Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:31]([CH2:40][Cl:41])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+:43].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.ClCCl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:31]([CH2:40][Cl:41])=[N:30][C:25]=3[C:26]([NH2:43])=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [NH4+]
Reactant: ClCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc(CCl)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Chloroperoxybenzoic acid (mCPBA) (1.4 g of 77% pure material, 4.74 mmol) was added over a period of five minutes to a solution of 7-(benzyloxy)-2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (2.0 g, 4.74 mmol) in chloroform (47 mL); the reaction mixture was stirred at ambient temperature for one hour. The reaction solution was partitioned between chloroform (50 mL) and saturated aqueous sodium carbonate (50 mL). The layers were separated and the aqueous layer extracted with chloroform (50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an oil. To the crude N-oxide dissolved in dichloromethane (24 mL) was added ammonium hydroxide (8 mL), and then p-toluenesulfonyl chloride (1.0 g, 3.11 mmol) was added in portions over a period of 2 minutes. The reaction mixture was stirred at ambient temperature for one hour, and then saturated aqueous sodium carbonate (50 mL) and chloroform (50 mL) were added. The aqueous layer was separated and extracted with chloroform (50 mL). The combined organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 2.1 g of crude product as a tan solid. The crude product was purified by column chromatography using a HORIZON HPFC system (an automated, modular high-performance flash purification product available from Biotage, Inc, Charlottesville, Va., USA) using a FLASH 40+M silica cartridge (also available from Biotage, Inc.) (eluting with dichloromethane:methanol in a gradient from 100:0 to 90:10) to provide 1.8 g of 7-(benzyloxy)-2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a tan solid.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[Cl-].[Cl-].[Cl-].[Al+3].[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:4][CH:3]([CH3:5])[CH2:2][C:1]([C:15]1[CH:16]=[CH:17][C:12]([CH3:18])=[CH:13][CH:14]=1)=[O:6]
Reactant: Cc1ccccc1
Reactant: CC(C)CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Add slowly isovaleryl chloride (3.0 g, 24.88 mmol) to an ice-cold stirred solution of aluminum trichloride (4.976 g, 37.32 mmol) in anhydrous toluene (60 mL). Stir the reaction mixture at ambient temperature overnight. Add slowly ice-cold water and extract the mixture twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to give the desired intermediate (4.38 g, 100%) that was used without any further purification. GC-MS m/z: 176 (M+).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([N:17]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:8](=[O:9])[C:3]=12)=[O:7]
Reactant: CC(C)CN
Reactant: O=C1OC(=O)c2c(F)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)CN1C(=O)c2cccc(F)c2C1=O
Temperature: 140 °C

Procedure:
3-Fluoro-N-isobutylphthalimide is prepared as described in Example 2, starting with 3.4 g of 3-fluorophthalic anhydride, 2.0 cm3 of isobutylamine and a catalytic amount of para-toluenesulfonic acid in 20 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 140° C. for 3 hours. After cooling to a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2 kPa). The residue is taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic phase is separated out after settling has taken place, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 4.0 g of 3-fluoro-N-isobutylphthalimide are thus obtained in the form of an off-white powder. (Rf=0.73, thin layer chromatography on silica gel, eluent: dichloromethane).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9]2[C:10](=[O:13])[CH2:11][O:12][C:8]=2[CH:7]=[C:6]([OH:14])[CH:5]=1.[CH2:15](Br)[CH:16]=[C:17]([CH3:19])[CH3:18]>CO>[OH:3][C:4]1[C:9]2[C:10](=[O:13])[CH2:11][O:12][C:8]=2[CH:7]=[C:6]([OH:14])[C:5]=1[CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18].[OH:3][C:4]1[C:9]2[C:10](=[O:13])[CH2:11][O:12][C:8]=2[CH:7]=[C:6]([OH:14])[CH:5]=1
Reactant: CC(C)=CCBr
Agent: O=C1COc2cc(O)cc(O)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=CCc1c(O)cc2c(c1O)C(=O)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
Aqueous sodium hydroxide (20% w/v)) (10 ml) was added to a stirred solution of 4,6-dihydroxy-3-benzofuranone (3 g, 18.1 mmol) in methanol (50 ml), the reaction mixture immediately turned to a brown color. Prenyl bromide (2.1 ml, 18.2 mmol) in methanol (10 ml) was added dropwise to the solution. After stirring for 30 minutes at room temperature, methanol was removed in vacuo, and ethyl acetate (200 ml) was added to the reaction mixture. The aqueous layer was acidified by adding dilute hydrochloric acid (1M, 50 ml). The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product mixture as a yellow foam. Silica gel chromatography eluting with a mixture of ethyl acetate and hexanes (1:2), gave 4,6-dihydroxy-5-prenyl-3-benzofuranone (1.25 g, 29.5%), unreacted 4,6-dihydroxy-3-benzofuranone (0.7 g, 23.3%) and a mixture of unidentified products (1.1 g) (could be a mixture of 4,6-dihydroxy-2-prenyl 3-benzofuranone and 4,6-dihydroxy-2,2-diprenyl-3 -benzofuranone).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1COCC1.CC(C)([O-])C.[K+].F[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>C(OCC)(=O)C>[CH2:1]([O:9][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[C:31]([F:32])([F:34])[F:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CCCCCCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 75 °C
Yield: 99.3 %

