Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C(O[C:5](=[O:23])[CH:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7][NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])C>C(O)C.C1(C)C=CC=CC=1>[O:16]=[C:9]1[CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5](=[O:23])[CH:6]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:7][NH:8]1
Reactant: CCOC(=O)CC(=O)NCC(C(=O)OCC)c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C1C(=O)NCC(c2ccccc2)C1=O
Reaction time: 1.5 h
Yield: 48.1 %

Procedure:
Sodium (380 mg, 16.52 mmol) was dissolved in anhydrous ethanol (13 mL) and the resulting solution was treated dropwise with 3-(2-ethoxycarbonyl-acetylamino)-2-phenyl-propionic acid ethyl ester (4.23 g, 13.76 mmol) dissolved in anhydrous toluene (35 mL). The reaction was kept at 80° C. for 1.5 hours. After cooling, the mixture was extracted with water. The aqueous extracts were acidified with 2 N HCl, extracted with ethyl acetate and the organic layers were collected, dried over Na2SO4 and evaporated to dryness to obtain ethyl 2,4-dioxo-5-phenylpiperidine-3-carboxylate (1.73 g, Y=48%) which was used for the next step without further purification. Ethyl 2,4-dioxo-5-phenylpiperidine-3-carboxylate (1.73 g, 6.63 mmol) was dissolved in acetonitrile containing 1% of water (30 mL) and the resulting solution was refluxed for 2 hours. After evaporating to dryness, the crude material was chromatographed on silica gel, eluting with methylene chloride/methanol 92/8, to give the title compound (780 mg, Y=62%) as a solid.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>C1C=CC=CC=1>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: On1nnc2ccc(Cl)cc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)On2nnc3ccc(Cl)cc32)cc1
Reaction time: 1 h
Yield: 78.1 %

Procedure:
In dry benzene (50 ml) are dissolved 1-hydroxy-6-chloro-1,2,3-benzotriazole (8.5 g) and triethylamine (7.0 ml), and thereto is added p-toluenesulfonyl chloride (9.5 g) at room temperature and the mixture is stirred for 1 hour. To the reaction mixture are added water and benzene. The benzene layer is separated, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The resulting residue is recrystallized from carbon tetrachloride to give 1-(p-toluenesulfonyloxy)-6-chloro-1,2,3-benzotriazole (12.6 g), melting point: 94°-96° C.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCCCC1.C(OCC)C.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(OCC)C>O>[C:1]1([C:27]2[N:26]=[C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)[CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccccn2)nc1
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: C1CCCCC1
Product: c1ccc(-c2cccc(-c3ccccn3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
A solution of phenyllithium.cyclohexane/diethyl ether (40.9 ml, 38.4 mmol) was dropwise added to a mixture of 2,2′-bipyridine (5.0 g, 32.0 mmol) and diethyl ether (50 ml) at 5° C. while 15 minutes. This reaction mixture was stirred at room temperature for 2 hours, then the mixture was poured into water, an organic layer was separated from the mixture, furthermore an aqueous layer was extracted with dichloromethane. The organic layer was combined, and the solvent was distilled off, and the residue was diluted with acetone (50 ml), then saturated potassium permanganate acetone solution (120 ml) was added thereto, the mixture was stirred at room temperature for 1 hour. The obtained reaction mixture was filtered by Celite, the solvent of the filtrate was distilled off, and the residue was purified by silica gel column chromatography and recrystallization, thereby obtaining 4.2 g of 6-phenyl-2,2′-bipyridine as white crystal. Yield: 55.4%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5](Br)=[C:6]([F:8])[CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[F:14])=[C:6]([F:8])[CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: COC(=O)c1nc(Br)c(F)cc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccccc2F)c(F)cc1N
Yield: 99 %

