Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([C:21]([O:23][CH3:24])=[O:22])([CH3:20])[CH3:19])=[CH:13][CH:12]=1)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:24][O:23][C:21]([C:18]([CH3:20])([CH3:19])[CH2:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][OH:1])=[CH:16][CH:15]=1)=[O:22]
Reactant: COC(=O)C(C)(C)Cc1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)(C)Cc1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of lithium diisopropylamide (0.1 mol/l solution in tetrahydrofuran, 15 ml) was added a solution of 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonylpropyl)benzene (0.62 g) in tetrahydrofuran (2 ml) at -78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a solution of iodomethane (0.20 g) in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of n-hexane and methylene chloride (3:1) as eluent to give 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonyl-2-methylpropyl)benzene (0.49 g) as an oily liquid. To a solution of 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonyl-2-methylpropyl)benzene (0.49 g) in tetrahydrofuran (1.5 ml) was added tetra-n-butylammonium fluoride (1 mol/l solution in tetrahydrofuran, 1.34 ml), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of methylene chloride and diethyl ether (7:1) as eluent to give 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl alcohol (0.300 g) as an oily liquid. To a solution of 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl alcohol (0.300 g) in methylene chloride (3 ml) were added carbon tetrabromide (0.48 g) and triphenylphosphine (0.38 g), and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of n-hexane and methylene chloride (3:1) as eluent to give 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl bromide (0.323 g) as an oily liquid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:15]([CH:16]=O)=[CH:14][CH:13]=[CH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:32]>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[C:24]([CH2:16][C:15]2[C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:23]1[CH3:32]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1cccnc1S(=O)(=O)c1ccccc1
Product: COC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 2-benzenesulfonylpyridine-3-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [NH2:1][NH2:2].C[O:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1>CO>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]([NH:1][NH2:2])=[O:4])=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: NN
Solvent: CO
Product: NNC(=O)Cc1ccc(F)cc1
Temperature: 60 °C

Procedure:
Neat anhydrous hydrazine 20 mL was added to a slurry of (4-fluorophenyl)acetic acid methyl ester (Acros Organics USA, Morris Plains, N.J., 25.66 g, 152.5 mmol) in MeOH (120 mL) and the mixture was heated to 60° C. with reflux condenser under nitrogen for 2 hrs. Cooled to room temperature, evaporated to dryness (room temperature to 60° C., 100 Torr to 7 Torr). The solid residue was re-crystallized from 1-propanol , 100 mL (reflux to room temperature, overnight). The crystallized product was collected by filtration, washed with 1-propanol and dried on high vacuum. [1st fraction]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28](OC)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:32][NH2:33]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([NH:33][CH3:32])=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CN
Reactant: COC(=O)c1ccc2c(n1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Solvent: CCO
Product: CNC(=O)c1ccc2c(n1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Temperature: 60 °C
Reaction time: 22 h
Yield: 91.3 %

Procedure:
In a dried reaction flask, the crude methyl 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxyl ate (prepared according to the step (2) of Example 1) (0.489 g, about 1.1 mmol) was dissolved in ethanol (22 mL). A 27% methylamine in ethanol solution (22.121 g) was added to the mixture. The resulting mixture was stirred at 60° C. for 22 h and filtered to produce a crude yellow solid, which was washed with ethanol to produce a purified product (0.436 g) in 91.3% yield.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c2ccoc12
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=Cc1ccc([N+](=O)[O-])c2ccoc12
Yield: 107.1 %