Procedure:
1-octanol (315 μL, 2.0 mmol), THF (5 mL), potassium t-butoxide (5 mL, 1M solution in THF), 4-Fluoro-3-trifluoromethylbenzoic acid (417 mg, 2.0 mmol) were mixed and heated at 75° C. for 3-4 hrs. The reaction mixture was then diluted with ethyl acetate and washed with water. The water layer was acidified and extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4 and concentrated to afford the title compound (632 mg, HPLC purity >95%), which was used for next reaction without further purification. HPLC retention time on a C8(2) column (30×3.00 mm, 3μ) was 3.28 min with gradient 50-98% acetonitrile-H2O (0.1% trifluoroacetic acid (TFA)) in 3.5 min as mobile phase.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:18]2[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=2[NH:12][C:11]([CH3:20])=[C:10]1[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=2[N:12]=[C:11]([CH3:20])[C:10]=1[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]
Reactant: CC1=C(C(=O)OC(C)C)C(c2cccc(Cl)c2Cl)C2=C(CCCC2=O)N1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1nc2c(c(-c3cccc(Cl)c3Cl)c1C(=O)OC(C)C)C(=O)CCC2

Procedure:
1.5 g (3.8 mmol) of the compound from Example IV are dissolved in 350 ml of CH2Cl2 and treated with 7.5 g of MnO2. The mixture is kept under reflux for 2 h, solid is filtered off with suction through Celite and the filtrate is concentrated. The residue is purified by MPLC (methylene chloride/ethyl acetate 10+1). After recrystallization, first from ether/petroleum ether and then from isopropanol/petroleum ether, 0.72 g (48% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[O:14])[CH:3]=1.C(NC(C)C)(C)C.Br[CH2:32][C:33]([O:35]C(C)(C)C)=[O:34].O>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][CH2:32][C:33]([OH:35])=[O:34])=[CH:21][CH:22]=2)=[O:14])[CH:3]=1
Reactant: CCOc1nc(C(=O)NCc2ccc(N)cc2)cc(N)c1C#N
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CCOc1nc(C(=O)NCc2ccc(NCC(=O)O)cc2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 115 (63 mg, 0.2 mmol) and N,N-diisopropylamine (40 μL, 0.22 mmol) in 0.5 mL of anhydrous N,N-dimethylformamide, was added tert-butyl bromoacetate (40 μL, 0.3 mmol). The resulting mixture was stirred at room temperature overnight, after which water was added, and the precipitate filtered. The solid was dissolved in 1 mL of trifluoroacetic acid, then stirred at room temperature for an additional hour. The mixture was concentrated, and purified via reverse phase HPLC (0-70% CH3CN in 10 mM aq. ammonium acetate) to give 35 mg (41%, 2 steps) of the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (t, J=7.1 Hz, 3H), 3.46 (s, 2H), 4.30 (d, J=6.1 Hz, 2H), 4.46 (q, J=7.3 Hz, 2H), 6.46 (d, J=8.5 Hz, 2H), 7.02 (d, J=8.3 Hz, 2H), 7.07 (s, 1H), 7.28 (bs, 2H), 8.76 (t, J=6.2 Hz, 1H). MS (ESI+) m/e=370 (M+H)+.
Reaction SMILES: N[CH2:2][C:3](=O)[CH2:4][CH2:5][C:6](O)=O.[CH3:10][O:11][C:12](=[O:19])[CH2:13][CH2:14][C:15]([CH2:17][NH2:18])=[O:16]>>[CH2:10]([O:11][C:12](=[O:19])[CH2:13][CH2:14][C:15]([CH2:17][NH2:18])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)CCC(=O)CN
Reactant: NCC(=O)CCC(=O)O
Product: CCCCCCOC(=O)CCC(=O)CN

