Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccccn1
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccccc1-c1ccccn1
Temperature: 25 °C

Procedure:
A mixture of 2-bromopyridine (6.37 g, 35 mmol), 2-fluorobenzeneboronic acid (6.86 g, 49 mmol) and 2 M sodium carbonate solution (35 mL, 70 mmol) in THF (70 mL) was degassed with nitrogen for 20 min. Tetrakis(triphenyl-phosphine)palladium(0) (1.21 g, 1.1 mmol) was added, and the mixture was stirred at reflux under nitrogen for 36 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate and sodium carbonate. The organic phase was washed with water and then with saturated sodium hydrogencarbonate solution, was dried over magnesium sulfate and then was absorbed on to silica gel. Purification by flash chromatography on silica gel, eluting with isohexane (+0.5% triethylamine and 0.5% MeOH) on a gradient of diethyl ether (5% to 20%) afforded 2-(2-fluorophenyl)pyridine as a yellow oil which crystallised upon standing (5.5 g, 91%). δH (400 MHz, CDCl3) 7.13-7.19 (1H, m), 7.24-7.28 (2H, m), 7.35-7.41 (1H, m), 7.73-7.81 (2H, m), 7.97 (1H, ddd, J 8, 8 and 2), 8.72-8.74 (1H, m); m/z (ES+) 174 (M++H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:20][C:21]([CH3:37])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29]CC2C=CC=CC=2)[CH3:22])[C:5](=[O:19])[N:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])[CH:7]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:8]([N:6]2[CH:7]=[CH:2][N:3]=[C:4]([NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[OH:29])([CH3:37])[CH3:22])[C:5]2=[O:19])[CH:9]=1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(NC(C)(C)c3ccccc3OCc3ccccc3)c2=O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1ccc(C)c(-n2ccnc(NC(C)(C)c3ccccc3O)c2=O)c1
Temperature: 75 °C
Yield: 100.8 %

Procedure:
To 3-[5-bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoic acid, methyl ester (Example 220a, 2 g) in ethanol (50 mL) was added ammonium formate (3.14 g) and 10% Pd/C (0.378 g) and the reaction heated at 75° C. for 1 h. The reaction was filtered through celite and the filtrate concentrated in vacuo. The reaction mixture was diluted with water (250 mL) and extracted with dichloromethane (250 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the subtitle compound (1.410 g).
Reaction SMILES: [N+:1]([C:4]1[C:5](N)=[C:6]([Cl:13])[C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH:12]=1)([O-:3])=[O:2].N(OS(=O)(=O)O)=O.CCOC(C)=O>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:5]=[C:6]([Cl:13])[C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH:12]=1)([O-:3])=[O:2]
Reactant: Nc1c([N+](=O)[O-])cc2ncsc2c1Cl
Agent: O=NOS(=O)(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Cl)c2scnc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.5 %

Procedure:
To a solution of 5-nitro-6-amino-7-chlorobenzothiazole (0.21 g, 0.91 mmol) in 4 mL of sulfuric acid was added nitrososulfuric acid (0.20 g, 1.6 mmol) in a portion. The resulting reaction mixture was stirred for 12 h at 25° C. It was then cooled to 0° C. and 0.3 mL of H3 PO2 was added into the mixture. Reaction mixture was stirred for another 12 h at 25° C. and for 2 h at 50° C., poured into EtOAc and washed with aq. NaHCO3. Organic layer was dried over Na2SO4 and concentrated in vacuo to provide an oil, which was purified on column chromatography (EtOAc, neat) to produce the desired product (0.12 g, 0.56 mmol, 62%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH:9](O)[CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][N:21]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12].CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[F:30][C:28]([F:29])([F:31])[CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH2:16][CH2:15][N:14]([S:11](/[CH:10]=[CH:9]/[CH2:8][CH2:7][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)(=[O:13])=[O:12])[CH2:19][CH2:18]2)=[N:21][CH:22]=1
Reactant: O=S(=O)(CC(O)CCc1ncccn1)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(/C=C/CCc1ncccn1)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
To a stirred solution of the 4-pyrimidin-2-yl-1-({4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazin-1-yl}sulfonyl)butan-2-ol (13.7 g, 28.8 mmol) in DCM (250 mL) at 0° C. was added methanesulfonyl chloride (2.68 mL, 34.6 mmol). The reaction was stirred at 0° C. for 20 minutes before dropwise addition of triethylamine (18.1 mL, 129 mmol). Warmed to room temperature and stirred for 16 hours. The reaction mixture was then diluted with DCM (1 L), washed with water (150 mL) and dried (brine, MgSO4), filtered and concentrated in vacuo. The residue was then purified by flash chromatography (silica, 0-5% MeOH in DCM) to give 2-[(3E)-4-({4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazin-1-yl}sulfonyl)but-3-en-1-yl]pyrimidine as a yellow solid (11.9 g, 18.6 mmol, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][CH:24]=[O:25])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[CH2:26](O)[CH2:27][OH:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:27]1[O:28][CH:24]([CH2:23][S:22][C:11]2[S:12][C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)[O:25][CH2:26]1
Reactant: OCCO
Reactant: COc1ccc(-c2nc(SCC=O)sc2-c2ccc(OC)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2nc(SCC3OCCO3)sc2-c2ccc(OC)cc2)cc1

