Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=1[C:9]1([CH2:18][CH3:19])[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]1=[O:17].Br>ClCCl.C(O)(=O)C>[CH2:18]([C:9]1([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[CH:2]=2)[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]1=[O:17])[CH3:19]
Reactant: CCC1(C2=C(Br)C(=O)CCC2)CCCCN(C)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC1(c2cccc(O)c2)CCCCN(C)C1=O
Reaction time: 3 h

Procedure:
A solution of 3-(2-bromo-3-oxocyclohex-1-enyl)-3-ethylhexahydro-1-methylazepin-2-one (6.57 g) in dichloromethane (70 ml) was treated with 48% HBr in acetic acid (1 ml). After 3 hours NMR indicated completion. The solvent was removed under reduced pressure and the residue triturated with aqueous ammonia to yield the title compound as a white crystalline solid, m.p. 178°-80° C. (EtOAc).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:20][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)=[CH:7][C:2]=1[CH3:1])=[O:26]
Reactant: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1N
Reactant: O=C(Cl)c1cccc(F)c1
Product: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1NC(=O)c1cccc(F)c1
Yield: 39 %

Procedure:
The title compound was prepared in a manner substantially the same as example 20 by coupling (2S,3R)-2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenylamine with 3-fluoro-benzoyl chloride in 39% yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:10]=2[N:11]=1.[Cl:19][C:20]1[C:25]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])(=[O:29])=[O:28])=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:21]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:19][C:20]1[C:25]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])(=[O:29])=[O:28])=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:10]=3[N:11]=2)=[CH:22][N:21]=1
Reactant: Clc1ccc2ncnc(NC3CCOCC3)c2n1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccc3ncnc(NC4CCOCC4)c3n2)cnc1Cl)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 28.7 %

Procedure:
A mixture of 6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,2-d]pyrimidin-4-amine (0.026 g, 0.098 mmol) (Intermediate 17), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.051 g, 0.118 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.802 mg, 0.982 μmol) and sodium bicarbonate (0.196 ml, 0.196 mmol) in dioxane (0.491 ml) was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (only EtOAc) to give N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-ylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.015 g, 29%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.68-1.83 (2H, m), 2.13-2.20 (2H, m), 3.58-3.65 (2H, m), 4.05-4.12 (2H, m), 4.41-4.50 (1H, m), 6.94-7.02 (2H, m), 7.18 (1H, d, J=8.0 Hz), 7.84-7.90 (1H, m), 8.09 (1H, d, J=8.8 Hz), 8.24 (1H, d, J=8.4 Hz), 8.65 (1H, s), 8.74 (1H, d, J=2.0 Hz), 8.84 (1H, d, J=2.4 Hz). NH peak was not observed. m/z=533.4 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][N:15]2[C:18]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)[N:22]=3)=[CH:19][N:20]=[C:14]2[N:13]=1)([O:4][Si](CC)(CC)CC)[CH3:3]>Cl>[N:30]1[CH:29]=[CH:28][C:27]([C:23]2[N:22]=[C:21]([C:18]3[N:15]4[CH:16]=[CH:17][C:12]([C:2]([OH:4])([CH3:1])[CH3:3])=[N:13][C:14]4=[N:20][CH:19]=3)[CH:26]=[CH:25][N:24]=2)=[CH:32][CH:31]=1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4ccncc4)n3)cnc2n1
Agent: Cl
Product: CC(C)(O)c1ccn2c(-c3ccnc(-c4ccncc4)n3)cnc2n1