Procedure:
5-aminolevulinic acid (ALA) and 5-aminolevulinic acid methyl ester (ALA-Me) were purchased from Sigma. St. Louis, Mo. 5-aminolevulinic acid hexyl ester (ALA-Hex) was obtained from PhotoCure AS (Oslo, Norway).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[S:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[S:22]([NH2:25])(=[O:24])=[O:23])(=[O:13])=[O:12])\[CH3:10])=[CH:4][CH:3]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[S:22]([NH2:25])(=[O:24])=[O:23])(=[O:12])=[O:13])[CH3:10])=[CH:4][CH:3]=1
Reactant: C/C(=C\c1ccc(Cl)cc1)S(=O)(=O)Nc1cc(F)ccc1S(N)(=O)=O
Solvent: CCOC(C)=O
Product: CC(Cc1ccc(Cl)cc1)S(=O)(=O)Nc1cc(F)ccc1S(N)(=O)=O
Yield: 41 %

Procedure:
2-[[(E)-1-(4-Chlorophenyl)prop-1-en-2-yl]sulfonylamino]-4-fluoro-benzenesulfonamide (60 mg, 0.15 mmol) was dissolved in ethyl acetate (3 mL) and mixture was subjected to reduction using the H-cube instrument. The reaction mixture was eluted through the Pd/C (10%) cartridge using full hydrogen (1 atm) at 1 ml/min. The mixture was subjected to the H-cube once again using the same conditions. The crude product was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (25 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[CH3:13][CH:14]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH3:15]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:13])[CH:9]=[CH:10][C:3]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A flask was charged with 4-chloro-1H-pyrrolo[2,3-b]pyridine (6.0 g, 39 mmol, Arkpharm) and THF (100 mL). The mixture was cooled to about 0° C. and 60 wt % NaH (1.89 g, 47.2 mmol) was added portion-wise. The mixture was warmed to rt and after about 45 min. TIPSCl (12.5 mL, 59.0 mmol) was added drop-wise and mixture was allowed to stir overnight at rt. The mixture was quenched with water (100 mL) and extracted with EtOAc (200 mL). The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography with a gradient of 0 to 10% EtOAc/heptane to give 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (11.0 g, 91%): 1H NMR (d-DMSO) δ 8.20 (d, J=5.17 Hz, 1H), 7.59 (d, J=3.55 Hz, 1H), 7.23 (d, J=5.16 Hz, 1H), 6.68 (d, J=3.50 Hz, 1H), 1.83 (m, 3H), 1.06 (m, 18H).
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].[C:13](=O)(OC)OC.C(P(CCCC)CCCC)CCC>>[CH3:13][O:3][C:2]1[C:1]([O:11][CH3:12])=[CH:10][C:6]([CH2:7][CH:8]=[CH2:9])=[CH:5][CH:4]=1
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: COC(=O)OC
Agent: CCCCP(CCCC)CCCC
Product: C=CCc1ccc(OC)c(OC)c1
Yield: 88 %

