Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:19][CH:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9]1.[NH2:25][OH:26].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:19][CH:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH:13]=[N:25][OH:26])=[CH:9]1
Reactant: CC(=O)NCC1CC(c2ccc(-n3ccc(C=O)c3)c(F)c2)=NO1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)NCC1CC(c2ccc(-n3ccc(C=NO)c3)c(F)c2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
(-)-5-Acetamidomethyl-3-(3-fluoro-4-(3-formylpyrrol-1-yl)phenyl)isoxazoline (Example 15) (329 mg) is suspended in 4 ml 95% ethanol in a 50 ml one neck round bottom flask under nitrogen. The suspension is treated with hydroxylamine (80 mg) followed by sodium hydroxide (60 mg) and 0.4 ml water. The reaction is stirred 1 hour at room temperature, the pH is adjusted to 7 with 5% hydrochloric acid, and the white solid is collected. The solid is collected, washed with water, and is dried to give 300 mg (87%) of the title compound as a white solid. The title compound is obtained via chromatography over silica gel (230-400 mesh), eluting with 5% methanol/dichloromethane, mp 216-217° C., [α]25D -67° (c 0.67, DMSO).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:30]5[CH:29]=[CH:28][N:27]=[C:26]([O:25][CH3:24])[CH:31]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: COc1cc(B(O)O)ccn1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)ccc2C)ccn1
Yield: 34.9 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (95 mg, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 2-methoxypyridin-4-ylboronic acid (66 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (33 mg, 0.03 mmol), and 2 M sodium carbonate (0.45 mL, 0.9 mmol). The reaction mixture was irradiated in the microwave at 120° C. for twenty minutes. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography eluting with (0-50% ethyl acetate/hexanes) to yield the product (42 mg, 34%). ESI-MS m/z calc. 401.17. found 402.5 (M+1)+. Retention time 1.88 minutes.
Reaction SMILES: [N:1]([CH2:4][C:5]([CH2:9][N:10]=[N+:11]=[N-:12])([CH3:8])[CH2:6][OH:7])=[N+:2]=[N-:3].[CH3:13]I>O1CCOCC1>[CH3:13][O:7][CH2:6][C:5]([CH2:4][N:1]=[N+:2]=[N-:3])([CH2:9][N:10]=[N+:11]=[N-:12])[CH3:8]
Reactant: CC(CO)(CN=[N+]=[N-])CN=[N+]=[N-]
Reactant: CI
Solvent: C1COCCO1
Product: COCC(C)(CN=[N+]=[N-])CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.3 g (43 mmol) of compound 1 were dissolved in 50 ml of dioxane, and 7.2 g of potassium tert.-butylate were added. 6.71 g (47 mmol) of methyl iodide, dissolved in 20 ml of dioxane, were added dropwise to the mixture. After stirring at room temperature for 3 hours, the reaction batch was concentrated in vacuo. The resultant syrup was purified by chromatography over 70 g of silica gel (eluent: hexane/diisopropyl ether 5:1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10](#[N:13])[CH:11]=[CH2:12].N12CCN(CC1)CC2>[OH-].[Na+]>[O:1]1[C:2]2[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:11]([C:10]#[N:13])[CH2:12]1
Reactant: O=Cc1ccccc1O
Reactant: C=CC#N
Agent: C1CN2CCN1CC2
Agent: [Na+]
Agent: [OH-]
Product: N#CC1=Cc2ccccc2OC1
Temperature: 90 °C