Procedure:
7-(1-Methyl-1-triethylsilanyloxyethyl)-3-[2-(pyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine from above was treated with conc. HCl (10 drops) as described in Example 39 to yield after purification by column chromatography on silica, using 6% MeOH/CH2Cl2 as the eluent, 2-[3-(2-(pyridin-4-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol (51 mg, 15%): 1H NMR (360 MHz, d6-DMSO) δ 10.23 (1H, d, J 7.2), 8.98 (1H, d, J 5.5), 8.88 (1H, s), 8.85-8.80 (2H, m), 8.36 (2H, dd, J 4.5, 1.6), 8.14 (1H, d, J 5.5), 7.77 (1H, d, J 7.2), 5.62 (1H, s), 1.55 (6H, s); m/z (ES+) 333 (M+H+).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[N:11]([C:12]([C:14]2[N:15]=[C:16]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=3)[CH:18]=2)=[O:13])[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7]1)(=[O:3])[CH3:2].C(OC1C=C(N2C=C(C(N3CCN(C(OCC4C=CC=CC=4)=O)C[C@@H]3CO)=O)N=C2C2C=CC(C)=CC=2)C=CC=1)C.C(N(CC)C(C)C)(C)C.C(OC(=O)C)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:4][CH2:5][C@H:6]1[CH2:7][NH:8][CH2:9][CH2:10][N:11]1[C:12]([C:14]1[N:15]=[C:16]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=2)[CH:18]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CCOc1cccc(-n2cc(C(=O)N3CCN(C(=O)OCc4ccccc4)C[C@@H]3COC(C)=O)nc2-c2ccc(C)cc2)c1
Agent: CCOc1cccc(-n2cc(C(=O)N3CCN(C(=O)OCc4ccccc4)C[C@@H]3CO)nc2-c2ccc(C)cc2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)OC(C)=O
Product: CCOc1cccc(-n2cc(C(=O)N3CCNC[C@@H]3COC(C)=O)nc2-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step, C: Benzyl (3R)-3-[(acetyloxy)methyl]-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate To a stirred solution of 3.40 g (6.13 mmol) of benzyl (3R)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-(hydroxymethyl)-piperazine-1-carboxylate from Step B in 60 mL of anhydrous dichloromethane was added 2.30 mL (13.4 mmol) of N,N-diisopropylethylamine, 1.20 ml (12.2 mmol) of acetic anhydride and 4.0 mg (0.30 mmol) of 4-(dimethylamino)-pyridine. The resulting solution was stirred at ambient temperature overnight, quenched with a saturated aqueous ammonium chloride solution (20 mL). The aqueous layer was separated and extracted with dichloromethane (2×75 mL), and the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude residue was purified on a Biotage® purification apparatus (silica gel, 50 to 75% ethyl acetate in hexanes gradient) to yield the title compound as a colorless foam. LC/MS 597.2 (M+1).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]2[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:16]=2)=[CH:4][CH:3]=1.[F-].[K+].[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])[CH2:26][OH:27].O>O1CCOCC1>[CH2:30]([O:29][C:25]([CH2:26][O:27][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]2[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:16]=2)=[CH:4][CH:3]=1)=[O:28])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOC(=O)CO
Reactant: Cn1c(C(F)(F)F)cnc(-c2ccc(F)c([N+](=O)[O-])c2)c1=O
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCOC(=O)COc1ccc(-c2ncc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 84 %

Procedure:
Then, 1.10 g of 3-(4-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-13) was dissolved in 4.0 ml of 1,4-dioxane, to which 0.812 g of potassium fluoride and 0.925 g of butyl glycolate, and the mixture was heated under reflux for 1.5 hours. After completion of the reaction, the reaction mixture was left cooling to room temperature. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 1.25 g (yield, 83%) of 3-[4-(butoxycarbonylmethoxy)-5-nitrophenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (the present compound depicted below).
Reaction SMILES: C[O:2][C:3]([CH:5]([N:9]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11](OCC2C=CC=CC=2)[C:10]1=[O:27])[CH:6]([CH3:8])[CH3:7])=[O:4].C([OH:30])C>[Pd]>[OH:30][C@@:5]([C:3]([OH:2])=[O:4])([CH:6]([CH3:8])[CH3:7])[NH:9][C:10](=[O:27])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C(C(C)C)N1C(=O)C(OCc2ccccc2)C1c1ccccc1
Reactant: CCO
Agent: [Pd]
Product: CC(C)[C@](O)(NC(=O)CCc1ccccc1)C(=O)O
Reaction time: 38 h
Yield: 93.7 %

