Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:15][O:16][C:17](=[O:41])[CH2:18][O:19][C:20]1[CH:21]=[C:22]([CH:38]=[CH:39][CH:40]=1)[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=2)[C:26]([CH3:36])=[C:25]1[CH3:37]>>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:33]([C:29]2[CH:28]=[C:27]3[C:32](=[CH:31][CH:30]=2)[N:24]([CH2:23][C:22]2[CH:21]=[C:20]([CH:40]=[CH:39][CH:38]=2)[O:19][CH2:18][C:17]([O:16][CH3:15])=[O:41])[C:25]([CH3:37])=[C:26]3[CH3:36])=[O:34])[CH3:13])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: C[C@H](N)c1ccc(C(C)(C)C)cc1
Reactant: COC(=O)COc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Agent: Cl
Product: COC(=O)COc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4ccc(C(C)(C)C)cc4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the 1-(3-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([N:25]2[C:33]3[C:28](=[N:29][CH:30]=[C:31]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=4[F:42])[CH:32]=3)[C:27]([CH3:44])([CH3:43])[CH2:26]2)=[O:24])[CH2:10][C@H:9]1[CH3:45])=O)(C)(C)C.C(OCC)(=O)C.[ClH:52]>O1CCOCC1>[ClH:52].[ClH:52].[F:42][C:36]1[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=1[CH2:34][C:31]1[CH:32]=[C:33]2[N:25]([C:23](=[O:24])[CH2:22][N:11]3[CH2:10][C@@H:9]([CH3:45])[NH:8][CH2:13][C@@H:12]3[CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][C@H:16]3[CH3:21])[CH2:26][C:27]([CH3:44])([CH3:43])[C:28]2=[N:29][CH:30]=1
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ncc(Cc3ccc(F)cc3F)cc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ncc(Cc4ccc(F)cc4F)cc32)[C@@H](CN2CCOC[C@H]2C)CN1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A mixture of (2R,5S)-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.103 g), ethyl acetate (10 mL) and 4 M HCl in dioxan (10 mL) was stirred at 20° C. for 18 h and the resulting solid collected by filtration to give the title compound (0.075 g). 1H NMR (Me-d3-OD): 8.76 (1H, s), 8.48 (1H, s), 7.56-7.44 (1H, m), 7.11-6.98 (2H, m), 4.27 (5H, d), 4.16-3.96 (5H, m), 3.82 (3H, s), 3.66-3.41 (5H, m), 3.18 (4H, d), 1.62 (6H, s), 1.41 (6H, br m). MS: [M+H]+=528.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:23]([O:30][C:31]([N:1]1[CH2:2][CH2:3][CH:4]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 74 h
Yield: 495.6 %