Procedure:
0.2 g of 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]acetaldehyde are dissolved in 50 ml of toluene. While stirring vigorously, 1 ml of ethylene glycol and then 0.2 g of p-toluenesulphonic acid are added. The mixture is heated for 40 hours in a water separator, cooled to 20°, filtered with suction, crystallised from hexane/benzene and dried under reduced pressure to constant weight. 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]acetaldehyde-ethyleneacetal is obtained in the form of a viscous oil.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:13]=1[NH2:14])([CH3:11])[CH3:10].O>CN(C=O)C>[Br:8][C:17]1[CH:18]=[C:12]([CH:9]([CH3:11])[CH3:10])[C:13]([NH2:14])=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc(Br)cc(C(C)C)c1N
Temperature: 2.5 °C
Yield: 100 %

Procedure:
A solution of NBS (24.59 g, 137 mmol) in DMF (160 mL) was added slowly to a solution of 2,6-diisopropylaniline (25 g, 137 mmol) in DMF (300 mL) at 0-5° C. under a nitrogen atmosphere over a period of 20 minutes. The reaction mixture was stirred at 0-5° C. After the reaction was complete, water was added and the oil suspension was stirred at rt. The aqueous layer was decanted out and the remaining oil was dissolved in ethyl acetate. The organic layer was separated, washed water and brine. Evaporation gave light brown oil (35.1 g, 100% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[BH4-].[Na+].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CO.CCOCC.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][O:8][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22])[O:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cc(Br)co1
Agent: [BH4-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)co1
Yield: 89 %

Procedure:
To a solution of 4-bromo-2-furaldehyde (5.0 g, 29 mmol) in methanol (40 ml) was added sodium borohydride (1.1 g, 29 mmol) at 0° C. with stirring, and the resulting mixture was stirred for 1 hour. After evaporating the reaction mixture in vacuo, the residue obtained was diluted with ether, poured into water and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained in N,N-dimethylformamide (30 ml) were added successively imidazole (3.9 g, 57 mmol) and t-butyldimethylchlorosilane (4.7 g, 31 mmol) with stirring, and the resulting mixture was stirred for 4 hours. After stirring, the reaction mixture was poured into water (50 ml) to quench the reaction and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:97) as the eluent to afford the title compound (7.4 g) in a yield of 89% as a colourless oily product.
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C@H:6]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5]1)(O)=[O:2].Cl.[CH3:30][NH:31][CH3:32].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl.O.C(N(CC)CC)C>[CH2:14]([O:13][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([C:1](=[O:2])[N:31]([CH3:32])[CH3:30])[CH2:5][C@H:6]1[NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)O)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1S,2R,4S)-4-Carboxy-N1-benzyloxycarbonyl-N2-(tert-butoxycarbonyl)-1,2-cyclohexanediamine was dissolved in dichloromethane (50 ml), and dimethylamine hydrochloride (240 mg), triethylamine (0.41 ml), 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (420 mg) and 1-hydroxybenzotriazole monohydrate (340 mg) were added to stir the mixture at room temperature for 1 hour. Dimethylamine hydrochloride (480 mg) and triethylamine (0.82 ml) were additionally added to the reaction mixture to stir the mixture at room temperature for additional 18 hours. The reaction mixture was poured into water to separate an organic layer. After the organic layer was washed with 1N hydrochloric acid and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:methylene chloride=3:47→2:23) to obtain the title compound (620 mg) as a colorless foamy substance.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[CH:8]=[C:9]2[C:14]=1[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]2[CH2:18][CH:19]([CH3:21])[CH3:20].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH3:33][S:34]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[CH:8]=[C:9]2[C:14]=1[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]2[CH2:18][CH:19]([CH3:21])[CH3:20])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)n(Cc3cccc4ccccc34)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCOS(C)(=O)=O)n(Cc3cccc4ccccc34)cc21
Reaction time: 8 h

