Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][NH:19][C:18]1=[O:22])(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][NH:19][C:18]1=[O:22]
Reactant: CC(C)(C)OC(=O)NCCn1cc[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCn1cc[nH]c1=O
Reaction time: 3 h

Procedure:
Add trifluoro-acetic acid (10 mL) to a solution of [2-(2-oxo-2,3-dihydro-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (2.5 g, 11 mmol) in dichloromethane (10 mL). Stir the mixture for 3 hours. Remove most of the solvent and trifluoro-acetic acid on a rotovap and dry the yellowish thick oil under vacuum to get the product. GCMS (EI) m/z 127 M+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:21]=[CH:20][C:6]2[N:7]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])=[N:9][C:5]=2[CH:4]=1.C(N(CC)C(C)C)(C)C.[C:31]([O:35][C:36]([NH:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[CH2:44][CH:43]([C:48](O)=[O:49])[CH2:42]2)=[O:37])([CH3:34])([CH3:33])[CH3:32].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[C:31]([O:35][C:36](=[O:37])[NH:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[CH2:44][CH:43]([C:48]([N:17]1[CH2:16][CH2:15][CH:14]([N:7]3[C:6]4[CH:20]=[CH:21][C:3]([CH3:2])=[CH:4][C:5]=4[N:9]=[C:8]3[C:10]([OH:13])([CH3:12])[CH3:11])[CH2:19][CH2:18]1)=[O:49])[CH2:42]2)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CC(C(=O)O)C2
Reactant: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCN(C(=O)C2Cc3ccc(NC(=O)OC(C)(C)C)cc3C2)CC1
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
To a solution of 2-(5-methyl-1-piperidin-4-yl-1H-benzoimidazol-2-yl)-propan-2-ol hydrochloride salt (158 mg, 0.55 mmol) in DMF (5 ml) was added N,N-diisopropylethylamine (150 mg, 1.15 mmol). After stirring for 10 minutes, 5-tert-butoxycarbonylamino-indan-2-carboxylic acid (140 mg, 0.55 mmol) was added to the reaction mixture followed by EDCI (195 mg, 1.10 mmol) and HOBT (137 mg, 1.10 mmol). After stirring at rt for 4 hours, the reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated NaHCO3, brine, and dried over Na2SO4. The extracts were filtered and concentrated in vacuo to afford (2-{4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-benzoimidazol-1-yl]-piperidine-1-carbonyl}-indan-5-yl)-carbamic acid tert-butyl ester (266 mg, 98%) as a white solid without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=O)[CH:17]=[N:18][CH:19]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:20][C:16]2[CH:17]=[N:18][CH:19]=[C:14]([Br:13])[CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=Cc1cncc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N=Cc2cncc(Br)c2)cc1
Temperature: 25 °C
Yield: 101.4 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (16.5 g, 100 mmol), 5-bromo-pyridine-3-carbaldehyde (18.6 g, 100 mmol) and p-toluenesulfonic acid (380 mg, 2 mmol) in toluene (200 mL) was heated to reflux for 12 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(5-bromo-pyridin-3-ylmethylene)-amino]-benzoic acid ethyl ester (33.8 g, quant.) as a light yellow solid: LC/MS m/e calcd for C15H13BrN2O2 (M+H)+: 334.19, observed: 332.9 & 335.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]1[C:21]([F:22])=[C:20]([CH:23]2[O:28][CH2:27][CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:25][O:24]2)[CH:19]=[CH:18][C:17]=1[OH:38]>>[F:22][C:21]1[C:16]([F:15])=[C:17]([O:38][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:18]=[CH:19][C:20]=1[CH:23]1[O:24][CH2:25][CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:27][O:28]1
Reactant: CCCCCCCBr
Reactant: CCCCCCCCCC1COC(c2ccc(O)c(F)c2F)OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCCC1COC(c2ccc(OCCCCCCC)c(F)c2F)OC1

Procedure:
Quantities: 1-bromoheptane (0.31 g, 1.46 mmol), potassium carbonate (0.4 g, 3 mmol) and compound from Example 126 (0.Sg, 1.46 mmol). The experimental procedure was as described in Example 38.
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[CH:55]=[C:54]([O:56][C@@H:57]([C@H:59]2[CH2:63][O:62][C:61]([CH3:65])([CH3:64])[O:60]2)[CH3:58])[N:53]=[C:52]([S:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[C:69]=2[F:75])[N:51]=1.[Cl-].[NH4+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:75][C:69]1[C:70]([F:74])=[CH:71][CH:72]=[CH:73][C:68]=1[CH2:67][S:66][C:52]1[N:51]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:55]=[C:54]([O:56][C@@H:57]([C@H:59]2[CH2:63][O:62][C:61]([CH3:64])([CH3:65])[O:60]2)[CH3:58])[N:53]=1
Reactant: NS(=O)(=O)N1CCC1
Reactant: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@H]1COC(C)(C)O1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@H]1COC(C)(C)O1
Temperature: 100 °C

