Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:14](#[N:19])[C:15]([CH3:18])([CH3:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>>[O:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:14](=[NH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][CH2:10]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CC(C)(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(C)C(=N)Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 4-(2-aminophenyl)morpholine (3.56 g). pivalonitrile (5 g) and anhydrous aluminium chloride (8 g) was heated at 160°-170° C. for six hours to yield N-(2-morpholinophenyl)pivalamidine (m.p. 126° C.) which was recrystallised from hexane and converted into its monofumarate salt (m.p. 211° C.) which was recrystallised from methanol.
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[H-].[Na+].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][N:25]=1.O>O1CCCC1>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][CH:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][CH:9]=1)[CH2:2][O:1][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][N:25]=1
Reactant: CC(C)(C)c1ccc(C(CO)OC2CCCCO2)cc1
Reactant: Clc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(COc2ncnc3ccccc23)OC2CCCCO2)cc1

Procedure:
1-Hydroxy-2-tetrahydropyranyloxy-2-(4-tert-butylphenyl)ethane (0.3 g, 1.07 mmol) is dissolved in dry tetrahydrofuran (7 ml) and to it is added sodium hydride (30.96 mg, 1.29 mmol). The resulting solution is stirred at room temperature for 30 minutes after which 4-chloroquinazoline (0.175 g, 1.07 mmol) is added to the above solution. The solution is then stirred for 6 hours after which water is added to the mixture. The solution is then extracted in dichloromethane. The organic layer is washed, dried and then concentrated to yield the crude product which is purified by flash chromatography (silica gel; ethyl acetate/hexanes) to give the product.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[CH:8]=[CH:9][C:10]([N+:16]([O-])=O)=[C:11]([C:14]#[N:15])[C:12]=2[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Ni]>[NH2:16][C:10]1[CH:9]=[CH:8][C:7]2[NH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:13][C:12]=2[C:11]=1[C:14]#[N:15]
Reactant: CC(C)(C)c1cc2c(C#N)c([N+](=O)[O-])ccc2[nH]1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc2c(C#N)c(N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 2-tert-butyl-5-nitro-1H-indole-4-carbonitrile (550 mg, 2.3 mmol) in EtOAc (10 mL) was added Raney Ni (0.1 g) under a nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 1 h. The catalyst was filtered over Celite and the filtrate was evaporated in vacuo to afford 5-amino-2-tert-butyl-1H-indole-4-carbonitrile (250 mg, 51%). 1H NMR (DMSO, 300 MHz) δ 10.93 (br s, 1H), 7.25 (d, J=8.7 Hz, 1H), 6.49 (d, J=8.7 Hz, 1H), 5.94 (d, J=2.1 Hz, 1H), 5.40 (br s, 2H), 1.30 (s, 9H). MS (ESI) m/z: 214.0 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[N:13]1([CH2:18][CH2:19][NH2:20])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:20][CH2:19][CH2:18][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NCCN1CCCC1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Product: COc1cc([N+](=O)[O-])ccc1NCCN1CCCC1
Temperature: 75 °C
Yield: 23.6 %

Procedure:
A neat mixture of 1-chloro-2-methoxy-4-nitrobenzene (2.0 g, 10.7 mmol) and 2-pyrrolidin-1-ylethanamine (2.5 g, 22 mmol) was heated to 75° C. overnight, then chromatographed on silica gel with ethanol (100%) to give a yellow solid (0.67 g, 24%).
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[S:11]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]12.[OH-].[Na+]>ClCCl>[CH:4]([C:18]1[N:17]=[CH:16][N:13]2[CH:14]=[CH:15][S:11][C:12]=12)=[O:5]
Reactant: c1cn2cncc2s1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ncn2ccsc12
Reaction time: 0.5 h

Procedure:
DMF (15.48 ml) was added to 80 ml of dichloromethane. A solution of 18.32 ml of phosphorus oxychloride in 80 ml of dichloromethane was dropwise added thereto under ice cooling. A reaction was allowed to proceed at room temperature for 30 min. A solution of imidazo[5,1-b]thiazole in 40 ml of dichloromethane was added dropwise thereto. The mixture was heated under reflux for 2.5 hr. The reaction solution was poured into ice. The reaction solution was adjusted to pH 9.8 by the addition of a 5 N aqueous sodium hydroxide solution, followed by extraction five times with 200 ml of dichloromethane. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (eluting with dichloromethane:ethyl acetate=5:1, ethyl acetate alone, and then dichloromethane:methanol=10:1) to give 2.37 g of 7-formylimidazo[5,1-b]thiazole.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][SH:4].[C:10](C1NC=CN=1)(C1NC=CN=1)=[O:11]>C1COCC1>[O:11]=[C:10]1[NH:1][C@H:2]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][S:4]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCOC(=O)[C@H](N)CS
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CSC(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 169.2 %