Procedure:
A microwave vessel was charged with 2-hydroxybenzaldehyde (Aldrich, 3.0 mL, 28.6 mmol), acrylonitrile (9.4 mL, 143 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.80 g, 7.2 mmol), and heated in a microwave Personal Chemistry at 90° C. for 13 hours. Sodium hydroxide (1N, 200 mL) was added and the mixture was extracted twice with ethyl acetate (200 mL), and the combined organic layer washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with O-to-20% ethyl acetate in hexane providing the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.88 (d, J=1.36 Hz, 2H), 6.90 (d, J=8.14 Hz, 1H), 7.01 (td, J=7.46, 1.01 Hz, 1H), 7.30 (m, 2H), 7.58 (s, 1H). MS (DCI) m/z 175.05 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[OH-].[Na+].[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([CH2:15][CH2:16][CH:17]=[O:18])=[CH:13][CH:12]=1.S(=O)(=O)(O)O>CO>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=[C:16]([CH:17]=[O:18])[CH2:15][C:14]1[CH:19]=[CH:20][C:11]([Cl:10])=[CH:12][CH:13]=1
Reactant: O=CCCc1ccc(Cl)cc1
Reactant: CC(C)(C)CC=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)CC=C(C=O)Cc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
79 g (0.79 mol) of 3,3-dimethylbutyraldehyde are added to a solution of 10.5 g of 50% strength by weight aqueous NaOH in 500 ml of methanol, after which 123 g (0.73 mol) of p-chlorodihydrocinnamaldehyde are added dropwise at 34° C. The mixture is stirred for one hour and then neutralized with dilute sulfuric acid, the solution is evaporated down and the residue is then subjected to fractional distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.Cl.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16].C(N(CC)CC)C>CN(C)C=O>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH:20][C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]2[CH:8]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1cn2nc(Cl)ccc2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
0.593 g of 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid was suspended in 7.5 ml of N,N-dimethylformamide; 0.535 g of N,N′-carbonyldiimidazole and 0.46 g of glycine ethyl ester hydrochloride were added, followed by stirring at room temperature for 30 minutes. To this mixture, 0.457 ml of triethylamine was added, followed by further stirring for 1 hour. Ice water was added to the reaction mixture; the crystal precipitated was collected by filtration, washed with water and dried to yield 0.749 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].Br[CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14].CCN(C(C)C)C(C)C.[I-].[K+]>C(#N)C>[CH2:16]([O:15][C:13](=[O:14])[CH:12]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17]
Reactant: CC(=O)c1ccccc1N
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(Nc1ccccc1C(C)=O)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
1-(2-Aminophenyl)ethanone (250 mg, 1.85 mmol), ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol), DIPEA (0.32 mL, 1.85 mmol) and a catalytic amount of potassium iodide are dissolved in acetonitrile (4 mL) and heated under MW irradiation at 100° C. for 2 hours and then at 120° C. for 1 hour. Acetonitrile is evaporated and the crude is purified by flash chromatography (petroleum ether/EtOAc=93/7) to obtain intermediate I110 as a yellow oil (367 mg, quantitative yield).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[OH-].[Na+].I[CH2:33][CH:34]([OH:37])[CH2:35][OH:36].CCOCC>O>[F:1][C:2]([F:28])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH2:33][CH:34]([OH:37])[CH2:35][OH:36])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: OCC(O)CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 7.34 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphoshoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield the product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][OH:10])[N:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[OH-].[Na+].Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19]>CCOC(C)=O>[Cl:23][C:22]([Cl:25])([Cl:24])[CH2:21][O:20][C:18](=[O:19])[NH:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][OH:10])[N:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1
Reactant: CC(C)(C)c1cc(N)n(CCCO)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCCO)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63.1 %

Procedure:
A solution of Intermediate 35a (0.94 g, 4.76 mmol) in EtOAc (15 mL) was treated with aqueous NaOH (1M, 8.58 mmol), followed by 2,2,2-trichloroethyl chloroformate (0.79 mL, 5.72 mmol) and stirred at RT for 1.5 h. The two layers were separated, and the organic layer was washed with water (2×10 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a white solid (1.12 g, 63%). LCMS (Method 3): Rt 3.72 min, m/z 372/374 [MH+].
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].[F:9][C:10]1([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH2:25][C:24]([C:30]4[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=4)([C:26]([F:29])([F:28])[F:27])[O:23][N:22]=3)=[CH:17][CH:16]=2)[CH2:13][CH:12]([NH2:14])[CH2:11]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:9][C:10]1([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH2:25][C:24]([C:30]4[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=4)([C:26]([F:27])([F:28])[F:29])[O:23][N:22]=3)=[CH:19][CH:20]=2)[CH2:13][CH:12]([NH:14][C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:11]1
Reactant: NC1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: CS(=O)(=O)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CC(=O)NC1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.2 %

