Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:6]=[O:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
76 g (0.5 mol) of 3-methoxy-4-hydroxybenzaldehyde were placed in a four-necked flask together with 228 g of dimethylformamide and 82.8 g (0.6 mol) of potassium carbonate. 66.4 g (0.525 mol) of benzyl chloride was added dropwise at a temperature of 60° C. for one hour. After the addition, the mixture was stirred at a temperature of 60° C. for five hours. The resulting reaction mixture was washed with 190 g of toluene and 330 g of water. 270 g of the solvent were removed by distillation under reduced pressure of 70 mmHg and then 265 g of n-heptane and 80 g of toluene were added to the distillation residue and the separated crystals were collected by filtration to provide 102.6 g of 3-methoxy-4-benzyloxybenzaldehyde as white crystals in a yield of 84.8%.
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[C:31]1([CH:41]=O)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][N:32]=1.[C:43]([BH3-])#[N:44].[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:44]([CH2:43][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:21][C:22]3[NH:26][CH:25]=[CH:24][N:23]=3)[CH2:41][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][N:32]=3)=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: [BH3-]C#N
Reactant: O=Cc1nccc2ccccc12
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3nccc4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (80 mg) obtained in Example 47-3 was dissolved in methanol (5.0 ml) and added with the compound (59.9 mg) obtained in Example 63-1, followed by the addition of sodium cyanoborohydride (35.9 mg). Then, the reaction solution was adjusted to about pH 5 with acetic acid, followed by stirring at room temperature for 14 hours. The reaction solution was added with a saturated aqueous sodium bicarbonate solution and then extracted with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The resulting crude product was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (97.1 mg) of the subject compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:13])[C:4](=[O:14])[C:3]=1[C:15]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:16]=1[C:17](O)=[O:18].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OC(=O)C)(=O)C>C(OCC)(=O)C>[OH:13][C:9]1[C:10]2[C:11](=[O:12])[C:2]3[O:1][C:17](=[O:18])[C:16]4[CH:20]=[C:21]([CH3:26])[CH:22]=[C:23]([O:24][CH3:25])[C:15]=4[C:3]=3[C:4](=[O:14])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc(C)cc(C(=O)O)c1C1=C(O)C(=O)c2c(O)cccc2C1=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(C)cc2c(=O)oc3c(c12)C(=O)c1cccc(O)c1C3=O
Temperature: 25 °C

Procedure:
The entire amount of the 2-(3,5-dihydroxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzoic acid obtained above was dissolved in ethyl acetate (10 ml) and while the solution was stirred at room temperature, a mixture (1 ml:10 ml) of trifluoroacetic anhydride and acetic anhydride was added. The mixture was further stirred at the same temperature for an hour. This reaction mixture was washed with water and dilute aqueous sodium carbonate in that order, followed by drying over magnesium sulfate. The solvent was then distilled off and the residual brown oil was subjected to silica gel column chromatography to give vermillion-colored crystals (20 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]3C(=O)C4C(=CC=CC=4)C3=O)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCn1cnc(-c2ccccc2)c1-c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCn1cnc(-c2ccccc2)c1-c1ccccc1

Procedure:
Batch size: 14.0 g (33.2 mmol) 2-[4-(4,5-diphenyl-imidazol-1-yl)-butyl]-isoindol-1,3-dione and 3.3 ml (66.4 mmol) hydrazine hydrate in 130 ml ethanol.
Reaction SMILES: [CH2:1]([C@H:8]([NH:31][C:32](=[O:38])[O:33][C:34](C)([CH3:36])[CH3:35])[C@@H:9]([OH:30])[CH:10]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39](=O)([O:47]C1C=CC([N+]([O-])=O)=CC=1)[O:40]C1COCOC1.C(N(C(C)C)CC)(C)C.C(#N)C>FC(F)(F)C(O)=O>[CH2:1]([C@H:8]([NH:31][C:32](=[O:38])[O:33][CH:34]1[CH2:35][O:47][CH2:39][O:40][CH2:36]1)[C@@H:9]([OH:30])[CH:10]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:20])=[O:21])[O:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1COCOC1
Reactant: COc1ccc(S(=O)(=O)NC(OC2CCCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)NC(OC2CCCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC2COCOC2)cc1
Reaction time: 20 h
Yield: 19.2 %

