Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]([O:10][CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])[CH3:13])=[O:9]>C1COCC1.CCOCC.O>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:12]([CH3:13])[CH2:11][O:10][C:8]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9])([O-:22])=[O:21]
Reactant: CC(COC(=O)Cl)c1ccccc1[N+](=O)[O-]
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(COC(=O)N1CCCCC1)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
A solution of piperidine (22.8 mL, 230 mmol) in anhydrous THF (50 mL) was added dropwise to a solution of 2-(2-nitrophenyl)propyl chloroformate (28.20 g) in anhydrous THF (100 mL). The reaction mixture was then brought to reflux for 3 h and stirred at room temperature overnight. The solvent was evaporated to afford light brown oil. The mixture was diluted with ether (100 mL) and water (100 mL) was added. The organic phase was separated and the aqueous phase was re-extracted with ether (3×50 mL). The organic extracts were combined and dried over MgSO4, filtered, and the solvent was removed in vacuo. The residue was purified on a silica gel column. Elution of the column with 20% ethyl acetate in hexanes gave 16.54 g (56.6 mmol, 63.6% yield, 56.6% total yield) of 2-(2-nitrophenyl)propoxycarbonyl piperidine. 1H-NMR (600 MHz, DMF-d7): δ 7.88 (d, J=8.1 Hz, 1H, Ar—H), 7.74 (m, 2H, Ar—H), 7.53 (t, J=7.1 Hz, 1H, Ar—H), 4.23 (m, 2H, CH2), 3.54 (m, 1H, CH), 3.24 (m, 4H, CH2), 1.50 (m, 2H, CH2), 1.35 (m, 7H, CH2 and CH3). 13C-NMR (150 MHz, DMF-d7): δ 155.09 (OCOR), 151.50 (C ipso to NO2), 137.90 (C ipso to CH(CH3)CH2OCOR), 133.49 (C para to NO2), 129.31 (C para to CH(CH3)CH2OCOR), 128.44 (C ortho to CH(CH3)CH2OCOR), 124.35 (C ortho to NO2), 69.45 (CH2OCOR), 45.08 (Cα to ring N), 34.26 (CH), 26.08 (Cβ to ring N), 24.69 (Cγ to ring N), 17.91 (CH3). TLC: 20% ethyl acetate in hexanes, Rf=0.4. Mass analysis (MALDI-TOF): calculated for C15H21N2O4 293.34, found 293.24.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[CH:23]([Si:25]([O:30][CH3:31])([O:28][CH3:29])[O:26][CH3:27])=[CH2:24]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH3:27][O:26][Si:25]([O:30][CH3:31])([O:28][CH3:29])[CH:23]=[CH:24][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)Oc1ccc(Br)cc1
Reactant: C=C[Si](OC)(OC)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CO[Si](C=Cc1ccc(OC(=O)OC(C)(C)C)cc1)(OC)OC

Procedure:
Into a mixture of 20 ml of triethylamine and 40 ml of acetonitrile, were dissolved 15.0 g (54.9 mmol) of 1-(t-butoxycarbonyloxy)-4-bromobenzene synthesized in the step (i) and 9.76 g (65.9 mmol) of vinyltrimethoxysilane, and the reaction system was substituted by argon by bubbling argon in thus obtained solution. In the reaction system, was added 246.5 mg (1.1 mmol) of palladium acetate as a catalyst, the mixture was refluxed for one night. After completion of the reaction, solvent was removed, and the obtained residue was extracted by hexane. Hexane was removed from the extraction to prepare 9.5 g of 1-(2-trimethoxysilylvinyl)-4-(t-butoxycarbonyloxy)benzene being the objective compound.