Procedure:
5-[(3-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (J. Med. Chem., 1995, 38, 2557) (260 mg), methanesulphonyl chloride (54 μl) and triethylamine (97 μl ) were dissolved in dichloromethane (15 ml) and the mixture was stirred overnight. The reaction mixture was poured onto sodium bicarbonate (aqueous) and extracted twice with ethyl acetate. The extracts were combined, dried, filtered and evaporated to give the subtitle compound as a gum (391 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:10]1([N:13]2[C:21]3[C:16](=[CH:17][C:18]([CH2:22][NH:23][S:24]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:19][CH:20]=3)[CH:15]=[N:14]2)[CH2:12][CH2:11]1>>[CH:10]1([N:13]2[C:21]3[C:16](=[CH:17][C:18]([CH2:22][N:23]([C:3]4[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=4)[S:24]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:19][CH:20]=3)[CH:15]=[N:14]2)[CH2:12][CH2:11]1
Reactant: Fc1ncc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C3CC3)c2)cc1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C3CC3)c2)c2ncc(Cl)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and methyl 4-(N-((1-cyclopropyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-5 of Example 28).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])(OCC)=O>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCCN1C(=O)c2ccccc2C1=O
Temperature: 52.5 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
5.41 g (28.74 mmol) of N-(tert-butoxycarbonyl)-1,4-diaminobutane was dissolved in 100 ml of 1,4-dioxane and 4.86 g (28.74 mmol) of N-carboethoxyphthalimide was added thereto. The mixture was heated at 45 to 60° C. and stirred for 4 hours. After the reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added thereto and the resulting solution was extracted with ethyl acetate. The extract was washed with brine and dried (Na2SO4). The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=200:1 (v/v)) to obtain 5.40 g (16.96 mmol) of N-[4-(tert-butoxycarbonylamino)butyl]phthalimide as a white solid. Its spectroscopic data are as follows:
Reaction SMILES: C(OC(=O)[N:7]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[C:10]([O:25][CH3:26])[N:9]=1)(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[C:10]([O:25][CH3:26])[N:9]=2)=[CH:33][CH:32]=1
Reactant: COc1nc(N(Cc2ccc(Cl)cc2)C(=O)OC(C)(C)C)ccc1C(O)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1nc(NCc2ccc(Cl)cc2)ccc1Cc1c[nH]c2ncccc12

Procedure:
To (4-Chloro-benzyl)-5-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-6-methoxy-pyridin-2-yl-carbamic acid tert-butyl ester (68, 40.0 mg, 0.081 mmol) in acetonitrile (10.0 mL) were added trifluoroacetic acid (0.30 mL, 0.0039 mol) and triethylsilane (0.60 mL, 0.0038 mol). The reaction was heated to reflux for 3 hours. The reaction was concentrated to remove the solvents, then purified with silica gel column chromatography eluting with 40% ethyl acetate in hexane to give compound (P-0081, 10 mg, 32.7%). MS (ESI) [M+H+]+=379.4.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([N:19]1[CH2:24][CH2:23][C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21][CH2:20]1)C1C=CC=CC=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH2:4]([O:3][C:1]([N:19]1[CH2:20][CH2:21][C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:23][CH2:24]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1ccc(CN2CCC(c3ccccc3)(N3CCCC3)CC2)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CCC(c2ccccc2)(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
60 g (3.5 eq) Cbz chloride were added dropwise to a solution of 33 g (1 eq) 1-benzyl-4-phenyl-4-(pyrrolidin-1-yl)piperidine in 330 ml chloroform over a period of 10 min and the reaction mixture obtained was stirred for 30 min at room temperature. The reaction course was monitored by thin-layer chromatography (ethyl acetate). Once the conversion was complete, the solvent was distilled off completely and the residue adjusted to a pH of ˜6 with 10% HCl solution and washed 3 times with 100 ml EtOAc. In an ice bath the aqueous solution was adjusted to a pH of ˜9 with NaOH solution and then extracted 3 times with 100 ml chloroform. The combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 20% EtOAc/heptane). 11 g (29%) of product were obtained in the form of a yellow solid.
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[CH3:14][C:15]1([CH3:22])[CH2:20][CH2:19][CH2:18][CH:17]([NH2:21])[CH2:16]1>CC(C)=O>[CH3:14][C:15]1([CH3:22])[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:11]([NH2:12])=[S:10])[CH2:16]1
Reactant: N#C[S-]
Reactant: CC1(C)CCCC(N)C1
Agent: [NH4+]
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Product: CC1(C)CCCC(NC(N)=S)C1
Temperature: 0 °C