Procedure:
To a solution of 3-1 (8.5 g, 22.6 mmol) in 200 mL THF was added of carbonyl diimidazole (12.5 g) and the solution was stirred overnight at room temperature. The solution was concentrated in vacuo, 200 mL of 5% Na2CO3 was added and the solution stirred for one hour whereupon 6M HCl was added until the pH of the solution remained at 2. The solution was extracted with EtOAc, the organic phases were then combined, dried over MgSO4, filtered and concentrated in vacuo. The compound was purified by flash chromatography using 40% EtOAc/hexanes to yield 6.7 g of 3-2 as a colorless oil. 1H NMR (400 MHz, acetone-d6): δ 7.5 (br s, 1H), 4.5 (dd, 1H), 4.2 (q, 2H), 3.8 (dd, 1H), 3.6 (dd, 1H), 1.2 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([C:13](O)=[O:14])[CH2:9][CH2:8]2.B.CSC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1CC(C(=O)O)CC2
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COc1cccc2c1CC(CO)CC2
Reaction time: 16 h
Yield: 81.5 %

Procedure:
A solution of 8-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (5 g) in tetrahydrofuran (50 ml) was brought to reflux temperature under nitrogen and borane-dimethyl sulphide complex (10M solution in dimethyl sulphide; 5 ml) was added dropwise. The mixture was then heated under gentle reflux for 5 hours, allowed to stand at ambient temperature for 16 hours, then cooled in ice and quenched by the cautious addition of water. The mixture was then acidified by the addition of 5M hydrochloric acid, heated to drive off dimethyl sulphide, cooled, basified by the addition of aqueous sodium hydroxide solution (5M), and the product extracted into ethyl acetate. The extracts were washed with water, dried over magnesium sulphate, and the solvents were removed to leave 1-(8-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methanol as a pale yellow syrup (3.8 g), which solidified slowly at ambient temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH3:27])=[C:20]([O:23][CH3:24])[CH:21]=3)[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][C@@H:14]([OH:28])[CH2:15]3)[N:10]=2)=[CH:7][CH:6]=[C:5]([O:29][CH3:30])[N:4]=1.[CH2:31]([S:33](O)(=[O:35])=[O:34])[CH3:32]>CC(C)CC(=O)C>[CH2:31]([S:33]([O:28][C@@H:14]1[CH2:13][CH2:12][C@@H:11]2[C@@H:16]([C:17]3[C:22]([C:9]([C:8]4[C:3]([O:2][CH3:1])=[N:4][C:5]([O:29][CH3:30])=[CH:6][CH:7]=4)=[N:10]2)=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=3)[CH2:15]1)(=[O:35])=[O:34])[CH3:32]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](O)C[C@H]21
Reactant: CCS(=O)(=O)O
Solvent: CC(=O)CC(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](OS(=O)(=O)CC)C[C@H]21
Temperature: 50 °C
Yield: 96.9 %

Procedure:
(2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a, 10b-hexahydro-phenanthridin-2-ol (1.5 g; 3.64 mmol) is dissolved in 9 ml of 4-methyl-2-pentanone. The solution is heated up to 50° C. 312 μl (3.82 mmol) of ethansulfonic acid are added. After crystallisation 3 ml 4-methyl-2-pentanon is added and the suspension is stirred over night. The crystals are filtered off and dried to obtain 1.78 g (94%) of the title compound (m.p.: 216° C.).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1([F:19])[O:17][C:8]2=[CH:9][C:10]3[N:14]=[C:13]([SH:15])[NH:12][C:11]=3[CH:16]=[C:7]2[O:6][CH:5]1[F:18].Cl.Cl[CH2:22][C:23]1[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=1>C(O)C>[F:19][C:4]1([F:3])[O:17][C:8]2=[CH:9][C:10]3[N:14]=[C:13]([S:15][CH2:22][C:23]4[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=4)[NH:12][C:11]=3[CH:16]=[C:7]2[O:6][CH:5]1[F:18]
Reactant: FC1Oc2cc3[nH]c(S)nc3cc2OC1(F)F
Reactant: COc1c(C)cnc(CCl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)OC(F)C(F)(F)O4)c1C
Temperature: 40 °C
Reaction time: 5 h
Yield: 75.7 %