Procedure:
Add 7-methyl-4-nitrobenzofuran (3.5 g, 19.7 mmol) to tert-butoxybis(dimethylamino)methane (10.3 g, 59.1 mmol), and reflux the mixture under nitrogen for 40 minutes. Concentrate under reduced pressure, dissolve in xylenes (50 mL), concentrate under reduced pressure, and dry under vacuum to obtain 4.9 g (100%) of the title compound as a deep red-brown solid. HRMS (M+H)=233.0928.
Reaction SMILES: [Na].[CH2:2]([OH:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].[CH2:9](Cl)[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18]>C(Cl)Cl>[CH2:2]([OH:8])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: COCCOCCOCCCl
Reactant: OCCOCCO
Agent: [Na]
Solvent: ClCCl
Product: COCCOCCOCCOCCOCCO
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Under argon, 630 mg (27.4 mmol) of sodium are added to 10 ml of diethylene glycol and the mixture is heated for one hour at 100° C. At that temperature, 5 g (27.4 mmol) of 3,6,9-trioxadecyl chloride are added dropwise thereto using a syringe. The mixture is stirred overnight at 100° C. to complete the reaction. After cooling, the reaction solution is taken up in CH2Cl2, washed with water and brine and dried over Na2SO4. Removal of the solvent yields 3,6,9,12,15-pentaoxa-hexadecanol in the form of an oil (Liebigs Ann. Chem. 1980, 858); NMR(CDCl3): 3.8-3.5 (m,20H); 3.75 (s,3H).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].[OH-].[Na+].[CH2:12](I)[CH3:13]>CO.O>[CH2:12]([O:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9])[CH3:13]
Reactant: Cc1occc(=O)c1O
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1c(C)occc1=O
Yield: 71.1 %

Procedure:
3-Hydroxy-2-methyl-4-pyrone (10 g, 79.4 mmol) was dissolved in methanol (10 mL) and sodium hydroxide (3.49 g, 87.3 mmol) in water (8 mL) was added, followed by ethyl iodide (6.97 mL, 87.3 mmol). The reaction mixture was stirred under reflux overnight. The reaction mixture was then partitioned between water (50 mL) and CH2Cl2 (100 mL). The organic phase was washed with sodium hydroxide (5%, aq.), water, dried (MgSO4) and evaporated to give the title product (8.7 g, 71%) as a solid. The crude product was used in the next step without further purification.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=[S:14])[CH3:11].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:10]([O:12][C:13]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([O:33][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[O:32])=[CH:34][CH:35]=1)=[S:14])[CH3:11]
Reactant: CCOC(=S)SCCCCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=S)SCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
p-Hydroxybenzaldehyde (0.37 g, 3.0 mmol), 8 (1.2 g, 3.0 mmol), and DMAP (0.04 g, 0.3 mmol) were dissolved in 300 mL of CH2Cl2. DCC (1.24 g, 6.0 mmol) was added to reaction flask which was stirred at room temperature for three days. The solvent was removed under reduced pressure, and the residue purified using column chromatography (CH2Cl2:EtOH, 10:0.05). The product was then recrystallized from ethanol. Yield 0.3 g (20%). 1HNMR: δH (CDCl3; 300 MHz): 1.24-1.52 (15 H, m, CH2/O—CH2—CH3), 1.69 (2 H, m, S—CH2—CH2), 1.81 (2 H, m, O—CH2—CH2), 3.11 (2 H, t, 3J=7.3 Hz, SCH2), 4.02 (2 H, t, 3J=6.5 Hz, O—CH2), 4.65 (2 H, q, 3J=7.1 Hz, O—CH2—CH3), 6.99 (2 H, d, 3J=8.9 Hz, Ar—H), 7.40 (2 H, d, 3J=8.5 Hz, Ar—H), 7.96 (2 H, d, 3J=8.6 Hz, Ar—H), 8.14 (2 H, d, 3J=8.9 Hz, Ar—H), 10.0 (1 H, s, COH). 13C NMR: δC (CDCl3; 75 MHz): 13.8, 25.9, 28.1, 28.3, 28.8, 29.1, 29.3, 29.4, 35.9, 68.4, 69.7, 114.4, 120.8, 122.6, 131.2, 132.4, 133.9, 155.9.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][O:12][C:11](=[O:14])[CH:10]=2)=[CH:5][CH:4]=1.[I:15]I>N1C=CC=CC=1.CCOCC>[I:15][C:10]1[C:11](=[O:14])[O:12][CH2:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(C2=CC(=O)OC2)cc1
Reactant: II
Solvent: c1ccncc1
Solvent: CCOCC
Product: CSc1ccc(C2=C(I)C(=O)OC2)cc1
Reaction time: 24 h