Procedure:
t-Butyl 4-piperidinyloxyacetate (521 mg, 2.42 mmol) and triethylamine (0.40 ml, 2.9 mmol) were dissolved in methylene chloride (20 ml) and benzyloxycarbonyl chloride (0.41 mmol, 2.9 mmol) was added. The mixture was stirred at room temperature for 74 hours. A saturated aqueous sodium hydrogencarbonate solution (50 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to give 710 mg of t-butyl [N-benzyloxycarbonyl-4-piperidinyloxy]acetate as a colorless oil (84%). Methylene chloride (30 ml) and trifluoroacetic acid (10 ml) were added to this oil (692 mg, 1.99 mmol) and the mixture was stirred at room temperature for 17 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure to give 555 mg of [N-benzyloxycarbonyl-4-piperidinyloxy]acetate as a colorless solid (96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9](Cl)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:14]([N:21]1[CH2:25][C@@H:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C@H:23]([NH:33][CH3:34])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:14]([N:21]1[CH2:25][C@@H:24]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C@H:23]([N:33]([CH3:34])[C:9](=[O:10])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)([CH3:13])[CH3:12])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C(=O)Cl)c1cccc(Cl)c1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)C(C)(C)c1cccc(Cl)c1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 2-(3-chloro-phenyl)-2-methyl-propionyl chloride (the preparation of which is described in DE2659404) (0.10 g, 0.46 mmol) in CH2Cl2 (4 ml) was added drop wise to a stirred solution of rac-[(3S,4R)-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-amine (the preparation of which is described herein above) (0.11 g, 0.38 mmol) and ethyl-diisopropyl-amine (0.10 ml, 0.58 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred 2 h, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/H, 1:3) yielded 0.14 g (80%) of the title product as light yellow oil. ES-MS m/e: 465.2 (M+H+).
Reaction SMILES: Cl.[N:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3]2.[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:18]1([C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([OH:17])[CH:3]2[C:4](=[O:9])[CH:5]3[CH2:8][N:2]2[CH2:7][CH2:6]3)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CN2CCC1C2
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C2CCN(C2)C1C(O)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 1-azabicyclo[2.2.1]heptan-3-one hydrochloride (1.06 g) and benzophenone (1.82 g) in dry THF (5 ml) at -78° C. under argon was added a solution of lithium bis(trimethylsilyl)amide (18 ml, 1.0M in THF). The solution was stirred at -78° C. for 1 h, allowed to warm to room temperature and stirred for 48 h. The mixture was poured onto water and extracted with dichloromethane (×4). The combined extracts were dried (Na2SO4), evaporated in vacuo, and the residue was purified by chromatography on silica using a gradient elution of 10-30% ethyl acetate in dichloromethane to afford the title compound as a white solid:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH2:8][C:9]([O:11]CC)=O)(=[O:4])=[O:3].[NH2:18][CH2:19][CH:20]([OH:31])[CH2:21][N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[OH:31][CH:20]([CH2:21][N:22]1[CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30]1)[CH2:19][NH:18][C:9](=[O:11])[CH2:8][O:7][C:6]1[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=1[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: CCOC(=O)COc1ccccc1S(C)(=O)=O
Reactant: NCC(O)CN1Cc2ccccc2C1
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1OCC(=O)NCC(O)CN1Cc2ccccc2C1
Temperature: 120 °C
Yield: 14 %

Procedure:
Ethyl 2-(2-(methylsulfonyl)phenoxy)acetate (50 mg, 0.19 mmol) and 1-amino-3-(isoindolin-2-yl)propan-2-ol (36 mg, 0.19 mmol) were dissolved in EtOH (1 mL) and heated under microwave conditions at 120° C. 0.5 h. The reaction mixture was concentrated and purified by preparative HPLC purification. (11 mg, yield 14%) MS (ESI+) e/z: 405.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.98-7.91 (m, 1H), 7.76-7.69 (m, 1H), 7.33-7.24 (m, 2H), 7.21 (d, J=2.76 Hz, 4H), 4.86-4.80 (m, 2H), 4.01-3.97 (m, 4H), 3.97-3.91 (m, 1H), 3.57-3.50 (m, 1H), 3.39-3.35 (m, 1H), 3.30 (s, 3H), 2.86-2.81 (m, 1H), 2.81-2.74 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:11]=[CH:12][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C=CC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(C)cc1

Procedure:
A suspension of 300 g of p-methylcinnamic acid (J. Chem. Soc., Chem. Comm., 471, 1976) and 25 ml of concentrated sulfuric acid in 1.7 liters of methanol is heated to reflux for 24 hours. The solution is concentrated, cooled and filtered to give as a white solid, p-methylcinnamic acid methyl ester, mp 55°-56° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Cl:9]C1C=C(C)C=CC=1.ClC1C=CC(C)=CC=1>C1(C)C=CC=CC=1>[Cl:9][C:7]1[C:2]([Cl:1])=[C:3]([CH3:8])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(Cl)c1
Reactant: Cc1ccccc1Cl
Solvent: Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc(Cl)c1Cl
Yield: 4.5 %

