Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:13][NH2:14])=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](C=O)[CH:16]=1>Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:13][N:14]=[C:19]2[CH:18]=[CH:17][CH:16]=[N:15][CH2:20]2)=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NNc1cc(N2CCCC2)c(Cl)nn1
Reactant: O=Cc1cccnc1
Agent: Cl
Product: Clc1nnc(NN=C2C=CC=NC2)cc1N1CCCC1

Procedure:
3-Chloro-6-hydrazino-4-(pyrrolidin-1-yl)pyridazine (1.0 g, 4.69 mmol) and 3-pyridinecarboxaldehyde (443 ml, 4.69 mmol) were stirred in 0.2M hydrochloric acid (20 ml) for 2 h. The precipitated imine was then collected by filtration and dried (1.06 g, 75%). MS (ES+) 303 [MH]+, 305 [MH]+.
Reaction SMILES: [OH:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>CC(C)=O>[CH2:27]([O:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH:26]=[CH2:25]
Reactant: O=C(N1CCc2cccc(O)c2CC1)C(F)(F)F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
Dissolve 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1 g, 3.9 mmol) in acetone (5 mL) and add powdered potassium carbonate (2.8 g, 20 mmol). Add dropwise a solution of allyl bromide (1.04 mL, 12 mmol) in acetone (3 mL) over 10 min and stir at ambient temperature overnight. Filter solids, wash with acetone and concentrate in vacuo to give the desired intermediate as an off-white solid (1.15 g, 98%). GC-MS m/z: 299 (M+).
Reaction SMILES: O[C:2]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(Nc2ccc(Cl)c(Cl)c2)c2ccccc2n1
Product: Clc1cc(Nc2ccc(Cl)c(Cl)c2)c2ccccc2n1
Yield: 68 %

Procedure:
Prepared using general procedure 3; 2-Hydroxy-4-(3,4-dichlorophenyl)aminoquinoline (1.5 g, 4.9 mmol) and 9.2 mL of POCl3 were heated to 120° C. for 4 h. Isolation afforded 1.075 g of material (3.32 mmol, 68%). 1H NMR (300 MHz, DMSO): 9.61(s, 1H), 8.40(d, 1H, J=8.07 Hz), 7.82(m, 2H), 7.65(m, 3H), 7.45(dd, 1H, J=8.68, 2.63 Hz), 6.87(s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([Cl:10])[N:3]=1.N1C=CC=CC=1.S(Cl)([Cl:19])=O.O>C1(C)C=CC=CC=1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:19])[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Cl)nc(Cl)c1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: ClCc1cc(Cl)nc(Cl)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
5.0 g of 2,6-dichloro-4-pyridinemethanol and 2.5 ml of pyridine were suspended in 10 ml of toluene, and the suspension was cooled in a salt-ice bath. To this, 2.7 ml of thionyl chloride were added dropwise for 1 hour, and subsequently the reacted solution was stirred at 110° C. for 3 hours. After cooling, water was added to the solution, and extraction was conducted using diethyl ether. The organic phase was washed with water, and was dried by adding sodium sulfate. The solvent was removed by evaporation, and the residue was purified by silica gel column chromatography to obtain 5.0 g of 2,6-dichloro-4-chloromethylpyridine.
Reaction SMILES: B(Cl)([C@H]1[C@H](C)C2C(C)(C)C(CC2)C1)[C@H]1[C@H](C)C2C(C)(C)C(CC2)C1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:45])[CH2:40][CH2:41][CH2:42][CH:43]=[CH2:44])=[CH:35][CH:34]=1>CCOCC>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:33]1[CH:38]=[CH:37][C:36]([C@@H:39]([OH:45])[CH2:40][CH2:41][CH2:42][CH:43]=[CH2:44])=[CH:35][CH:34]=1
Reactant: C=CCCCC(=O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Agent: C[C@@H]1C2CCC(C[C@H]1B(Cl)[C@@H]1CC3CCC([C@H]1C)C3(C)C)C2(C)C
Solvent: CCOCC
Product: C=CCCC[C@H](O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(−)DIP-Chloride (2.4 g) was dissolved in dry ether (10 mL) and cooled in an ethanol/CO2 bath. 1-(2′,4′-Dichloro-biphenyl-4-yl)hex-5-en-1-one (1 g) was dissolved in dry ether (5 mL) and added dropwise to the DIP solution. The mixture was allowed to warm to room temperature and stirred for 24 hours. Petrol (50 mL) was added and the organic layer separated. The aqueous was diluted with water and extracted with a further 50 mL petrol. The organics were combined, dried and evaporated to give a thick oil. It was not possible to obtain a pure sample by column chromatography, but no trace of starting material remained, as assessed by thin layer chromatography.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.Cl.NO.[N:40]1C=CC=CC=1.C(O)C>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24]#[N:40])=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2C#N)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 63.6 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.57 g), hydroxylamine hydrochloride (0.13 g), pyridine (0.24 g) and ethanol (20 mL) was heated under reflux for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Acetic anhydride (20 mL) was added to residue, and the mixture was heated under reflux for 2 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy)-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbonitrile as colorless crystals (0.36 g, 62%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 167-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:16](N)[CH2:17][NH2:18].[S]>>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[CH:8]([C:9]1[NH:18][CH2:17][CH2:16][N:10]=1)[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: N#CC(c1ccc(Cl)cc1)c1nccs1
Reactant: NCCN
Agent: [S]
Product: Clc1ccc(C(C2=NCCN2)c2nccs2)cc1

