Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[C:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>C(#N)C.O.C(OCC)(=O)C>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:7]3=[O:22])=[O:32])=[CH:34][CH:35]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)c1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
TEA was added to a mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol) and 4-(t-butyl)benzoyl chloride (0.61 g, 3.1 mmol) in acetonitrile (35 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (100 mL) and ethyl acetate (100 mL), and the organic phase separated and concentrated. The residue was chromatographed on silica gel using a hexanes-ethyl acetate gradient, eluting 1.1 g of the product at 80-90% ethyl acetate, in 80% yield as a white solid; mp 164-166° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 4.26 (99.57%); 1H NMR (DMSO-d6) δ 1.30 (s, 9H), 2.01-2.09 (m, 1H), 2.46-2.63 (m, 2H), 2.84-2.96 (m, 1H), 4.65 (d, J=6.0 Hz, 2H), 5.15 (dd, J=12.9 Hz, J=5.4 Hz, 1H), 7.49-7.52 (m, 2H), 7.79-7.91 (m, 5H), 9.16 (t, J=6.0 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 34.6, 42.5, 49.0, 121.9, 123.5, 125.1, 127.1, 129.7, 131.1, 131.6, 133.3, 147.8, 154.3, 166.3, 167.0, 167.1, 169.8, 172.7; Anal. Calcd for C25H25N3O5.25H2O: C, 66.43; H, 5.69; N, 9.30. Found: C, 66.49; H, 5.62; N, 8.96.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:19][CH:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9]1.[NH2:25][OH:26].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:19][CH:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH:13]=[N:25][OH:26])=[CH:9]1
Reactant: NO
Reactant: CC(=O)NCC1CC(c2ccc(-n3ccc(C=O)c3)c(F)c2)=NO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)NCC1CC(c2ccc(-n3ccc(C=NO)c3)c(F)c2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
(-)-5-Acetamidomethyl-3-(3-fluoro-4-(3-formylpyrrol-1-yl)phenyl)isoxazoline (Example 15) (329 mg) is suspended in 4 ml 95% ethanol in a 50 ml one neck round bottom flask under nitrogen. The suspension is treated with hydroxylamine (80 mg) followed by sodium hydroxide (60 mg) and 0.4 ml water. The reaction is stirred 1 hour at room temperature, the pH is adjusted to 7 with 5% hydrochloric acid, and the white solid is collected. The solid is collected, washed with water, and is dried to give 300 mg (87%) of the title compound as a white solid. The title compound is obtained via chromatography over silica gel (230-400 mesh), eluting with 5% methanol/dichloromethane, mp 216-217° C., [α]25D -67° (c 0.67, DMSO).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.S(Cl)(Cl)=O.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:1][C:2]1[S:3][C:4]([S:13]([Cl:12])(=[O:15])=[O:14])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1csc(Cl)n1
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Product: Cc1nc(Cl)sc1S(=O)(=O)Cl
Temperature: 120 °C
Reaction time: 48 h
Yield: 42.7 %

Procedure:
2-Chloro-4-methyl-thiazole (33 g, 180 mmol) was added dropwise to a solution of thionyl chloride (32.7 mL, 451 mmol) and chlorosulfonic acid (60.2 mL, 902 mmol). The reaction mixture was stirred for 48 h at 120° C., cooled then poured onto ice-water and extracted 3 times with CH2Cl2, dried over Na2SO4, filtered, and concentrated to give a crude liquid. The product was isolated by simple distillation (17 mbar at 85-95° C.) to give 2-Chloro-4-methyl-thiazole-5-sulfonyl chloride (17.85 g, 43%) as a light-yellow liquid. MS (ISP) 233.0[(M+H)+].
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11]>C(O)C(C)C>[Br:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:11][C:8]1[NH:9][CH2:10][CH2:6][N:7]=1
Reactant: Nc1ccc2nc[nH]c2c1Br
Solvent: CC(C)CO
Product: Brc1c(NC2=NCCN2)ccc2nc[nH]c12
Yield: 171.1 %

