Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:3](C)=[CH:4]C=[CH:6][CH:7]=1.[C:9]([CH2:11][C:12]([OH:14])=[O:13])#[N:10].O[N:16]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:3]1([CH3:4])[C:11]([C:12]([NH2:16])=[O:14])=[CH:9][CH:6]=[CH:7][CH:2]=1.[C:9]([CH2:11][C:12]([OH:14])=[O:13])#[N:10]
Reactant: On1nnc2ccccc21
Reactant: Cc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccccc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
A mixture of o-toluidine (5.0 mL, 47 mmol), methylene chloride (15 mL), cyanoacetic acid (8.0 g, 94 mmol), 1-hydroxybenzotriazole (12.7 g, 94 mmol), 4-dimethylaminopyridine (5 crystals, catalytic amount), and 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.2 g, 94 mmol) was stirred at ambient temperature overnight. The reaction was concentrated and the residual pale yellow oil was partitioned between ethyl acetate and water. The phases were separated and the organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, and concentrated to 5.2 g of off-white solid. This solid was recrystallized from methylene chloride in two crops to afford cyanoacetic acid o-toluamide (4.71 g, 57%) as white crystals.
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]([C@H:20]2[CH2:22][O:21]2)[N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([NH:27][C:28]([C@@H:30]1[CH2:39][C@H:38]2[C@H:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][NH:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>CN(C)C=O>[C:23]([NH:27][C:28]([C@@H:30]1[CH2:39][C@H:38]2[C@H:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][N:31]1[CH2:22][C@@H:20]([OH:21])[C@@H:8]([N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C1c2ccccc2C(=O)N1[C@@H](Cc1ccccc1)[C@H]1CO1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 18 h
Yield: 59.8 %

Procedure:
A stirred solution of 4.39 g (15 mmol) of 2(S)-[2-phenyl-1(S)-phthalimidoethyl]oxirane and 3.57 g (15 mmol) of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide in 30 ml of dimethylformamide was heated at 120° C. for 10 hours and then left to stand at room temperature for 18 hours. The mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 50 ml of ethyl acetate, washed with 30 ml of water, dried over anhydrous sodium sulphate, filtered and evaporated. The crude product was crystallized from ethyl acetate/n-hexane and there were obtained 4.77 g of N-tert.butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-phthalimidobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide in the form of a cream coloured solid; MS: m/e 532 [M+H]+.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH2:5])=[NH:4].C(=O)([O-])[O-].[K+].[K+].C([O:16][C:17](=O)[CH:18]([Cl:22])[C:19]([CH3:21])=O)C>O>[Cl:22][C:18]1[C:17]([OH:16])=[N:4][C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])=[N:5][C:19]=1[CH3:21]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: N=C(N)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Reaction time: 18 h
Yield: 31 %

Procedure:
A mixture of 30.0 g (0.18 mole) trichloroacetamidine, 25.2 g (0.18 mole) potassium carbonate, 30.3 g (0.18 mole) ethyl-2-chloroacetoacetate, and 300 ml water was stirred 18 hours. The aqueous solution was decanted from heavier tars and acidified with hydrochloric acid. The precipitate that was formed, was filtered, washed, and dried to give 14.7 g (31% yield; mp 130°-145° C.) of crude product. An analytical sample recrystallized from cyclohexane had mp 156°-157° C. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.C([O-])([O-])=O.[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[C:17]1([C:13]2[CH:14]=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][C:9]=2[C:10]([OH:12])=[O:11])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: Clc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: CN(C)C=O
Product: O=C(O)c1cc(-c2ccccc2)ccc1-c1ccccc1
Yield: 70.7 %

Procedure:
Palladium acetate (5.6 mg, 0.025 mmol), 3-phenylbenzoic acid (99 mg, 0.5 mmol) and 4-chlorobenzene (169 mg, 1.5 mmol), butyldi-1-adamantylphosphine (19.2 mg, 0.05 mmol), Cs2CO3 (358 mg, 1.1 mmol), molecular sieves 3 Å (155 mg) and anhydrous DMF (2.5 mL). After flash chromatography and preparative HPLC 97 mg (71%) of a white solid was obtained. Analytical data are consistent with that of previously reported data.6 1H NMR (300 MHz, CDCl3) δ 7.36-7.50 (m, 10H), 7.63-7.66 (m, 2H), 7.75-7.78 (m, 1H), 8.15-8.18 (m, 1H). Carboxylate proton signal was not observed. The 1H NMR spectrum is shown in FIG. 43.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=S)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][NH2:30])=O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[NH:18][C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:30][N:29]=2)=[CH:22][CH:21]=1
