Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:26][OH:27])[NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[C:9]([CH3:24])[CH:8]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH2:17]([O:16][C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[O:27][CH2:26][CH:4]([C:3]([O:2][CH3:1])=[O:28])[N:5]=2)=[CH:8][C:9]=1[CH3:24])=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)[C@H](CO)NC(=O)c1ccc(NC(=O)OCc2ccccc2)c(C)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COC(=O)C1COC(c2ccc(NC(=O)OCc3ccccc3)c(C)c2)=N1
Yield: 83.3 %

Procedure:
The same operation as in Example (97b) was performed using N-(4-{[(benzyloxy)carbonyl]amino}-3-methylbenzoyl)serine methyl ester obtained in Example (109b) (1.8 g, 4.66 mmol), the Burgess reagent (1.44 g, 6.06 mmol) and THF (15 mL). Purification by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1, 2/1) gave 1.43 g of the title compound as a colorless solid (83%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45]OS(C)(=O)=O)=[CH:41][C:40]([C:51]3[CH:56]=[CH:55][C:54]([S:57][CH3:58])=[CH:53][CH:52]=3)=[N:39]2)[CH2:36][CH2:35]1.CN1CCNCC1>>[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[CH:41][C:40]([C:51]3[CH:56]=[CH:55][C:54]([S:57][CH3:58])=[CH:53][CH:52]=3)=[N:39]2)[CH2:35][CH2:36]1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: CSc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1
Agent: CN1CCNCC1
Product: CSc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC3CC3)n2)cc1
Yield: 85.7 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and 1-methyl-piperazine were reacted to yield the title compound as a yellow oil (yield: 85.7 %)
Reaction SMILES: Cl[C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].[I:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[CH3:5][C:2]([O:14][C:11]1[CH:12]=[CH:13][C:8]([I:7])=[CH:9][CH:10]=1)([CH3:6])[C:3]#[CH:4]
Reactant: C#CC(C)(C)Cl
Reactant: Oc1ccc(I)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C#CC(C)(C)Oc1ccc(I)cc1
Yield: 29.5 %

Procedure:
A solution of 3-chloro-3-methyl-1-butyne (10.0 g, 97.9 mmol), 4-iodophenol (15.0 g, 68.4 mmol), sodium hydroxide (3.90 g, 97.5 mmol) and tetrabutylammonium hydrogen sulfate (9.33 g, 27.5 mmol) in methylene chloride (50 mL) and water (50 mL) was stirred for 19 days at room temperature. After separating the two layers, the organic layer was washed with 1 N sodium hydroxide followed by water, dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed successively with 1 N hydrochloric acid, 1 N sodium hydroxide, water, brine and dried over anhydrous magnesium sulfate. After removing drying agent, the solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel eluting with toluene/hexane (1:10) to give the title compound as an oil (5.78 g, 20.2 mmol) in 30% yield: 1H NMR (CDCl3) δ 7.56 (d, J=8.7 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 2.56 (s, 1H), 1.63 (s, 6H); 13C NMR (CDCl3) δ 155.4, 137.8, 123.5, 86.0, 85.6, 74.3, 72 6, 29.5.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](=[O:24])[N:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])[CH2:9]1)=O)(C)(C)C.[ClH:25]>ClCCl>[ClH:25].[F:23][C:20]1[CH:19]=[CH:18][C:17]([N:15]([CH3:16])[C:14]([C@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:24])=[CH:22][CH:21]=1
Reactant: CN(C(=O)[C@H]1CCCN(C(=O)OC(C)(C)C)C1)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Product: CN(C(=O)[C@H]1CCCNC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a cooled solution of (S)-3-[(4-fluoro-phenyl)-methyl-carbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (0.205 g, 0.61 mmol) in dichloromethane (4 mL) was added dropwise 3 mL of HCl 4N (dioxane solution) and the solution was stirred at R.T. for 1 h. The solvent was evaporated under reduced pressure to give the title compound as a white solid (0.16 g).
Reaction SMILES: CN1CCN(C)[C:4]2[CH:9]=NC=[CH:12][C:3]1=2.[C:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=O)[CH3:23])[C:18]2[CH:25]=[CH:26][N:27]=[CH:28][C:17]1=2)(=O)[CH3:14]>CCOC(C)=O.CO>[CH2:22]([N:19]1[CH:20]2[CH:21]([CH2:12][CH2:3][CH2:4][CH2:9]2)[N:16]([CH2:13][CH3:14])[C:17]2[CH:28]=[N:27][CH:26]=[CH:25][C:18]1=2)[CH3:23]
Reactant: CC(=O)N1CCN(C(C)=O)c2cnccc21
Reactant: CN1CCN(C)c2cnccc21
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN1c2ccncc2N(CC)C2CCCCC21