Reaction SMILES: [Cl:1][C:2]1[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.O.C([NH:34][C@H:35]([C:42]([N:44]1[CH2:51][CH2:50][CH2:49][C@H:45]1[C:46]([NH2:48])=[O:47])=[O:43])[CH2:36][C:37]1[N:41]=[CH:40][NH:39][CH:38]=1)(=O)C1NC(=O)NC(=O)C=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:3]=1[C:4]([NH:34][C@H:35]([C:42]([N:44]1[CH2:51][CH2:50][CH2:49][C@H:45]1[C:46]([NH2:48])=[O:47])=[O:43])[CH2:36][C:37]1[N:41]=[CH:40][NH:39][CH:38]=1)=[O:6]
Reactant: O=C(O)c1[nH]c(=O)[nH]c(=O)c1Cl
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)c1cc(=O)[nH]c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)c1[nH]c(=O)[nH]c(=O)c1Cl
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
4.8 g of 5-chloro orotic acid, 3.6 g of 1-hydroxybenzotriazole and L-histidyl-L-prolinamide dihydrobromide (prepared from 9.7 g N-benzyloxycarbonyl-L-histidyl-L-prolinamide as described in Example 2) are mixed with 150 ml of dimethylformamide. After chilling to -5° C. while stirring 7.0 ml of triethylamine and then the solution of 5.2 g of N,N'-dicyclohexylcarbodiimide in 20 ml of dimethylformamide are added. Under continuous stirring the mixture is stored for 90 minutes at -5° to 0° C. and thereafter for 24 hours, during which time it is allowed to warm to room temperature. The precipitate formed is separated by filtration and the filtrate is evaporated under reduced pressure at a temperature of about 35° C. The residue is treated with 75 ml of water, stored for 12 hours at 0° C. and filtered. The filtrate is stirred for 10 minutes with 75 g of a cationic exchanger in the free acid form (as, for instance, the product named in Example 2). After separating the resin it is washed four times with 250 ml of water each and four times with 50 ml of methanol each. Then the cationic exchanger resin is suspended in 100 ml of water, while stirring treated with 120 ml of 1n ammonia, sucked off and washed six times with 20 ml of 1n ammonia each. The combined ammoniacal filtrates are, at about 35° C. under reduced pressure, evaporated to a small volume and finally lyophylized. The residue is two times recrystallized from water/ethanol (1:1) and thereafter dried in vacuum over phosphorus pentoxide. Thus, 4.7 g (44.8% of the theoretical yield) of 5-chloro-orotyl-L-histidyl-L-prolinamide, melting at 204° - 206° C. are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:20]=[C:19]([NH:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:18]=2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:36]I>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:20]=[C:19]([N:30]([CH3:36])[C:31]([N:33]([CH3:34])[CH3:35])=[O:32])[CH:18]=2)=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(-n2nc(NC(=O)N(C)C)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(N(C)C(=O)N(C)C)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Sodium hydride 60% dispersion in mineral oil 93.1 mg was added in one portion to a solution of N-[5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N′,N′-dimethylurea 1.43 g in DMF 10 ml under ice bath cooling. The reaction mixture was stirred at ambient temperature for 1 hour. MeI 688 mg was added the reaction mixture was stirred at ambient temperature overnight. The mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt-n-hexane=75%, 80% to give N-[5-[4-(benzyloxy)phenyl]-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-N,N′,N′-trimethylurea 1.45 g as an oil.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[H-].[Na+].[O:15]([CH2:22][CH2:23][CH2:24]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[O:15]([CH2:22][CH2:23][CH2:24][N:4]1[C:5](=[O:6])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:1]1(=[O:2])=[O:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCCOc1ccccc1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCOc1ccccc1

Procedure:
The title compound was synthesized analogously to 83.8 (see experimental below), using a solution of saccharin (92 mg, 0.5 mmol) in DMF (anhydrous, 4 mL), NaH (60% dispersion in mineral oil, 21 mg, 0.52 mmol) and a solution of 3-phenoxypropyl bromide (130 mg, 0.6 mmol) in anhydrous DMF (1 mL). The crude obtained after workup was purified by flash column chromatography on silica gel (25% ethyl acetate-petroleum ether) to give 83.4 as a white solid (m p 83-86° C.) in 65% yield (130 mg). 1H NMR (500 MHz, CDCl3) δ 8.08 (dd, J=7.5 Hz, J=1.5 Hz, 1H), 7.95 (dd, J=7.5 Hz, J=1.5 Hz 1H), 7.89 (td, J=7.5 Hz, J=1.5 Hz, 1H), 7.85 (td, J=7.5 Hz, J=31.5 Hz, 1H), 7.30 (t, J=8.0 Hz, 2H), 6.97 (t, J=8.0 Hz, 1H), 6.93 (d, J=8.0 Hz, 2H), 4.11 (t, J=6.2 Hz, 2H), 4.04 (t, J=7.1 Hz, 2H), 2.36 (quintet, J=7.5 Hz, 2H).