Procedure:
Under a nitrogen atmosphere, heat (110°-115° C), under reflux conditions, a mixture containing 23.5 g. of α-p-chlorphenyl-2-thiazolylacetonitrile, 7 g. of ethylene diamine and 0.2 g. of sulphur for 3 hrs. Extract the black tarry product with 200 ml. of hot benzene, cool and wash the extract with 50 ml. of water. Treat the benzene extract with a cooled solution of 4 ml. of concentrated hydrochloric acid in 25 ml. of water and separate the dark aqueous phase from the benzene. Basify the water extract with sodium carbonate and extract the precipitated oil with two 100 ml. portions of ether. Dry the ether extract and evaporate the ether to obtain 2-[α-(2-thiazolyl)-p-chlorbenzyl]-imidazoline, a viscous red product which is dissolved in acetonitrile and converted to the maleate salt which melts at 145°-147° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:27]=O)=[CH:9][N:10]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH3:31][NH2:32].[BH4-].[Na+]>CO.O1CCCC1>[C:1]1([C:7]2[C:8]([CH2:27][NH:32][CH3:31])=[CH:9][N:10]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1cn(S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Reaction time: 0.25 h
Yield: 87 %

Procedure:
4,5-Diphenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (202 mg) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL), 40% methylamine methanol solution (0.5 mL) was added at room temperature, and the mixture was stirred for 15 min. To the reaction mixture was added sodium borohydride (22 mg) at room temperature, and the mixture stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, to the residue was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate) to give the title compound as white crystals (yield 181 mg, 87%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:24][CH3:25])[C:9]3[C:14]([CH2:15][N:16]4[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]4)=[CH:13][N:12]=[CH:11][C:10]=3[N:23]=2)=[N:4][O:5][N:6]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:24][CH3:25])[C:9]3[C:14]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:29][CH:26]5[CH2:28][CH2:27]5)[CH2:18][CH2:17]4)=[CH:13][N:12]=[CH:11][C:10]=3[N:23]=2)=[N:4][O:5][N:6]=1
Reactant: NC1CC1
Reactant: CCn1c(-c2nonc2N)nc2cncc(CN3CCC(=O)CC3)c21
Product: CCn1c(-c2nonc2N)nc2cncc(CN3CCC(NC4CC4)CC3)c21

Procedure:
The title compound was prepared from the product of Step 2 and cyclopropylamine using the method of Example 200. MS (ES+) m/e 383 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH2:8][C:6](=[O:7])[CH2:5][C:4]([CH3:10])([CH3:9])[CH:3]=1.[O:11]=O>CC(CC(C)=O)=O.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cr].[Cr].[Cr].[Cr].[Cr].[Cr+6].N1C=CC=CC=1>[O:11]=[C:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][C:6](=[O:7])[CH:8]=[C:2]1[CH3:1]
Reactant: CC1=CC(C)(C)CC(=O)C1
Reactant: O=O
Agent: [Cr+6]
Agent: [Cr]
Solvent: c1ccncc1
Solvent: CC(=O)CC(C)=O
Product: CC1=CC(=O)CC(C)(C)C1=O

Procedure:
3,5 g. of chromium (III) acetylacetonate in 100 ml. of pyridine are treated with 69 g. of β-isophorone. The mixture is gassed with oxygen at 70° C. for 2 hours with intensive stirring and subsequently worked up by distillation. The conversion of β-isophorone used amounts to 49,6 g. corresponding to 72%. Ketoisophorone is obtained in a yield of 41 g. corresponding to 75%.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:21])[N:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[Li+].[Cl-].O1[CH2:29][CH2:28]OCC1>C1(P([Pd-3](Cl)(Cl)(P(C2C=CC=CC=2)C2C=CC=CC=2)[C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].[Cu]I>[CH3:4][C:5]1[C:6]([C:2]2[CH:10]=[C:9]3[C:5]([C:6](=[O:21])[N:7]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=4)[NH:8]3)=[CH:4][CH:3]=2)=[N:7][CH:11]=[CH:28][CH:29]=1
Reactant: O=c1c2ccc(Br)cc2[nH]n1-c1ccc(C(F)(F)F)cc1
Reactant: C1COCCO1
Agent: Cl[Pd-3](Cl)([c-]1cccc1)(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Fe+2]
Product: Cc1cccnc1-c1ccc2c(=O)n(-c3ccc(C(F)(F)F)cc3)[nH]c2c1
Yield: 54 %