Procedure:
The chlorination of toluene in the presence of catalysts is known to produce the ring-chlorinated isomeric o-, m- and p-monochlorotoluenes in a ratio which varies according to the type of catalyst used and the reaction conditions chosen. Thus, for example, the chlorination of toluene at 50° C. in the presence of FeCl3 as catalyst up to a density of 1.043 g/cm3 (20° C.) leads to a product comprising 19% by weight of toluene, 49% by weight of o-chlorotoluene, 2% by weight of m-chlorotoluene and 25.5% by weight of p-chlorotoluene. Apart from these, 4.5% of dichlorotoluene are additionally formed (Ullmanns Encyl. der techn. Chemie [Ullmann's Encyclopedia of Industrial Chemistry] (1975), Volume 9, page 512). The use of TiCl4, SnCl4, WCl6 or ZrCl4 as catalysts at a chlorination temperature of 10°-30° C. increases the o-chlorotoluene content to 75% by weight (U.S. Pat. No. 3,000,975), while the use of disulfide dichloride and the metal chlorides mentioned or of sulfur and SbCl3 shifts the isomeric ratio in favor of p-chlorotoluene (U.S. Pat. No. 1,946,040). There is no successful instance of obtaining a single isomer by a suitable choice of catalyst or reaction conditions. All these processes therefore require a subsequent separation of the reaction mixture into the pure isomers, which separation is customarily carried out in two stages where, in a first working-up stage, which is expensive in outlay and energy, o-chlorotoluene (boiling point 158.5° C.) is separated as top product by distillation, for example in a bubble cap column having over 200 theoretical plates, from a bottom comprising m- and p-chlorotoluene. Due to the small difference in the boiling points of these isomers (161.2° C. and 161.5° C. respectively), it is no longer possible to separate their mixture by distillation. Pure p-chlorotoluene (melting point 7.6° C.) must therefore be separated in a second step by crystallization from the m-isomer, which has a lower melting point (melting point -48.7° C.).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:14][CH:13]=1)[C:6](OCC)=[O:7])(=[O:3])[CH3:2].[NH3:33].[OH-].[Na+]>CO.O1CCCC1>[C:1]([NH:4][CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[O:24][C:25]=2[CH3:26])=[CH:16][CH:17]=1)[C:6]([NH2:33])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)NC(C)=O
Reactant: N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)NC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 36 %

Procedure:
Ethyl 2-acetylamino-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionate (1.63 g, 3.73 mmol) obtained in Example 33 was dissolved in methanol-tetrahydrofuran (1:1, 50 ml). 28% Aqueous ammonia (20 ml) was added and the mixture was stirred at room temperature for 2 days. Thereto was added 1N aqueous sodium hydroxide solution (30 ml) and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure and the obtained residue was partitioned between tetrahydrofuran-ethyl acetate (1:1, 100 ml) and water (50 ml). The organic layer was washed with saturated brine (50 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue (1.00 g) was washed with hot methanol to give the title compound (560 mg, yield 36%) as a white solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH2:5]([O:7][C:8]([N:10]1[CH2:19][CH2:18][C:17]2[N:16]=[CH:15][C:14]([C:20]([O-:22])=O)=[C:13]([OH:23])[C:12]=2[CH2:11]1)=[O:9])[CH3:6]>>[CH2:5]([O:7][C:8]([N:10]1[CH2:19][CH2:18][C:17]2[N:16]=[CH:15][C:14]([C:20](=[O:22])[NH:4][CH2:1][CH2:2][CH3:3])=[C:13]([OH:23])[C:12]=2[CH2:11]1)=[O:9])[CH3:6]
Reactant: CCCN
Reactant: CCOC(=O)N1CCc2ncc(C(=O)[O-])c(O)c2C1
Product: CCCNC(=O)c1cnc2c(c1O)CN(C(=O)OCC)CC2