Procedure:
To a solution of 3 g of the product of Step 2 in 30 ml of pyridine is added 8.7 g of I2. The mixture is stirred for 24 h and then diluted with 200 ml of ether, washed with 100 ml of 5N HCl and 50 ml of 5N Na2S2O3. The ether layer is dried over Na2SO4 and concentrated to give the title compound.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[S:14][C:13]([NH2:15])=[N:12][N:11]=2)=[CH:2]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:24][C:25](O)=[O:26])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C.CN(C=O)C>C1COCC1.[Cl-].[Na+].O.C(OCC)(=O)C.O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[S:14][C:13]([NH:15][C:25](=[O:26])[CH2:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=3)=[N:12][N:11]=2)=[CH:2]1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: Nc1nnc(-c2c[nH]c3ncccc23)s1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cccc(CC(=O)Nc2nnc(-c3c[nH]c4ncccc34)s2)c1
Yield: 21.5 %

Procedure:
A suspension of 5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,3,4-thiadiazol-2-amine (0.050 g, 0.23 mmol), 3-methoxyphenylacetic acid (0.038 g, 0.23 mml), triethylamine (0.1 mL) and BtSO2CH3 (0.055 g, 0.28 mml) in THF (3 mL) and DMF (0.3 mL) was heated in a microwave oven for 20 min. The brown solution was added to water (50 mL) and ethyl acetate (50 mL). Brine (10 ml) was added to separate the layers. The organic phase was separated and washed with water (2×50 mL). The organic layer was concentrated to give a solid which was placed in a small Buchner funnel and washed with methanol (2×5 mL) and ethyl acetate (2×5 mL). The brown solid collected was dried under vacuum to afford the desired product (0.018 g, 21%).
Reaction SMILES: CS(O)(=O)=O.[NH:6]1[CH2:10][CH2:9][N:8]=[C:7]1[NH:11][C:12]1[CH:38]=[CH:37][C:15]([C:16]([O:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:29](=[NH:31])[NH2:30])[CH:25]=3)[C:20]=2[CH2:32][C:33]([O:35]C)=[O:34])=[O:17])=[CH:14][CH:13]=1>>[NH:8]1[CH2:9][CH2:10][N:6]=[C:7]1[NH:11][C:12]1[CH:38]=[CH:37][C:15]([C:16]([O:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:29](=[NH:30])[NH2:31])[CH:25]=3)[C:20]=2[CH2:32][C:33]([OH:35])=[O:34])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)Cc1c(OC(=O)c2ccc(NC3=NCCN3)cc2)ccc2cc(C(=N)N)ccc12
Agent: CS(=O)(=O)O
Product: N=C(N)c1ccc2c(CC(=O)O)c(OC(=O)c3ccc(NC4=NCCN4)cc3)ccc2c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 48.8 %

Procedure:
45 Milliliters of 10% aqueous methanesulfonic acid solution was added to 500 mg of 6-amidino-1-methoxycarbonylmethyl-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoate.dimethanesulfonate, followed by stirring for 5 hours at 80° C. After leaving the mixture for cooling, 350 mg of active carbon was added to the reaction mixture, followed by stirring for 30 minutes at room temperature. Insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. To the residue was added a small amount of water. The solution was added dropwise to a mixed liquid of 150 ml of acetone and 50 ml of ether, followed by stirring for 1 hour under cooling with ice. Then, the precipitate was collected by filtration and washed with a small amount of acetone to obtain 236.1 mg of the desired product.
Reaction SMILES: [CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH:15][C:16]4[N:21]=[CH:20][C:19]([C:22]([O:24]CC)=[O:23])=[CH:18][N:17]=4)=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]12[C:14]3[C:10](=[CH:9][C:8]([NH:15][C:16]4[N:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][N:17]=4)=[CH:7][C:6]=3[CH2:5][CH2:4][CH2:3]1)[CH2:11][CH2:12][CH2:13]2
Reactant: CCOC(=O)c1cnc(Nc2cc3c4c(c2)CCCC4(C)CCC3)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC12CCCc3cc(Nc4ncc(C(=O)O)cn4)cc(c31)CCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
A suspension of ethyl 2-[(5,6,6a,7,8,9-hexahydro-6a-methyl-4H-2-phenalenyl)amino]pyrimidine-5-carboxylate (0.043 g) in ethanol (5 ml) was added with 20% aqueous sodium hydroxide (1 ml), and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was left to cool and then made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethanol-chloroform to obtain the title compound (0.029 g, yield: 74%) as colorless needles (melting point: >300° C.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]2[O:10][CH2:11][O:12][C:7]2=[CH:6][C:3]=1[CH:4]=O.[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].N1CCCCC1.C(O)(=O)C>C(O)C>[CH2:11]1[O:10][C:8]2=[CH:9][C:2]3[O:1][C:13](=[O:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][C:3]=3[CH:6]=[C:7]2[O:12]1
Reactant: O=Cc1cc2c(cc1O)OCO2
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2cc3c(cc2oc1=O)OCO3
Yield: 70.5 %