Procedure:
tert-butyl N-((1S,2R)-1-benzyl-3-(cyclohexyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (0.09 mmol, 50 mg) was stirred in 1 mL trifluoroacetic acid (TFA) at room temperature for 5 hours. The TFA was removed under vacuum, and the resulting residue was dissolved in ethyl acetate, washed with 5% aq. potassium carbonate solution, brine, dried over magnesium sulfate, and concentrated to a residue. The resulting free amine, 1,3-dioxan-5-yl 4-nitrophenyl carbonate (0.09 mmol, 25 mg), diisopropylethylamine (0.14 mmol, 0.024 mL), a crystal of N,N-dlmethylaminopyridine, 4 A molecular sieves and acetonitrile (0.5 mL) were combined and stirred at room 'temperature for 20 hours. The reaction solution was concentrated to a residue, dissolved in ethyl acetate, washed with 1N HCl, 5% aq. potassium carbonate solution, brine, dried over magnesium sulfate, and concentrated under vacuum. The crude residue was purified by silica gel chromatography (2:1 hexanes/ethyl acetate) and crystallization from ether and hexanes to yield 10 mg (19%) of white solid. Rf=0.2 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.69 (2H,d), 7.29-7.18 (6H,m), 6.96 (2H,d), 5.01-4.93 (1H, m), 4.93-4.85 (1H,m), 4.74-4.70 (1H,m), 4.51-4.45 (1H,m), 4.22-4.11 (1H,m), 3.95-3.72 (7H,m), 3.86 (3H,s), 3.00-2.80 (3H,m), 2.10-1.97 (2H,m), 1.79-1.67 (2H,m), 1.61-1.53 (2H,m), 1.38-1.02 (6H,m); MS (ESI): M+H=580.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25].Cl>ClC1C=CC=CC=1.O>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([NH:15][C:27]([NH:26][CH2:22][CH2:23][CH2:24][CH3:25])=[O:28])(=[O:13])=[O:14])[CH:3]=1
Reactant: CCCCN=C=O
Reactant: COC(=O)c1ccc(I)cc1S(N)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Clc1ccccc1
Product: CCCCNC(=O)NS(=O)(=O)c1cc(I)ccc1C(=O)OC
Temperature: 90 °C
Reaction time: 2 h

Procedure:
34.1 g (0.1 mol) of the sulfonamide of the formula (IV) from Example 1 and 14.7 g of K2CO3 (0.105 mol) are admixed with 10.6 g of n-butyl isocyanate (98% pure) (0.105 mol) in 250 ml of chlorobenzene, and the mixture is kept at 55 to 60° C. for 2 hours. The mixture is then stirred at 90° C. for 8.5 h. The mixture is cooled to room temperature and initially 200 ml of water and then 2n of hydrochloric acid are added until the pH has reached 1-2. The organic phase is separated off and washed free of acid using four times 50 ml of water. The solvent is removed under reduced pressure, and 43.8 g of the desired compound of the formula (I) (99.3% of theory) of melting point 128 to 130° C. remain.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:28])[CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11]([C:20]([F:23])([F:22])[F:21])([O:15][Si](C)(C)C)[CH:10]([C:24]([F:27])([F:26])[F:25])[CH2:9][CH2:8][C:7]2=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([F:28])[CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11]([C:20]([F:22])([F:23])[F:21])([OH:15])[CH:10]([C:24]([F:27])([F:25])[F:26])[CH2:9][CH2:8][C:7]2=1
Reactant: C[Si](C)(C)OC1(C(F)(F)F)c2[nH]c3c(Cl)cc(F)cc3c2CCC1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)c2[nH]c3c(Cl)cc(F)cc3c2CCC1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
8-Chloro-6-fluoro-1,2-bis(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.2 g, 0.44 mmol) was dissolved in THF (10 mL) and KOH (0.125 g, 2.2 mmol), water (2 mL), was added. The reaction mixture was stirred at room temperature for 2 h, diluted with water (25 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried over Na2SO4, concentrated in vacuo and purified by column chromatography [EtOAc-hexane (1:19) as eluant] to obtain the title compound (0.070 g, 42%) (HPLC 99%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.49 (br s, 1H), 7.26-7.23 (d, J=11.0 Hz, 1H), 7.14-7.11 (dd, J=8.5, 2.0 Hz, 1H), 3.71-3.67 (m, 1H), 2.60-2.57 (m, 1H), 5.54 (s, 1H), 2.40-2.37 (m, 1H), 2.30-2.24 (m, 1H), 2.10-2.07 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([NH:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:37])[CH2:23][CH2:22]1)=[O:20])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH2:15][CH3:16])[CH:14]=1)[NH:11][N:10]=[C:9]2[CH3:17].O1CCCC1.CO.O.[OH-].[Li+]>O>[CH2:15]([C:13]1[CH:14]=[C:6]([CH2:5][CH:4]([NH:18][C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]3[CH2:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH2:25][CH2:26]2)=[O:20])[C:3]([OH:38])=[O:2])[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH3:17])[CH3:16]
Reactant: CCc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)OC)cc2c(C)n[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc2c(C)n[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A suspension of (±)-3-(7-ethyl-3-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (0.94 g, 1.81 mmol) in 1:1 tetrahydrofuran/methanol (30 mL) at room temperature was treated with a solution of lithium hydroxide monohydrate in water (10 mL). The solution was stirred at room temperature for 1 hand the solvents evaporated. The resultant residue was diluted with water (10 mL) and the pH adjusted to ca. 1 with 1N hydrochloric acid. The resultant white suspension was stored at 4° C. overnight and the product was collected by filtration, washed by a small amount of water and dried in vacuo for several hours to give 0.82 g (90%) of the desired product. LC/MS: tR=1.57 min, 505.29 (MH)+.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.C1(C)C=CC(S([N:21]2[C:29]3[C:24](=[C:25]([O:30][CH2:31][CH:32]4[O:34][CH2:33]4)[CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)(=O)=O)=CC=1>C(O)C.C(OCC)(=O)C>[CH:2]1([NH:1][CH2:33][CH:32]([OH:34])[CH2:31][O:30][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:24]=2[CH:23]=[CH:22][NH:21]3)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(OCC4CO4)cccc32)cc1
Reactant: NC1CCCc2ccccc21
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC(CNC1CCCc2ccccc21)COc1cccc2[nH]ccc12
Yield: 12.8 %