Procedure:
Reaction of N-propylamine with 6-ethoxycarbonyl-4-hydroxy-5,6,7,8-tetrahydro[1,6]naphthyridine-3-carboxylate yields 6-ethoxycarbonyl-4-hydroxy-5,6,7,8-tetrahydro-3-(N-propylcarbamoyl)[1,6]-naphthyridine, mp 199°-201°.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:12][OH:13].CCO.[OH-].[Na+]>O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[N:12]/[OH:13]
Reactant: O=Cc1ccc(F)cc1F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O/N=C/c1ccc(F)cc1F
Temperature: 0 °C
Yield: 49.7 %

Procedure:
2,4-Difluorobenzaldehyde (2.27 g, 16.0 mmol) and hydroxylamine hydrochloride (6.67 g, 96.0 mmol) were added to EtOH (25 mL) and water (25 mL) along with about 40 g of ice. The mixture was stirred and 50% aqueous NaOH (7.68 g, 96 mmol) was added dropwise. The mixture was stirred at ambient temperature for about 15 min then the solid was collected by filtration, washed with water (10 mL) and dried to give the title compound (1.25 g, 50%): 1H NMR (DMSO-d6) δ 11.58 (d, 1H), 8.18 (s, 1H), 7.78 (m, 1H), 7.33 (m, 1H), 7.14 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[O:24][N:23]=[C:22]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])[CH:21]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[O:24][N:23]=[C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])[CH:21]=2)[N:7]=1)[CH3:4]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)on1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cc(OCc3nc(-c4ccccc4)oc3C)no2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) and 5-chloromethyl-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)isoxazole (457 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethyl]-1H-pyrazol-4-yl]propionate (653 mg, yield: 91%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 82–83° C.
Reaction SMILES: [CH:1]1([C:6](O)([CH2:23][C:24]2[O:25]C(C)(C)[O:27][C:28](=[O:30])[CH:29]=2)[C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:11]([F:22])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C(C)(C)C#N)=C(F)C=2)CCCC1>>[CH:1]1([C:6]2([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4([C:20]#[N:21])[CH2:16][CH2:17][CH2:18][CH2:19]4)=[C:11]([F:22])[CH:10]=3)[CH2:23][C:24](=[O:25])[CH2:29][C:28](=[O:30])[O:27]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CCCC3)c(F)c2)C2CCCC2)O1
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1
Product: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CCCC1