Procedure:
Method 1 was followed using methyl 3-amino-6-bromo-5-fluoropicolinate (1.0 equiv.) and 2-fluoro-phenylboronic acid (1.5 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give methyl 3-amino-5-fluoro-6-(2-fluorophenyl)picolinate in >99% yield. LC/MS=265.0 (M+H), Rt=0.77 min.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[S:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[CH:9]=1)(C)(C)C.N1C=CC=CC=1.F>C1COCC1>[C:20]1([C:17]2[S:16][C:15]([NH:14][C:10]3[CH:9]=[C:8]([CH2:7][OH:6])[CH:13]=[CH:12][N:11]=3)=[N:19][CH:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(Nc2ncc(-c3ccccc3)s2)c1
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: OCc1ccnc(Nc2ncc(-c3ccccc3)s2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
[4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-(5-phenyl-thiazol-2-yl)-amine (8-6), 0.805 g (2.03 mmol) was dissolved in 10 mL THF and the resulting solution was cooled to 0° C. Hydrogen fluoride-pyridine (Aldrich, HF ˜70%, pyridine ˜30%) 1.20 mL was added. After 1 h the reaction was allowed to arm to RT. The THF was removed in vacuo and the residue was diluted with sat Na2CO3 (aq). The resulting precipitate was filtered to provide the pure title compound. 1H NMR (DMSO-d6): δ11.35 (bs, 1H), 8.25 (d, 1H, J=5.2 Hz), 7.79 (s, 1H), 7.59 (d, 2H, J=7.4 Hz), 7.39 (t, 2H, J=7.6 Hz), 7.25 (t, 1H, J=7.3 Hz), 7.08 (s, 1H), 6.86 (d, 1H, J=5.2 Hz), 5.42 (bs, 1H), 4.51 (s, 2H). Mp 236-237° C. M+1: 284.0.
Reaction SMILES: [O:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH2:18]Br)[C:12]([NH2:14])=[O:13])[Si](C(C)(C)C)(C)C.[OH2:20]>CC#N.[F-].[K+]>[OH:1][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH2:18][OH:20])[C:12]([NH2:14])=[O:13]
Reactant: O
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C(N)=O)ccc1CBr
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1ccc(CO)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of 3-t-butyldimethylsiloxy-4-bromomethylbenzamide (Compound 7.2) (0.101 g, 0.293, mmol) in 8 mL CH3CN, KF.2H2O (0.041 g, 0.44 mmol) in 4 mL H2O was added dropwise. The mixture was then stirred at room temperature for half hour. After the solvent was removed, the residue was absorbed on 500 mg silica gel. The product was obtained by flash chromatography (ethyl acetate:ethyl alcohol=10:1, Rf=0.8) as a white solid (0.0439 g, y==90.7%). 1H NMR (CD3CN) δ4.68(s,2H), 5.95(b,1H), 6.69(b,1H), 7.23-7.26(m,3H), 7.77(b,1H); 13C NMR (CD3Cl) δ60.66, 115.13, 119.44, 128.69, 133.07, 134.94, 156.10, 203.64.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([N+:25]([O-])=O)=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[O:6])[CH2:3][CH2:2]1.[H][H]>CO.CC(O)=O.[Pt]>[NH2:25][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([O:14][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:6])[CH:13]=2)=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1)NC1CC1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(Oc2ccnc(NC(=O)NC3CC3)c2)c2ccccc12

Procedure:
A solution of 1-cyclopropyl-3-(4-((4-nitronaphthalen-1-yl)oxy)pyridin-2-yl)urea (118 mg, 0.324 mmol) in a mixture of MeOH (20 mL) and AcOH (0.5 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 25° C., 70 mm, 10% Pt—C Cat-Cart, full hydrogen mode). The reaction mixture was evaporated in vacuo and the residue was partitioned between DCM (20 mL) and saturated aq. NaHCO3 (10 mL). The organic phase was separated and was washed with brine (10 mL), and then dried and evaporated in vacuo to afford the title compound, Intermediate D3, as a brown solid (90 mg, 83%); Rt 1.52 min (Method 2); m/z 335 (M+H)+ (ES+).
Reaction SMILES: I[C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]([NH:11][C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.[K]>CO.[Pd]>[C:12]([NH:11][C:5]1[C:6]2[O:10][CH2:9][O:8][C:7]=2[C:2]([C:9]([O:8][CH3:7])=[O:10])=[CH:3][CH:4]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc(I)c2c1OCO2
Agent: [Pd]
Agent: [K]
Solvent: CO
Product: COC(=O)c1ccc(NC(C)=O)c2c1OCO2
Temperature: 150 °C
Reaction time: 16 h
Yield: 128.6 %