Reactant: NNC(=O)Cc1ccc(Cl)cc1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nnc(Cc3ccc(Cl)cc3)[nH]2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 71c) starting with [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (150 mg, 0.57 mmol) and (4-chloro-phenyl)-acetic acid hydrazide (116 mg, 0.57 mmol). Obtained as a brownish solid (36 mg, 16%) after chromatography of the crude reaction product on amino-modified silica gel (Merck HPTLC Silica Gel 60 NH2F254S) using ethyl acetate as eluent.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[N:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:20]O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:23]>CCOCC.C(Cl)Cl.O.CCOC(C)=O>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[N:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:20][Br:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: O=S(=O)(c1ccccc1)n1c(CO)cc2nc(Cl)ccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=S(=O)(c1ccccc1)n1c(CBr)cc2nc(Cl)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (1-benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)-methanol (0.16 g, 0.50 mmol) in 4 mL Et2O/CH2Cl2 (1:1) at 0° C. is added phosphorous tribromide (0.023 mL, 0.25 mmol) dropwise. The reaction vessel is kept in the dark and stirred at 0° C. for 1 hour, then at room temperature for 2 hours. The mixture is diluted with water and EtOAc and the layers are separated. The aqueous layer is extracted with EtOAc. The combined organic layers are washed with water, saturated NaHCO3 solution and saturated NaCl solution, then dried over MgSO4, filtered and concentrated. The crude product (0.16 g, 0.41 mmol) is used in the subsequent step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[O:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1>>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([O:8][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[N:6][CH:7]=1
Reactant: OC1CCOCC1
Reactant: Cc1cc(O)ncc1Br
Product: Cc1cc(OC2CCOCC2)ncc1Br

Procedure:
The title compound was prepared from 5-bromo-2-hydroxy-4-methylpyridine and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): colorless solid.
Reaction SMILES: N([O-])=[O:2].[Na+].[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:10](N)[CH:9]=1)(=[O:7])[CH3:6]>O.S(=O)(=O)(O)O>[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:10]([OH:2])[CH:9]=1)(=[O:7])[CH3:6]
Reactant: O=N[O-]
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2)c(N)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(F)cc2)c(O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of sodium nitrite (12.0 g.) in water (40 ml.) was added to a stirred solution of 4-acetyl-2-amino-4'-fluorobiphenyl (36.6 g.) in 5N sulphuric acid (480 ml.), whilst maintaining the temperature of the reaction mixture at 0° - 5°C. The reaction mixture was stirred at 0° - 5°C. for a further 1 hour. The resulting cold solution of diazonium salt was poured slowly into stirred refluxing 5N sulphuric acid (400 ml.). When the addition was complete, refluxing was continued for 0.5 hour. The resulting solution was poured into ice/water, causing the precipitation of a solid which was collected, dried and dissolved in ether. The ethereal solution was extracted with dilute aqueous sodium hydroxide and the extract was acidified to precipitate a product which was extracted into ether. The ethereal extract was washed with water, dried over anhydrous sodium sulphate, and evaporated to give a product which was recrystallized from light petroleum (b.p. 80° - 100°C.) to give the novel intermediate 4-acetyl-4'-fluoro-2-hydroxybiphenyl, m.p. 152° - 154°C. A mixture of this compound (36.5 g.), dimethyl sulphate (25.2 g.) and potassium carbonate (25 g.) in anhydrous acetone (200 ml.) was refluxed with stirring overnight. Acetone was removed by evaporation, the residue poured into water, and the resulting mixture extracted with ether. The ether extract was washed with dilute sodium hydroxide solution, then with water and dried over anhydrous sodium sulphate. Ether was removed by evaporation and the residue was distilled in vacuo to give a product, b.p. 142° - 144°C./0.2 mm. which solidified on cooling. This solid was recrystallized from light petroleum (b.p. 62° - 68°C.) to give the novel intermediate 4-acetyl-4'-fluoro-2-methoxybiphenyl, m.p. 75° - 77°C.
