Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:38]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:40]1[CH2:45][CH2:44][S:43](=[O:47])(=[O:46])[CH2:42][CH2:41]1.O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([S:8][CH:9]([CH2:38][N:40]1[CH2:45][CH2:44][S:43](=[O:47])(=[O:46])[CH2:42][CH2:41]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:30])=[O:31])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCNCC1
Reactant: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(C=O)SCc3ccccc3)cc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(CN3CCS(=O)(=O)CC3)SCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
A mixture of N-[2-(benzylthio)-3-oxopropyl]-5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (500 mg), thiomorpholine 1,1-dioxide (240 mg) and tetrahydrofuran (10 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (280 mg) was added at room temperature, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (3:7-1:9, volume ratio) to give the title compound (210 mg, yield 35%) as a colorless amorphous solid.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)C.Cl>CO>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:17])=[O:5])=[CH:10][CH:11]=1)#[N:16]
Reactant: CCOC(=O)COc1ccc(C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(OCC(=O)O)cc1
Yield: 72 %

Procedure:
A 1 N solution of NaOH (7.6 mL; 7.6 mmol) was added dropwise to a solution of (4-cyanophenoxy)acetic acid ethyl ester B (1.55 g; 7.6 mmol) in MeOH (15 mL). After 1 h the solution was acidified with 1 N HCl (7.6 mL; 7.6 mmol) and evaporated. The residue was taken up with water (20 mL) and extracted with CHCl3 (2×30 mL). The organic phases were evaporated and the crude was purified by flash chromatography to give (4-cyanophenoxy)acetic acid C (0.97 g; 5.5 mmol) as a white solid. Yield 72%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[C:40](O)(=[O:44])[CH:41]([CH3:43])[CH3:42]>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)C(=O)O
Reactant: Nc1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.7 %

Procedure:
To a stirred solution of 5-Indole amine (0.5 g, 3.78 mmol), 1-ethyl-3(3-dimethylaminopropyl)carbodiimidehydrochloride (1.45 g, 7.56 mmol), 1-hyroxybenzotriazole (0.578 g, 3.78 mmol) in anhydrous DMF (25 mL), triethylamine (1.0 mL, 7.5 mmol) and isobutyric acid (0.31 mL, 3.4 mmol) were added and stirred at room temperature for 12 h. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo and the resultant residue was purified by flash column chromatography to give N-(1H-indol-5-yl)isobutyramide (0.596 g, 77.8%); MS: 203.1 (M+1)
Reaction SMILES: [CH2:1]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7](=[O:20])[CH:8]=[C:9]([C:15]([O:17]CC)=[O:16])[NH:10]2)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7](=[O:20])[CH:8]=[C:9]([C:15]([OH:17])=[O:16])[NH:10]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cccc2[nH]c(C(=O)OCC)cc(=O)c12
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1cccc2[nH]c(C(=O)O)cc(=O)c12
Yield: 89.1 %