Procedure:
A suspension of 0.77 g (5.80 mmol) of AlCl3 in 30 ml of MTBE was stirred at room temperature for 45 minutes and subsequently cooled to 0° C. and 1.32 g (9.35 mmol) of LiAlH4 were then added in small portions. After the addition was complete and the mixture had been stirred for another 15 minutes, compound 14 (0.64 g, 2.23 mmol) was added and the mixture was stirred at 0° C. for 1 hour. It was subsequently refluxed for 8 hours and then cooled to room temperature and poured into ice water. The inorganic precipitate was filtered off with suction and washed twice with 30 ml of DCM. The aqueous phase was brought to a pH of 12 and extracted three times with 40 ml of DCM. The combined organic phases were dried over Na2SO4 and the solvent was distilled off on a rotary evaporator. The crude product obtained was purified by flash chromatography on silica gel (EtOAc/MeOH/NEt3, 10:2:1) and on basic aluminum oxide (EtOAc/MeOH, 10:1). This gave 0.30 g (1.22 mmol, 55%) of a colorless solid. Rf=0.32 (basic alumina, EtOAc/MeOH, 10:1). 1H NMR: (400 MHz, CDCl3): δ=1.11, 1.13 (t, 3J=7.2 Hz, H3C—CH2—N-5, 3J=7.2 Hz, H3C—CH2—N-10, 6-H), 1.37 (m, 2H, H-7,8), 1.56 (m, 3Jaa=6.8 Hz, 3Jee=3.2 Hz, 4H, H-6, H-9, H-7, H-8), 1.76 (m, 3Jae=3.2 Hz, 1H, H-9), 1.89 (m, 3Jae=3.2 Hz, 1H), 3.18 (dq, 3J=7.2 Hz, 2J=14.4 Hz, 2-H, H3C—CHAB—N-5, H3C—CHAB—N-10), 3.23 (ddd, 3Jae=2.8 Hz, 3Jae=3.2 Hz, 3Jaa=6.8 Hz, 1H, H-5a), 3.34 (ddd, 3Jae=2.8 Hz, 3Jae=3.2 Hz, 3Jae=3.2 Hz, H-1, H-9a), 3.43 (dq, 3J=7.2 Hz, 2J=14.4 Hz, H3C—CHAB—N-5, H3C—CHAB—N-10, 2H, H-1), 6.33 (d, 3J=5.6 Hz, 1H, H-4), 7.67 (s, 1H, H-1), 7.72 (d, 1H, H-3) ppm. 13C NMR (100 MHz, CDCl3): δ=10.8 (H3C—CH2—N-5), 11.8 (H3C—CH2—N-10), 21.7 (C-7), 22.9 (C-8), 27.3 (C-6), 27.8 (C-9), 40.4 (H3C—CH2—N-5), 41.7 (H3C—CH2—N-10), 52.8 (C-9a), 56.4 (C-5a), 104.3 (C-4), 130.6 (C-10a, C-1), 139.4 (C-3), 141.2 (C-4a) ppm. GC-MS (EI): RT 10.58 min, m/e (%) 246 (18), 245 (M+, 100), 231 (9), 230 (57), 217 (7), 216 (44), 207 (6), 186 (7), 174 (15), 162 (6), 160 (16), 158 (6), 148 (12), 146 (6), 132 (8); IR (neat): ν=3436 (s), 2970 (m), 2860 (vs), 2860 (s), 1628 (w), 1576 (vs), 1513 (vs), 1473 (w), 1447 (m), 1348 (s), 1317 (w), 1267 (s), 1211 (s), 1167 (w), 1125 (w), 1107 (w), 1077 (w), 1059 (w), 1040 (w), 920 (w), 798 (s) 777 (m), 746 (m) cm−1. HRMS (EI): calculated for C15H23N3 245.1892 [M+], found: 245.1889.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[CH3:19][O:20][C:21]([C:23]([CH3:42])([CH3:41])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][N:33]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35][CH2:34]2)=[CH:27][CH:26]=1)=[O:22]>C(O)CCC>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:6]2[C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[N:3]=[C:2]2[N:37]2[CH2:38][CH2:39][CH2:40][N:33]([CH2:32][CH2:31][C:28]3[CH:29]=[CH:30][C:25]([CH2:24][C:23]([C:21]([O:20][CH3:19])=[O:22])([CH3:42])[CH3:41])=[CH:26][CH:27]=3)[CH2:34][CH2:35][CH2:36]2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(Cn2c(Br)nc3ccccc32)cc1
Reactant: COC(=O)C(C)(C)Cc1ccc(CCN2CCCNCCC2)cc1
Solvent: CCCCO
Product: COC(=O)C(C)(C)Cc1ccc(CCN2CCCN(c3nc4ccccc4n3Cc3ccc(Cl)cc3)CCC2)cc1
Yield: 58 %