Reaction SMILES: C([O:3][C:4](=[O:43])[CH:5]([O:7][P:8]([CH2:17][CH2:18][NH:19][C:20](=[O:42])[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:29][C:30]2[N:31]=[C:32]3[C:37](=[N:38][CH:39]=2)[N:36]=[C:35]([NH2:40])[N:34]=[C:33]3[NH2:41])[CH3:28])=[CH:23][CH:22]=1)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[CH3:6])C.[OH-].[Na+]>CN(C=O)C.C(#N)C.O>[NH2:40][C:35]1[N:34]=[C:33]([NH2:41])[C:32]2[C:37](=[N:38][CH:39]=[C:30]([CH2:29][N:27]([CH3:28])[C:24]3[CH:25]=[CH:26][C:21]([C:20]([NH:19][CH2:18][CH2:17][P:8]([O:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)([O:7][CH:5]([CH3:6])[C:4]([OH:43])=[O:3])=[O:9])=[O:42])=[CH:22][CH:23]=3)[N:31]=2)[N:36]=1
Reactant: CCOC(=O)C(C)OP(=O)(CCNC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3n2)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CC(OP(=O)(CCNC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3n2)cc1)Oc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
To a solution of 2-[(2 {4-[(2,4-diaminopteridin-6-ylmethyl)methyl-amino]benzoylamino}ethyl)phenoxy-phosphinoyloxy]propionic acid ethyl ester (mixture of diastereomers at phosphorus; 40.0 mg, 65.7 μmol) in DMF (0.4 mL), acetonitrile (0.2 mL) and water (0.2 mL) was added aqueous sodium hydroxide (1 N. 131.4 μL). The solution was stirred at ambient temperature for 4 hours. The solvents were removed in vacuo and the crude product was purified by RP HPLC on C18 column using H2O/acetonitrile (2-95%) to provide 23.7 mg (71.3%) of the pure product. 1H NMR (300 MHz, DMSO-d6) δ 1.30 (d, 2H, J=6.9 Hz), 1.79 (m, 2H), 3.21 (s, 3H), 3.37 (m, 2H), 4.61 (m, 1H), 4.81 (s, 2H), 6.79 (d, 2H, J=8.7 Hz), 7.64 (d, 2H, J=9.7 Hz), 8.25 (br 5, 1H), 8.63 (s3 1H); 31P (121.4 MHz, DMSO-d6) δ 25.1. MS (m/z) 505.2 [M+H]+.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]#N.[CH3:11][CH2:12]O.CCOC(C)=O>[Pd]>[NH2:9][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:2]([C:1]#[N:8])=[CH:3][CH:4]=1
Reactant: N#N
Reactant: N#Cc1ccccc1
Reactant: CCO
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CCN)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-2-azidoethyl)benzonitrile (500 mg, 2.90 mmol) in 1:1 EtOH/EtOAc (3 mL) at 0° C. was purged with N2. Then Pd/C (440 mg) was added and a H2 balloon was placed over the reaction. After stirring at 0° C. for two hours, the reaction mixture was filtered through a pad of celite and concentrated to give 4-(2-aminoethyl)benzonitrile, which was used without further purification. LCMS (ES) 147.3 m/z (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[CH3:26]>O>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[CH3:26])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCCCn1ccnc1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1NCCCn1ccnc1
Temperature: 90 °C

Procedure:
A mixture of 250.4 g (2 mol) of 3-imidazol-1-ylpropylamine and 82.8 g (0.6 mol) of potassium carbonate in 280 ml of water was heated to 90° C. 155.1 g (1 mol) of 1-fluoro-2-methyl-4-nitrobenzene were added dropwise over 30 minutes and the mixture was maintained at a temperature of 90-95° C. for 4 hours.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.NC1C=C(NC(=O)C)C=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:30]([NH:29][C:25]1[CH:24]=[C:23]([N:15]([CH2:16][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][N:9]=2)[CH:28]=[CH:27][CH:26]=1)(=[O:32])[CH3:31]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCCC2)c2cccc(NC(C)=O)c2)s1
Agent: CC(=O)Nc1cccc(N)c1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Product: CC(=O)Nc1cccc(N(CC2CCCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-cyclohexylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-amino-phenyl)-acetamide, cyclohexylcarbaldehyde and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)c3ccc(Cl)cc3)cc2C(C)(c2ccccc2)CC1(C)C
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), 4-chlorobenzoyl chloride (11 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was stirred for 18 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with 0.5 HCl, water, 5% aq. NaHCO3, water and brine. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/0=>0/1 (v/v) as eluent.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]2[C:21](=[CH:22][CH:23]=1)[CH2:20][C@:10]1([C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]1=[O:19])[CH2:9]2.[OH:24]S(O)(=O)=O>O>[OH:24][C:6]1[CH:7]=[C:8]2[C:21](=[CH:22][CH:23]=1)[CH2:20][C@:10]1([C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]1=[O:19])[CH2:9]2
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1Nc2ncccc2[C@]12Cc1ccc(O)cc1C2
Temperature: 25 °C

Procedure:
