Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N+:9]([O-])=O)=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:20][C:19]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=2[N:9]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: Cc1cccc(Br)c1[N+](=O)[O-]
Product: Cc1cccc2c1nc(C)n2-c1ccccc1
Yield: 33.3 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 3-Bromo-2-nitrotoluene (108 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol), as starting materials to yield the title compound as brown solid (37 mg, 33%). 1H NMR (DMSO) δ 2.46 (s, 3 H), 2.55 (s, 3 H), 6.88 (d, J=7.3 Hz, 1 H), 7.04-7.11 (m, 2 H), 7.50-7.64 (m, 5 H); 13C NMR δ 13.8, 16.3, 107.5, 122.5, 122.6, 126.8, 129.9, 135.1, 135.3, 150.3, 158.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39]([O:41][CH2:42][CH:43]3[C:55]4[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=4[C:49]4[C:44]3=[CH:45][CH:46]=[CH:47][CH:48]=4)=[O:40])=[O:33])=[CH:27][CH:26]=2)[CH2:9][C:10]2[CH:23]=[CH:22][C:13]3[NH:14][C:15]([C@@H:17]4[CH2:21][CH2:20][CH2:19][NH:18]4)=[N:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.[OH:56][C:57]([CH3:68])([CH3:67])[C@H:58]([NH:62][C:63]([O:65][CH3:66])=[O:64])[C:59](O)=[O:60]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:32]([C@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39]([O:41][CH2:42][CH:43]3[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=4[C:50]4[C:55]3=[CH:54][CH:53]=[CH:52][CH:51]=4)=[O:40])=[O:33])=[CH:29][CH:30]=2)[CH2:9][C:10]2[CH:23]=[CH:22][C:13]3[NH:14][C:15]([C@@H:17]4[CH2:21][CH2:20][CH2:19][N:18]4[C:59](=[O:60])[C@@H:58]([NH:62][C:63]([O:65][CH3:66])=[O:64])[C:57]([OH:56])([CH3:68])[CH3:67])=[N:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(CN(Cc2ccc3[nH]c([C@@H]4CCCN4)nc3c2)c2ccc(F)cc2)cc1)[C@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(CN(Cc3ccc(NC(=O)[C@H]4CCCN4C(=O)OCC4c5ccccc5-c5ccccc54)cc3)c3ccc(F)cc3)ccc2[nH]1)C(C)(C)O
Yield: 101.3 %

Procedure:
The product from Example 99F (0.092 g, 0.125 mmol), (S)-3-hydroxy-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.029 g, 0.15 mmol) was processed as in Example 99E to give 0.115 g (100%) of the title compound.
Reaction SMILES: [C:1]1([CH:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13][C:12]2=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[BrH:20].BrBr>C(O)C>[Br:20][C:11]1([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13][C:12]1=[O:19]
Reactant: Br
Reactant: O=C1NC(=O)C(c2cccc3ccccc23)C(=O)N1
Agent: BrBr
Solvent: CCO
Product: O=C1NC(=O)C(Br)(c2cccc3ccccc23)C(=O)N1
Temperature: 0 °C

Procedure:
A suspension of 5-naphtylbarbituric Acid (0.2 g) in 1.5 ml of 95% ethanol, cooled at 0° C. and kept under stirring, is added dropwise with 48% hydrobromic acid (0.5 ml) and successively with 4.4 μl of bromine. After 4 hours under stirring at room temperature the solid is filtered and washed with water, then it is dried under vacuum at 40° C. overnight. 0.25 g of the product are obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]1[C:17]2([CH2:22][CH2:21][CH2:20][CH:19]=[C:18]2[C:23](=[O:25])[CH3:24])[CH2:16][CH2:15][CH2:14]1.[CH:26](=[O:28])[CH3:27].[NH4+].[Cl-]>O1CCCC1>[OH:28][CH:26]([CH3:27])[CH2:24][C:23]([C:18]1[C:17]2([CH2:22][CH2:21][CH2:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:25]
Reactant: CC(=O)C1=CCCCC12CCCC2
Reactant: CC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)CC(=O)C1=CCCCC12CCCC2
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 125.7 %

