Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([S:6][CH2:7][CH2:8][CH:9]1[S:13][CH2:12][CH2:11][S:10]1)=[O:5].C(N(CC)CC)C.C1(C)C=CC=CC=1.O>CC(C)=O>[C:4]([S:6][CH2:7][CH2:8][CH:9]1[S:10][CH2:11][CH2:12][S:13]1)(=[O:5])[CH:3]=[CH2:2]
Reactant: O=C(CCCl)SCCC1SCCS1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=CC(=O)SCCC1SCCS1
Yield: 98.2 %

Procedure:
To a solution of the 2-[2-(3-chloropropionylthio)-ethyl]-1,3-dithiolane (127 g, 0.49 mole) obtained as described above and dissolved in acetone (200 g) in a glass-made 1-L reaction vessel, triethylamine (74 g, 0.73 mole) was added dropwise at 25° C. over 1 hour. After the contents were stirred and reacted at 25° C. for 6 hours, toluene (400 g) and water (400 g) were added to the reaction mixture, and a toluene layer with the reaction product extracted therein was allowed to separate and was taken out. The toluene solution was washed with a 5 wt. % aqueous solution of hydrochloric acid, and the resulting mixture was washed with water until the water layer became neutral. Toluene was then distilled off under reduced pressure to afford the target compound, 2-(2′-acryloylthioethyl)-1,3-dithiolane, (106 g) as a colorless viscous clear liquid. Yield: 80%, purity>99% [analyzed by liquid chromatography (percent by area method)]. 1H-NMR δ (CDCl3): 2.0-2.1 (m, 2H), 2.5-2.7 (m, 2H), 3.2-3.3 (m, 4H), 4.7-4.8 (t, 1H), 5.0-7.0 (m, 3H). FD-MS: 220(M).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[C:21]([N:24]2[C:28]4[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=4[N:26]=[CH:25]2)[CH:20]=[CH:19]3)[CH2:10][CH2:9]1)(C)(C)C>FC(F)(F)C(O)=O>[CH3:34][O:33][C:31]1[CH:30]=[CH:29][C:28]2[N:24]([C:21]3[CH:20]=[CH:19][C:18]4[C:23](=[C:14]([N:11]5[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]5)[CH:15]=[CH:16][CH:17]=4)[N:22]=3)[CH:25]=[N:26][C:27]=2[CH:32]=1
Reactant: COc1ccc2c(c1)ncn2-c1ccc2cccc(N3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)ncn2-c1ccc2cccc(N3CCC(N)CC3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester G (8.40 g, 17.7 mmol) was dissolved in 50 mL of trifluoroacetic acid (TFA) under an atmosphere of dry N2. The reaction mixture was stirred at ambient temperature for 15 minutes after which time it was concentrated under vacuum to give a yellow oil. The oil was partitioned between DCM and 0.1N aqueous NaOH. The DCM layer was washed again with 0.1N aqueous NaOH. The DCM layer was dried over Na2SO4, filtered and concentrated to give 5.85 g of 1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine as a yellow solid. C.I. m/z 374 [M+1]; 1H NMR (CDCl3) δ 8.66 (s, 1 H), 8.37 (d, J=8.9 Hz, 1 H), 8.30 (d, J=8.7 Hz, 1 H), 7.68 (d, J=8.9 Hz, 1 H), 7.47 (m, 2 H), 7.35 (d, J=2.3 Hz, 1 H), 7.25 (m, 1 H), 7.06 (dd, J=2.5, 8.9 Hz, 1 H), 3.91 (s, 3 H), 3.88 (m, 2 H), 2.90 (m, 3 H), 2.05 (m, 2 H), 1.83 (m, 2 H), 1.50 (brs, 2 H).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([CH:19]=[O:20])[CH:26]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: O=Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(C=O)c4)cc3CC[C@@H]12
Yield: 65.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3-formylphenylboronic acid (117 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 141 mg (65%) of the title compound as a white solid. mp 163°. FDMS: m/e =333.
Reaction SMILES: I[CH2:2][C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH2:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=1)[C:22]#[C:23][CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:21]([O:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][CH2:2][C:3]2([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)=[CH:30][CH:31]=1)[C:22]#[C:23][CH3:24]
Reactant: CC#CCOc1ccc(S)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(SCC2(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A mixture of 0.294 g (0.74 mmol) of 1-(tert-Butyl) 4-ethyl 4-(iodomethyl)piperidine-1,4-dicarboxylate, 0.145 (0.814 mmol) of 4-but-2-ynyloxy-benzenethiol and 0.204 g (1.48 mmol) of K2CO3 in 2.0 mL of DMF was stirred at room temperature for 18 h. The resulting mixture was diluted with EtOAc, washed with H2O, brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc:Hexanes (1:19) to provide 0.328 g (99%) of the desired product as a colorless oil. Electrospray Mass Spec: 448.3 (M+H)+
Reaction SMILES: [Na].[CH3:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10]([CH2:12][C:13](=O)[CH3:14])=[O:11])=[CH:5][N:4]=1.[ClH:16].S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[ClH:19].[CH3:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH:10]([OH:11])[CH2:12][CH:13]([Cl:16])[CH3:14])=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC(=O)CC(=O)c1cnc(C)nc1C
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Product: Cc1ncc(C(O)CC(C)Cl)c(C)n1