Procedure:
A solution of 4-bromo-5-aminobenzimidazole (0.22 g, 0.97 mmol) and ISA (0.34 g, 2.5 mmol) in 5 ml of isobutanol was stirred at reflux for 12 h. Reaction mixture was concentrated in vacuo and subjected to silica gel column chromatography (NH3 saturated 20% MeOH/EtOAc) to yield 0.23 g (0.83 mmol, 84%) of the product. The product obtained was converted to the fumarate salt and recrystallized from MeOH to afford 0.12 g (30%) of the product as a white solid: mp 199-202° C.; Anal. Calc. for CO10H10N5Br.1.0C4H4.0.7H2O requires C, 41.13; H, 3.80; N, 17.13. Found: C, 41.60; H, 3.81; N, 16.97.
Reaction SMILES: C([O:8][C:9](=[O:25])[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([Cl:23])[CH:20]=[N:19]2)=[C:14]([Cl:24])[CH:13]=1)[CH3:11])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[Cl:24][C:14]1[CH:13]=[C:12]([CH:10]([CH3:11])[C:9]([OH:25])=[O:8])[CH:17]=[CH:16][C:15]=1[N:18]1[CH:22]=[C:21]([Cl:23])[CH:20]=[N:19]1
Reactant: [H][H]
Reactant: CC(C(=O)OCc1ccccc1)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Yield: 80.7 %

Procedure:
375 mg (1 mmole) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid benzyl ester are hydrogenolyzed in the presence of 50 mg of 10% palladium/activated charcoal at room temperature and at atmospheric pressure in a mixture of 100 ml of ethyl acetate and 10 ml of glacial acetic acid in a rotary hydrogenation apparatus until the theoretical amount of hydrogen has been absorbed. Filtration from the catalyst is effected, the filtrate is concentrated in a vacuum, and the residue is dissolved in a 1 N solution of sodium hydroxide. The resulting aqueous solution is extracted with benzene; acidification is effected with 1 N hydrochloric acid, followed by extraction again with benzene. The organic phase is dried and concentrated to yield 230 mg (80.7% of theory) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid (m.p. 102° to 103° C.).
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([NH:19][CH:12]2[CH2:13][CH2:14][N:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=3)[CH2:10][CH2:11]2)[CH2:18][CH2:17]1
Reactant: CC(C)c1noc(N2CCC(=O)CC2)n1
Reactant: NC1CC1
Product: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1

Procedure:
The title compound is prepared from 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 7. Mass spectrum (ESI+): m/z=251 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:15]([O:19][C:20]([NH:22][C:23]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=S)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:29]([O:28][C:26]([NH:25][C:23]([NH:22][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])=[N:11][C:10]1[CH:12]=[CH:13][CH:14]=[C:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:9]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: Cc1cccnc1-c1cccc(N)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1-c1cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To a suspension of 3-(3-methylpyridin-2-yl)aniline (184 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (331 mg) and diisopropylethyl-amine (0.4 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (332 mg), and the mixture was stirred for 3 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 30 g, n-hexane:ethyl acetate=2:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-methylpyridin-2-yl)phenyl)guanidine (327 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:33])[N:28]5[CH2:31][OH:32])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.N1C=CC=CC=1.[CH:40]1([C:46](Cl)=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.O>ClCCl>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:33])[N:28]5[CH2:31][O:32][C:46]([CH:40]5[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]5)=[O:47])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1CO
Reactant: O=C(Cl)C1CCCCC1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)C1CCCCC1
Yield: 25.3 %

Procedure:
To a solution (15 ml) of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (550 mg) synthesized in the same manner as in Example 1 in dichloromethane was added pyridine (0.287 ml), cyclohexanecarbonyl chloride (0.158 ml) with stirring under ice-cooling and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the to mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 1:3), and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography, and concentrated to dryness under reduced pressure to give the title compound (yield 172 mg, 25.3%) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[N:5][N:6]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:5][N:6]=1
Reactant: CC(C)(C)N
Reactant: Cc1nnc(C=Cc2ccccc2OCC2CO2)s1
Solvent: Cc1ccccc1
Product: Cc1nnc(C=Cc2ccccc2OCC(O)CNC(C)(C)C)s1

Procedure:
7 g (0.025 mole) of 2-methyl-5-[2-(2,3-epoxy-propoxy)-styryl]-1,3,4-thiadiazole and 2.1 g (0.028 mole) of tert.-butylamine are reacted by the method described in Example 1. 3.8 g (44% of theory) of yellow crystals are obtained from toluene; melting point 110°-112° C.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([Li])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].[CH2:21]1[CH2:25]O[CH2:23][CH2:22]1>O1CCCC1>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:2]2[N:4]=[C:5]([C:21]3[CH:25]=[CH:15][C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:23][CH:22]=3)[N:7]=[C:8]([Cl:9])[N:1]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: C1CCOC1
Reactant: [Li]c1ccc(C(C)(C)C)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: CC(C)(C)c1ccc(-c2nc(Cl)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -70 °C
Reaction time: 4 h