Procedure:
At −70° C., a solution of diisopropylamine (40.9 g, 0.4 mol) in tetrahydrofuran (200 ml) was treated within 10 min. with n-butyl lithium (271 ml, 1.6M in hexane, 0.437 mol). The resulting solution was stirred at −40° C. for 20 min., cooled to −78° C., and treated within 20 min. with a solution of 1-(spiro[4.5]dec-6-en-6-yl)ethanone (62 g, 0.35 mol). The resulting solution was stirred 20 min. at −70° C. and treated with a solution of acetaldehyde (76.6 g, 1.75 mol) in tetrahydrofuran (100 ml). After 90 min. stirring, the reaction mixture was poured into a cold saturated aqueous solution of NH4Cl (400 ml) and extracted twice with MTBE (400 and 200 ml). The combined organic phases were washed with a water (200 ml), and twice with a saturated solution of NaCl, dried (MgSO4), and concentrated to give the desired intermediate 3-hydroxy-1-(spiro[4.5]dec-6-en-6-yl)butan-1-one (97.8 g) which was dissolved in acetic anhydride (70 ml, 0.73 mol). The resulting solution was treated with sodium acetate (31.4 g, 0.383 mol), heated at 80° C. for 8 h, treated with sodium acetate (10 g, 0.122 mol), heated at 80° C. for 15 h, treated with sodium acetate (10 g, 0.122 mol), heated at 80° C. for 2 h. The reaction mixture was cooled to 0° C., poured into ice/water and extracted three times with MTBE (200 ml). The combined organic phases were washed with 2N aqueous NaOH (300 ml), with a saturated aqueous NaCl solution (250 ml), dried (30 g MgSO4) and concentrated. Short-path Vigreux distillation (0.08 mbar, bath temperature 140-180° C., head temperature: 80-146° C.) of the crude product (89.6 g) followed by distillation (0.08 mbar, bath temperature 150-180° C., head temperature: 98° C.) using a microdistillation column (20×1.5 cm, filled with 3×3 mm rolled wire netting) gave (E)-1-(spiro[4.5]dec-6-en-6-yl)but-2-en-1-one (55.6 g, 58%).
Reaction SMILES: C([C:6]1[C:7](=[O:17])[O:8][C:9]2[C:14](C=1)=CC=C(O)C=2)(OCC)=O.[CH2:18]([O:20][CH:21]=[CH2:22])[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[K+]>C(Cl)Cl>[CH2:18]([O:20][CH:21]([O:17][CH:7]([O:8][CH2:9][CH3:14])[CH3:6])[CH3:22])[CH3:19]
Reactant: CCOC(=O)c1cc2ccc(O)cc2oc1=O
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(C)OC(C)OCC
Reaction time: 0.25 h
Yield: 26 %

Procedure:
To a slurry of 5.0 g (21 mMol) of 3-carbethoxy-7-hydroxycoumarin [H. Pechmann and E. Graezer, Chem. Ber. 34:378(1901)] in 100 mL of CH2Cl2 containing 5 mL of ethylvinyl ether was added 30 mg of p-toluenesulfonic acid. After 15 minutes, the reaction was poured into 100 mL of 10% potassium hydroxide (KOH) solution. The organic phase was separated, washed with H2O, dried and evaporated. The residue was taken up in toluene and precipitated with hexane to give 1.73 g (26% yield) of the 1-ethoxyethyl ether as a solid, m.p. 70°-71° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[N+:20]([O-])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C1COCC1.C(O)C.[Pt]>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[NH2:20])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(Nc2ccc(F)cc2[N+](=O)[O-])CC1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)N1CCC(Nc2ccc(F)cc2N)CC1
Reaction time: 4 h