Procedure:
A mixture of 1-aminotetralin (5.15 g) and 1-[1-(p-toluenesulfonyl)indol-4-yloxy]-2,3-epoxypropane (12 g) in absolute ethanol (150 ml) is refluxed for 6 hours. The solvent is then evaporated off and the oily residue is dissolved in absolute ethanol (100 ml). A solution of sodium hydroxide (7.5 g) in water (30 ml) is added thereto. The obtained reaction mixture is refluxed for 6 hours and then evaporated under reduced pressure. The residue which is obtained is then dissolved in ethyl acetate (150 ml), the organic solution is thoroughly washed with water, dried over sodium sulfate, and filtered. Ethyl acetate is then evaporated off and the obtained oily residue is chromatographed on a silica gel column eluting with a mixture ethyl acetate/cyclohexane 7/3 v/v. The combined fractions are evaporated to dryness, the oily residue is taken up in a very small amount of ethyl ether which is then removed under vacuum yielding 1.5 g of N-(1,2,3,4-tetrahydronaphth-l-yl)-2-hydroxy-3-(4-indolyloxy)propanamine, as a vitreous solid.
Reaction SMILES: C(O[CH:4](OCC)[C:5](=[NH:8])OC)C.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][NH2:20])=[CH:17][CH:18]=1>CO>[CH3:12][C:13]1[CH:14]=[C:15]2[C:4](=[CH:17][CH:18]=1)[CH:5]=[N:8][C:19]([NH2:20])=[CH:16]2
Reactant: Cc1ccc(CN)cc1
Reactant: CCOC(OCC)C(=N)OC
Solvent: CO
Product: Cc1ccc2cnc(N)cc2c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 63.2 %

Procedure:
To a solution of methyl 2,2-diethoxyacetimidate (1.1 g, 6.82 mmol) in methanol (8 mL) was added p-tolylmethanamine (0.788 g, 6.50 mmol) dropwise at ambient temperature. The reaction flask was then placed into a preheated oil-bath and stirred at 70° C. for 16 h, then removed and allowed cooled. The volatiles were removed under reduced pressure and the crude material was added dropwise to sulfuric acid (5 mL) at ambient temperature. The reaction mixture was stirred for 72 h, then the flask was placed into an ice-water bath, diluted with water (50 mL), and slowly neutralized to pH=10 with sodium hydroxide (10 N). As the reaction mixture became basic, a grey precipitate formed. This precipitate was filtered, washed with water, and dried to afford 6-methylisoquinolin-3-amine (0.65 g, 63%), as a grey powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (s, 1H), 7.69 (d, J=8.28 Hz, 1H), 7.29 (s, 1H), 7.00 (d, J=8.28 Hz, 1H), 5.81 (s, 1H), 2.40 (s, 3H). MS (LC/MS) R.T.=1.37; [M+H]+=159.10.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[C:10]([C:12]3[CH:16]=[CH:15][O:14][CH:13]=3)[N:9]=[CH:8][C:7]=2[OH:17])=[CH:2]1.[C:18]([C:20]1[CH:21]=[C:22]([S:27]([NH:30][C:31]2[S:32][CH:33]=[CH:34][N:35]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1F)#[N:19].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:18]([C:20]1[CH:21]=[C:22]([S:27]([NH:30][C:31]2[S:32][CH:33]=[CH:34][N:35]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[O:17][C:7]1[CH:8]=[N:9][C:10]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)=[CH:11][C:6]=1[C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)#[N:19]
Reactant: Oc1cnc(-c2ccoc2)cc1-c1ccoc1
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(-c2ccoc2)cc1-c1ccoc1
Reaction time: 2 h
Yield: 23.4 %