Procedure:
A suspension of the sodium salt of (2,4-dimethyl-5-pyrimidylcarbonyl)-acetone in anhydrous toluene is saturated with hydrogen chloride and then reacted with thionyl chloride in a known manner. Reduction of the reaction product gives 1-(2,4-dimethyl-5-pyrimidyl)-3-chloro-butan-1-ol hydrochloride which is used without additional purification.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[Cl:16])[CH2:5]O.C(N(S(F)(F)[F:23])CC)C>ClCCl>[CH3:1][O:2][N:3]=[C:4]([CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[Cl:16])[CH2:5][F:23]
Reactant: CCN(CC)S(F)(F)F
Reactant: CON=C(CO)Cc1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Product: CON=C(CF)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 111.1 %

Procedure:
To a stirred brown suspension of 1-hydroxy-3-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime (33 g; 117 mmol) in dichloromethane (235 ml) at −20° C. under nitrogen was added dropwise a solution of diethylaminosulfur trifluoride (16 ml; 123 mmol) in dichloromethane (62 ml). During addition, temperature rose to −10° C. The mixture turned to a brown orange solution which was allowed to warm at 20° C. and was stirred for 2 hours. The organic solution was washed with saturated hydrogen carbonate solution (200 ml), 1N hydrochloric acid (200 ml), brine (200 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford 37 g (110% of theory) of crude 1-fluoro-3-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime (isomers E/Z) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(C(C)O)c1OC
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COc1cc(Cl)cc(C(C)=O)c1OC
Reaction time: 3 h
Yield: 63.5 %

Procedure:
To a solution of 1-(5-chloro-2,3-dimethoxy-phenyl)-ethanol (5.67 g, 26.8 mmol) in acetone (200 mL) at room temperature was added a previously prepared solution of Jones Reagent (H2O—H2SO4—CrO3, 100 mL/22 mL/20 g) (100 mL, dropwise). The reaction was stirred for 3 h, and then concentrated. The mixture was dissolved in ethyl acetate (200 mL) and washed with 3.0 N aqueous NaOH and brine. The organic phase was dried over Na2SO4, filtered over silica gel, and concentrated to the crude compound which was purified by silica gel column (20% ethyl acetate in hexanes) to afford 1-(5-chloro-2,3-dimethoxy-phenyl)-ethanone (3.65 g, 63%): 1H NMR (400 MHz, CDCl3): δ 7.20 (d, 1 H), 7.00 (d, 1 H), 3.89 (s, 6 H), 2.62 (d, 3 H).
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:17]([OH:21])[C:18](O)=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:30]([NH:34][C:35](=[O:41])[C@@H:36]1[CH2:40][CH2:39][CH2:38][NH:37]1)([CH3:33])([CH3:32])[CH3:31].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]([C@@H:16]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@H:17]([OH:21])[C:18]([N:37]1[CH2:38][CH2:39][CH2:40][C@H:36]1[C:35]([NH:34][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:41])=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1
Reactant: O=C(O)[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 5 h