Procedure:
59 g (0.42 mol) of benzoyl chloride were added dropwise over the course of 10 minutes to a solution of 33 g (0.44 mol) of ammonium thiocyanate in 100 ml of absolute acetone. The mixture was refluxed for 10 minutes and then 50.8 g (0.40 mol) of 3,3-dimethylcyclohexylamine were added dropwise, and the mixture was refluxed for a further 20 minutes and then stirred into 500 ml of ice-water. The precipitated solid was filtered off with suction, washed with water, dissolved in a hot mixture of 500 ml of 10% strength sodium hydroxide solution and 125 ml of ethanol and refluxed for 30 minutes. The reaction mixture was then diluted with ice-water, and the pH was initially adjusted to 1 with concentrated hydrochloric acid and then to 9 with solid sodium bicarbonate. The resulting precipitate was filtered off with suction, washed with water and dried at 80° C. under reduced pressure.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:15]=[C:14]([C:16]#[C:17][C@@H:18]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1>CO.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:15]=[C:14]([CH2:16][CH2:17][C@@H:18]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C#Cc1cc(-c2ccc3cnccc3c2)no1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CCc1cc(-c2ccc3cnccc3c2)no1)Cc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl(S)-4-(3-(isoquinolin-6-yl)isoxazol-5-yl)-1-phenylbut-3-yn-2-ylcarbamate (0.089 g, 0.20 mmol) in 10 mL of MeOH was added 10% palladium on carbon (0.089 g). Hydrogen was bubbled through the reaction mixture for 5 minutes. The reaction was kept under a balloon atmosphere of hydrogen for 2 hours. The reaction mixture was then filtered through Celite and concentrated under reduced pressure. The obtained tert-butyl(R)-4-(3-(isoquinolin-6-yl)isoxazol-5-yl)-1-phenylbutan-2-ylcarbamate was used without any purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.F[C:13]1[CH:27]=[CH:26][C:16]([CH2:17][N:18]2[CH2:23][CH2:22]O[CH:20]([CH2:24][NH2:25])[CH2:19]2)=[CH:15][CH:14]=1>>[CH2:17]([N:18]1[CH2:23][CH2:22][CH:24]([NH:25][C:4]2[C:5]([C:6]([NH:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=3)=[O:7])=[CH:10][CH:11]=[CH:2][N:3]=2)[CH2:20][CH2:19]1)[C:16]1[CH:26]=[CH:27][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Product: COC(=O)c1ccc(NC(=O)c2cccnc2NC2CCN(Cc3ccccc3)CC2)nc1
Yield: 28.6 %

Procedure:
The title compound was prepared in the same manner as in Example 32, with the exception that methyl 6-aminonicotinate, instead of 4-(4-fluorobenzyl)morpholin-2-ylmethylamine, was used in the same molar amount (Total yield: 28.6%). 1H NMR (CDCl3) δ 8.92 (s, 1H), 8.63 (s, 1H), 8.35 (s, 1H), 8.29 (d, 1H), 8.18 (d, 1H), 7.78 (d, 1H), 7.35 (m, 5H), 6.53 (m, 1H), 4.13 (m, 1H), 3.97 (s, 3H), 3.56 (s, 2H), 2.86 (d, 2H), 2.28 (t, 2H), 2.09 (d, 2H), 1.65 (m, 2H) ppm.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(O)C.O.Cl>O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCCCCCCCCCc2ccccc2)cc1

Procedure:
A mixture of 7.0 g. of ethyl p-[(10-phenyldecyl)amino]benzoate (prepared as described in Example 28), 7 g. of potassium hydroxide and 100 ml. of ethanol-water (9:1) is refluxed for 3.5 hours. The mixture is acidified while hot with concentrated hydrochloric acid, diluted with water, cooled and filtered to give white crystals, m.p. 80°-87° C. Recrystallization from ethanol gives white crystals m.p. 96°-98° C.
Reaction SMILES: [OH-].[Na+:2].[O:3]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([NH:17][C:18](=[O:32])[C:19]3[CH:24]=[C:23]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=[CH:21][C:20]=3[OH:31])[CH:9]=2)=[CH:4]1>C(O)C>[O:3]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([O-:14])=[O:13])=[C:10]([NH:17][C:18](=[O:32])[C:19]3[CH:24]=[C:23]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=[CH:21][C:20]=3[OH:31])[CH:9]=2)=[CH:4]1.[Na+:2]
Reactant: O=C(Nc1cc(-c2ccoc2)ccc1C(=O)O)c1cc(-c2cccnc2)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1cc(-c2ccoc2)ccc1C(=O)[O-])c1cc(-c2cccnc2)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethanol (1.5 mL) and a 1 mol/L aqueous solution of sodium hydroxide (0.19 mL) were added to the obtained 4-(furan-3-yl)-2-(2-hydroxy-5-(pyridin-3-yl)benzamido)benzoic acid (0.081 g), followed by stirring at room temperature for 1 hour. The solid substance was collected by filtration to obtain 0.048 g of sodium 4-(furan-3-yl)-2-(2-hydroxy-5-(pyridin-3-yl)benzamido)benzoate as a white solid.