Procedure:
This 1-ethoxycarbonyl-4-(4-fluoro-2-nitroanilino)piperidine (5.7 g, 18.3 mmol.) was dissolved in THF (50 mL) and diluted with ethanol (100 mL). After addition of 5% platinum/carbon catalyst (1.2 g), the hydrogenation of the nitro functional group was carried out at atmospheric pressure via a balloon over a four hour period. The catalyst was removed and the solvents evaporated to give 1-ethoxycarbonyl-4-(2-amino-4-fluoroanilino)-piperidine as a viscous oil which was used as is.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1.S(Cl)([Cl:15])=O>>[Cl:15][CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(CO)nc2ccccc21
Product: Cn1c(CCl)nc2ccccc21
Yield: 36 %

Procedure:
A solution of 2-hydroxymethyl-1-methylbenzimidazole (1.1 g, 6.7 mmol) in thionyl chloride (10 ml) was stirred at ambient temperature for 15 minutes and then heated at reflux for 15 minutes. The volatiles were removed by evaporation and the residue purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 2-chloromethyl-1-methylbenzimidazole (506 mg, 36%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:12][CH2:13][C:14]#[CH:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH:4]([N:12]([C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:25]=1[Cl:24])[CH2:13][C:14]#[CH:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCNC(Cc1ccccc1)C(=O)OC
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN(C(=O)c1ccc(Cl)cc1Cl)C(Cc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-Phenyl-2-prop-2-ynylamino-propionic acid methyl ester (75 mg, 0.346 mmol) in anhydrous CH2Cl2 (2 mL) was cooled to 0° C. in an ice bath, then triethylamine (0.1 mL) and 2,4-dichlorobenzoyl chloride (0.06 mL, 0.45 mmol) were added. The mixture was stirred at room temperature for 3 h. Excess of benzoyl chloride was quenched by adding ice-cold water and then the reaction mixture was partitioned between water and CH2Cl2. The organic layer was separated, dried (Na2SO4), and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 2-[(2,4-Dichloro-benzoyl)-prop-2-ynyl-amino]-3-phenyl-propionic acid methyl ester as a syrup, 125 mg (93%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([C:16]([N:18]2[CH2:27][CH2:26][C:25]3[N:24]=[CH:23][C:22]([C:28]([F:31])([F:30])[F:29])=[CH:21][C:20]=3[CH2:19]2)=[O:17])[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH3:1][O:2][CH2:3][C:4]1([C:16]([N:18]2[CH2:27][CH2:26][C:25]3[N:24]=[CH:23][C:22]([C:28]([F:30])([F:29])[F:31])=[CH:21][C:20]=3[CH2:19]2)=[O:17])[CH2:8][CH2:7][NH:6][CH2:5]1
Reactant: COCC1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CCNC1
Reaction time: 17 h

Procedure:
The title compound was prepared according to general procedure D described in connection with Scheme 2. tert-Butyl 3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidine-1-carboxylate (1.7 g, 3.84 mmole) was dissolved in 50 mL CH2Cl2 and 16 mL TFA was added at RT. The reaction mixture was stirred for 17 h and the solvents evaporated. The residue was dissolved in CH2Cl2 and the organic layer was washed twice with 50 mL of saturated NaHCO3 and then dried over Na2SO4. The solvent was evaporated to give product (1.3 g, quantitative yield) of the desired product. 1H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 7.70 (s, 1H), 4.81 (s, 2H), 4.13-3.89 (m, 2H), 3.52-3.43 (m, 3H), 3.29 (s, 3H), 3.12-2.97 (m, 5H), 2.22-2.18 (m, 1H), 2.04-1.97 (m, 1H); MS (ESI) m/z: Calculated for C16H20F3N3O2(free base): 343.2. found: 344 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:10]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cc(F)ccc1Nc1ccccc1
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cc(F)ccc2n1-c1ccccc1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A solution of [(S)-1-(5-fluoro-2-phenylaminophenylcarbamoyl)ethyl]carbamic acid tert-butyl ester (2.15 mmol) in AcOH (10 mL) was stirred for 18 h at 70° C. After cooling to RT, the volatiles were evaporated in vacuo and the residue partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cyclohexane) to afford the title compound as an orange oil (661 mg, 86% over two steps). LCMS (Method J): RT 3.52 min [M+H]+ 356.1.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:25]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[C@H:26]([C:42](O)=[O:43])[CH2:27][CH2:28][CH2:29][CH2:30][NH:31][S:32]([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33].CN1CCOCC1.ClC(OCC(C)C)=O>CN(C)C=O.O1CCCC1.C(OCC)C.C(N(CC)CC)C>[NH:25]([C:45]([O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:46])[C@H:26]([C:42]([NH:1][C@H:2]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:43])[CH2:27][CH2:28][CH2:29][CH2:30][NH:31][S:32]([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33]
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CCC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1
Temperature: -15 °C
Reaction time: 0.02 h