Reaction SMILES: [C:1]([C:4]1[CH:41]=[CH:40][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12](I)=[CH:11][C:10]=2[CH:16]2[C:21]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:20]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=3)[CH2:19][C:18](=[O:39])[NH:17]2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].C[Si]([C:46]#[CH:47])(C)C.C(N(CC)CC)C.[OH-].[Na+]>CN(C)C=O.CO.[Cu]I>[C:1]([C:4]1[CH:41]=[CH:40][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:46]#[CH:47])=[CH:11][C:10]=2[CH:16]2[C:21]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:20]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=3)[CH2:19][C:18](=[O:39])[NH:17]2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1ccc(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: C#Cc1ccc(Oc2ccc(C(N)=O)cc2)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1

Procedure:
In a manner similar to the method described in example 6a, racemic(2′R, 3R, 4′S)-2′-[2-(4-carbamoyl-phenoxy)-5-iodo-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.35 g, 0.5 mmol) was reacted with trimethylsilyl acetylene (0.49 g, 5 mmol), CuI (3 mg), triethylamine (1.52 mL, 15 mmol), and dichlorobis(triphenylphosphine) palladium (0) (28 mg, 0.04 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic(2′R, 3R, 4′S)-2′-[2-(4-carbamoyl-phenoxy)-5-ethynyl-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off white solid (Yield 0.25 g, 84%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[N:21]1[C:30]2[C:29](=O)[CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:20])[C@@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9][CH2:10][NH:11][CH:29]1[C:30]2[N:21]=[CH:22][CH:23]=[CH:24][C:25]=2[CH2:26][CH2:27][CH2:28]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCc2cccnc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC1CCCc2cccnc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 53.6 %

Procedure:
To a solution of (2S)-5-amino-2-(tert-butoxycarbonylamino)-pentanoic acid tert-butyl ester (free base) (0.905 g, 3.11 mmol) in CH3OH (15 mL) was added 6,7-dihydro-5H-quinolin-8-one (0.504 g, 3.43 mmol) and the resultant solution was stirred at room temperature for 5 hours. Powdered NaBH4 (0.379 g, 9.98 mmol) was added, and the mixture was stirred at room temperature for 25 minutes then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL) and brine (20 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1 CH2Cl2—CH3OH) provided 0.700 g (54%) of (2S)-2-tert-butoxycarbonylamino-5-(5,6,7,8-tetrahydroquinolin-8-ylamino)-pentanoic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([N+:20]([O-])=O)=[CH:18][C:6]2[CH2:7][CH2:8][N:9]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:10][CH2:11][C:5]=2[CH:4]=1>CO.[Pd]>[NH2:20][C:19]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:8][CH2:7][C:6]=2[CH:18]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCN(CC(=O)N(C)C)CC2
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 2-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide (767 mg, 1.75 mmol) in methanol (30 mL) was added palladium 10% wt on Carbon (50% wet; 100 mg). The mixture was shaken in a Parr apparatus under an atmosphere of hydrogen (50 PSI) for 30 minutes. Filtration through Celite and evaporation of the solvent provided the crude product, which was purified by flash chromatography on SiO2 (MeOH/dichloromethane 0-6%) to give 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide (332 mg, 69%) as a white solid. 1H-NMR (CDCl3) δ 6.54 (s, 1H), 6.48 (s, 1H), 3.81 (s, 3H), 3.53 (br s, 2H), 3.23 (s, 2H), 3.13 (s, 3H), 2.96 (s, 3H), 2.80 (m, 4H), 2.65 (m, 4H); LC/MS (ESI+): 278.67 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][C@H:27]([OH:30])[CH2:28][NH2:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:29][CH2:28][C@@H:27]([OH:30])[CH3:26])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@H](O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: C[C@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and S-(+)-1-amino-2-propanol employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.82 (1H, br s), 10.35 (1H, br s), 8.50 (1H, s), 7.45 (1H, s), 7.31-7.27 (2H, m), 7.15 (2H, t, J=8.7 Hz), 4.93 (1H, d, J=4.2 Hz), 4.11 (2H, s), 3.80-3.75 (1H, m), 3.42-3.39 (1H, m), 3.20-3.14 (1H, m), 1.07 (3H, d, J=6.1 Hz); HRMS calcd for C19H18FN3O4+H+: 372.1360. Found 372.1355.