Procedure:
6.1 ml of 2M sodium hydroxide solution are added dropwise to a mixture of 1.6 g of 6,6,7-trifluoro-6,7-dihydro-1H-[1,4]-dioxino[2,3-f]benzimidazole-2-thiol and 1.4 g of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride in 40 ml of ethanol at room temperature and the mixture is stirred at 40° C. for 5 h. The solvent is distilled off in vacuo, water is added, the mixture is extracted with methylene chloride, the organic solution is concentrated and the residue is recrystallized from ethanol and water. 1.9 g (77%) of the title compound of m.p. 138°-140° C. are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: NC(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NC(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and commercially available 4-bromobenzamide (180 mg, 0.9 mmol) according to general procedure II. Obtained as a yellow solid (290 mg, 61%). MS (ISP) 475.1 [(M+H)+]; mp 260° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3]>CC(O)=O>[C:5]([OH:7])(=[O:6])[CH2:4][C:2]([CH2:4][C:5]([OH:7])=[O:6])([C:1]([OH:9])=[O:8])[OH:3]
Reactant: O=C(O)CC(O)C(=O)O
Solvent: CC(=O)O
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O

Procedure:
To 1.1 kg of hen's whole eggs, a solution formed of 3 liters of brewed vinegar and 3 g each of citric acid and malic acid was added and mixed with a mixer. Then 0.05% by weight each of Saccharated Pepsin (Mikuni Chemical Industries Co., Ltd.), Lipase (Amano Pharmaceutical Co., Ltd.) and Pancreatin (Amano Pharmaceutical Co., Ltd.) to the whole eggs were added to the mixture, followed by 2 days' standing. After removing the solid components, the remaining liquid decomposition product was low temperature-concentrated under reduced pressure to ½ of its original volume. Into this concentrate an aqueous solution containing 15 g of gelatin was added, and the resulting solution was spray-dried at an inlet temperature of 200° C. and outlet temperature of 125° C., to provide 610 g of gelatin- and alginic acid-coated solubilized pickled egg powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:36][CH2:35][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][C@@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26]([N:39]5[CH2:40][CH2:41][CH2:42][C@H:38]5[CH3:37])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:35][CH2:36]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(OS(C)(=O)=O)CC3)cc1F)C2=O
Reactant: C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1C1CCC(c2ccc(N3CCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)c(F)c2)CC1

Procedure:
The title compound was synthesized in the same manner as Example 13 by condensing 2-[2-fluoro-4-(4-methanesulfonyloxy-cyclohexyl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (Intermediate 28) (150 mg, 0.3 mmol, 1 equiv.) with (R)-2-methyl-pyrrolidine (101.2 mg, 1.19 mmol) to obtain 45 mg (67% yield) of the compound.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:16])[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1.[CH3:17]I.Cl>CO>[O:16]=[C:12]([CH:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=1)[CH3:17])[C:13]([OH:15])=[O:14]
Reactant: CI
Reactant: COc1ccc(CC(=O)C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(C)C(=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
A 1N aqueous solution of sodium hydroxide (20 ml; 20 mmoles) was slowly added to 1.94 g (10 mmoles) of p-methoxyphenylpyruvic acid and a solution of 1.0 ml of methyl iodide in 50 m 1 of methanol. After addition, the mixture was stirred at room temperature for 4 hours. The mixture was acidified with 1N hydrochloric acid and extracted with three 30 ml portions of ether. The ether layers were dried over magnesium sulfate, and the ether was evaporated under reduced pressure to give a pale yellowish white solid. The NMR spectral analysis of this product led to the determination that this product was nearly pure 2-oxo-3-(p-methoxyphenyl)butanoic acid (1.40 g; yield 67 %).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])=[N:17][CH:18]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cn1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-amino-5-chloro-pyridine by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[NH:13][CH:12]1/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20])=O)C1C=CC=CC=1>C(O)C.[Pd]>[O:16]=[C:14]1[CH2:15][NH:11][CH:12]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20])[NH:13]1
Reactant: CC(C)COC(=O)/C=C/C1NC(=O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)COC(=O)CCC1NCC(=O)N1
Yield: 86.2 %

Procedure:
To a solution of isobutyl (E)-1-benzyloxycarbonyl-4-oxo-2-imidazolidineacrylate (7.7 g, 22.2 mmol) in 96% ethanol (200 ml), 5% palladium on charcoal (0.5 g) was added and hydrogen was bubbled at 20° C. and at atmospheric pressure for 2 hours. Removal of the catalyst and evaporation of the solvent gave a residue which was triturated with diisopropyl ether to give 4.1 g (86%) of the title compound, m.p. 50°-52° C. NMR (CDCl3): deltaH =4.45 (t, J=6 Hz, 1H, N--C--N), 3.10 (s, 2 H, N--CH2 --CO). MS (E.I., 70 eV, 1.5 mA) m/z=214 (M+), 157 (M--C4H9)+, 85 (M--C7H13O2)+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl.C(=O)(O)[O-].[Na+]>CO.[Fe]>[NH2:1][C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2cccnc2)c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: Nc1cccnc1Nc1cccc(/C=C/c2cccnc2)c1
Yield: 65.2 %