Procedure:
1-bromo-4-tert-butylbenzene (125 g, 587 mmol) and tetrahydrofuran (470 mL) were charged into a reaction vessel in an argon stream and cooled to −70° C. A n-butyllithium/hexane solution (1.6 M, 367 mL, 587 mmol) was added dropwise thereto at −70° C. over 90 minutes. After the completion of dropwise addition, the mixture was stirred at −70° C. for 2 hours to obtain a 4-tert-butylphenyllithium/THF solution. Cyanuric chloride (50.8 g, 276 mmol) and tetrahydrofuran (463 mL) were charged into another reaction vessel in an argon stream and cooled to −70° C. The 4-tert-butylphenyllithium/THF solution thus prepared was gradually added dropwise thereto, while cooled to keep the reaction temperature to −60° C. or lower. After the completion of dropwise addition, the reaction solution was stirred at −40° C. for 4 hours and at room temperature for 4 hours. The mixture was quenched by addition of water (50 mL), and tetrahydrofuran was evaporated. From this residue, the organic layer was extracted by the addition of water (1 L) and chloroform (2 L) and the organic layer was washed with water (1 L), and evaporated to dryness. This residue was dissolved in acetonitrile (600 mL), and insoluble solid was filtered off hot. The obtained filtrate was concentrated to approximately 100 mL and cooled to −70° C., and the deposited solid was collected by filtration. The collected solid was dissolved in a chloroform (200 mL)/hexane (600 mL) mixed solvent and purified by silica gel column chromatography (eluent: chloroform/hexane). The eluate was evaporated to dryness, and this residue was recrystallized from acetonitrile to obtain 2,4-di(4′-tert-butylphenyl)-6-chloro-1,3,5-triazine (41.3 g, 109 mmol).
Reaction SMILES: CS(C)=O.C[O-].[Na+].[C:8]1(=[O:14])[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1.[Cl:15][C:16]1[C:17]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[C:18]2[C:26]3[CH2:27][CH2:28][S:29][CH2:30][C:25]=3[S:24][C:19]2=[N:20][C:21]=1[CH2:22]Cl>O.CO>[Cl:15][C:16]1[C:17]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[C:18]2[C:26]3[CH2:27][CH2:28][S:29][CH2:30][C:25]=3[S:24][C:19]2=[N:20][C:21]=1[CH2:22][N:12]1[C:11](=[O:13])[CH2:10][CH2:9][C:8]1=[O:14]
Reactant: O=C1CCC(=O)N1
Reactant: COc1ccc(-c2c(Cl)c(CCl)nc3sc4c(c23)CCSC4)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CS(C)=O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCSC4)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To dimethyl sulfoxide (2450 ml) was added 28% sodium methoxide (97.4 g), followed by addition of succinimide (178.9 g). The mixture was stirred at about 20° C. for 30 minutes and then 3-chloro-2-chloromethyl-5,8-dihydro-4-(4-methoxyphenyl)-6H-thiopyrano[4′,3′:4,5]thieno-[2,3-b]pyridine (490 g) was added thereto. The mixture was stirred at room temperature for 2.5 hours and then a mixture of methanol (1225 ml) and water (490 g) was added dropwise thereto. The mixture was stirred at 10° C. or lower and crystals deposited were filtered off to the titled compound (546 g, 96.3%).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>CN(C=O)C>[N:22]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNCC1
Reactant: COC(=O)c1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCCCC2)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 4-fluoro-2-(trifluoromethyl)benzoate in DMF were added K2CO3 and piperidine, followed by stirring at 100° C. for 3 hours. The reaction mixture was cooled to 0° C., and water was added thereto, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0 to 90:10) to obtain methyl 4-piperidin-1-yl-2-(trifluoromethyl)benzoate as a colorless oily substance.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[Cl:12].[C-:13]#[N:14].[Na+].[ClH:16]>CN(C=O)C.O>[Cl:12][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:3]=1[CH2:2][C:13]#[N:14])[C:7]([Cl:16])=[O:9]
Reactant: Cl
Reactant: [C-]#N
Reactant: O=C(O)c1ccc(CBr)c(Cl)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(C(=O)Cl)cc1Cl
Temperature: 80 °C