Procedure:
Treatment of ethyl 5-butyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.5 g) with sodium hydroxide (0.293 g), as described in Example 1c, gave 5-butyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.4 g), mp 269°-270° C., δ (360 MHz, DMSO-d6) 0.89 (3H, t, CH3), 1.53 (2H, m, CH2CH3), 1.49 (2H, m, CH2CH2CH2), 3.25 (2H, t, CH2CH2CH2), 6.53 (1H, s, 3-H), 7.03 (1H, dd, 6-H), 7.50 (1H, t, 7-H) and 7.78 (1H, dd, 8-H), (Found: C, 67.55; H, 6.60: N, 5.88%, C14H15NO3. 0.2H2O requires C, 67.56; H, 6.24, N, 5.62%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](I)[CH:3]=1.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>ClC1C=CC=CC=1.C(OCC)(=O)C.[Cu]>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: COC(=O)c1ccc(Cl)cc1I
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of methyl 4-chloro-2-iodobenzoate (5.93 g, 20 mmol), 4-bromo-2-nitroaniline (4.34 g, 20 mmol), copper (1.26 g, 20 mmol), and K2CO3 (2.76 g, 20 mmol) in chlorobenzene (300 mL) was heated to reflux for 2 days, cooled to room temperature, diluted with ethyl acetate, and filtered through diatomaceous earth (Celite®). The solution was washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 9:1 hexanes/ethyl acetate to provide 6.86 g (89%) of the desired product. MS (DCI) m/e 386 (M+H)+, 403 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.28 (d, J=2.4 Hz, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.82 (dd, J=9.1, 2.4 Hz, 1H), 7.63 (d, J=9.1 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.17 (dd, J=8.5, 2 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[C:26]1(B(O)O)[CH2:30][CH2:29][CH2:28][CH:27]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:26]2[CH2:30][CH2:29][CH2:28][CH:27]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Reactant: OB(O)C1=CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C2=CCCC2)Cc2ccccc2C1
Yield: 85 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (800 mg, 1.78 mmol) and cyclopenten-1-ylboronic acid (796 mg, 7.11 mmol) in dioxane (20 mL) is added Pd(PPh3)4 (412 mg, 0.36 mmol) and 2M aqueous solution of CsCO3 (5.34 mL, 10.7 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 2.7 h. After concentration in vacuo, the residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5-40% EtOAc in heptane) to give a pure product (131) as a brown solid (589 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:34])[CH:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:9]/[C:10](=[N:36]\[OH:37])/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[C:4]([CH3:34])[CH:3]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(Cl)cc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 4′-[(R)-1-(4-chloro-2-methyl-phenyl)-3-(2-methyl-pyridin-4-yl)-3-oxo-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light yellow solid, MS (ESI+): m/z=485.3 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[C:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:14][CH:15]=1)(=[O:18])[CH3:17]
Reactant: CCOC(=O)CC(=O)c1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)c1ccc(OC(C)=O)cc1
Yield: 93.1 %

Procedure:
1.85 grams of ethyl 4-hydroxybenzoylacetate was added to 15 ml of anhydrous pyridine. 0.91 grams of acetic anhydride was added along with a few crystals of dimethylaminopyridine (Aldrich). After 1 hour at room temperature the pyridine was removed exvacuo. The oily residue was stirred with 25 ml of water and 25 ml of ether. The aqueous phase was separated and extracted twice with 50 ml of ether. The combined ether extracts were washed with 0.5N HCl (25 ml), then with saturated sodium bicarbonate solution (25 ml), and finally with 25 ml of brine. The extracts were then dried with magnesium sulfate, filtered and the ether removed exvacuo. To yield 2.07 grams of ethyl 4-acetoxybenzoylacetate.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Cl[CH2:24][C:25]1[C:26]([CH3:31])=[N:27][O:28][C:29]=1[CH3:30]>>[CH3:31][C:26]1[C:25]([CH2:24][N:15]2[C:16]([CH3:19])([CH3:20])[C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:22])[CH:12]=3)[C:14]2=[O:21])=[C:29]([CH3:30])[O:28][N:27]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Reactant: Cc1noc(C)c1CCl
Product: Cc1noc(C)c1CN1C(=O)N(c2cnn(Cc3c(C)noc3C)c2)C(=O)C1(C)C