Procedure:
20.0 mg of 4,6-di(furan-3-yl)pyridin-3-ol and 24.9 mg of 3-cyano-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide were dissolved in DMF, and 86.0 mg (3.0 eq) of Cs2CO3(86.0 mg, 3.0 eq) was added thereto. After reacting at room temperature for 2 hours, the resulting mixture was reacted at 60° C. for 16 hours. The solvent was removed by concentrating under reduced pressure. AS work-up with EA/H2O, the ethyl acetate layer was treated with magnesium sulfate, and concentrated under reduced pressure. The residue was separated by PLC (developing solvent, EA:n-Hex=1:4) to obtain 10.1 mg (24% yield) of the title compound.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([CH3:21])[CH2:15][CH2:14]3)[CH2:6]1)=[N+]=[N-].[H][H]>C1COCC1.CO.[Pd]>[NH2:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([CH3:21])[CH2:15][CH2:14]3)[CH2:6]1
Reactant: CN1CCc2cc(N3C[C@@H](CN=[N+]=[N-])OC3=O)ccc2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCc2cc(N3C[C@H](CN)OC3=O)ccc2C1

Procedure:
184 mg (0.6 mmol) (S)-5-azidomethyl-3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-6-yl)-oxazolidin-2-one are dissolved in a mixture of 2 ml THF and 10 ml of methanol, combined with 50 mg palladium/charcoal (5%) and hydrogenated for two hours at 3 bar hydrogen pressure. The catalyst is filtered off and the filtrate is evaporated to dryness i. vac.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C@H:12]([NH:27][C:28]([N:30]1[CH2:39][CH2:38][C:37]2[CH:36]=[N:35][C:34]([NH:40][CH:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[N:33][C:32]=2[CH2:31]1)=[O:29])[C@H:13]1[N:17](C(OC(C)(C)C)=O)[C:16]([CH3:26])([CH3:25])[CH2:15][CH2:14]1.Cl.CC(O)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:25][C:16]1([CH3:26])[NH:17][C@H:13]([C@H:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:7][C:2]=2[F:1])[NH:27][C:28]([N:30]2[CH2:39][CH2:38][C:37]3[CH:36]=[N:35][C:34]([NH:40][CH:41]4[CH2:42][CH2:43][O:44][CH2:45][CH2:46]4)=[N:33][C:32]=3[CH2:31]2)=[O:29])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](NC(=O)N2CCc3cnc(NC4CCOCC4)nc3C2)c2ccc(C(F)(F)F)cc2F)CCC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CC1(C)CC[C@@H]([C@@H](NC(=O)N2CCc3cnc(NC4CCOCC4)nc3C2)c2ccc(C(F)(F)F)cc2F)N1
Reaction time: 1 h

Procedure:
To a solution of 324 (0.380 g, 0.584 mmol) and DCM (5 mL). was added 6M HCl in IPA (0.973 mL, 5.84 mmol) and the reaction was stirred for 1 h and then poured into Na2CO3 and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:40 to 500:50) to afford 0.210 g (65.3%) of I-86: MS m/z (APCI-pos) M+1=551.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:36])[CH2:23][C:24]([C:26]1[N:27]=[C:28]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)[S:29][CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[N:27]=[C:28]([N:31]5[CH:35]=[CH:34][N:33]=[CH:32]5)[S:29][CH:30]=4)[CH2:23][C:22](=[O:36])[NH:21][C:9]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1csc(-n2ccnc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2csc(-n3ccnc3)n2)=Nc2ccc(-c3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4′-fluoro-3-[3-(2-imidazol-1-yl-thiazol-4-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K83) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown solid (64 mg).
Reaction SMILES: [CH3:1][CH2:2][CH:3](P(OCC)(OCC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:17]([O-])([O-])=O.[K+].[K+].C=O.O>CCOCC>[CH2:17]=[C:3]([CH2:2][CH3:1])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: C=C(CC)C(=O)OCC
Temperature: 80 °C
Yield: 86.2 %