Procedure:
A suspension of 4-(bromomethyl)-3-chlorobenzoic acid (4.0 g, 16 mmol) in DMF (120 mL) and H2O (40 mL) was treated with NaCN (2.4 g, 49 mmol) and heated to 80° C. for 2 h. The mixture was cooled to rt and acidified with 1N HCl. The aqueous mixture was extracted with CH2Cl2 (3×25 mL). The combined organic layers were concentrated under reduced pressure and dissolved in MTBE. The organic mixture was washed with H2O and brine (3×25 mL), dried over MgSO4, filtered and concentrated to afford 3-chloro-4-(cyanomethyl)benzoyl chloride.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]([OH:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])=[N+:2]=[N-:3].Cl[C:16]1[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[N:1]([CH2:4][CH2:5][CH:6]([O:14][C:16]1[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19])[C:7]([F:12])([F:13])[C:8]([F:10])([F:11])[F:9])=[N+:2]=[N-:3]
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Reactant: [N-]=[N+]=NCCC(O)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(F)(F)F)nc1OC(CCN=[N+]=[N-])C(F)(F)C(F)(F)F
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of 5-azido-1,1,1,2,2-pentafluoro-3-pentanol (500 mg, 2.28 mmol) in dimethylformamide (10 ml) was added 2-chloro-6-(trifluoromethyl)nicotinonitrile (565 mg, 2.74 mmol) followed by caesium carbonate (2.20 g, 6.75 mmol). The reaction mixture turned brown. After 2 h, the reaction mixture was added to water (10 ml) and extracted with diethyl ether (2×15 ml). The combined organics were washed with brine (20 ml) and dried over anhydrous sodium sulfate. Removal of the solvents yielded a brown liquid. Purification by silica gel chromatography using hexanes/ethyl acetate (10:1 then 1:1) gave the title compound as a yellow liquid (780 mg, 88%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:37])=[C:11]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][C:21]4[CH:22]=[C:23]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH:24]=[CH:25][CH:26]=4)[C:14]3=[O:36])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:28][CH2:27][C:23]1[CH:22]=[C:21]([CH2:20][NH:19][C:15]2[C:14](=[O:36])[N:13]([C:11]3[CH:12]=[C:7]([CH:8]=[CH:9][C:10]=3[CH3:37])[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:6])[CH:18]=[CH:17][N:16]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NCc2cccc(CNC(=O)OC(C)(C)C)c2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NCc2cccc(CN)c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
A mixture of [[3-[[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]methyl]phenyl]methyl]-carbamic acid, 1,1-dimethylethyl ester (Example 51, 90 mg), dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 30 min. The mixture was concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (22 mg).
Reaction SMILES: BrC1C=CC=C2C=1C(=O)C(=O)N2CCCCC.[CH2:18]([O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[C:24]1=[O:33])[CH3:19].O1C2C=CC(O)=CC=2OC1.[CH:45]1[C:54]2[CH2:53][CH2:52][CH2:51][CH2:50][C:49]=2[CH:48]=[CH:47][C:46]=1[OH:55]>>[CH2:18]([O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([OH:32])([C:47]2[C:46]([OH:55])=[CH:45][C:54]3[CH2:53][CH2:52][CH2:51][CH2:50][C:49]=3[CH:48]=2)[C:24]1=[O:33])[CH3:19]
Reactant: CCOC(=O)CN1C(=O)C(=O)c2ccccc21
Reactant: Oc1ccc2c(c1)CCCC2
Agent: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)CCCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with ethyl(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and 1,3-benzodioxol-5-ol with 5,6,7,8-tetrahydronapthalen-2-ol, the title compound was obtained (81%): 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 7.54 (dd, 1H), 7.38 (td, 1H), 7.20 (t, 1H), 6.80 (d, 1H), 6.76 (s, 1H), 6.50 (s, 1H), 4.45 (ABq, 2H), 4.21 (q, 2H), 4.18-4.14 (br, 1H), 2.73-2.47 (m, 4H), 1.77-1.63 (m, 4H), 1.24 (t, 3H); MS (ES+) m/z 364 (M−17), 404 (M+23)