A solution of sodium nitrite (275 mg, 3.98 mmol) in water (1.6 mL) was slowly added to a cooled mixture of (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (1 g, 3.98 mmol, described in Intermediate 3) in of 10% aqueous H2SO4 (8 mL) at 0° C. The ice bath was removed and the reaction allowed to stir at ambient temperature. The reaction mixture was then placed into a 70° C. oil bath and the bath was heated to 100° C. Bubbling was observed and heating was continued until LCMS indicated that the reaction was complete. The reaction was slowly neutralized by addition of 30% NH4OH (ca. 2 mL) and the precipitate was collected by filtration and washed with water. The solid was then air dried and chromatographed by first mixing with silica and dry loading on a silica gel column. The product was eluted. with (10% MeOH/CH2Cl2). Concentration of the product containing fractions gave the title compound. MS: m/z=253 (M+1).
Reaction SMILES: N1C=CC=C(CCC[CH2:10][C:11]([OH:13])=[O:12])C=1.[N:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22]Br)=[CH:16][CH:15]=1>>[N:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:10][C:11]([OH:13])=[O:12])=[CH:16][CH:15]=1
Reactant: BrCCCc1ccncc1
Reactant: O=C(O)CCCCc1cccnc1
Product: O=C(O)CCCCc1ccncc1
Yield: 24 %

Procedure:
4-Pyridinevaleric acid was prepared according to the procedure employed in the preparation of 3-pyridinevaleric acid. From 56.0 g of the hydrobromide salt of 3-(4-pyridyl)propyl bromide there was obtained 10.4 g (24%) of 4-pyridinevaleric acid, mp 195°-200° C. The analytical sample was obtained from isopropanol, mp 200°-201° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH:8]1[NH:12][CH:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C:10]2([CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[S:9]1)[C:5]([OH:7])=[O:6].[C:34](Cl)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C.P(=O)(O)(O)O>ClCCl>[CH2:16]([O:15][C:13]([CH:11]1[C:10]2([CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)[S:9][CH:8]([CH:4]([NH:3][C:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:5]([OH:7])=[O:6])[NH:12]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(C(=O)O)C1NC(C(=O)OCc2ccccc2)C2(CCN(c3ccccc3)CC2)S1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C(NC(c1ccccc1)(c1ccccc1)c1ccccc1)C1NC(C(=O)OCc2ccccc2)C2(CCN(c3ccccc3)CC2)S1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
9.1 g (0.0177 mole) of alpha-amino-4-benzyloxycarbonyl-8-phenyl-1-thia-3,8-diazaspiro[4.5]decane-2-acetic acid dihydrochloride (obtained in 5.3) are suspended in 150 ml of dichloromethane. After cooling to -20° C., 18,6 g (0.0668 mole) of trityl chloride are added all at once. While maintaining the temperature at about -20° C., the suspension is slowly treated over the course of 1 hour with 17.6 g (0.17 mole) of triethylamine in 100 ml of dichloromethane. The reaction mixture is stirred for 1 hour at a temperature of from -10 to -20° C. and then left to stand overnight in a refrigerator, whereafter it is poured onto an ice-water mixture (pH about 11) and neutralized to about pH 6 by the addition of 85% phosphoric acid. The aqueous phase is extracted three times with 100 ml of dichloromethane. The combined extracts are washed with water and dried over anhydrous sodium sulfate, followed by evaporation to dryness under high vacuum on a waterbath at a temperature of from 20° to 25° C. The 4-benzyloxycarbonyl-8-phenyl-alpha-tritylamino-1-thia-3,8-diazaspiro[4.5]-decane-2-acetic acid thus obtained is used, without further purification, in step 7.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[CH3:14])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[BrH:19].BrBr>C(O)(=O)C>[Br:19][C:7]1[CH:6]=[C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[CH3:14])[CH:4]=[C:3]([C:15]([F:18])([F:17])[F:16])[C:2]=1[NH2:1]
Reactant: Br
Reactant: Cc1cn(-c2ccc(N)c(C(F)(F)F)c2)c(C)n1
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1cn(-c2cc(Br)c(N)c(C(F)(F)F)c2)c(C)n1

Procedure:
1-(4-Amino-3-trifluoromethylphenyl)-2,4-dimethylimidazole (10 g) was dissolved in glacial acetic acid (70 cm3). A solution of 45% w/w hydrogen bromide in glacial acetic acid (7.4 cm3) was added. A solution of bromine (2.1 cm3) in glacial acetic acid (30 cm3) was then added dropwise. The mixture was heated at 70° for 3 hours, cooled, concentrated to a small volume by evaporation in vacuo, and basified to pH 8 by addition of aqueous sodium carbonate solution. The aqueous phase was extracted with chloroform (3×200 cm3) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]), eluting with ethyl acetate. Combination and evaporation of appropriate fractions afforded 1-(3-bromo-4-amino-5-trifluoromethylphenyl)-2,4-dimethylimidazole (4.76 g), a small sample of which was recrystallised from ethyl acetate/hexane, m.p. 149°.