Procedure:
A mixture of azetidine-1-sulphonamide (prepared according to patent WO 2004/011443, 0.20 g), tris(dibenzylideneacetone)-dipalladium (0) (33 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (17 mg), cesium carbonate (0.18 g) and 4 chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy]-pyrimidine (the product of step v) (0.15 g) in dioxane (5 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 25 min. Saturated aqueous ammonium chloride was added and the resulting mixture extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using EtOAc/isohexane (1:19 to 3:7 gradient) as eluent to give the subtitle compound as a yellow oil. Yield: 0.14 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](OCC)=[O:14])[CH:5]=[CH:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][OH:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnoc1-c1cccc(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of ethyl 5-(3-chlorophenyl)isoxazole-4-carboxylate (8.50 g) in tetrahydrofuran (80 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 80 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(3-chlorophenyl)-4-isoxazolylmethanol (6.87 g, yield 97%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 80–81° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([CH2:20][C:21](OCC)=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)C>C1(C)C(C)=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:21](=[O:22])[CH2:20][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: Cc1ccccc1C
Product: Nc1ccc(NC(=O)CC(=O)c2ccccc2)cc1[N+](=O)[O-]

Procedure:
15.3 gm (0.1 mol) of 1,4-diamino-2-nitrobenzene were suspended in 100 ml of xylol. This suspension was heated. After the addition thereto of 42.3 gm (0.22 mol) of ethyl benzoylacetate, this suspension was heated on an oil bath at 130°C with the simultaneous distillation of ethanol, formed in the reaction. The precipitate was separated from the cold reaction mixture and processed, as described in Example I. The product had a melting point of 182°-183°C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:12]=[CH:11][C:10]2[CH2:9][CH:8]([NH:13][C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:38])[C@H:22]([NH:30]C(=O)OC(C)(C)C)[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:15])[CH2:7][CH2:6][C:5]=2[N:4]=1>C(O)(=O)C>[ClH:1].[ClH:1].[NH2:30][C@H:22]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:14]([NH:13][CH:8]1[CH2:7][CH2:6][C:5]2[N:4]=[C:3]([NH2:2])[N:12]=[CH:11][C:10]=2[CH2:9]1)=[O:15])=[O:38]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCc2nc(N)ncc2C1
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ncc2c(n1)CCC(NC(=O)[C@@H]1CCCN1C(=O)[C@H](N)Cc1ccccc1)C2
Yield: 62 %

Procedure:
HCl gas was bubbled for 50 minutes through a solution of tert-butyl (1R)-2-((2S)-2-{[(2-amino-5,6,7,8-tetrahydro-6-quinazolinyl)amino]carbonyl}pyrrolidinyl)-1-benzyl-2-oxoethylcarbamate (240 mg, 0.47 mmol) in 15 mL of anhydrous acetic acid at room temperature. Acetic acid was evaporated under reduced pressure and the residue was triturated several times with diethyl ether to yield 141 mg (62%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](=[O:21])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[OH:1][C:2]1[C:3]([C:12](/[C:13](=[CH:22]\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)/[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[O:21])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC(C)(C)OC(=O)CC(=O)c1cc2ccccc2cc1O
Reactant: O=Cc1ccccc1
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)/C(=C/c1ccccc1)C(=O)c1cc2ccccc2cc1O
Yield: 56.9 %

Procedure:
Prepared according to general procedure A using tert-butyl 3-(3-hydroxynaphthalen-2-yl)-3-oxopropanoate (286 mg, 1.0 mmol), benzaldehyde (100 μL, 1.00 mmol), 15.0 mL benzene, piperidine (10 μL, 0.10 mmol) and glacial acetic acid (5.7 μL, 0.10 mmol), refluxed for 4 h. Purified via recrystallization from hexanes/CH2Cl2, yielding 213 mg (57%) of yellow solid. mp=132-135° C.; IR (film) 2977.6; 1716.6; 1639.5; 1154.5 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.20 (bs, 1H), 8.19 (s, 1H); 7.96 (s, 1H), 7.70 (t, J=7.3 Hz, 2H), 7.51 (t, J=8.0 Hz, 1H), 7.40-7.25 (m, 7H), 1.38 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 201.9, 163.9, 157.1, 142.8, 138.7, 135.1, 132.8, 131.6, 130.8, 130.4, 130.2, 129.8, 129.2, 127.3, 126.6, 124.4, 121.7, 112.6, 83.0, 28.1; LRMS (electrospray): Mass calculated for C24H22O4 [M]+, 374.15. Found [M+23]+, 397.0.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]([CH2:11][C:12]([O:14]C)=[O:13])[CH2:9][O:10][C:6]=2[CH:5]=[C:4]([OH:16])[CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[C:7]2[CH:8]([CH2:11][C:12]([OH:14])=[O:13])[CH2:9][O:10][C:6]=2[CH:5]=[C:4]([OH:16])[CH:3]=1
Reactant: COC(=O)CC1COc2cc(O)cc(F)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC1COc2cc(O)cc(F)c21
Yield: 94 %