Procedure:
According to the same procedure as in Example 1, 1-(1-methoxycarbonyl-2-methylpropyl)-3-benzyloxy-4-phenylazetidin-2-one (560 mg.) was subjected to hydrogenolysis at room temperature in ethanol (30 ml.) under a hydrogen pressure of one atmosphere in the presence of a 10% Pd-C (170 mg.). The reaction was completed in 38 hours. The same after-treatment as in Example 1 was followed to give methyl ester of α-hydroxy-β-phenylpropionylvaline (400 mg., yield: 93.7%), which was an oil.
Reaction SMILES: [OH:1][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[NH2:4].[O:13]=[C:14]1[O:20][C@H:19]([C@H:21]([CH2:23][OH:24])[OH:22])[C:17]([OH:18])=[C:15]1[OH:16]>>[O:13]=[C:14]1[O:20][C@H:19]([C@H:21]([CH2:23][OH:24])[OH:22])[C:17]([O-:18])=[C:15]1[OH:16].[OH:1][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[NH2:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O

Procedure:
The procedure described in Example 1 was followed, starting from glucosamine base and ascorbic acid.
Reaction SMILES: [OH:1][CH:2]1[CH2:15][C:4]2([CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]2)[CH2:3]1.CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:23][S:24]([O:1][CH:2]1[CH2:3][C:4]2([CH2:7][N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:5]2)[CH2:15]1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CC2(CC(O)C2)C1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2(CC(OS(C)(=O)=O)C2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (505 mg, 2.37 mmol) was dissolved in DCM (6.0 mL). The solution was cooled to 0° C. with an external ice-bath. Et3N (330 μL, 2.37 mmol) and DMAP (3.0 mg, 0.0237 mmol) were added. Methanesulfonyl chloride (184 μL, 2.37 mmol) was then added dropwise by syringe. The solution was stirred at 0° C. for 2.0 hrs, was then allowed to warm to room temperature and stirred at room temperature for 18 hrs. A saturated solution of NH4Cl (20 mL) was added and stirred at room temperature for 10 min. The layers were separated. The aqueous phase was extracted with DCM (3×30 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated by evaporation in vacuo to afford tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (684 mg, 99%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][N:8]=2)[CH2:2]1.Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CCO>[C:7]1([CH:3]2[CH2:4][CH2:5][CH2:6][N:1]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=3)[CH2:2]2)[C:11]2=[C:12]3[CH:18]=[CH:17][NH:16][C:13]3=[N:14][CH:15]=[C:10]2[NH:9][N:8]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: c1cc2c(ncc3[nH]nc(C4CCCNC4)c32)[nH]1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCCC(c3n[nH]c4cnc5[nH]ccc5c34)C2)nc1
Temperature: 120 °C
Yield: 5.4 %

Procedure:
A mixture of 1-(piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.16 g, 0.65 mmol, Example #26, Step E) and 6-chloronicotinonitrile (0.090 g, 0.65 mmol) with DIEA (0.37 mL, 2.12 mmol) in EtOH (3 mL) was heated at about 120° C. for about 15 min in a microwave reactor. The crude material was purified by RP-HPLC (Table 2, Method h) to give 6-(3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)piperidin-1-yl)nicotinonitrile (0.012 g, 6%): LC/MS (Table 2, Method a) Rt=1.96 min; m/z: 344 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:23])[C:10]([F:22])=[C:11]([N:14]4[CH2:19][CH2:18][N:17](C=O)[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:24])[C:6]([CH:25]=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.Cl>>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:23])[C:10]([F:22])=[C:11]([N:14]4[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]4)[CH:12]=3)[C:7](=[O:24])[C:6]([CH:25]=[O:26])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)c(N2CCN(C=O)CC2)cc2c1c(=O)c(C=O)cn2C1CC1
Agent: Cl
Product: Cc1c(F)c(N2CCNCC2)cc2c1c(=O)c(C=O)cn2C1CC1
Yield: 51.5 %