Procedure:
33 parts of eugenol, 50 parts of dimethyl carbonate and 2 parts of tri-n-butylphosphine are kept for 15 hours at 190° C. Working up takes place as described in Example 24. 31 parts (88% of theory, based on converted eugenol) of eugenol methyl ether of boiling point 69°-70° C./0.13 mbar are obtained. The conversion is virtually quantitative.
Reaction SMILES: C([N:14]1[CH2:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH2:29][C:28]([C:34]4[CH:39]=[C:38]([Cl:40])[C:37]([Cl:41])=[C:36]([Cl:42])[CH:35]=4)([C:30]([F:33])([F:32])[F:31])[O:27][N:26]=3)=[CH:21][C:20]=2[Br:43])([F:18])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>CC#N.C(Cl)Cl>[Br:43][C:20]1[CH:21]=[C:22]([C:25]2[CH2:29][C:28]([C:34]3[CH:39]=[C:38]([Cl:40])[C:37]([Cl:41])=[C:36]([Cl:42])[CH:35]=3)([C:30]([F:33])([F:31])[F:32])[O:27][N:26]=2)[CH:23]=[CH:24][C:19]=1[C:16]1([F:18])[CH2:17][NH:14][CH2:15]1
Reactant: FC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Br)CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CC#N
Product: FC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Br)CNC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
To a solution of 3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)-3-bromophenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Preparation 29, 515 mg, 0.76 mmol) in MeCN/DCM (5:1, 60 mL) at 0° C. was added 1-chloroethyl chloroformate (275 uL, 2.5 mmol). The reaction was heated to reflux for 3 hours then allowed to cool to room temperature while stirring for 18 hours. Next, the reaction mixture was concentrated under vacuum, re-dissolved in anhydrous MeOH (50 mL), and refluxed for 1 hour. The reaction was cooled, concentrated under reduced pressure, and diethyl ether was added to residue. The resulting precipitate was filtered, rinsed with diethyl ether, and air dried to afford the intermediate (365 mg, 87%) as a solid. M/z (Cl) 713 ([M+H]+.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[Br:31][CH:32]([CH2:36][CH2:37][CH2:38]Br)[C:33](Cl)=[O:34].[OH-].[Na+].C(=O)([O-])O.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:23])[CH2:21][N:22]1[CH2:38][CH2:37][CH2:36][CH:32]([Br:31])[C:33]1=[O:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: O=C(Cl)C(Br)CCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CN1CCCC(Br)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
67.7 g (0.2 mol) of glycine benzyl ester tosylate and 61.2 ml (0.44 mol) of triethylamine are dissolved in 200 ml of methylene chloride and added in drops at 0° C. to a solution of 55.7 g (0.2 mol) of 2,5-dibromovaleric acid chloride (Okawara et al. Chem. Pharm. Bull. (1982), (30), 1225) in 200 ml of methylene chloride within 45 minutes, and it is stirred for 18 hours at room temperature. The reaction mixture is now added in drops at 0° C. to a solution of 400 ml of aqueous 32% sodium hydroxide and 2 g of tetrabutylammonium hydrogen carbonate (about 15 minutes), and it is stirred for 30 minutes. Then, the phases are separated, and the aqueous phase is extracted three times with 200 ml of dichloromethane each. The organic phases are dried on sodium sulfate, the solution is evaporated to the dry state and chromatographed on silica gel (methylene chloride). The fractions that contain the product are combined and concentrated by evaporation.
Reaction SMILES: [C:1]([O-])([O-])=O.[Cs+].[Cs+].[C:7]([NH:17][C@H:18]([C:27]([OH:29])=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].CN(C=O)C.CI>CCOC(C)=O>[CH3:1][O:28][C:27](=[O:29])[C@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)[NH:17][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1