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 4-(chloromethyl)-3,5-dimethylisoxazole. MS 413 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.08 μM.
Reaction SMILES: [OH:1][C@@:2]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:24])[C:3]([N:5]1[CH2:23][CH2:22][CH2:21][C@H:6]1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][CH2:19][NH2:20])=[O:8])=[O:4].[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33]>CCO>[OH:1][C@@:2]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([CH3:24])[C:3]([N:5]1[CH2:23][CH2:22][CH2:21][C@H:6]1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][CH2:19][NH:20][CH2:33][CH2:32][C:31]([O:35][CH2:36][CH3:37])=[O:34])=[O:8])=[O:4]
Reactant: C=CC(=O)OCC
Reactant: C[C@](O)(C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CCN)c1ccccc1
Solvent: CCO
Product: CCOC(=O)CCNCCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@](C)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 1-((2R)-2-hydroxy-2-phenylpropanoyl)-N-(2-(2-aminoethyl)-5-chlorobenzyl)-L-prolinamide (90 mg, 0.21 mmol) in EtOH (2 mL) was added ethyl acrylate (25 microliters, 0.22 mmol). The mixture was stirred at ambient temperature for 48 h. The solvent was removed under reduced pressure and the residue was purified by flash silica gel column chromatography using a gradient elution of 5% to 7.5% MeOH in CH2Cl2. The product-containing fractions were combined to give the title compound as an amorphous solid upon removal of the solvents in vacuo (TLC Rf=0.4 (95:5 CH2Cl2:MeOH); HPLC RT=2.95 min, method A; LC-MS m/z=530).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7](OS(C)(=O)=O)[NH:6][C:5]2[C:19]([CH3:24])=[CH:20][C:21]([CH3:23])=[N:22][C:4]1=2)[CH3:2].Cl.[O:26]([NH2:28])[CH3:27].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[N:28][O:26][CH3:27])[NH:6][C:5]2[C:19]([CH3:24])=[CH:20][C:21]([CH3:23])=[N:22][C:4]1=2)[CH3:2]
Reactant: CON
Reactant: CCN1c2ncccc2C(OS(C)(=O)=O)Nc2c(C)cc(C)nc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN1c2ncccc2C(=NOC)Nc2c(C)cc(C)nc21
Yield: 31.4 %

Procedure:
A solution of 5,11-dihydro-11-ethyl-6-methanesulfonyloxy-2,4-dimethyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepine (0.3 g, 0.75 mmol), methoxylamine hydrochloride (0.15 g, 1.8 mmol) and diisopropylethylamine (0.3 g, 2 mmol) in methylene chloride was stirred at room temperature for 4 days. The organic phase was washed with water, dried, and filtered. The solution was concentrated in vacuo and the residue was chromatographed over silica with 20% ethyl acetate/hexane to give 0.07 g of the title compound, m.p. 164°-166° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[C:3]=1[NH2:14].CN(C=O)C.[H-].[Na+].[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26]([Cl:30])=[CH:25][N:24]=1>>[Cl:22][C:23]1[N:28]=[C:27]([NH:14][C:3]2[C:4]([S:8]([CH:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:26]([Cl:30])=[CH:25][N:24]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)S(=O)(=O)c1cccc(F)c1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Fluoro-6-(propane-2-sulfonyl)-phenylamine (3.10 g, 14 mmol) in DMF (10 mL, 0.1 mol) was treated with Sodium hydride, 60% disp. in mineral oil (1.14 g) at 0° C., then 2,4,5-Trichloro-pyrimidine (1.80 mL, 0.0157 mol) was added. The reaction was stirred for 30 minutes at 0° C. and then allowed to warm to rt and stirred at rt for 3 hrs. The reaction mixture was quenched with sat'd NH4Cl Product isolated as an off-white solid: 3.24 g, 62%. MP 192-193, LCMS 365.97 (M+H), HPLC purity 97%, 1H-NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 8.31 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.53-7.50 (m, 2H), 3.10-3.00 (m, 1H), 1.28 (d, J=5.8 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:10][CH2:9][C:8]=2[CH:19]=1)([O-])=O>[Pd].CO>[N:14]1([CH:11]2[CH2:10][CH2:9][C:8]3[CH:19]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=3[CH2:13][CH2:12]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCC(N1CCCC1)CC2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CCC(N1CCCC1)CC2
Reaction time: 1 h

Procedure:
A mixture of 1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)pyrrolidine (2.0 g; 7.69 mmol) and 10% palladium on carbon (0.2 g, ˜50% water) in methanol (150 mL) was shaken under hydrogen (40 psi) for 1 h. After this time the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to afford 7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-amine as an oil (quantitative yield); MS (m/e): 231 (M+H+).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27]CC1C=CC=CC=1)[OH:20])C1C=CC=CC=1>C(OCC)(=O)C.C(O)C>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH:19]([OH:20])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27]
Reactant: O=c1ccn(CCO)c(C(O)c2ccccc2OCc2ccccc2)c1OCc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1ccn(CCO)c(C(O)c2ccccc2O)c1O