Procedure:
A mixture of 3-nitro-2-[3-[(E)-2-(3-pyridyl)vinyl]phenylamino]pyridine (493 mg), iron powder (0.35 g) and hydrochloric acid (35%, 1 ml) in methanol (5 ml) was stirred under reflux for 4 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-amino-2-[3-[(E)-2-(3-pyridyl)vinyl]phenylamino]pyridine (291 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Se](O)(O)=[O:22].O1CCOCC1>O>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9](=[O:22])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:20])=[CH:11][CH:12]=1)(=[O:17])=[O:18]
Reactant: O=[Se](O)O
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)C(=O)c2ccc(F)cc2)cc1

Procedure:
A mixture of ketone from step 3 (1 g, 3.5 mmol), selenious acid (H2SeO3) (550 mg, 1.25 equiv.), dioxane (10 ml) and water (1 ml) were heated to reflux for 4 hours and cooled. The mixture was filtered and the filtrate evaporated. The residue was triturated with cold methanol and filtered to give 620 mg (60%) of the dione: m.p. 174-175° C. Anal. Calc'd. for C15H11FO4S (M.W. 306.31): C, 58.82; H, 3.62; S, 10.47. Found: C, 58.70; H, 3.60; S, 10.70.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24](=[O:25])[CH:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:22]([C:33](=[O:35])[CH3:34])[CH:21]2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:16][CH:15]=1)[NH:5][C:6](OC(C)(C)C)=[O:7].Cl.[Cl:44][C:45]1[CH:53]=[CH:52][CH:51]=[C:50]([CH3:54])[C:46]=1C(O)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O1CCOCC1.CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:42])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[C:24](=[O:25])[CH:23]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:22]([C:33](=[O:35])[CH3:34])[CH:21]2[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:18][CH:19]=1)[NH:5][C:6]([C:46]1[C:50]([CH3:54])=[CH:51][CH:52]=[CH:53][C:45]=1[Cl:44])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(N2C(=O)C(Cc3ccccc3)N(C(C)=O)C2c2ccccc2)cc1)NC(=O)OC(C)(C)C
Reactant: Cc1cccc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(N2C(=O)C(Cc3ccccc3)N(C(C)=O)C2c2ccccc2)cc1)NC(=O)c1c(C)cccc1Cl

Procedure:
4-(3-acetyl-5-oxo-2-phenyl-4-phenylmethyl-1-imidazolidinyl)-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (Diastereomer 1) (415 mg, 0.7 mmol) was treated with 10 mL of 4N HCl in dioxane at room temperature for 2 hr. After removal of solvent, the residue was dried overnight under vacuum. The residue (241 mg, 0.471 mmol) was dissolved in DMF (4 mL) and was treated with 2-chloro-6methylbenzoic acid (105 mg, 0.617 mmol), HBTU (234 mg, 0.617 mmol) and DIEA (246 μL, 1.42 mmol) at room temperature for 4 hr. The mixture was diluted with 30 mL of ethyl acetate, the mixture was washed with 1N HCl, water and brine (8 mL each), After it was dried over MgSO4, the solvent was removed and the residue was filtered through silica gel eluting with ethyl acetate:hexane (4:1 ) to give 4-(3-acetyl-5-oxo-2-phenyl-4-phenylmethyl-1-imidazolidinyl)-N-[(2-chloro-6-methylphenyl)carbonyl]-L-phenylalanine methyl ester diastereomer 1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=1[NH:18][C:19](=O)[CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.O.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[NH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: COc1cccc([N+](=O)[O-])c1NC(=O)CN1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(N)c1NCCN1CCOCC1
Yield: 43.2 %

Procedure:
To a suspension of lithium aluminum hydride (5.2 g, 136 mmol) in THF (35 mL) was added a solution of N-(2-methoxy-6-nitrophenyl)-2-morpholin-4-ylacetamide (Step 2, 6.7 g, 23 mmol) in THF (40 mL) at 0° C. and stirred at reflux for 2 h. Then to this mixture was added water (5.2 mL) followed by addition of 15% sodium hydroxide (5.2 mL), water (15.6 mL) at 0° C. The mixture was diluted with ethyl acetate (100 mL) and stirred for 3 h at rt. The resultant mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (30/1) to afford 2.5 g (44%) of the title compound.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@H:10]1[NH:19][C:20]([C:22]1[S:23][C:24]2[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=2[N:30]=1)=[O:21])=[O:7])(C)(C)C.Cl.[Cl:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](C(O)=O)=[CH:37]2>O1CCOCC1>[ClH:33].[Cl:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38]([C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@H:10]1[NH:19][C:20]([C:22]1[S:23][C:24]3[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=3[N:30]=1)=[O:21])=[O:7])=[CH:37]2
Reactant: COC(=O)[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1

Procedure:
(1S,2R,4R)—N1-tert-Butoxycarbonyl-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with 5-chloroindole-2-carboxylic acid in a similar manner to Example 118 to obtain the title compound.