Procedure:
A suspension of Cs2CO3 (0.65 g, 2.0 mmol), N-Cbz-L-tyrosine (1.3 g, 4.0 mmol; Bachem) and DMF (40 mL) at ambient temperature was treated with methyl iodide (0.5 mL, 4.0 mmol). After 2.0 h the reaction mixture was diluted with EtOAc and then washed with H2O and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 25% EtOAc/hexanes) gave 6-4 as a white solid.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][C:14]3[C:15]4[N:16]([CH:30]=[CH:31][N:32]=4)[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=4)[C:23]([O:25]C)=[O:24])[CH:19]=3)[CH:10]=[CH:9][CH:8]=1)[CH2:2]2.[OH-].[Na+]>O1CCOCC1.O>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][C:14]3[C:15]4[N:16]([CH:30]=[CH:31][N:32]=4)[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=4)[C:23]([OH:25])=[O:24])[CH:19]=3)[CH:10]=[CH:9][CH:8]=1)[CH2:2]2
Reactant: COC(=O)c1cccc(-c2cc(Nc3cccc(N4CC5CC5C4)n3)c3nccn3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(-c2cc(Nc3cccc(N4CC5CC5C4)n3)c3nccn3n2)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 68.2 %

Procedure:
To a solution of methyl 3-(8-(6-(3-aza-bicyclo[3.1.0]hexan-3-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (70 mg, 0.16 mmol) in dioxane (5 mL) and water (4 mL) was added NaOH (63 mg, 1.6 mmol), then the mixture was heated to 40° C. with stirring for 4 h. The solution was concentrated in vacuo. Water (10 mL) was added to the residue and was washed with dichloromethane (15 mL×3). The aqueous layer was adjusted to pH=4 by the addition of concentrated HCl. The solid formed was collected by filtration to give 3-(8-(6-(3-aza-bicyclo[3.1.0]hexan-3-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (0.045 g, 67%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.88 (s, 1H), 8.92 (s, 1H), 8.54 (s, 1H), 8.31-8.10 (m, 3H), 7.80-7.72 (m, 2H), 7.47 (s, 1H), 6.76 (s, 1H), 6.11 (s, 1H), 3.71-3.54 (m, 4 h), 1.72 (s, 2H), 0.78 (s, 1H), 0.22 (s, 1H). LC-MS: [M+H]+, 413, tR=1.665 min, HPLC: 95.09% at 214 nm, 95% at 254 nm, tR=5.831 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:3][CH2:2]1.[C:28]1([CH:36]=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[C:28]1([CH2:36][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[CH2:11][CH2:12][O:13][C:14]4[CH:20]=[CH:19][C:18]([C:21]5[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=5)=[CH:17][C:15]=4[CH:16]=3)=[O:9])[CH2:5][CH2:6]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCNCC2)CCO3)cc1
Reactant: O=CC1=CCCCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(CC4=CCCCCCC4)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (0.15 g) and cyclooctene-1-carbaldehyde (0.08 g) dissolved in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.12 g) under ice cooling, and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was neutralized with a 1 N aqueous solution of sodium hydroxide, was then concentrated and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent. The residue was subjected to purification using a silica gel column (ethyl acetate) to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/diethyl ether/hexane to obtain N-(1-(cycloocten-1-yl)methylpiperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 57) (0.11 g) as colorless prisms.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(=O)C)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=[C:6]([NH2:8])[CH:7]=1.[Cl-].[NH4+]>[OH-].[Na+]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([S:10]([NH:9][C:4]2[CH:5]=[C:6]([NH2:8])[CH:7]=[C:2]([NH2:1])[CH:3]=2)(=[O:12])=[O:11])=[CH:18][CH:17]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(N)cc(N)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: Nc1ccc(S(=O)(=O)Nc2cc(N)cc(N)c2)cc1
Yield: 54.4 %

Procedure:
0.105 g (0.00033 mol) of N-[4-(3,5-diamino-phenylsulfamoyl)-phenyl]-acetamide was dissolved in 6.5 ml of 1N NaOH and boiled at reflux for 15 hours. The reaction mixture was treated with 50 ml of saturated ammonium chloride solution and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed with saturated sodium chloride solution and dried over MgSO4. After removal of the solvent the residue was chromatographed on aluminium oxide (neutral, activity 1), firstly with 5% and then 10% methanol in dichloromethane. There was obtained 0.05 g (55%) of 4-amino-N-(3,5-diamino-phenyl)benzenesulfonamide as a beige solid; m.p.: 188-190° C.