Procedure:
4.18 Grams of H-Glu(OBzl)-OBzl.Tos was dissolved in 30 ml of dimethylformamide (DMF), then 1.21 ml of triethylamine (TEA) was added and the mixture was stirred under cooling. On the other hand, 4.35 g of Z-Lys(Tos)-OH was dissolved in 30 ml of tetrahydrofuran (THF), and 0.98 ml of N-methylmorpholine was added thereto, then this mixture was cooled to -15° C. and under stirring condition 1.27 ml of isobutyl chloroformate was added dropwise. 30 Seconds after the addition, then the cooled DMF solution mentioned above was added thereto and this mixture was stirred at 0° C. for 5 minutes, then at 40° C. in a water bath for 1 minute, further at 15° C. for 30 minutes. THF and DMF were removed from the reaction mixture under a reduced pressure, the residue thus obtained was extracted with ethyl acetate. The extract was washed with 1N-citric acid, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium hydrogencarbonate then a saturated aqueous solution of sodium chloride in this order, then was dried with anhydrous sodium sulfate, and ethyl acetate was removed distillation. The oily residue obtained was solidified by adding ethyl ether and reprecipitated from ethyl acetate-ether to obtain 5.37 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].O=S(Cl)Cl.[CH3:15][NH2:16].C1COCC1>O1CCOCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:16][CH3:15])=[O:6]
Reactant: CN
Reactant: O=C(O)c1cccc(O)c1
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(O)c1
Reaction time: 4 h

Procedure:
To a solution of 3-hydroxybenzoic acid (10 g, 72 mmol, 1.0 eq.) in 100 mL of anhydrous dioxane was added SOCl2 (6.5 mL, 72 mmol, 1.0 eq.). The solution was heated to reflux and stirred for 4 h. The solvent was removed and the crude was dissolved in anhydrous THF (100 mL). A solution of 2 M CH3NH2 in THF (7.2 mL, 144 mmol, 2.0 eq.) was added upon which a white suspension was formed. The solvent was evaporated and the residue was dissolved in MTBE, washed with sat. NH4Cl (aq.). The organic layer was dried (MgSO4), filtered and concentrated. Further purification by column chromatography (0-100% EtOAc in hexanes) yielded 3-hydroxy-N-methyl-benzamide.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:28][CH2:27]2)=[O:25])=[CH:20][C:19]=1[F:40]>>[CH3:39][C:33]1[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=1[N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:21]2[CH:22]=[CH:23][C:18]([N:11]3[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]3(=[O:15])=[O:16])=[C:19]([F:40])[CH:20]=2)=[O:25])[CH2:31][CH2:30]1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](CO)CCS4(=O)=O)c(F)c3)CC2)c(C)c1
Yield: 13.4 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (1.07 g) described in Preparation Example 1 and (4-bromo-3-fluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (1.74 g) described in Preparation Example 132 and by the reaction and treatment in the same manner as in Example 32, the title compound (274 mg) was obtained.
Reaction SMILES: [OH:1][CH:2]1[C:13]2[C:14](=[O:15])[C:9]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])([CH2:10][CH2:11][CH:12]=2)[C:8]#[C:7][CH:6]=[CH:5][C:4]#[C:3]1.N1C=CC=CC=1.[O:30]([CH2:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.CCOCC>[O:30]([CH2:37][C:38]([O:1][CH:2]1[C:13]2[C:14](=[O:15])[C:9]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])([CH2:10][CH2:11][CH:12]=2)[C:8]#[C:7][CH:6]=[CH:5][C:4]#[C:3]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)[Si](C)(C)OC12C#CC=CC#CC(O)C(=CCC1)C2=O
Reactant: O=C(Cl)COc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC12C#CC=CC#CC(OC(=O)COc3ccccc3)C(=CCC1)C2=O
Reaction time: 15 h
Yield: 32.3 %