Procedure:
A mixture of methyl 2-(4-fluoro-6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate (254 mg), a 1 M aqueous sodium hydroxide solution (4.5 mL), and methanol (3 mL) was stirred at room temperature for 3 hours. To the reaction mixture, 1 M hydrochloric acid (4.5 mL) was added, followed by extraction with ethyl acetate. The extract was washed with brine and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (224 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Mg].II.[C:13]([N:20]1[CH2:23][C:22](=[O:24])[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Cl-].[NH4+]>O1CCCC1.C(OCC)C.O>[Cl:9][C:4]1[CH:3]=[C:2]([C:22]2([OH:24])[CH2:21][N:20]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:23]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2cc(F)cc(Cl)c2)C1
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
A mixture of 1-bromo-3-chloro-5-fluorobenzene (1.47 g, 7.01 mmol), magnesium turnings (0.82 g, 31.1 mmol) and a small piece of iodine in dry tetrahydrofuran (50 mL), under nitrogen was gently heated until reaction started and stirred for 1 h at ambient temperature after which a solution of 1-Boc-3-azetidinone (1.0 g, 5.85 mmol) in dry diethyl ether (10 mL) was added dropwise. The resulting mixture was stirred for 15 min and water (70 ml) and saturated aqueous ammonium chloride (20 mL) was added and the mixture was extracted with ethyl acetate (2×50 ml). The combined organic phase was dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography on silica gel (ethylacetate/isooctane 1:4 to 1:1) to give the title compound (1.25 g). MS m/z (rel. intensity, 70 eV) 285 (M+, 1), 156 (60), 141 (43), 127 (80), 57 (bp).
Reaction SMILES: C(N1CCOCC1)C.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:24][C@H:25]([C:38]([NH:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:39])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:29][CH:28]=1.Cl.[NH:48]([C:65]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:66])[C@H:49]([C:62](O)=[O:63])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[CH:53][CH:52]=1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[NH:48]([C:65]([O:67][CH2:68][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)=[O:66])[C@H:49]([C:62]([NH:24][C@H:25]([C:38]([NH:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:39])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:29][CH:28]=1)=[O:63])[CH2:50][C:51]1[CH:52]=[CH:53][C:54]([O:57][C:58]([CH3:59])([CH3:61])[CH3:60])=[CH:55][CH:56]=1
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: CCOC(=O)CNC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1

Procedure:
5.12 ml (40 mmoles) of N-ethylmorpholine and 8.65 g (42 mmoles) of DCC are added at 0° C. to a solution of 14.35 g (40 mmoles) of H-Tyr(But)-Gly-OEt.HCl, 14.84 g (40 mmoles) of Z-Tyr(But)-OH and 5.4 g (40 mmoles) of HOBt in 100 ml of dimethylformamide. The mixture is worked up as in Example 1 a. The residue is triturated with petroleum ether. Yield 26.3 g. The substance is purified by chromatographing a solution in 9:1 methylene chloride/acetone over 150 g of silica gel. The fractions were concentrated and the residue triturated with ether. Yield 19.74 g (73%), melting point 113°, [α]D22 =-28.7° (c=1, methanol).
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([N:17]1C(=O)C2C(=CC=CC=2)C1=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6](=[O:8])[O-:7])(C)C.CN.NN>CO>[NH2:17][CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:5][C:6](=[O:8])[O:7][C:11]([CH3:16])([CH3:12])[CH3:10]
Reactant: CC(C)(C)N(CC(c1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)[O-]
Agent: CN
Agent: NN
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Reaction time: 12 h
Yield: 170.5 %

Procedure:
A solution of 1,1-dimethylethyl[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-phenylethyl]carbamate (2 g, 5.46 mmol) and either MeNH2 (40 wt % in H2O, 10 eq.) or NH2NH2 (10 eq.) in MeOH (0.5M, 10 mL) was heated to 60° C. in a sealed tube. After 12 h, the solution was concentrated and purified via column chromatography (silica-dry load, 2% MeOH in DCM (1% NH4OH)) affording the title compound (1.1 g, 85%) as a white solid: LC-MS (ES) m/z=237 (M+H)+.
Reaction SMILES: N.Cl.[CH2:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[NH:8][CH2:7][C:6]1=[O:12])[CH3:4].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(Cl)(Cl)Cl>[CH2:21]([O:20][C:18](=[O:19])[C:17](=[CH:16][N:8]1[CH2:7][C:6](=[O:12])[N:5]([CH2:3][CH3:4])[CH2:10][C@@H:9]1[CH3:11])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCN1C[C@H](C)NCC1=O
Agent: Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=CN1CC(=O)N(CC)C[C@@H]1C)C(=O)OCC
Temperature: 100 °C