Procedure:
3-Benzyloxy-2-[(2-benzyloxy-phenyl)-hydroxy-methyl]-1-(2-hydroxy-ethyl)-.1H-pyridin-4-one: From 2.42 g of 3-benzyloxy-2-[(2-benzyloxy-phenyl)-(tetrahydropyran-2-yloxy)-methyl]-1-(2.-hydroxy-ethyl)-1H-pyridin-4-one there is obtained analogously to Example 6e, after chromatography: 3-benzyloxy-2-[(2-benzyloxy-phenyl)-hydroxy-methyl]-1-(2-hydroxy-ethyl)-1H-pyridin-4-one. Beige foam. Rf value: 0.17 (silica gel 60, ethyl acetate/ethanol 9/1).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:12]([N:19]=[C:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:20]([NH:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=NCc1ccccc1
Product: O=C(NCc1ccccc1)Nc1ccc([N+](=O)[O-])cc1O
Yield: 63 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(benzyl)urea was prepared from 2-hydroxy 4-nitro aniline (308 mg, 2.0 mmol) and benzyl isocyanate (2 mmol) according to the procedure in General Method A. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (362 mg, 52%). EI-MS m/z 288 (M+H)+
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[C:11]([C:10]1[CH:19]=[CH:20][C:7]([CH2:6][O:5][CH2:4][CH2:3][NH:2][C:35]([NH:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:36])=[CH:8][CH:9]=1)(=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C=Nc1ccccc1
Reactant: NCCOCc1ccc(C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCOCc1ccc(C(=O)c2ccccc2)cc1)Nc1ccccc1
Reaction time: 16 h
Yield: 67 %

Procedure:
To a stirred suspension of (X) (3.49 g, 12 mmol) in dry DCM (10 ml) was added dry triethylamine (10 ml). After 0.25 h. stirring a solution of phenyl isocyanate (2.14 g, 18 mmol) in dry DCM (10 ml) was added in one portion. The mixture was stirred for a further 16 h. then quenched with water (10 ml). The organic layer was collected and washed sequentially with water, 2M HCl, and water. The organic layer was dried over MgSO4 and purified by flash chromatography on silica gel eluting with 2:1 petrol 40/60:ethyl acetate (Rf=0.1) to yield (XI) (3.01 g, 67%) as a white solid; m.p. 129-132° C.; δH (DMSO-d, 200 MHz) 3.39 (q, 2H, J=5.1 Hz, NHCH2), 3.58 (t, 2H, J=5.0 Hz, OCH2CH2), 4.65 (s, 2H, OCH2Ar), 6.32 (t, 1H, J=5.2 Hz CH2NHC(O)NHAr), 6.90 (t, 1H, J=7.3 Hz, 4″-H), 7.24 (t, 2H, J=7.4 Hz, 3″-, 5″-H), 7.44 (d, 2H, J=7.6 Hz, 2″-, 6″-H), 7.56 (m, 4H, 3-, 5-, 3′-, 5′-H), 7.70 (m, 5H, 2-, 4-, 6-, 2″-, 6″-H) 8.63 (s, 1H, CH2NHC(O)NHAr) ppm; δC (DMSO-d, 400 MHz) 39.9 (CH2CH2NH), 70.4 (CH2CH2O), 72.1 (ArCH2O), 118.4 (2″-, 6″-C), 121.9 (4″-C), 128.1 (2-, 6-, 2′-, 6′-C), 129.4 (3″-, 5″-C), 130.4, 130.6 (3-, 5-, 3′-, 5′-C), 133.5 (4′-C), 136.9, 138.0 (1-, 1″-C), 141.3 (4-C), 144.4 (1″-C), 156.1 (N(H)C(O)NH), 196.3 (Ar2C(O)) ppm; max 3431 (N—Hstr), 1724 ((R(H)N)2C═Ostr), 1658 (Ar2C═Ostr) cm−1; m/z 375 [M+H]+ (5%), 397 [M+Na]+ (10%), 433 [M+MeCN+NH4]+ (100%); found 375.1703, C23H23N2O3 requires 375.1709.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31](=[O:46])[C@H:32]([CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:33][CH3:34])=[CH:24][CH:23]=1>>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31](=[O:46])[C@H:32]([CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[N:33]([C:18](=[O:20])[C@H:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:34])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(C)cc1
Product: Cc1ccc(CCNC(=O)[C@H](CCCNC(=O)OC(C)(C)C)N(C)C(=O)[C@H](CCc2ccccc2)NC(=O)OC(C)(C)C)cc1