Procedure:
To a solution of compound 6 (175 mg, 0,533 mmol) in 10 mL tetrahydrofuran was added pyridine (0.20 mL, 2.47 mmol) and phenoxyacetyl chloride (0.17mL, 1.23 mmol) and stirred for 15 h. The solution was diluted with ether and washed with water and saturated bicarbonate. The organic fraction was dried over MgSO4 and concentrated and the residue chromatographed over silica gel (10:1 hexane/ethyl acetate) to give 8-[(phenoxymethyl)carbonyloxy]-1-(t-butyldimethylsilyloxy)-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyn-13-one (11a) (184 mg, 75%).
Reaction SMILES: C([O:5][C:6](=[O:17])[C@H:7](C)[N:8]=CC1C=CC=CC=1)(C)(C)C.[S:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=2)=[CH:19]1.N1C=CC=CC=1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[S:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C@@H:7]([C:6]([OH:17])=[O:5])[NH2:8])=[CH:25][CH:24]=2)=[CH:19]1
Reactant: BrCc1ccc(-c2ccsc2)cc1
Reactant: C[C@H](N=Cc1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N[C@@H](Cc1ccc(-c2ccsc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of N-(phenylmethylene)alanine t-butyl ester (210 mg, 0.90 mmol), 4-(3-thienyl)phenylmethyl bromide (250 mg, 0.99 mmol), and pyridine (7 ml, 0.09 mmol) in methylene chloride (1.8 ml) are added potassium hydroxide (505 mg, 9.0 mmol) and potassium carbonate (1.24 g, 9.0 mmol). The mixture is stirred at room temperature for 2 days, then filtered and washed with methylene chloride. The filtrate and washings are concentrated in vacuo to give a crude 3-[4-(3-thienyl)phenyl]alanine as a yellow oil.
Reaction SMILES: CO[C:3](=[O:11])[CH:4]([N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH3:5].O.[NH2:13][NH2:14]>C(O)CCC>[N:6]1([CH:4]([CH3:5])[C:3]([NH:13][NH2:14])=[O:11])[CH:10]=[N:9][CH:8]=[N:7]1
Reactant: NN
Reactant: COC(=O)C(C)n1cncn1
Solvent: CCCCO
Solvent: O
Product: CC(C(=O)NN)n1cncn1
Yield: 91 %