Procedure:
A mixture of intermediate (2-b) (38.8 g), potassium acetae (20 g) and Pd/C (10%; 2 g) in CH3OH (500 ml) was stirred at 150° C. under 4.9×106 Pa (50 kg) pressure of CO, during 16 hours. The reaction mixture was cooled, filtered over dicalite, and the filtrate was evaporated. The residue was diluted with water, then extracted three times with DCM. The combined organic layers were dried, filtered and the solvent evaporated. The residue was dissolved in acetic acid (250 ml) and acetic anhydride (6 ml) was added dropwise. The mixture was stirred for 30 minutes at room temperature, then diluted with water (250 ml) and the resulting precipitate was filtered off, washed with water, then dried, yielding 19.4 g (64.7%) of methyl 7-(acetylamino)-1,3-benzodioxole-4-carboxylate (intermediate 2-c).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:17](=[O:18])[N:16]([CH3:15])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(-c2ccc(Br)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-bromo-4′-hydroxybiphenyl and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol) (72%, white crystals). HPLC-MS m/z=382.0) (M+1), Rt: 5.41 min.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: ClCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCCCCCl)C(C)=O
Temperature: 100 °C
Yield: 102.4 %

Procedure:
A mixture of ethyl acetoacetate [VI-1] (260.6 g, 2.0 mol), toluene (300 g) and 1-bromo-5-chloropentane [V-1] (311.0 g, 1.68 mol) is heated to 80°-90° C. Thereto is added anhydrous potassium carbonate (300 g), and the temperature thereof is raised to 100° C. The mixture is reacted at the same temperature for 18 hours. After completion of the reaction, the mixture is filtered, and the toluene layer is washed with water, and concentrated under reduced pressure to give crude ethyl 7-chloro-2-(1-oxo-ethyl)-heptanoate [II-1] (403.8 g, content; 68.8 %, yield; 69.1 %).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.[CH:29]([N:32]([CH2:36][CH2:37]Cl)[CH:33]([CH3:35])[CH3:34])([CH3:31])[CH3:30]>>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:37][CH2:36][N:32]([CH:33]([CH3:35])[CH3:34])[CH:29]([CH3:31])[CH3:30])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1
Reactant: Cc1cccc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)c1
Reactant: CC(C)N(CCCl)C(C)C
Product: Cc1cccc(-c2nc3ccc(OCCN(C(C)C)C(C)C)cc3n2Cc2ccccc2C(F)(F)F)c1

Procedure:
The title compound was prepared essentially as described in Example 113 except that the compound of Example 120 was reacted with 2-(N,N-diisopropylamino)ethyl chloride. MS 510.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12](=[O:35])[CH2:13][NH:14][C:15](=[O:34])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:7]1.[C:41](OC(=O)C)(=[O:43])[CH3:42].CO>N1C=CC=CC=1>[C:41]([NH:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12](=[O:35])[CH2:13][NH:14][C:15](=[O:34])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:7]1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)C2)cc1N
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)C2)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-(3-amino-4-methoxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (50.5 mg)in pyridine (1 mL) was added acetic anhydride (1 mL). The reaction mixture was stirred at room temperature overnight and methanol was added. The mixture was evaporated, and 1 N NaOH solution was added. The mixture was extracted with ethyl acetate and the organic layer was concentrated. Preparative TLC gave (R)-1-(3-acetylamino-4-methoxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine.
Reaction SMILES: C([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH:13]([O:18][CH3:19])([O:16][CH3:17])OC>CO.S(=O)(=O)(O)O.C(Cl)Cl>[CH3:19][O:18][CH:13]([O:16][CH3:17])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(OC)OC
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(C(OC)OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.5 %