Procedure:
The product of Example 1, Step 4 (0.35 g, 1 mmol)), bis(diphenylphosphino) ferrocenyl palladium(II) dichloride 0) (40 mg), CuI (19 mg, 0.1 mmol), LiCl (126 mg, 3 mmol), 3-methyl-2-(tri-nbutylstannyl)pyridine (530 mg, 1.4 mmol) and dioxane (4 mL) were heated at 150° C. for 15 min under microwave irradiation. The resulting mixture was purified by column chromatography (silica; EtAc:hexane 1:2->EtAc) to give 0.2 g (54%) of the title compound as a colourless solid. 1H NMR (360 MHz, DMSO): 2.5 (3H, s), 7.30-7.40 (2H, m), 7.50 (1H, m), 7.78 (1H, d, J 7.7 Hz), 7.85 (1H, d, J 8.0 Hz), 7.90 (2H, d, J 8.5 Hz), 8.19 (2H, d, J 8.5 Hz), 8.53 (1H, d, J 4.6 Hz), 10.8 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([CH2:11][CH2:12][OH:13])[CH:3]=1.[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Na+].BrCCl.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]2[O:10][CH2:14][O:13][CH2:12][CH2:11][C:4]=2[CH:3]=1
Reactant: COc1cc(Br)cc(CCO)c1O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: ClCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Br)cc2c1OCOCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
To a solution of 898 mg of 4-bromo-2-(2-hydroxyethyl)-6-methoxyphenol in 10 ml of DMF there was added 1 g of sodium bistrimethylsilylamide while cooling on ice, and the mixture was stirred at room temperature for 30 minutes. After adding 1 ml of bromochloromethane to the reaction mixture, it was stirred at 80° C. for 20 hours under a nitrogen atmosphere. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (420 mg) as an oil.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH3:18])[C:4]=1[S:19][CH2:20][CH3:21].C1C=C(Cl)C=C(C(OO)=[O:31])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:22][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH3:18])[C:4]=1[S:19]([CH2:20][CH3:21])=[O:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(SCC)c1C
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(=O)CC)c1C