Reaction SMILES: [H-].[Na+].C([C:6]1[S:10][C:9]2[C:11]([C:15]3[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[C:17]([CH:24]([CH3:26])[CH3:25])[C:16]=3[O:27][CH2:28][CH3:29])=[CH:12][CH:13]=[CH:14][C:8]=2[CH:7]=1)(=O)C.CN([CH:33]=[O:34])C>>[CH2:16]([O:27][C:33](=[O:34])[CH:6]=[C:7]([C:6]1[S:10][C:9]2[C:11]([C:15]3[CH:20]=[C:19]([CH:21]([CH3:22])[CH3:23])[CH:18]=[C:17]([CH:24]([CH3:26])[CH3:25])[C:16]=3[O:27][CH2:28][CH3:29])=[CH:12][CH:13]=[CH:14][C:8]=2[CH:7]=1)[CH3:8])[CH3:15]
Reactant: CN(C)C=O
Reactant: CCOc1c(-c2cccc3cc(C(C)=O)sc23)cc(C(C)C)cc1C(C)C
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=C(C)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC)c2s1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
To a mixture of 38 mg (0.79 mmol) of NaH in 1 mL of dry DMF was added dropwise a solution of 148 mg (0.66 mmol, 0.13 mL) of triethylphosphonoacetate at 0° C. After 10 minutes, 125 mg of 2-acetyl-7-(2-ethoxy-3,5-diisopropylphenyl)-benzo[b]thiophene (diluted in 2 mL of dry DMF) was added slowly and the mixture is warmed-up to 40° C. After complexion of the reaction (TLC), and work-up, the crude ester was purified over a short pad of silica gel (eluent: ethyl acetate/hexane: 95/5) to afford 87 mg (0.193 mmol, yield=59%) of 3-[7-(2-ethoxy-3,5-diisopropylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid ethyl ester (ratio E/Z=85/15)1. 1H-NMR (CDCl3), δ: 7.73 (d, J=7.8 Hz, 1H), 7.60 (s, 1H), 7.45 (d, J=1.0 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.17 (m, 2H), 6.29 (s, 1H), 4.19 (dd, J=14.5, 7.3 z, 2H), 3.44 (dt, J=13.7, 6.9 Hz, 1H), 3.36 (dd, J=14.0, 7.0 Hz, 2H), 2.92 (dt, J=13.7, 6.8 Hz, 1H), 2.66 (s, 3H), 1.28 (m, 12H), 0.90 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]([C:13]2[CH2:20][S:19][CH:18]3[N:15]([C:16](=[O:29])[CH:17]3[NH:21][C:22](OC(C)(C)C)=[O:23])[C:14]=2[C:30]([O:32][CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O)(=O)=O.[S:51]1[CH:55]=[CH:54][CH:53]=[C:52]1[CH2:56]C(Cl)=O.C(N(CC)CC)C>C(#N)C.O1CCCC1>[NH:1]([C:8]1[S:9][C:10]([C:13]2[CH2:20][S:19][CH:18]3[N:15]([C:16](=[O:29])[CH:17]3[NH:21][C:22](=[O:23])[CH2:56][C:52]3[S:51][CH:55]=[CH:54][CH:53]=3)[C:14]=2[C:30]([O:32][CH:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:31])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4ccccc4)s3)CSC12
Reactant: O=C(Cl)Cc1cccs1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4ccccc4)s3)CSC12

Procedure:
3-(2-Anilinothiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.3 g) is treated with methanesulphonic acid (2.3 cc) in acetonitrile (23 cc) by following the procedure described in Reference Example 1. This gives crude 7-amino-3-(2-anilinothiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.85 g), which is acylated with (thien-2-yl)-acetyl chloride (0.445 cc) in tetrahydrofuran (25 cc), in the presence of triethylamine (0.505 cc), by following the procedure described in Reference Example 1. The crude product obtained is chromatographed on a column (height: 30 cm; diameter: 2.5 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 1.2 bars (120 kPa) with a 70/30 (by volume) mixture of cyclohexane and ethyl acetate (3 liters), and 50 cc fractions being collected. Fractions 20 to 50 are combined and concentrated to dryness. After trituration in isopropyl ether, 3-(2-anilinothiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.9 g) is obtained in the form of a yellow solid.