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:17]=2)[N:10]([C:25](=[O:35])[CH:26]([NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]([CH3:29])[CH3:28])[CH2:9]1)=O)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.C(Cl)(=O)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[CH3:34][O:33][C:31](=[O:32])[NH:30][CH:26]([C:25]([N:10]1[CH:11]([C:13]2[N:14]=[CH:15][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:17]=2)[CH2:12][N:8]([C:6](=[O:5])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:9]1)=[O:35])[CH:27]([CH3:29])[CH3:28]
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C(=O)N1CN(C(=O)c2ccccc2)CC1C1=NC(c2ccc(Br)cc2)C=N1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(4-Bromo-phenyl)-3′-(2-methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-1′-carboxylic acid tert-butyl ester (55.6 mg, 0.101 mmol) was dissolved in dichloromethane (0.5 mL) and HCl (4M dioxane, 0.5 mL) was added. The resultant suspension was stirred at room temperature for 20 minutes, after which all volatiles were removed in vacuo. The crude material was dissolved in THF (1 mL) and diisopropyl ethylamine (26.0 mg, 0.202 mmol) was added, followed by benzoyl chloride (15.6 mg, 0.11 mmol). The reaction was stirred at room temperature. After 10 minutes, all starting material was consumed. All volatiles were removed in vacuo and the crude brown solid {1-[1′-Benzoyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester was used in the coupling reaction without further analysis or purification: LCMS-ESI+: calc'd for C26H28BrN5O4: 554.4 (M+). Found: 554.3/556.4 (M+H+).
Reaction SMILES: C([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH:14][C:15]3[O:16][C:17]([CH3:20])=[CH:18][N:19]=3)=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)C.C(OC1CC2C(NC3OC(C4C=CC(C(F)(F)F)=CC=4)=CN=3)=CC=CC=2CC=1)C>>[CH3:20][C:17]1[O:16][C:15]([NH:14][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:12]=2[CH2:13][C:4](=[O:3])[CH2:5][CH2:6]3)=[N:19][CH:18]=1
Reactant: CCOC1=CCc2cccc(Nc3ncc(C)o3)c2C1
Agent: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: Cc1cnc(Nc2cccc3c2CC(=O)CC3)o1

Procedure:
The title compound was prepared using the procedure as described in Example 1I, substituting the product of Example 13B for the product of Example 1H.
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]([O:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1)=O.[C:16]([O:20][C:21](=[O:37])[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][N:30]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:1][C:3]1[C:8]([C:9]([O:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][N:30]=1)=[O:37])([CH3:17])([CH3:19])[CH3:18]
Reactant: Cc1cnc(CNCCCCNC(=O)OC(C)(C)C)c(C)c1
Reactant: CC(=O)OC(C)(C)c1cccnc1C=O
Product: CC(=O)OC(C)(C)c1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1ncc(C)cc1C

Procedure:
Using general procedure B with acetic acid 1-(2-formyl-pyridin-3-yl)-1-methyl-ethyl ester and {4-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester gave acetic acid 1-(2-{[(4-tert-butoxycarbonylamino-butyl)-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-1-methyl-ethyl ester was obtained as a colorless oil. 1H NMR (CDCl3) δ 1.35 (m, 2H), 1.43 (s, 9H), 1.55 (m, 2H), 1.76 (s, 6H), 1.95 (s, 3H), 2.13 (s, 3H), 2.26 (s, 3H), 2.60 (t, 2H, J=6.0 Hz), 2.98 (m, 2H), 3.79 (s, 2H), 3.96 (s, 2H), 5.29 (br s, 1H), 7.16 (dd, 1H, J=6.0, 3.0 Hz), 7.20 (s, 1H), 7.65 (d, 1H, J=9.0 Hz), 8.17 (s, 1H), 8.50 (d, 1H, J=3.0 Hz).