Procedure:
2-(methylsulfonyl)acetic acid (22 mg, 0.16 mmol) was added to 3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)cyclobutanamine (Preparation 16, 50.0 mg, 0.10 mmol) in DMF (1.5 mL) along with DIPEA (54 μL, 0.31 mmol) and HATU (61 mg, 0.16 mmol). The mixture is stirred for 3 days at room temperature. The reaction mixture is partitioned between brine (5 mL) and EtOAc (5 mL). The organics are separated, dried over MgSO4, filtered and evaporated to give a residue, which is purified on regular silica eluting from neat DCM to 15% MeOH/DCM to give the title compound (20 mg): 1H NMR (DMSO-d6) δ: 8.83 (1H, d), 7.85 (2H, s), 7.79 (2H, d), 7.58 (2H, d), 4.60-4.51 (1H, m), 4.42-4.30 (2H, m), 4.04 (2H, s), 3.12 (3H, s), 2.96-2.86 (2H, m), 2.65-2.54 (2H, m); m/z (Cl) 602.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]2[N:21]([CH2:22][CH3:23])[C:20](=[O:24])[N:19]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[C:16]2=[N:17][CH:18]=1.[H-].[Na+]>CN(C=O)C.CO>[Cl:12][C:13]1[CH:14]=[C:15]2[N:21]([CH2:22][CH3:23])[C:20](=[O:24])[N:19]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:2]4[N:6]([CH3:7])[C:5]5[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=5[N:3]=4)=[CH:27][CH:26]=3)[C:16]2=[N:17][CH:18]=1
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3C)cc2)c2ncc(Cl)cc21
Temperature: 180 °C
Yield: 79.4 %

Procedure:
2-Chloro-1-methyl-1H-benzimidazole (50 mg) was added to a solution of 6-chloro-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (90 mg) and NaH (13.2 mg) in DMF (2 mL) at room temperature. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 6-chloro-1-ethyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:29]4[CH:30]=[N:25][CH:26]=[N:27][CH:28]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: OB(O)c1cncnc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cncnc1
Yield: 15.2 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and pyrimidine-5-boronic acid (available from Combi-Blocks Inc.; 50 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-pyrimidin-5-yl-benzoic acid (13 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ 13.42 (br s, 1H), 9.21 (s, 1H), 8.86 (s, 2H), 8.58 (s, 1H), 8.50 (s, 1H), 8.29-8.37 (m, 2H), 8.10 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1.[CH2:12]([C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][CH:26]2[CH2:28][O:27]2)=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[Na+].[Cl-]>CN(C=O)C>[N:3]1([CH2:28][CH:26]([OH:27])[CH2:25][O:24][C:23]2[CH:29]=[CH:30][C:20]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:21][CH:22]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: CCCCCCCCc1ccc(OCC2CO2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(OCC(O)Cn2ncc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.048 g (1.20 mmol) sodium hydride as a 60% dispersion in mineral oil is suspended in 10 ml absolute DMF, stirred at room temperature for 10 min and mixed with a solution of 0.135 g (1.14 mmol) indazole. Having stirred for 1 hour, a solution of 0.300 g (1.14 mmol) 2-(4-octylphenoxymethyl)oxirane in 10 ml absolute DMF is added drop-wise. The mixture is stirred for 40 hours, hydrolyzed with a semi-saturated NaCl solution and extracted four times using diethyl ether. The combined organic phases are concentrated to half the volume on the rotary evaporator and washed three times with saturated NaCl solution. Drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave a white solid which is recrystallized from petroleum ether/ethyl acetate (80:20).
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])=[O:4].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH3:29])[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[CH3:29][C:21]1[C:22]([C:3]([C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]=2[O:15][CH3:16])=[O:4])=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=1
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: COC(=O)c1c(OC)ccc2ccccc12
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(OC)ccc3ccccc23)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5B (2.02 g, 10 mmol), 3,4,5-trimethoxytoluene (1.82 g; 10 mmol), P2O5 (10.0 g) and dichloromethane is stirred at room temperature for 16 hours. Subsequently, the dichloromethane is distilled off and the residue is diluted with ethyl acetate. The organic phase is washed with water and concentrated. The residue is purified by column chromatography (petrol ethers:ethyl acetate, 8:2 v/v) and recrystallized from petrol ether: diisopropylether (1:1 v/v). The solid material is collected by vacuum filtration, washed with cold petrol ether: diisopropylether (1:1 v/v) and dried, yielding white crystals, 0.9 g, (24.6%) mp 72° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])[C:25](O)=[O:26]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:30]([F:31])=[C:22]([F:21])[CH:23]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(F)c(F)c1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 3,4-difluorobenzoic acid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:39]>C(O)C>[ClH:39].[F:1][C:2]1[C:3]([CH2:23][NH:24][CH3:25])=[CH:4][N:5]([S:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)N2CCOCC2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)N2CCOCC2)c(-c2cccnc2F)c1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
tert-Butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(morpholin-4-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (370 mg) was dissolved in ethanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 50° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from a mixed solvent of ethyl acetate-ethanol (9:1) to give the title compound as colorless crystals (yield 105 mg, 33%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18]>C(O)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:13])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc(F)cc1C(F)(F)F
Solvent: CC(=O)O
Product: Cc1ccc(C)n1-c1ccc(F)cc1C(F)(F)F
Temperature: 100 °C
Yield: 50.6 %