Procedure:
To a solution of 2-bromo-1-(4-chlorophenylmethyl)-1H-benzimidazole (0.029 g) in n-butanol (0.5 ml) was added 1-[2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl]-1,5-diazacyclooctane (0.102 g), and the mixture was refluxed for 3 hours. The reaction mixture was quenched with a saturated aqueous NaHCO3 solution (30 ml), and the mixture was extracted with methylene chloride (20 ml). The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of methylene chloride, diethyl ether and methanol (1:1:0.2) as eluent to give 1-[1-(4-chlorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl]-1,5-diazacyclooctane (0.030 g) as a colorless oily liquid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)(C)C>[O:14]1[CH2:15][CH2:16][N:11]([C:4]2[CH:3]=[C:2]([N:25]3[CH2:29][CH2:28][CH2:27][C:26]3=[O:30])[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=2)[CH2:12][CH2:13]1
Reactant: O=C1CCCN1
Reactant: O=[N+]([O-])c1cc(Cl)cc(N2CCOCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)(C)O
Product: O=C1CCCN1c1cc(N2CCOCC2)cc([N+](=O)[O-])c1

Procedure:
Prepared according to Procedure W using palladium (II) acetate (4.63 mg, 0.021 mmol), tetramethyl t-butyl XPhos (0.030 g, 0.062 mmol), 4-(3-chloro-5-nitrophenyl)morpholine (0.100 g, 0.412 mmol), tripotassium phosphate (0.122 g, 0.577 mmol), 2-pyrrolidinone (0.044 mL, 0.577 mmol), and tert-butanol (1 mL). Purification by column chromatography (silica; 0-50% EtOAc in hexanes) afforded 1-(3-morpholino-5-nitrophenyl)pyrrolidin-2-one as an orange amorphous solid. Mass Spectrum (ESI) m/e=292.2 (M+1).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:7]=1.C(=O)([O-])O.[Na+]>CS(C)=O>[F:15][C:14]([F:17])([F:16])[CH2:13][O:12][C:8]1[N:7]=[C:6]([CH2:5][C:1]#[N:2])[CH:11]=[CH:10][CH:9]=1
Reactant: FC(F)(F)COc1cccc(CCl)n1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1cccc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.5 %