Reaction SMILES: [C:1]1([CH3:22])[C:2]([S:7]([N:10]([CH2:18][C:19](O)=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:23]([NH:25][CH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1)[C:19](=[O:20])[CH2:18][N:10]([S:7]([C:2]1[C:1]([CH3:22])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:9])[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:24]
Reactant: CCNCc1nccs1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cc1
Product: CCN(Cc1nccs1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(toluene-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]([CH:8]=[CH:9][CH:10]1[CH2:14][CH2:13][CH:12]([CH3:15])[C:11]1([CH3:17])[CH3:16])[C:5](=[O:7])[CH3:6]>C(O)C>[CH3:3][CH:4]([CH:8]=[CH:9][CH:10]1[CH2:14][CH2:13][CH:12]([CH3:15])[C:11]1([CH3:17])[CH3:16])[CH:5]([OH:7])[CH3:6]
Reactant: CC(=O)C(C)C=CC1CCC(C)C1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)C(C)C=CC1CCC(C)C1(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 0.58 g of NaBH4 (18 mmoles) in 50 ml of ethanol cooled to 0° C. are added drop by drop within one hour 5 g (24 mmoles) of 3-methyl-5-(2,2,3-trimethyl-cyclopent-1-yl)-pent-4-en-2-one. The reaction mixture is stirred for 90 minutes at room temperature. The ethanol is removed by rotary evaporation and the reaction mass is extracted with ether and washed with water. After evaporation of the solvent the crude product is vacuum distilled, to yield 3-methyl-5-(2,2,3-trimethyl-cyclopent-1-yl)-pent-4-en-2-ol: 4.4 g (mixture of isomers)
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6].[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:18]1[O:22][C:21](=[O:23])[C:20]2([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:19]=1.O>CN(C)C=O>[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:18]([NH:19][C:20]1([C:21]([NH:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:23])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]
Reactant: O=C1OC(c2cc3ccccc3s2)=NC12CCCCC2
Reactant: CSCC[C@H](N)CO
Solvent: O
Solvent: CN(C)C=O
Product: CSCC[C@@H](CO)NC(=O)C1(NC(=O)c2cc3ccccc3s2)CCCCC1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
284 mg (2.1 mmol) of L-methioninol was added to a solution of 500 mg (1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 3 ml of N,N-dimethylformamide, and the mixture was stirred overnight. Water was slowly added to the mixture and the precipitated crystal was collected by filtration. The obtained crystal was dried under reduced pressure to give 722 mg (98%) of the title compound.
Reaction SMILES: [C:1]([N:3]=[C:4]1[N:8]([C@@H:9]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH2:23][CH3:24])([CH2:21][CH3:22])[C@H:10]2[OH:25])[CH2:7][CH2:6][S:5]1)#[N:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1.C(OCC)(=O)C>[C:26]([O:25][C@H:10]1[C@H:9]([N:8]2[CH2:7][CH2:6][S:5][C:4]2=[N:3][C:1]#[N:2])[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]1([CH2:23][CH3:24])[CH2:21][CH3:22])(=[O:28])[CH3:27]
Reactant: CCC1(CC)Oc2ccc(C#N)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC1(CC)Oc2ccc(C#N)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of trans-4-(2-cyanoiminothiazolidin-3-yl)-2,2-diethyl-3,4-dihydro-3-hydroxy-2H-1-benzopyran-6carbonitrile -(0.28 g) and acetic anhydride (0.15 ml) in pyridine (1.4 ml) was stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate, and then washed with 5% aqueous hydrochloric acid, saturated sodium bicarbonate solution and brine successively. The extract was dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue of trans-3-acetoxy-4-(2-cyanoiminothiazolidin-3-yl)-2,2-diethyl-3,4-dihydro-2H-1-benzopyran-6-carbonitrile, which was dissolved in toluene (12.5 ml) and thereto was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 ml). The reaction mixture was heated at 100° C. with stirring for an hour and 40 minutes. The solvent was evaporated in vacuo. The residue was triturated with ethyl acetate and recrystallized from 85% aqueous acetonitrile to give 4-(2-cyanoiminothiazolidin-3-yl)-2,2-diethyl-2H-1-benzopyran-6-carbonitrile (0.18 g).