Procedure:
To 1-cyclopropyl-6-fluoro-7-(4-formyl-1-piperazinyl)-5-methyl-3-formyl-1,4-dihydro-4-oxoquinoline (1.2 g) is added 3N hydrochloric acid (15 ml) and the mixture is refluxed for 1 hour. After distilling off hydrochloric acid under reduced pressure, water is added to the resulting residue. The mixture is made weakly alkaline with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The chloroform layer is washed with water, dried over sodium sulfate, and the chloroform is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent, chloroform → chloroform : methanol =50 : 1) and recrystallized from ethanol to give 1-cyclopropyl-6-fluoro-7-(1-piperazinyl)-5-methyl-3-formyl-1,4-dihydro-4oxoquinoline (0.57 g), as pale yellow powdery crystals, m.p. 21020 -213° C. (dec.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8].[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[C:16]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=2)=[N:15][N:14]=1>C(O)C>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[C:16]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:9]([CH2:10][CH3:11])[CH2:7][CH3:8])=[CH:27][CH:26]=2)=[N:15][N:14]=1
Reactant: CCNCC
Reactant: COc1ccc2c(-c3ccc(CCl)cc3)nnc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN(CC)Cc1ccc(-c2nnc(Cl)c3cc(OC)ccc23)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
280 mg (2 mmol) of potassium carbonate and 0.3 mL of diethylamine are added to a solution of 319 mg (1 mmol) of 1-chloro-4-(4-chloromethylphenyl)-7-methoxyphthalazine (synthesized in 30.3) in 3 mL of ethanol. The mixture is stirred at 85° C. for 4 hours. The ethanol is evaporated off and the residue is taken up in water and extracted with dichloromethane. The organic extracts are washed with brine, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel (solvent: 95/5 to 85/15 (v/v) dichloromethane/methanol). 287 mg of product are obtained (80% yield).
Reaction SMILES: O=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C[C:14]1[NH:15]C(C)=C(C(OCC)=O)C[C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(CC(OCC)=O)#N.N1CCC[C@H]1C(O)=O>CS(C)=O>[C:14]([CH:19]([CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:15]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Solvent: CCOC(=O)CC#N
Product: CCOC(=O)C(C#N)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.2 %

Procedure:
To a solution of tert-butyl 3-oxoazetidine-1-carboxylate (3.4 g), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (5.0 g) and ethyl cyanoacetate (2.2 g) in dimethylsulfoxide (40 mL) was added L-proline (460 mg), and the mixture was stirred at room temperature for 48 hr. The insoluble substance was removed by filtration, saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (4.3 g).
Reaction SMILES: [CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCc4ccccn4)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(OCc3ccccn3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
Ethyl 3-[{[4-({cyclohexyl[3-methyl-5-(pyridin-2-ylmethoxy)-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (0.19 g) synthesized in the above-mentioned (2) was dissolved in ethanol (5 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (1.0 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title object compound (0.11 g, 41%) as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([NH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[O:26])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: NC1CCc2ccccc2NC1=O
Product: CC(C)(C)OC(=O)NCCCC(=O)NC1CCc2ccccc2NC1=O