Procedure:
To a solution of methyl 4-formylbenzoate (CAS [1571-08-0] 5.33 g, 32.5 mmol) in methanol (40 mL) were added trimethyl orthoformate (7.5 mL, 68.25 mmol) and sulfuric acid (fuming, 3 drops). After heating to reflux with stirring for 16 h, the reaction mixture was cooled to RT and diluted with methylene chloride. The mixture was washed with a saturated solution of sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated to afford 7 g of methyl 4-(dimethoxymethyl)benzoate as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(4-fluorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[CH:12]1([N:22]=[C:23]=[S:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH3:2][O:3][NH:4][C:23]([NH:22][CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1)=[S:24]
Reactant: CON
Reactant: S=C=NC1CCCc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(=S)NC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cold, stirred mixture of 0.02 mole of methoxyamine hydrochloride and methylene chloride is added 0.02 mole of triethylamine. The mixture is then allowed to warm to about 15° C. to 25° C. while a solution of 0.01 mole of 1,2,3,4-tetrahydro-1-naphthyl isothiocyanate in methylene chloride is added dropwise. The mixture is stirred overnight at room temperature and then filtered. The filtrate is washed with water, dried (sodium sulfate), and the solvent evaporated at reduced pressure to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][C:5]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[O:10].[C:23]([NH:30][CH2:31][C:32](O)=[O:33])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1>C1COCC1.CCOC(C)=O>[C:23]([NH:30][CH2:31][C:32]([NH:1][CH2:2][C:3]1[S:4][C:5]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[O:10])=[O:33])([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24]
Reactant: Cc1ccc(NC(=O)Nc2cc(C(C)(C)C)sc2CN)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2cc(C(C)(C)C)sc2CNC(=O)CNC(=O)OC(C)(C)C)cc1
Reaction time: 18 h
Yield: 40.1 %

Procedure:
To a solution of N-(2-aminomethyl-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea (0.20 g, 0.63 mmol) and N-carbo-tert-butoxyglycine (0.11 g, 0.63 mmol, 1.0 equiv) in THF (2 mL) at room temp. were added dicyclohexylcarbodiimide (0.13 g, 0.63 mmol, 1.0 equiv) and 1-hydroxybenzotriazole monohydrate (0.008 g, 0.06 mmol, 10 mol %). The resulting mixture was allowed to stir 18 h, diluted with EtOAc (5 mL), and washed with a saturated NaCl solution. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient from 30% EtOAc/hexane to 50% EtOAc/hexane) to afford N-(2-(N-(N-carbo-tert-butoxyglycyl)aminomethyl)-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea (0.12 g, 40%, Example 52): mp 174-176° C.; 1H NMR (CDCl3) δ1.38 (s, 9H), 2.27 (m, 3H), 4.38 (m, 2H), 6.67 (bs, 1H), 6.89 (m, 1H), 7.27 (m, 1H), 7.33 (m, 2H), 8.58 (bs, 1H); FAB-LRMS m/z 475 (M+H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([C:17]2[CH:22]=[C:21]([I:23])[C:20]([O-:24])=[C:19]([I:25])[CH:18]=2)=[C:8]2[CH:14]=[C:13]([I:15])[C:11](=[O:12])[C:10]([I:16])=[CH:9]2)[C:4]([C:26]([O-:28])=[O:27])=[CH:3][CH:2]=1.[Na+:29].[Na+].[CH2:31]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([C:42](=[O:53])[C@H:43]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([NH2:52])[CH:47]=2)[NH2:44])[CH2:38][CH2:37]1)=[O:35])[CH3:32].C([O-])(=O)C.[Na+].[N:59]#[C:60]Br>C(O)C>[CH:1]1[CH:6]=[C:5]([C:7]([C:8]2[CH:9]=[C:10]([I:16])[C:11]([O-:12])=[C:13]([I:15])[CH:14]=2)=[C:17]2[CH:18]=[C:19]([I:25])[C:20](=[O:24])[C:21]([I:23])=[CH:22]2)[C:4]([C:26]([O-:28])=[O:27])=[CH:3][CH:2]=1.[Na+:29].[Na+:29].[CH2:31]([O:33][C:34]([N:36]1[CH2:37][CH2:38][N:39]([C:42](=[O:53])[C@H:43]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([NH:52][C:60]#[N:59])[CH:47]=2)[NH2:44])[CH2:40][CH2:41]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)Cc2cccc(N)c2)CC1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: O=C1C(I)=CC(=C(c2cc(I)c([O-])c(I)c2)c2ccccc2C(=O)[O-])C=C1I
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)Cc2cccc(NC#N)c2)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
TIPPS-3-amino-(L)-phenylalanine-4-ethoxycarbonylpiperazide (14.6 g; 24.9 mmol), sodium acetate (anhydrous) (5.11 g; 62.2 mmol) and cyanogen bromide (2.9 g; 27.4 mmol) were dissolved in ethanol and the solution was stirred at RT for 10 h. After evaporating the solvent, the residue was taken up in ethyl acetate and the solution was extracted with 5% KHSO4, 5% NaHCO3 and distilled water. After evaporating the solvent, the crude product was purified chromatographically over silica gel.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10](Cl)(=[O:14])[C:11](Cl)=[O:12].[NH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>CCOCC.O1CCCC1>[N:20]1[CH:21]=[CH:22][C:17]([NH:16][C:10](=[O:14])[C:11]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:12])=[CH:18][CH:19]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccncc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Nc1ccncc1)C(=O)c1c[nH]c2ccccc12
Reaction time: 3 h