Procedure:
A mixture of 2-hydoxy-4,5-methylenedioxybenzaldehyde (1.16 g), diethyl malonate (1.34 g), piperidine (0.3 g), acetic acid (0.035 ml) and ethanol (30 ml) was refluxed for 4 hours. After the reaction mixture was cooled, the resulting crystal was collected by filtration to yield ethyl 6,7-methylenedioxy-2-oxo-1-benzopyran-3-carboxylate (1.29 g, 70%) having a melting point of 200°-201° C.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:18]=C(C(O)=O)O[N:15]=1>C1COCC1>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:18]=[C:2]([C:1]([Cl:6])=[O:5])[O:3][N:15]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(-c2ccccc2F)no1
Solvent: C1CCOC1
Product: O=C(Cl)c1cc(-c2ccccc2F)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
Oxalyl chloride (0.07 mL, 0.74 mmol) was added dropwise to a stirred solution of 3-(2-fluorophenyl)isoxazole-5-carboxylic acid (77 mg, 370 μmol) in THF (10 mL). The mixture was stirred at room temperature for 2 hours, then concentrated to yield the title compound (79 mg), which was used without further purification.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:16]=2)[CH:7]=[CH:8][CH:9]=1.[C:31](Cl)(=[O:33])[CH3:32].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[C:31]([N:28]1[CH2:29][CH2:30][CH:25]([C:12]2[S:13][C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:16]=3)=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[N:11]=2)[CH2:26][CH2:27]1)(=[O:33])[CH3:32]
Reactant: CC(=O)Nc1cc(-c2sc(C3CCNCC3)nc2-c2cccc(Cl)c2)ccn1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(-c2sc(C3CCN(C(C)=O)CC3)nc2-c2cccc(Cl)c2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a suspension of N-[4-[4-(3-chlorophenyl)-2-(4-piperidyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide dihydrochloride (0.41 g, 0.84 mmol) in tetrahydrofuran (20 mL) were added acetyl chloride (0.13 mL, 1.8 mmol) and triethylamine (0.50 mL, 3.6 mmol) sequentially, and the resulting mixture was stirred at room temperature for 30 minutes. Aqueous sodium hydrogen carbonate was added to the reaction mixture and extracted with ethyl acetate. The extracts were washed with water, dried, and concentrated. The residue was recrystallized from ethyl acetate-hexane to give a title compound (0.24 g, yield 62%).
Reaction SMILES: [N:1]1([CH2:14][CH2:15][NH:16][C:17](=O)[CH3:18])[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>O.C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH3:18][C:17]1[C:2]2=[CH:3][C:4]3[CH2:5][CH2:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[N:1]2[CH2:14][CH2:15][N:16]=1
Reactant: CC(=O)NCCn1ccc2c1-c1ccccc1CC2
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CC1=NCCn2c1cc1c2-c2ccccc2CC1
Yield: 67 %

Procedure:
N-[2-(4,5-Dihydro-1H-benzo[g]indol-1-yl]ethyl]-acetamide (5.3 g) was stirred with 60 ml of phosphorus oxychloride at room temperature for 1 hour. The reaction mixture was hydrolyzed at 0° C. with 500 ml of 28% sodium hydroxide solution, diluted with 4000 ml of water and extracted three times with 300 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. 2.0 g of a total of 5.0 g of crude product were dissolved in a 30-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 2.3 g (67%) of 5,6,10,11-tetrahydro-8-methyl-benzo[g]pyrazino[1,2-a]indole fumarate (2:3); m.pt.: 181° C. (dec.).
Reaction SMILES: [C:1]1([C:7]2([C:11](Cl)=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][NH2:22])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][NH:22][C:11]([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:10][CH2:9][CH2:8]2)=[O:12])=[CH:18][CH:17]=1
Reactant: O=C(Cl)C1(c2ccccc2)CCC1
Reactant: COc1ccc(CCN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)C2(c3ccccc3)CCC2)cc1
Reaction time: 1 h