Procedure:
Sodium cyanide (0.823 g, 16.8 mmol) is added to a solution of 2-(chloromethyl)-6-(2,2,2-trifluoroethoxy)pyridine (2.0 g, 7.63 mmol, Step-4) in DMSO (38 mL) and stirred at rt for 20 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (60 mL) and extracted with EtOAc (100 mL). The organic layer is washed with water (50 mL×2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on amine gel eluting with n-hexane/EtOAc (3:1) to give 1.13 g (69% yield) of the title compound as yellow oil.
Reaction SMILES: C(N1C(=O)C(N[C:12](=[O:23])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=2[F:22])(C)C(=O)NC1=O)C.[NH2:26][C:27]1([CH2:39][CH3:40])[C:32](=[O:33])[N:31]([CH:34]([CH3:36])[CH3:35])[C:30](=[O:37])[NH:29][C:28]1=[O:38]>>[CH2:39]([C:27]1([NH:26][C:12](=[O:23])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=2[F:22])[C:32](=[O:33])[N:31]([CH:34]([CH3:36])[CH3:35])[C:30](=[O:37])[NH:29][C:28]1=[O:38])[CH3:40]
Reactant: CCN1C(=O)NC(=O)C(C)(NC(=O)c2cc(F)c(F)c(F)c2F)C1=O
Reactant: CCC1(N)C(=O)NC(=O)N(C(C)C)C1=O
Product: CCC1(NC(=O)c2cc(F)c(F)c(F)c2F)C(=O)NC(=O)N(C(C)C)C1=O

Procedure:
Compound 20g was prepared by the same method described for 20f using 5-amino-5-ethyl-1-isopropylbarbituric acid (0.37 g, 2 mmol). The crude 5-ethyl-1-isopropyl-5-(tetrafluoro-benzamido)barbituric acid (20g) was obtained as white crystals and did not require further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:26])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]2[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:27][N:28]=[C:29]=S.Cl>O1CCCC1>[OH:26][C:9]1([C:4]2[CH:5]=[CH:6][C:7]3[NH:8][C:27]([NH:28][CH3:29])=[N:1][C:2]=3[CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ccc(C2(O)c3ccccc3C(=O)N2Cc2ccccc2)cc1N
Reactant: CN=C=S
Agent: Cl
Solvent: C1CCOC1
Product: CNc1nc2cc(C3(O)c4ccccc4C(=O)N3Cc3ccccc3)ccc2[nH]1
Temperature: 65 °C
Reaction time: 3 h
Yield: 3 %

Procedure:
To a solution of 3-(3,4-diaminophenyl)-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one (100 mg, 0.289 mmol) and methyl isothiocyanate (31 mg, 0.434 mmol) in tetrahydrofuran (30 mL) was added 1-[3-dimethylamino)propyl]-3-ethylcarbodiimmide hydrochloride (89 mg, 0.462 mmol) at room temperature. The reaction mixture was heated to 65° C. and stirred for 3 h, at which time it was cooled to room temperature and partitioned with water and a mixture of acetonitrile-ethyl acetate (1:9, 200 mL). The organic layer was washed with water and brine then dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography (SiO2, methanol/dichloromethane) to afford 3-hydroxy-3-[2-(methylamino)-1H-benzimidazol-5-yl]-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one (3.3 mg). 1H NMR (400 MHz, CD3OD): 7.79 (d, 1H), 7.54-7.48 (m, 2H), 7.29-7.26 (m, 2H), 7.18-7.16 (m, 2H), 7.11-7.01 (m, 4H), 6.86 (dd, 1H), 4.57 (d, 1H), 4.34 (d, 1H), 2.96 (s, 3H); MS (EI) for C23H20N4O2: 385 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[Br:23])[CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[Br:23])[CH2:9][CH2:10][CH:11]=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCCO)Cc1cc([N+](=O)[O-])ccc1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCC=O)Cc1cc([N+](=O)[O-])ccc1Br
Reaction time: 1.5 h