Procedure:
Using Procedure D, Boc-homophenylalanine (143 mg) and Nδ-Boc-Nα-methylornithine 2-(4-methylphenyl)ethylamide (crude product from B) afforded titled product (195 mg) as a glassy solid after silica gel chromatography: 1H NMR (400 MHz, CDCl3) δ1.44 (2 s, 18H), 1.63 (m, 2H), 1.83 (m, 2H, 2.33 s, 3H), 2.63-279 (m, 7H), 3.09 (m, 2H), 3.45 (m, 2H), 4.51 (m, 1H), 4.98 (m, 1H), 7.09 (m, 4H) (m, 3H), and 7.31 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6]([CH:14]=[CH2:15])=[CH:7][N:8]=[CH:9]2)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:24])C=1.C(=O)([O-])O.[Na+]>ClCCl>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6]([CH:14]=[CH2:15])=[CH:7][N+:8]([O-:24])=[CH:9]2)([O-:3])=[O:2]
Reactant: C=Cc1cncc2cccc([N+](=O)[O-])c12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=Cc1c[n+]([O-])cc2cccc([N+](=O)[O-])c12
Reaction time: 3.5 h
Yield: 108.7 %

Procedure:
The 5-nitro-4-vinylisoquinoline (23 g) obtained in Step A mentioned above was dissolved in dichloromethane (400 ml), then slowly added with m-chloroperbenzoic acid (43 g, Tokyo Kasei Kogyo), and stirred for 3.5 hours. The reaction mixture was cooled on ice, and then neutralized by addition of saturated aqueous sodium hydrogencarbonate. Then, the organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (27 g).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Br:12][C:13]1[CH:14]=[N:15][C:16]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])[CH:26]=3)[C:21]([S:36][CH3:37])=[CH:20]2)=[N:17][CH:18]=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Br:12][C:13]1[CH:18]=[N:17][C:16]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:29])[CH:26]=3)[C:21]([S:36]([CH3:37])=[O:6])=[CH:20]2)=[N:15][CH:14]=1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
m-Chloroperoxybenzoic acid (77%, 2.10 g, 9.42 mmol) in dichloromethane (20 mL) was added at 0° C. to a solution of (1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indol-6-yl)(morpholino) methanone (4.8 g, 11.08 mmol) in dry dichloromethane (300 mL). The mixture was stirred at room temperature for 3 h and then poured onto saturated sodium sulfite solution. The organic layer was separated after stirring for 15 min and washed with saturated sodium hydrogen carbonate solution and brine. The organic phase was dried over sodium sulfate and concentrated and the remnant was purified by flash column chromatography [dichloromethane with 2.5% methanol]. White solid. Yield: 3.2 g
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[CH2:14]([NH2:17])[CH2:15][NH2:16]>O1CCCC1>[C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:16][CH2:15][CH2:14][NH2:17])#[N:2]
Reactant: NCCN
Reactant: N#Cc1ccccc1OCC1CO1
Solvent: C1CCOC1
Product: N#Cc1ccccc1OCC(O)CNCCN
Reaction time: 16 h

Procedure:
A solution of 1-(2-cyanophenoxy)-2,3-epoxypropane (93.3 g.) in tetrahydrofuran (700 ml.) is added dropwise during 5 hours to stirred ethylenediamine (600 g.) and the mixture is stirred for a further 16 hours and then evaporated to dryness under reduced pressure. The residue is twice dissolved in water (500 ml.) and then evaporated to dryness, and then twice dissolved in toluene (500 ml.) and then evaporated to dryness. There is thus obtained as residue 1-(2-cyanophenoxy)-3-(β-aminoethylamino)-2-propanol.