Procedure:
Prepared from 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step A) and 4-(t-butoxycarbonylamino)butyric acid by the procedure described in Example 25, Step A. 1H NMR (200 MHz, CDCl3); 1.42 (s,9 H), 1.7-2.1 (m,3 H), 2.24 (t,5 Hz,2 H), 2.58-3.29 (m,5 H), 4.57 (m,1 H), 4.86 (br s,1 H), 7.0-7.3 (m,4 H), 8.32 (s,1 H), FAB-MS: calculated for C19H27N3O4 361; found 362 (M+H,60%).
Reaction SMILES: II.C(OC(N[C@@H:11]([CH2:16]I)[C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C.BrC1[CH:24]=[CH:23][C:22]([C:25]2[S:26][CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:32][CH:31]=3)[N:29]=2)=[CH:21][CH:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CN(C=O)C.[Zn].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]>[C:12]([O:14][C:15]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][CH:27]=[C:28]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:34][CH:35]=3)[N:29]=2)=[CH:21][CH:20]=1)(=[O:13])[CH2:11][CH3:16]
Reactant: CCCCCCCOc1ccc(-c2csc(-c3ccc(Br)cc3)n2)cc1
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: II
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2csc(-c3ccc(OC(=O)CC)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring suspension of zinc (228 mg, 3.49 mmol) in DMF (2 mL) was added diiodine (44 mg, 0.17 mmol). When the color was discharged, (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (382 mg, 1.16 mmol) and further diiodine (44.2 mg, 0.17 mmol) were added. After stirring at RT for 30 min, the reaction mixture was de-gassed by bubbling through N2 then 2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl)thiazole (500 mg, 1.16 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (23.8 mg, 0.06 mmol), Pd2dba3 (26 mg, 0.03 mmol) and DMF (2 mL) were added. The reaction mixture was heated to 50° C. for 3 h, cooled and purified by column chromatography (10-80% EA in iso-hexanes) to afford 620 mg (96%) of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl propanoate. LCMS-ESI (m/z) calculated for C31H40N2O5S: 552.3; no ion observed, tR=3.37 min. (Method 4).
Reaction SMILES: [NH2:1][C:2]([NH:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16]Cl)[CH:10]=1)[C:6]([OH:8])=[O:7])=[O:3].[H][H]>O.[Pd]>[NH2:1][C:2]([NH:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:16])[CH:10]=1)[C:6]([OH:8])=[O:7])=[O:3]
Reactant: NC(=O)NC(C(=O)O)c1ccc(O)c(CCl)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: Cc1cc(C(NC(N)=O)C(=O)O)ccc1O

Procedure:
A mixture of α-(aminocarbonyl)amino-3-chloromethyl-4-hydroxybenzeneacetic acid (0.1 mole) and 10% Pd on charcoal (1 g) catalyst in 50 ml of water is subjected to hydrogen gas at a pressure of about 60 pounds/in2 at room temperature for a period of about 16 hours. Removal of the catalyst followed by evaporation of the water gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:14]=1[N+:26]([O-:28])=[O:27].[Cl:29][C:30]([SH:33])([Cl:32])[Cl:31].O.ClCCCC.CCCCCC>O1CCCC1>[Cl:29][C:30]([Cl:32])([Cl:31])[S:33][N:12]([C:3]1[CH:4]=[C:5]([C:8]([F:10])([F:9])[F:11])[CH:6]=[CH:7][C:2]=1[Cl:1])[C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:14]=1[N+:26]([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2cc(C(F)(F)F)ccc2Cl)c(C(F)(F)F)c1
Reactant: SC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCCCCl
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(N(SC(Cl)(Cl)Cl)c2cc(C(F)(F)F)ccc2Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
Sodium hydride (0.6 g, 57% mineral oil), washed free of mineral oil with hexane under a nitrogen atmosphere, is slurried in 25 ml of anhydrous tetrahydrofuran and cooled to 0°. A solution of 2-chloro-N-[2,4-dinitro-6-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-benzenamine (4.3 g, 0.010 mole) in 25 ml of anhydrous tetrahydrofuran is then added dropwise with stirring at 0°. When the addition is complete, the solution is allowed to warm to ambient temperature and stirred for one hour. Perchloromethyl mercaptan (1.9 g, 0.010 mole) is then added and stirring is continued for two hours. The reaction mixture is then poured into water, extracted with methylene chloride, dried over anhydrous magnesium sulfate and stripped under vacuum to afford an orange resin. Chromatography on silica gel utilizing 1-chlorobutane/hexane (1:1 by vol) as the eluent affords 3.5 g of 1,1,1-trichloro-N-[2-chloro-5-(trifluoromethyl)phenyl]-N-[2,4-dinitro-6-(trifluoromethyl)phenyl]methanesulfenamide as a yellow oil which crystallizes on standing, m.p. 134°-137°.