic acid was added, and the mixture was stirred at 0° C. for 4 h. It was diluted with dichloromethane and added to saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 175 mg (64% of theory) of the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:14]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH:12]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc(Cl)cc1
Solvent: CCO
Product: O=C(C=Cc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of benzaldehyde (2 g) in EtOH (40 ml) 3 M NaOH solution (3 eq) and 4-chloroacetophenone (2.91 g) were added. The resulting mixture was stirred at rt for 2 h forming a yellow precipitate. The solid was separated by suction filtration and washed with water. The crude was purified by recrystallisation from methanol to give 1-(4-chlorophenyl)-3-phenylprop-2-en-1-one (4.2 g) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([N+]([O-])=O)[C:6]=1[CH:17]=[CH:18][N:19](C)C)[CH3:2].Cl[Sn]Cl>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[CH:17]=[CH:18][NH:19][C:7]=2[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:22])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C=CN(C)C
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCOC(=O)c1cc(N)cc2[nH]ccc12
Yield: 39.7 %

Procedure:
A mixture of 2-(2-dimethylamino-vinyl)-3,5-dinitro-benzoic acid ethyl ester (11.3 g, 0.037 mol) and SnCl2 (83 g. 0.37 mol) in ethanol was heated at reflux for 4 h. The mixture was concentrated to dryness and the residue was poured into water and basified with sat. Na2CO3 solution to pH 8. The precipitate was filtered off and the filtrate was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water (2×100 mL) and brine (150 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give 6-amino-1H-indole-4-carboxylic acid ethyl ester (B-18) (3 g, 40%). 1H NMR (DMSO-d6) δ 10.76 (br s, 1H), 7.11-7.14 (m, 2H), 6.81-6.82 (m, 1H), 6.67-6.68 (m, 1H), 4.94 (br s, 2H), 4.32-4.25 (q, J=7.2 Hz, 2H), 1.35-1.31 (t, J=7.2, 3 H). ESI-MS 205.0 m/z (MH+).
Reaction SMILES: [CH3:1][C:2]([O:16][Si](C)(C)C)([CH3:15])[C:3]#[C:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=[O:6].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[OH:16][C:2]([CH3:15])([CH3:1])[C:3]#[C:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=1)=[O:6]
Reactant: CC(C)(C#CC(=O)c1ccc(C#N)cc1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)C#CC(=O)c1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 112.6 %

Procedure:
To a stirred solution of 4-(4-methyl-4-(trimethylsilyloxy) pent-2-ynoyl)benzonitrile (1.7 g, 5.00 mmol) in DCM (15 mL) was added PTSA (1.70 g, 8.90 mmol) at RT and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 4-(4-hydroxy-4-methylpent-2-ynoyl)benzonitrile (1.20 g) as a yellow oil.
Reaction SMILES: C(OC([N:11]1[CH2:17][C@@H:16]2[C@@:13]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:14][CH:15]2[CH2:18][F:19])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[C:24]([O:23][C:21]([NH:20][C@@:13]12[CH2:14][CH:15]([CH2:18][F:19])[C@@H:16]1[CH2:17][NH:11][CH2:12]2)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@]12CC(CF)[C@@H]1CN(C(=O)OCc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@]12CNC[C@H]1C(CF)C2

Procedure:
(1S,5R)-3-Benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-6-fluoromethyl-3-azabicyclo[3.2.0]heptane (derived from isomer A) (625 mg, 1.65 mmol) was dissolved in tetrahydrofuran (12 mL). 20% palladium hydroxide-carbon (50% wet) (200 mg) was added, and the mixture was stirred in a hydrogen atmosphere for one hour. The catalyst was removed by filtration, and then the filtrate was concentrated under reduced pressure. A 1 M sodium hydroxide solution was added to the residue under ice-cooling, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 403 mg of the title compound as a colorless syrup.
Reaction SMILES: O(C([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=[CH:9]2)(C)C)O.[OH:19]C(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C)C.OO.Cl(O)(=O)(=O)=O>C(#N)C>[OH:19][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=[CH:9]2
Reactant: CC(C)(OO)c1ccc2cc(C(=O)O)ccc2c1
Reactant: CC(C)(O)c1ccc2cc(C(=O)O)ccc2c1
Agent: OO
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC#N
Product: O=C(O)c1ccc2cc(O)ccc2c1

Procedure:
The thus obtained white microcrystals consisting of 6-(2-hydroperoxy-2-propyl)naphthalene-2-carboxylic acid and 6-(2-hydroxy-2-propyl)naphthalene-2-carboxylic acid were reacted in acetonitrile at 50° C. for 30 minutes in the presence of hydrogen peroxide and perchloric acid. Thus, the two compounds were subjected to acid decomposition to form 6-hydroxynaphthalene-2-carboxylic acid almost quantitatively.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]([CH:25]2[CH2:27][CH2:26]2)O)[N:12]=[N:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[CH2:16]([O:15][C:14]1[N:13]=[N:12][C:11]([CH:23]=[C:25]2[CH2:27][CH2:26]2)=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC(c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)C1CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C(=C1CC1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
(5,6-bis(Benzyloxy)pyridazin-3-yl)(cyclopropyl)methanol (Intermediate 64, 0.34 g, 0.94 mmol) was dissolved in dichloromethane (10.2 ml) and cooled at 0-5° C. under nitrogen atmosphere. Triethylamine (0.474 g, 4.70 mmol) and methanesulfonylchloride (0.162 g, 1.401 mmol) were added to the reaction and it was allowed to stir at room temperature for 3 hours. Upon completion the reaction was quenched by pouring into saturated aqueous sodium bicarbonate solution (25 ml) and the product was extracted into ethyl acetate (2×50 ml). The combined organics were separated, washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude compound was purified by column chromatography (silica, 0-10% ethyl acetate in n-hexane) to afford 3,4-bis(benzyloxy)-6-(cyclopropylidenemethyl)pyridazine (0.18 g, 56% yield).