Procedure:
14.0 g (37.0 mmol) of (2S, 3S)-3-(N,N-dibenzylamino)-2-hydroxy-4-phenylbutyric acid [prepared as described in step (a) above] and the whole of the N-t-butyl-L-prolinamide hydrochloride were suspended in 250 ml of methylene chloride, and 6.7 g (41.1 mmol) of diethyl cyanophosphate and 11.2 g (110.9 mmol) of triethylamine were slowly added dropwise to the suspension. The mixture was then stirred for 5 hours. At the end of this time, the reaction mixture was washed with a 10% w/v aqueous solution of citric acid, with a 10% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The mixture was then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure, and the resulting residue was recrystallized from hexane, to give 16.6 g of the title compound as colorless crystals, melting at 122°-123° C.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@H:4]([CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)[NH:5][C:6](=[O:28])[CH2:7][CH2:8][C:9](=[O:27])[C@@H:10]([NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1COCC1.CO.[Li+].[OH-]>C(O)(=O)C>[C:19]([NH:18][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9](=[O:27])[CH2:8][CH2:7][C:6]([NH:5][C@H:4]([C:3]([OH:39])=[O:2])[CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:28])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a stirred solution of the compound (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoyl-L-tryptophan methyl ester (170 mg, 0.3222 mmol, 1.0 eq.) in a mixture THF-MeOH (ratio 3:2) (10 mL) was added 0.5N LiOH (5.0 mL). The resulting yellowish mixture was stirred at room temperature for 30 min during which TLC shows the complete disappearance of the starting material. The reaction mixture was then neutralized with glacial acetic acid and the extracted with EtOAc (3×25 mL), dried over anhydrous MgSO4 and evaporation of the solvent gave a crude residue, which was subjected to column chromatography on silica gel elution with 30% MeOH-EtOAc afforded the free acid (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoyl-L-tryptophan 5b as a pale yellow solid (0.158 g, 95%); mp 171-173° C.; Rf 0.38 (30% MeOH-EtOAc); IR (KBr) ν 1720 (CO), 3250 (broad, COOH) cm−1; 1H NMR (400 MHz, CDCl3) δH 2.31 (2H, m, —CH2CO), 2.70 (2H, m, —CH2CO), 2.96 (1H, m, —CHαPh), 3.24 (3H, m, —CHβPh and —CH2Trp),), 4.84 (1H, m, —CH—), 4.90 (1H, m, —CH—), 6.49 (1H, t, J=7.2 Hz, —NH), 6.92-7.66 (16H, m, Ar—H and —NH) and 8.48 (1H, d, J=6.0 Hz, —NH); 13C NMR (100 MHz, CDCl3) δC 27.2, 29.5, 35.0, 35.1, 36.5, 53.2, 59.5, 59.6, 109.5, 111.4, 118.5, 119.6, 122.0, 123.5, 127.0, 127.1 (2C), 127.4, 128.6, 128.7 (2C), 129.2, 132.0, 133.5, 136.1, 167.7, 172.4, 174.6 and 207.8; HRMS m/z calcd for C30H29N3O5 (M+) 511.21072, found 511.21072. [± The carboxylic acid and amide protons were not observed, presumably, due to rapid exchange with water in the deuteriated NMR solvent.]
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([CH:30]=[O:31])[CH:24]=[CH:23]2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([CH:30]=[O:31])[CH:24]=[CH:23]4)[CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc(B(O)O)cc1C1(C)CCCCC1
Reactant: O=Cc1ccc2cc(Br)ccc2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3cc(C=O)ccc3c2)cc1C1(C)CCCCC1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
A mixture of 3-(1-methylcyclohexyl)-4-methoxyphenyl boronic acid (0.315 g, 1.27 mmol), 6-bromo-2-naphthaldehyde (0.250 g, 1.06 mmol) and sodium carbonate (0.337 g, 3.18 mmol) in 10 mL of toluene:ethanol (4:1) and water (1 mL) was degassed with argon for 30 minutes. Tetrakis(triphenylphosphine) palladium(0) (0.035 g, 0.03 mmol) was added and the mixture heated at reflux for 17 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:EtOAc, 9:1) to give 0.28 g of 6-[3-(1-methylcyclo-hexyl)-4-methoxyphenyl]-2-naphthaldehyde (75%) as a solid. 1H NMR (300 MHz; CDCl3, 300 MHz): δ 1.36 (s, 3H), 1.40–1.65 (m, 6H), 1.70–1.85 (m, 2H), 2.10–2.25 (m, 2H), 3.90 (s, 3H), 7.02 (d, J=8.7 Hz, 1H), 7.56 (dd, J1=8.4 H, J2=2.4 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.84 (dd, J1=8.1 Hz, J2=1.8 Hz, 1H), 7.97 (s, 2H), 8.02–8.07 (m, 2H), 8.35 (s, 1H), 10.16 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C:14]23[O:21][CH:18]([CH2:19]C2)[CH:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:15]3)[N:6]=1.F[C@H]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)[O:43][CH2:42]1.CO[C@H]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)OC1>>[Br:1][C:2]1[S:3][C:4]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:15][CH2:16][C@@H:17]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C@H:19]([O:43][CH3:42])[CH2:18][O:21]2)[N:6]=1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1C12CCC(NC(=O)OC(C)(C)C)C(CC1)O2
Agent: CO[C@@H]1CO[C@H](c2c([N+](=O)[O-])cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C