Procedure:
A mixture of 4-fluoro-2-(trifluoromethyl)aniline (4.4 g, 24.6 mmol), 2,5-hexanedione (2.8 g, 24.5 mmol) and acetic acid (0.28 mL) was heated to 100° C. After 3 h the reaction mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (SiO2), eluting with EtOAc/Hex (0:100 to 10:90) to afford 1-[4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole as a yellow oil (3.19 g, 50%); 1H NMR (CDCl3): δ 7.52 (dd, J=8, 3 Hz, 1H), 7.35 (dt, J=3, 8 Hz, 1H), 7.25 (dd, J=5, 8 Hz, 1H), 5.90 (s, 2H), 1.91 (s, 6H); MS (ESI) m/z 258 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7].[CH2:28]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([CH:35]1[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][C:14]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][N:38]5[CH2:39][CH2:40][CH:35]([CH2:28][C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[CH2:36][CH2:37]5)=[CH:15][CH:16]=4)[CH2:11][C:10]=3[CH:9]=2)=[O:7])[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCCl)ccc1-2
Product: O=C(CCCCN1CCC(Cc2ccccc2)CC1)c1ccc2c(c1)Cc1cc(C(=O)CCCCN3CCC(Cc4ccccc4)CC3)ccc1-2

Procedure:
Following the procedure of Example 7, 20.2g (0.05 mole) of 2,7-bis(5-chlorovaleryl)fluorene, prepared in Example 2, and 70.0g (0.4 mole) of 4-benzylpiperidine were reacted to give the desired product which was recrystallized three times from chloroform-acetone. M.P. 147°-149° C, λmaxEtOH 329, E1cm1% 577.
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C(C)=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36].S>C(O)C>[C:1]1([C:7]2[S:36][C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc(C(=O)CC(C(=O)c2ccccc2)c2ccccc2)cc1
Agent: S
Solvent: CCO
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc1
Yield: 142.8 %

Procedure:
In a 1-liter steel autoclave fitted with a mechanical stirrer, a thermometer and a pressure gauge were placed 32 g (0.09 mole) of 1,2-diphenyl-4-p-methoxyphenylbutane-1,4-dione, 100 ml of xylene, 20 g (0.045 mole) of phosphorus pentasulfide and 130 g of hydrogen sulfide. The mixture was stirred and heated 3 hours at 157°-162° C. (1190-1220 psig). The vessel was cooled and the hydrogen sulfide vented into an aqueous sodium hydroxide trap. The semisolid residue was stirred with 150 ml of absolute ethanol. Filtration gave 23 g (72%) of crude product, m.p. 130°-132° C. and a second crop of 3.7 g (11.6%) m.p. 124°-126° C. The two crops were combined and recrystallized from a mixture of 30 ml of dioxane and 60 ml of absolute ethanol to give 22 g (69%) of pure product m.p. 133°-134° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:20][NH:21][C:22](=[O:29])[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:3]=[C:2]2[N:26]1[CH2:27][CH2:28][CH:23]([C:22]([NH:21][CH3:20])=[O:29])[CH2:24][CH2:25]1
Reactant: CNC(=O)C1CCNCC1
Reactant: Fc1ccc2nc(-c3ccc(Cl)cc3)cc(Cl)c2c1
Product: CNC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccc(F)cc23)CC1

Procedure:
The named compound was made in a manner analogous to that of Example 4(c) using 4-chloro-2-(4-chlorophenyl)-6-fluoroquinoline, prepared as described in Example 4(b), and N-methylisonipecotamide as starting materials. It was obtained as colorless needles, mp 279°-282°dec on recrystallization from pyridine.