Procedure:
To a stirring solution of (tert-butoxy)-N-[(2-bromo-5-nitrophenyl)methyl]-N-(3-hydroxypropyl)carboxamide (1 eq) in methylene chloride (0.1 M) at room temperature was added Dess-Martin reagent (1.2 eq). After stirring for 1.5 hr, the reaction mixture was quenched with ether, saturated sodium bicarbonate, and followed by the addition of solid sodium thiosulfate. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford product. EI-MS m/z 387 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])[C:5]([NH:7][C@H:8]([CH2:27][CH2:28][OH:29])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([C:22](=[N:24][O:25]C)[CH3:23])[N:19]([CH3:21])[CH:20]=2)=[CH:12][CH:11]=1)=[O:6].C[Mg+].[Br-].CCOCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])[C:5]([NH:7][C@H:8]([CH2:27][CH2:28][OH:29])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:17]=[C:18]([C:22](=[N:24][OH:25])[CH3:23])[N:19]([CH3:21])[CH:20]=2)=[CH:14][CH:15]=1)=[O:6]
Reactant: CON=C(C)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=NO)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To a solution of 2 (3.7 g, 11.4 mmol) in THF (40 mL) was added dropwise MeMgBr in Et2O (3M, 11.4 ml, 34.2 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min. The solution was quenched by saturated NH4Cl at 0° C. and diluted between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give 3 (3.0 g, 94%) without further purification. LRMS (M+H+) m/z 279.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:21])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)c1ccc(OCc2ccccc2)cc1

Procedure:
In the synthesis of an alcohol to be reacted with the ester (v), 4-benzyloxybenzoic acid (vi) is first reacted with a halogenating agent such as oxalyl chloride to obtain 4-benzyloxybenzoyl chloride (vii).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:20]=O>C(O)=O>[CH3:1][C:2]1([CH3:19])[CH:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[CH2:6][CH2:7][N:8]1[CH3:20]
Reactant: CC1(C)NCCc2ccccc2C1c1ccccc1
Reactant: C=O
Solvent: O=CO
Product: CN1CCc2ccccc2C(c2ccccc2)C1(C)C
Yield: 76 %

Procedure:
A solution of 2,3,4,5-tetrahydro-4,4-dimethyl-5-phenyl-1H-3-benzazepine (7.54 g., 0.03 mole) and 15 ml. of 36% aqueous formaldehyde in 25 ml. of 90% formic acid is refluxed for 8 hours. After the solution is concentrated to a low volume, ice and K2CO3 are added to pH 8.5 and extracted twice with 50 ml. of ethyl acetate. The combined organic extracts were washed, dried (Na2SO4) and evaporated to dryness in vacuo. Crystallization of the residue from isopropanol gives 6.0 g. (76% yield) of pure product as white crystals, m.p. 92°-93° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11](=[N:30][C:31]([O:33]CC)=O)[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])[CH3:2].ClCCCl>[Ti](Cl)(Cl)(Cl)Cl.CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:30][C:31](=[O:33])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:22][CH:21]=4)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N=C(Nc1ccc(Oc2cccc3ccccc23)cc1)n1cc(C(=O)OCC)cn1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCO
Solvent: ClCCCl
Product: CCOC(=O)c1cnn(-c2nc3ccc(Oc4cccc5ccccc45)cc3c(=O)[nH]2)c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Titanium (IV) chloride (0.86 mL, 7.8 mmol) was added to a solution of 1-{ethoxycarbonylimino-[4-(naphthalen-1-yloxy)-phenylamino]methyl}-1H-pyrazole-4-carboxylic acid ethyl ester (0.74 g, 1.6 mmol) and DCE (10 mL), and the resulting mixture was heated to 90° C. for 16 h. The reaction mixture was cooled to room temperature and poured into 50 mL EtOH. The mixture was stirred for 30 min and the solid precipitate was collected by vacuum filtration (0.46 g, 69%). MS (ESI): mass calcd. for C24H18N4O4, 426.1; m/z found, 427.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.87 (s, 1H), 8.99 (s, 1H), 8.29 (s, 1H), 8.05 (d, J=7.5 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.70 (dd, J=8.9, 2.9 Hz, 1H), 7.64-7.60 (m, 1H), 7.60-7.53 (m, 2H), 7.39 (d, J=2.8 Hz, 1H), 7.23 (d, J=7.4 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([OH:28])[CH:3]=1.[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[N:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:28][C:4]2[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=2[O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[N:34][CH:33]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1O
Reactant: COC(=O)c1ccc(CBr)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2OCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)nc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 86.6 %