Procedure:
Anhydrous ammonia gas was bubbled into a cold (0° C.) solution of (5S)-1-Ethyl-5-methylpiperazin-2-one hydrochloride (5.8 g, 32.3 mmol) in chloroform for 30 minutes. The resultant slurry was filtered and concentrated under vacuum. The residual oil was concentrated as a solution in toluene under vacuum, redissolved in toluene (120 mL) and treated with diethyl ethoxymethylenemalonate (7.0 g, 32.3 mmol) and heated in a sealed flask in an oil bath at 100° C. overnight. The resultant solution was concentrated under vacuum. The residual oil was concentrated as a solution in toluene under vacuum to provide the corresponding diethyl{[(2S)-4-ethyl-2-methyl-5-oxopiperazin-1-yl]methylene}malonate. Without further purification, to a solution of the malonate (10.5 g, 33.5 mmol) in anhydrous THF (330 mL) warmed with an external oil bath at 65° C. under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide (35.1 mL, 1 M, 35.1 mmol) was added. The solution was heated at the same temperature for one hour and concentrated under vacuum. The residue was partitioned between dichloromethane and hydrochloric acid (1M). The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with diethyl ether. The solid precipitated was filtered, washed with diethyl ether to provide the title compound as pale brown solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][NH2:53])=[CH:50][CH:49]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:53][CH2:52][C:51]4[CH:54]=[CH:55][C:48]([Cl:47])=[CH:49][CH:50]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: NCc1ccc(Cl)cc1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 4-chlorobenzylamine (Aldrich) to give the title product. LC-MS (ES+) 788 [(M+H)+].
Reaction SMILES: [I:1][C:2]1[CH:25]=[C:24]([I:26])[CH:23]=[C:22]([I:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=O.C(OCC)(=O)[CH2:29][C:30]([O:32]CC)=[O:31]>>[I:1][C:2]1[CH:25]=[C:24]([I:26])[CH:23]=[C:22]([I:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:29][C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(O)CCCCCCCCCCCCCCOc1c(I)cc(I)cc1I
Product: O=C(O)CCCCCCCCCCCCCCCCOc1c(I)cc(I)cc1I

Procedure:
According to the method described in Arch. Pharm. (Weinheim) 328, 271 (1995), addition of two carbon atoms was performed to 15-(2,4,6-triiodophenoxy)pentadecanoic acid by using diethyl malonate to obtain 17-(2,4,6-triiodophenoxy)heptadecanoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[O:20](C(C(F)(F)F)=O)[C:21]([C:23]([F:26])([F:25])[F:24])=O.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:20])[C:23]([F:26])([F:25])[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (10 g, 53.69 mmol) and pyridine (8.7 mL, 107.57 mmol) in CH2Cl2 (100 mL) was added dropwise (CF3CO)2O (10.5 mL, 75.54 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 2 h. 2N HCl (60 mL) was then added. The organic layer was dried over MgSO4, filtered, and then concentrated. The resulting residue, the title compound, was used in the next reaction without further purification. MS m/z (MH+-Boc) 183.1, (MH+-C4H9) 227.1; NMR (300 MHz, CDCl3): δ 3.45-3.7 (m, 8H), 1.5 (s, 9H).
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:18][CH:17]=1)[C:11]([O:13]C)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34]>>[ClH:34].[C:1]([NH:9][C@@H:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:18][CH:17]=1)[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(OCCCCNc2ncccn2)cc1)NC(=O)c1ccccc1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(OCCCCNc2ncccn2)cc1)C(=O)O)c1ccccc1

Procedure:
A solution of 26-2 (250 mg, 0.56 mmol), in 6N HCl (6 mL) was heated at 60° C. for 2.0 h. The solution was concentrated to give 26-3 as a solid, which was used directly in the next step.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]1=[O:11].[CH2:12](I)[CH3:13]>>[CH2:12]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[N:1]=1)[CH3:13]
Reactant: O=c1ccc2c([nH]1)CCCC2
Reactant: CCI
Product: CCOc1ccc2c(n1)CCCC2

Procedure:
Following the procedure described in Example 1A, step 2, 5,6,7,8-tetrahydroquinolin-2 (1H)-one and EtI gave the title compound as a pale yellow oil.