Procedure:
A mixture of 5.0 g (0.019 mol) of triethyl 2-phosphonobutyrate, 5.5 g (0.039 mol) of K2CO3, 6.2 g (0.076 mol) of 37% aqueous formaldehyde solution, and 15 ml of water was heated to about 80° C. for about 45 min. After cooling to RT, 75 ml of ether was added and the organic layer was separated, washed with brine (1×20 ml), dried (MgSO4), and filtered. The ether was carefully removed by distillation, leaving behind 2.1 g (87%) of the title compound as a clear oil which was used directly without further purification. 1H NMR (CDCl3): δ 1.01 (3H, t, J=7), 1.24 (3H, t, J=7), 2.26 (2H, q, J=7) 4.14 (2H, q, J=7), 5.45 (1H, s), 6.06 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([C:8]2[C:17](=[O:18])[N:16]([CH3:19])[C:15]3[C:10](=[CH:11][N:12]=[C:13]4[NH:22][CH:21]=[CH:20][C:14]4=3)[CH:9]=2)[CH:7]=1.[CH2:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=2)[C:35](O)=[O:36])[CH2:28][CH2:27]1)[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C>>[CH2:24]([N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=2)[C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([C:8]3[C:17](=[O:18])[N:16]([CH3:19])[C:15]4[C:10](=[CH:11][N:12]=[C:13]5[NH:22][CH:21]=[CH:20][C:14]5=4)[CH:9]=3)[CH:7]=2)=[O:36])[CH2:30][CH2:31]1)[CH3:25]
Reactant: Cc1ccc(N)cc1-c1cc2cnc3[nH]ccc3c2n(C)c1=O
Reactant: CCN1CCN(c2cc(C(=O)O)cc(C(F)(F)F)c2)CC1
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: CCN1CCN(c2cc(C(=O)Nc3ccc(C)c(-c4cc5cnc6[nH]ccc6c5n(C)c4=O)c3)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-(5-amino-2-methyl-phenyl)-9-methyl-3,9-dihydro-3,4,9-triaza-cyclopenta[a]naphthalen-8-one (22 mg, 0.07 mmol), 3-(4-Ethyl-piperazin-1-yl)-5-trifluoromethyl-benzoic acid (24 mg, 0.08 mmol), HATU (30 mg, 0.08 mmol) and DIEA (27 mg, 0.21 mmol) in 0.5 mmol DMF is stirred at room temperature for 2 hours. The solvent is removed by rotary evaporation. The crude product is purified by reverse phase HPLC to give the title compound as white solid. 1H NMR 400 MHz (DMSO-d6) δ 12.19 (s, 1H), 10.32 (s, 1H), 9.71 (s, 1H), 8.54 (s, 1H), 8.01 (s, 1H), 7.72 (s, 1H), 7.66 (m, 2H), 7.58 (s, 1H), 7.50 (t, 1H, J=2.8 Hz), 7.45 (s, 1H), 7.23 (d, 1H, J=8.4), 7.04 (s, 1H), 4.06 (m, 2H), 3.99 (s, 3H), 3.55 (b, 2H), 3.15 (m, 2H), 3.06 (m, 4H), 2.09 (s, 3H), 1.20 (t, 3H, J=7.2). MS m/z 589.2 (M+1).
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.C1C=CC=CC=1.Cl[CH2:26][N:27]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=2[CH:39]([CH3:41])[CH3:40])[S:28]1(=[O:30])=[O:29].[N-:44]=[N+:45]=[N-:46].[Na+]>O>[N:44]([CH2:26][N:27]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=2[CH:39]([CH3:41])[CH3:40])[S:28]1(=[O:30])=[O:29])=[N+:45]=[N-:46]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CN=[N+]=[N-])C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
A solution of 18-crown-6 ether (0.60 g) and benzene (60 mL) was heated under reflux with a water separator for 1 hour, then cooled to room temperature. 2-Chloromethyl-4-isopropyl-6-methoxysaccharin (3.03 g) and sodium azide (0.65 g) were added, and the mixture was stirred for a week at room temperature, then chromatographed on a column of silica gel (silica gel 60, 83 g) using benzene as eluant. The fractions containing the product, which were identified by thin layer chromatography, were combined and concentrated affording 2-azidomethyl-4-isopropyl-6-methoxysaccharin as a solution in benzene (250 mL).