Reaction SMILES: [NH:1]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl-:16].[Mn+2:17].[Cl-:18]>CO>[Cl:16][CH:2]1[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][N:1]1[Cl:18].[Mn+2:17]
Reactant: C1CNCCNCCNCCNCCN1
Reactant: [Cl-]
Agent: [Mn+2]
Solvent: CO
Product: ClC1CNCCNCCNCCNCCN1Cl
Yield: 88 %

Procedure:
A solution of 1,4,7,10,13 -pentaazacyclopentadecane prepared as in Example 1E (2.0 g, 9.3 mmole) and anhydrous manganese(II) chloride (1.2 g, 9.3 mmole) in anhydrous methanol (50 ml) was refluxed under a dry nitrogen atmosphere for 3 h. The solution was filtered and the solvent removed in vacuo. The resulting solid was recrystallized from ethanol-ethyl ether to give 2.79 g (88% yield) of the product as an off-white crystalline solid: FAB mass spectrum (NBA) m/z (relative intensity) 340 (M+, 2), 305/307 ((M-Cl)+ 100/45)); Anal. Calcd. for C10H25Cl2 nN5 : C, 35.17; H, 7.38; Cl, 20.76; N 20.60. Found: C, 34.95; H, 7.31; Cl, 20.49; N, 20.22.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:13])=[O:6].[OH-:15].[Na+]>>[O:6]=[C:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH3:14])[CH2:7][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([OH:13])=[O:15]
Reactant: CC(C)CCC(=O)C1CCCCC1=O
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)CCC(=O)CCCCCC(=O)O

Procedure:
10 g of 2-(4'-methyl valeryl) cyclohexanone are added to 70ml of a 5% aqueous solution of sodium hydroxide. The mixture is heated under reflux for 2 hours. The aqueous solution is then made acidic with a 4 N solution of hydrochloric acid and is extracted with ether. The ethereous phase is separated, is washed with a saturated solution of sodium chloride, is dried on sodium sulphate, is filtered and is evaporated to dryness. The solid residue weighing 9g is left to stand at room temperature. The crystallization begins quickly. The crystals are recovered and are recrystallized from n- pentane (yield 6.2g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]1[C:20](=[O:37])[CH2:21][NH:22][C:23](=[O:36])[NH:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([O:34]C)=[O:33])[CH:28]=[CH:29][CH:30]=1>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:10]1[C:20](=[O:37])[CH2:21][NH:22][C:23](=[O:36])[NH:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([OH:34])=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(c3ccccc3)CCC2c2ccccc2OC)c1
Solvent: CO
Product: COc1ccccc1C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 51.4 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 1.2 g of methyl (2RS,5SR)-3-{3-{2-[2-(2-methoxyphenyl)-5-phenyl-1-pyrrolidinyl]-2-oxoethyl}ureido}phenylacetate in solution in 20 cm3 of methanol and 0.19 g of potassium hydroxide in solution in 4 cm3 of water, and after treatment and recrystallization in diethyl ether, 0.6 g of (2RS,5SR)-3-{3-{2-[2-(2-methoxyphenyl)-5-phenyl-1-pyrrolidinyl]-2-oxoethyl}ureido}phenylacetic acid, melting at 140° C., is obtained.