Procedure:
Prepared from product of Example 4 (7.0 g, 20.4 mmol) and MCPBA (4.15 g of an 85% mixture with MCBA, 20.4 mmol) as described above. Recrystallization (ether) afforded the product as a white solid (6.74 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:19][O:20][CH2:21][CH3:22])[N:15]([CH2:16][CH2:17][CH3:18])[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([OH:23])=[CH:6][C:5]=2[N:4]=1.[Cl:24][CH2:25][CH2:26][CH2:27]I.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].ClCCCBr>CN(C=O)C.CO.O.C(N(CC)CC)C>[Cl:24][CH2:25][CH2:26][CH2:27][O:23][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:15]([CH2:16][CH2:17][CH3:18])[C:14]([CH2:19][O:20][CH2:21][CH3:22])=[N:13][C:12]=3[C:3]([NH2:2])=[N:4][C:5]=2[CH:6]=1
Reactant: CCCn1c(COCC)nc2c(N)nc3cc(O)ccc3c21
Reactant: ClCCCI
Agent: Cl
Agent: ClCCCBr
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCCn1c(COCC)nc2c(N)nc3cc(OCCCCl)ccc3c21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol hydrochloride (prepared using a modification on the procedure described in Parts A and B of Example 51, 2.5 g, 7.4 mmol), 1-chloro-3-iodopropane (1.7 g, 8.2 mmol), and potassium carbonate (3.1 g, 22 mmol) in DMF (25 mL) was stirred overnight, then triethylamine (2 mL) was added and the reaction mixture was heated to 70° C. for 8 hours. The mixture was allowed to cool to room temperature and was stirred overnight. The mixture was poured into water (500 mL) and solid sodium hydroxide was added to adjust the mixture to pH 14. The mixture was extracted with chloroform (300 mL followed by 3×75 mL). The organic layers were thrown away and the aqueous layer was adjusted to pH 10 with 10% aqueous hydrochloric acid. A precipitate formed and was isolated by filtration. The solid was subjected to the initial reaction conditions, and this time methanol (25 mL) was added. After 3 hours at room temperature, the reaction mixture was heated at 90° C. and potassium carbonate (1 g) and 1-chloro-3-bromopropane (1 mL) were added. After 3 hours, the reaction mixture was allowed to cool to room temperature, was filtered, and the methanol was removed under reduced pressure. The solution was poured into water (300 mL) and sodium chloride (200 g) was added, causing a precipitate to form within 30 minutes. After 1 hour, the precipitate was filtered, dissolved in a minimal amount of chloroform, and purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-15% CMA in chloroform) to yield 900 mg of 7-(3-chloropropoxy)-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:9]([NH2:12])[C:10]#[CH:11]>C(Cl)Cl>[O:6]=[C:5]([NH:12][CH2:9][C:10]#[CH:11])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: C#CCN
Reactant: O=C1CCCC(=O)O1
Solvent: ClCCl
Product: C#CCNC(=O)CCCC(=O)O
Temperature: 43 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Glutaric anhydride (2.34 g, 0.2 mmol) was dissolved in 100 ml dry DCM in a round bottom flask and degassed with Ar. Propargyl amine (1.4 ml, 20 mmol) was added and the reaction mixture was refluxed at 43° C. for 2 hours and then stirred at room temperature for 2 hours. The solvent was evaporated and the crude product was purified by column chromatography using 95:5 CH2Cl2/MeOH. Yield: 75%. 1H NMR (CDCl3, 200 MHz) δ (ppm): 1.67-1.76 (m, 2H), 2.09-2.26 (m, 4H), 2.38-2.41 (m, 1H), 3.75-3.76 (d, 2H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C:16](=[O:25])[C:17]([Br:24])=[CH:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[CH3:26][Al](C)C.O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C:16](=[O:25])[C@H:17]([Br:24])[C@@H:18]1[CH3:26])[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C(Br)=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)[C@H](Br)[C@H](C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
14.3 mg (0.1 mmol) of CuBr is added at room temperature to 818 mg (2 mmol) of 17β-acetoxy-2-bromo-5α-androst-1-en-3-one (produced according to J. Org. Chem. 1982, 47, 5090; from 17β-acetoxy-2-brom-5α-androst-1-en-3-one) in 4 ml of ethyl acetate. 1.9 ml (2.2 mmol) of a 10% solution of trimethyl aluminum in toluene is instilled at room temperature. It is stirred at room temperature for 45 minutes. For hydrolysis, 0.18 ml of water is added, the solid is suctioned off and washed again with ethyl acetate. The solution is concentrated by evaporation and the residue is chromatographed on silica gel with hexane/ethyl acetate as eluent. After concentration by evaporation of the chromatography fractions, 600 mg of 17β-acetoxy-2α-bromo-1α-methyl-5α-androstan-3-one is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:33]=[CH:32][C:20]3[CH2:21][CH2:22][N:23](C(=O)C(F)(F)F)[CH2:24][CH2:25][C:19]=3[CH:18]=2)[C:11](=[O:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:33]=[CH:32][C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:19]=3[CH:18]=2)[C:11](=[O:34])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N1CCc2ccc(CCn3ccc(OCc4ccccc4)cc3=O)cc2CC1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=c1cc(OCc2ccccc2)ccn1CCc1ccc2c(c1)CCNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 200 mg (0.43 mmol) 4-benzyloxy-1-{2-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-ethyl}-1H-pyridin-2-one (example 23.1) in 5.0 mL MeOH is added 0.85 mL (0.85 mmol) aqueous 1 M sodium hydroxide solution. The reaction mixture is stirred 2 h at RT. The solvent is evaporated, the residue is taken up in water and is extracted twice with DCM/MeOH. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:47])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[C:37]([CH2:38][O:39]C3CCCCO3)=[CH:36][N:35]=[N:34]2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:39][CH2:38][C:37]1[N:33]([C:29]2[CH:28]=[C:27]([C:26]3[CH2:25][C:24](=[O:47])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:21])([F:20])[F:22])[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[N:34]=[N:35][CH:36]=1
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-(isopropyl-methyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M106) (0.50 g, 0.74 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (156 mg, 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]>C(O)C>[F:12][C:13]1[CH:20]=[CH:19][C:16](/[CH:17]=[N:1]/[C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: COC(=O)c1ccc(/N=C/c2ccc(F)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A mixture of methyl 4-aminobenzoate (4.57 g, 30.2 mmol) and 4-fluoro-3-nitrobenzaldehyde (5.00 g, 29.6 mmol) in ethanol (30 mL) was stirred at room temperature for 16 hours (precipitates formed within 30 min). The solid product was collected by filtration and the trace amount of solvent was removed under vacuum. 8.32 g (83%) of (E)-methyl 4-(4-fluoro-3-nitrobenzylideneamino)benzoate was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Reactant: Oc1cnc(-c2ccc(Cl)cc2)nc1
Product: CCOC(=O)C1(COc2cnc(-c3ccc(Cl)cc3)nc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 2-(4-chloro-phenyl)-pyrimidin-5-ol (Preparation 27) and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (110 mg, 45.2%)