Procedure:
To a solution of 2-(4-chloro-2-hydroxy-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.11 g, 0.27 mmol) in dioxane (1 mL) was added 6-bromomethyl-nicotinic acid methyl ester (0.075 g, 0.32 mmol) and cesium carbonate (0.15 g, 0.47 mmol). The reaction was stirred at ambient temperature for 6 days, then concentrated. Chromatography on silica gel gave the title compound (0.13 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:27]=[C:26](F)[C:25]([Cl:29])=[CH:24][C:20]=2[C:21]([OH:23])=O)(=[O:17])=[O:16])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].CNC.C[N-]C>C1COCC1.CCCCCC>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:27]=[CH:26][C:25]([Cl:29])=[CH:24][C:20]=2[C:21]([Cl:3])=[O:23])(=[O:17])=[O:16])=[CH:11][CH:10]=1)([CH3:7])([CH3:8])[CH3:6]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)c(Cl)cc2C(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: CNC
Agent: C[N-]C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)Cl)cc1

Procedure:
Thionyl chloride (220 mL, 3.02 mol) was introduced to a 1 L round bottom flask fitted with a magnetic stir bar. 2-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-4-fluoro-benzoic acid (22 g, 57.0 mmol) was added under rapid agitation and the mixture was heated at reflux under a nitrogen atmosphere. The reaction progress was monitored by the addition of a few drops of the reaction mixture into ˜1 mL of 2.0 M dimethylamine in THF, followed by LCMS analysis. Complete conversion to the dimethyl amide was observed at 1.25 h. The crude mixture was subsequently concentrated in vacuo to produce an orange oil. Hexane (50 mL) was added to the flask and the mixture concentrated again to afford 2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-benzoyl chloride as an orange crystalline solid which was utilized direction in the next step.
Reaction SMILES: [Br-].CN([CH:5]=[N:6][C:7]1[S:8][C:9]2[CH2:20][CH2:19][CH2:18][C:10]=2[N+:11]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])C.C1CCN2C(=NCCC2)CC1.C(O)(=O)C>CN(C=O)C>[CH2:16]([O:15][C:13]([C:12]1[N:11]2[C:7]([S:8][C:9]3[CH2:20][CH2:19][CH2:18][C:10]=32)=[N:6][CH:5]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)C[n+]1c(N=CN(C)C)sc2c1CCC2
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2sc3c(n12)CCC3

Procedure:
A suspension of 2-[[(Dimethylamino)methylene]amino]-3-(2-ethoxy-2-oxoethyl)-5,6-dihydro-4H-cyclopentathiazolium bromide (Formula E-3) (4.0 g) in DMF (20 mL) dissolved on addition of DBU (2.48 mL). The solution was reacted at 25° for 18 hours, poured into cold 10% acetic acid solution, and precipitated 6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-carboxylic acid ethyl ester (Formula E-4) (1.95 g) was filtered. Crystallization of an aliquot from isopropanol gave pure 6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-carboxylic acid ethyl ester (Formula E-4), m.p. 101-102°.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].C(N(C(C)C)CC)(C)C>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)CCCCN
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCCNC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
2-Acetylthiomethyl-3-phenylpropanoic acid is reacted with oxalyl chloride and the resulting acid chloride is then reacted with 5-aminopentanoic acid, methyl ester, hydrochloride in the presence of diisopropylethylamine as more fully described in Example 5 of European Patent Application 136,883 to give (±)-5-[[2-[(acetylthio)methyl]-1-oxo-3-phenylpropyl]amino]pentanoic acid, methyl ester.