Procedure:
A solution of 10 g (85.3 mmol) of indole in 100 ml of ether is added dropwise at 0° C. to a solution of 9 ml of oxalyl chloride in 100 ml of anhydrous ether. The mixture is kept under reflux for 3 hours. A suspension of 12 g (127.9 mmol) of 4-aminopyridine in 500 ml of tetrahydrofuran is then added dropwise at −5° C., and the reaction mixture is heated to reflux temperature with stirring for 3 hours and allowed to stand overnight at room temperature. The precipitate is filtered and treated with water and the dried compound is purified on a silica gel column (silica gel 60, Merck AG, Darmstadt) using the eluent methylene chloride/ethanol (10:1, v/v).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]=[O:13].[H-].[Na+].[CH3:16]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:16])[CH:7]=[C:6]2[CH:12]=[O:13]
Reactant: CI
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)c(C=O)cn2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-methoxyindole-3-carboxaldehyde (80 g) in dimethylformamide (1L) under nitrogen was treated portion-wise with sodium hydride (20.1 g, 60% dispersion in mineral oil) over 15 minutes. After stirring at ambient temperature for 30 minutes the mixture was treated dropwise with methyl iodide (31.3 mL) over 10 minutes and stirring was then continued for a further 2 hours. The reaction mixture was poured cautiously into water then extracted with ethyl acetate. The organic phase was washed with water, then dried over sodium sulfate and then evaporated. The residue was triturated with pentane to give the title compound (76 g) as a pale brown solid, m.p. 133–134° C. 1H NMR [(CD3)2SO]: δ 9.86 (1H, s); 8.20 (1H, s); 7.60 (1H, d, J=2.6 Hz); 7.50 (1H, d, J=8.9 Hz); 6.96 (1H, dd, J=8.9 and 2.6 Hz); 3.86 and 3.80 (6H, s).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][CH2:11][C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][CH:23]([CH3:26])[CH2:24][OH:25]>>[OH:25][CH2:24][CH:23]([NH:22][C:18]([C:14]1[S:13][C:12]([CH2:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20])[CH3:26]
Reactant: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)O)s1
Reactant: CC(N)CO
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)NC(C)CO)s1
Yield: 58 %

Procedure:
As described for example 49, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid (80 mg, 0.26 mmol) was converted, using rac-2-amino-1-propanol instead of 1-amino-2-methyl-propan-2-ol, to the title compound (55 mg, 58%) which was obtained as a light brown oil. MS: m/e=366.1 [M+H]+.