Procedure:
The title compound was prepared analogously to step 4 from Example A(97) where 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1ynyl]-2-fluoro-phenyl}-cyclopentanecarbonitrile (from step 2 below) was substituted in place of 2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile. 1H NMR (CDCl3) δ: 1.18-1.74 (m, 16H), 1.92-2.17 (m, 2H), 2.5-2.52 (m, 1H), 2.66-2.68 (m, 2H), 2.77 (s, 2H), 3.43 (s, 2H), 6.89-6.94 (m, 2H), 7.33-7.37 (m, 1H). MS (ESI): 398 (M+H)+.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15](=[O:34])[C@H:16]([CH2:24][C:25]1[CH:30]=[C:29]([I:31])[C:28]([OH:32])=[C:27]([I:33])[CH:26]=1)[NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20].[OH:35][C:36]1[CH:50]=[CH:49][C:39]([O:40][C:41]2[CH:48]=[CH:47][C:44]([CH2:45]O)=[CH:43][CH:42]=2)=[CH:38][CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:13][O:14][C:15](=[O:34])[C@H:16]([CH2:24][C:25]1[CH:26]=[C:27]([I:33])[C:28]([O:32][CH2:45][C:44]2[CH:47]=[CH:48][C:41]([O:40][C:39]3[CH:49]=[CH:50][C:36]([OH:35])=[CH:37][CH:38]=3)=[CH:42][CH:43]=2)=[C:29]([I:31])[CH:30]=1)[NH:17][C:18](=[O:23])[C:19]([F:22])([F:20])[F:21]
Reactant: OCc1ccc(Oc2ccc(O)cc2)cc1
Reactant: COC(=O)[C@H](Cc1cc(I)c(O)c(I)c1)NC(=O)C(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1cc(I)c(OCc2ccc(Oc3ccc(O)cc3)cc2)c(I)c1)NC(=O)C(F)(F)F
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
Diethylazodicarboxylate (40% toluene solution 0.55 ml) was added dropwise to a solution of N-trifluoroacetyl-3,5-diiodo-L-tyrosine methyl ester (272 mg, 0.5 mmol), 4-(4-hydroxyphenoxy)benzylalcohol (119 mg, 0.55 mmol) and triphenylphosphine (328 mg, 1.25 mmol) in tetrahydrofuran (5 ml) under argon atmosphere at −15° C., and the mixture was stirred at the same temperature for 1.5 hrs. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2) to give N-trifluoroacetyl-O-[4-(4-hydroxy-phenoxy)benzyl]-3,5-diiodo-L-tyrosine methyl ester (280 mg, 76%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH2:15]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[CH2:24]O)[CH3:16]>>[CH2:15]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[CH2:24][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CCc1cc(C)ccc1CO
Product: CCc1cc(C)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-ethyl-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.20 (3H, t, J=7.6 Hz), 2.35 (3H, s), 2.68 (2H, q, J=7.6 Hz), 5.21 (2H, s), 5.79 (1H, d, J=1.6 Hz), 7.03 (1H, d, J=7.6 Hz), 7.07 (1H, s), 7.27 (1H, d, J=8.4 Hz), 7.36 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.58 (1H, d, J=1.6 Hz), 7.96-7.97 (1H, s), 8.66 (1H, dd, J=0.8 Hz, 5.2 Hz). [M+H] Calc'd for C19H18N4O, 319; Found, 319.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6](/[CH:8]=[C:9](\[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])/[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:7]=1.[H][H]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:5]([F:28])=[CH:4][CH:3]=1)[CH2:8][C@@H:9]([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22]
Reactant: CC(C)(C)OC(=O)N/C(=C\c1cc(Br)ccc1F)C(=O)OCc1ccccc1
Reactant: [H][H]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(Br)ccc1F)C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
6.0 g (13.3 mmol) of benzyl (2Z)-3-(5-bromo-2-fluorophenyl)-2-[(tert-butoxycarbonyl)amino]acrylate are dissolved in 100 ml of ethanol. Under an argon atmosphere, 40 mg (0.055 mmol) of (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I)trifluoromethanesulfonate are added, and argon is passed through the solution for 30 min. The mixture is then hydrogenated under a pressure of 3 bar of hydrogen for 4 days. The mixture is filtered through silica gel, which is carefully washed with ethanol. The filtrate is concentrated in vacuo, and the crude product is dried under high vacuum.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=3[C:11]2=[O:26])[CH:5]=1.[CH:28](OCCl)=[O:29]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:25][S:24][C:21]1[N:22]=[CH:23][C:12]2[C:11](=[O:26])[N:10]([C:6]3[CH:5]=[C:4]([C:3]4[NH:27][C:28](=[O:29])[O:1][N:2]=4)[CH:9]=[CH:8][CH:7]=3)[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]=2[N:20]=1
Reactant: O=COCCl
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(N)=NO)c1)C2=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(=O)[nH]3)c1)C2=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 110.6 %

Procedure:
(S)—N′-hydroxy-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamidine (200 mg, 0.52 mmol) obtained in Step 1 of Example 75 was dissolved in pyridine (3.0 mL), and the mixture was stirred at 90° C. for 4 hours after adding chloromethyl formate (0.12 mL, 1.56 mmol) under ice-cooled conditions. The mixture was diluted with chloroform, washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-3-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazol-5(4H)-one (236 mg, quantitative).