Procedure:
A solution of 1-phenylcyclobutanecarbonyl chloride (129 g) in dichloromethane (500 ml) was added under nitrogen over 1.5 hours to a stirred mixture of 4-methoxyphenethylamine (99.5 g), dichloromethane (500 ml) and triethylamine (110 ml). The mixture was stirred at 20°-25° C. for one hour and allowed to stand for 16 hours. The reaction mixture was washed with 2N hydrochloric acid, water and 2N aqueous sodium hydroxide solution, dried and evaporated to give N-[2-(4-methoxyphenyl)ethy]-1-phenylcyclobutane carboxamide.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:20]=[CH:19][N:18]=[C:17]3[C:8]=2[CH:9]=[CH:10][C:11]2[C:16]3=[N:15][CH:14]=[CH:13][C:12]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:3][CH:2]=1>CO.C(Cl)Cl>[C:21]1([C:12]2[C:11]3[C:16](=[C:17]4[C:8](=[CH:9][CH:10]=3)[C:7]([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)=[CH:20][C:19]([C:16]3[CH:17]=[CH:8][CH:9]=[CH:10][C:11]=3[CH3:12])=[N:18]4)[N:15]=[C:14]([C:5]3[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=3[CH3:7])[CH:13]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(-c2ccccc2)c2ccc3c(-c4ccccc4)cc(-c4ccccc4C)nc3c2n1
Yield: 20 %

Procedure:
This yellow compound was prepared in a process analogous to the synthesis of m-TBP. However, the reaction product consisted of mono-substituted and di-substituted bathophenanthroline. O-TBP was obtained after running chromatography in a silica/mixture of methanol/CH2Cl2 (1:1) column as the first eluent in a 20 percent yield. Mono-o-TBP was obtained as the second eluent in a 50 percent yield. 1H NMR (500 MHz, CDCl3), ppm: 7.97 (s, 2H), 7.85 (s, 2H), 7.77 (s, 2H), 7.64-7.59 (m, 4H), 7.95-7.50 (m, 6H), 7.35 (m, 6H), 2.65 (s, 6H). Analysis for o-TBP.⅛CH2Cl2. Found: C, 87.03, H, 5.41, N, 5.23. Calculated: C, 87.51, H, 5.44, N, 5.35.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[C:19]([C:22]([NH:24][CH2:25][C:26]([OH:28])=O)=[O:23])[CH:18]=2)=[CH:13][CH:12]=1.FC1C=CC(C(=O)C)=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:62][C:63]1[C:68]([O:69][CH:70]2[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]2)=[CH:67][CH:66]=[CH:65][N:64]=1>CN(C=O)C.O>[Cl:62][C:63]1[C:68]([O:69][CH:70]2[CH2:75][CH2:74][N:73]([C:26](=[O:28])[CH2:25][NH:24][C:22]([C:19]3[CH:18]=[C:17]([C:14]4[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=4)[O:21][N:20]=3)=[O:23])[CH2:72][CH2:71]2)=[CH:67][CH:66]=[CH:65][N:64]=1
Reactant: Clc1ncccc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccc(F)cc2)on1
Agent: CC(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cccnc2Cl)CC1)c1cc(-c2ccc(F)cc2)on1
Reaction time: 8 h
Yield: 49.6 %

Procedure:
DIPEA (186 mg, 1.43 mmol) was added to a stirred solution of {[5-(4-fluoro-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid (76 mg, 0.29 mmol) (prepared by the method used for the synthesis of Intermediate 26, starting from 4′-fluoroacetophenone) in DMF (2 mL) followed by HOBt (41 mg, 0.3 mmol) and EDCI.HCl (58 mg, 0.3 mmol). After 2 minutes 2-chloro-3-(piperidin-4-yloxy)-pyridine hydrochloride (72 mg, 0.29 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Purification by recrystallisation from 10% ethyl acetate in hexane to afford 66 mg (50% Yield) of 5-(4-fluoro-phenyl)-isoxazole-3-carboxylic acid {2-[4-(2-chloro-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 459, 94.53%. 1H NMR (300 MHz, DMSO-d6): δ 8.65 (s, 1H), 7.98 (m, 3H), 7.72 (m, 1H), 7.38 (m, 4H), 4.8 (m, 1H), 4.2 (d, 2H), 3.7 (m, 2H), 3.4 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).