Procedure:
As described for example 112a, (rac.)-2-[1,2,4]triazol-1-yl-propionic acid methyl ester in butanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 16 h. The mixture was concentrated and triturated with toluene to afford the title compound as a white solid (yield: 91%). MS: m/e=155.0 [M]+.
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[CH2:4][C:3](=[O:8])[CH2:2]1.[Na].S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[CH2:15]([O:7][C:5]1[CH2:6][O:1][CH2:2][C:3](=[O:8])[CH:4]=1)[CH3:16]
Reactant: CCO
Reactant: O=C1COCC(=O)C1
Agent: O=S(=O)(O)O
Agent: [Na]
Product: CCOC1=CC(=O)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a solution of 2H-pyran-3,5(4H,6H)-dione, sodium salt (1.36 g, 10 mmol) in 50 mL of ethanol were added 1.5 mL of concentrated sulphuric acid and the reaction mixture was stirred at room temperature overnight. Most of the solution was evaporated under vacuum, the residue was neutralized with saturated sodium bicarbonate, product extracted with ethyl acetate (4×50 mL), organics combined dried with sodium sulfate, filtered and concentrated. Residue purified by column chromatography (silica gel. 200-300 mesh, eluting with ethyl acetate/petroleum ether=1/1) to afford 5-ethoxy-2H-pyran-3(6H)-one (641 mg, 45%) as yellow solid. LCMS: (M+H)+=143; 1H NMR (300 MHz, CDCl3): δ 5.44 (s, 1H), 4.25 (s, 2H), 4.06 (s, 2H), 3.98 (q, 2H, J=6.9 Hz), 1.38 (t, 3H, J=6.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[N:10]([C:18](=[O:31])[CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]2=3)=[CH:4][CH:3]=1.[C:38]1([C@H:44]([N:46]=[C:47]=[O:48])[CH3:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(OCC)(=O)C.C(OCC)C>[C:38]1([C@H:44]([NH:46][C:47](=[O:48])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:13](=[O:14])[C@H:12]4[CH2:15][CH2:16][CH2:17][C@H:11]4[N:10]([C:18](=[O:31])[CH2:19][N:20]4[C:21](=[O:30])[C:22]5=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]5[C:24]4=[O:25])[C:9]4[CH:32]=[CH:33][CH:34]=[CH:35][C:8]3=4)=[CH:36][CH:37]=2)[CH3:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Reactant: C[C@@H](N=C=O)c1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1)c1ccccc1
Yield: 54 %

Procedure:
Using (3aR*,10aS*)-9-(4-aminobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one and (R)-1-phenylethyl isocyanate, the title compound was synthesized in otherwise the same manner as Example 26. Yield 54%, m.p. 158°-163° C. (ethyl acetate-diethyl ether).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH2:7][CH2:8][C@H:9]([OH:13])[C:10]([OH:12])=[O:11].[CH3:14][C:15](=[CH2:17])[CH3:16]>C(COC)OC>[NH2:6][CH2:7][CH2:8][C@H:9]([O:13][C:15]([CH3:17])([CH3:16])[CH3:14])[C:10]([O:12][C:15]([CH3:16])([CH3:14])[CH3:17])=[O:11]
Reactant: NCC[C@H](O)C(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)[C@H](CCN)OC(C)(C)C
Temperature: -78 °C
Reaction time: 96 h

Procedure:
The following reaction was carried out in a Fischer-Porter tube. Dimethoxyethane (76 ml) and 3.2 ml of concentrated sulfuric acid were added in that order to 4.0 g of 4-amino-(2S)-hydroxybutyric acid (AHBA), and the mixture was then cooled to −78° C. Isobutylene (38 ml) was added thereto, and the tube was sealed, followed by stirring at room temperature for 96 hr. The tube was then slowly opened, and isobutylene was removed by distillation at room temperature. The reaction mixture was then added dropwise to 128 ml of ice water, and the mixture was washed twice with 250 ml of ether, was cooled to 0° C., and was then neutralized with a 6 N aqueous sodium hydroxide solution. Further, solid sodium chloride was added to prepare a saturated solution, and the mixture was extracted four times with 100 ml of chloroform. The chloroform layers were combined, and the combined chloroform layers were dried over anhydrous sodium sulfate and were then concentrated under the reduced pressure to give 250 mg of a yellow oil. The yellow oil was purified by column chromatography on silica gel (30 g, chloroform-methanol-concentrated aqueous ammonia=20:1:0.05→9:2:0.1) to give 37.9 mg of intermediate 3 and 161 mg of intermediate 4.