Procedure:
Following the procedure for Intermediate 65, starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 21) gave tert-Butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][S:4][CH:3]1[C:8]([O:10]C)=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH2:18])=[NH:17]>C(O)C>[Cl:12][C:13]1[CH:14]=[C:15]([C:16]2[N:17]=[C:8]([OH:10])[C:3]3[S:4][CH2:5][CH2:6][CH2:7][C:2]=3[N:18]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)C1SCCCC1=O
Reactant: N=C(N)c1cccc(Cl)c1
Solvent: CCO
Product: Oc1nc(-c2cccc(Cl)c2)nc2c1SCCC2
Temperature: 25 °C

Procedure:
A 100-mL round bottomed flask was charged with methyl 3-oxotetrahydrothiopyran-2-carboxylate (1.5 g, 8.6 mmol, 1.47 eq.), 3-chlorobenzamidine (HCl salt, 1.1 g, 5.75 mmol, 1 eq.) and ethanol (20 ml). The resulting mixture was stirred under reflux for 48 hrs. After cooling to room temperature, the volatile material was removed under reduced pressure and the residue was treated with hydrochloric acid (2N, 10 ml) and water (20 ml). The precipitate was collected by filtration and washed with water (3×10 ml) followed by ether (3×10 ml). After drying, the title compound was obtained as white solid (1.15 g, 72% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][P:9]2(=[O:14])[O:13][CH2:12][CH2:11][O:10]2)=[CH:6][CH:5]=1)([O-])=O>[C].[Pd].CO>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][P:9]2(=[O:14])[O:10][CH2:11][CH2:12][O:13]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CP2(=O)OCCO2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CP2(=O)OCCO2)cc1
Yield: 56.6 %

Procedure:
A mixture of 2-(4-nitrobenzyl)-1,3,2-dioxaphospholane-2-oxide (8.56 g), palladium-carbon (5%, 50% wet, 4.0 g) and methanol (300 ml) was subjected to a catalytic hydrogenation at room temperature and under 1 atm. After the catalyst was filtered off, the flitrate was concentrated under reduced pressure to yield 2-(4-aminobenzyl)-1,3,2-dioxaphospholane-2-oxide (4.25 g, 57%), which was then recrystallized from ethanol-hexane to yield colorless prisms having a melting point of 183° to 184° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>CCCCCCC.ClCCl.O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:11][C:12]([O:14][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CC(C)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(C)[C@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 50 mL, one-neck round bottom flask (equipped with a magnetic stirrer and a nitrogen inlet) was charged with (S)-4-tert-butoxycarbonylamino-5-methyl-hexanoic acid prepared as in Example 63 above (500 mg, 2.04 mmol), cesium carbonate (1.99 g, 6.11 mmol), benzyl chloride (773 mg, 6.11 mmol), and tetrahydrofuran (15 mL). The reaction was stirred at room temperature for three days (weekend) and then was heated to a mild reflux for 6 h. The reaction mixture was poured into saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl ether (2×100 mL). The combined organics were dried and concentrated to give 1 g of crude product. The residue was dissolved in heptane-dichloromethane (9:1, ˜7 mL) and eluted through a 12 g Isco silica gel cartridge to yield the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:10]=[C:9]2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH3:36][S:37]SC.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:37][CH3:36])=[C:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[N:10]=[C:9]2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[CH:4][CH:3]=1
Reactant: CSSC
Reactant: CC(C)(C)OC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1c(C(=O)OC(C)(C)C)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a cooled (−20° C.) and magnetically stirred solution of tert-butyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (10.59 g, 25.0 mmol), in anhydrous THF (100 ml) was added LDA (15.0 ml, 2 M solution in heptane/THF, 30.0 mmol) and the resulting mixture was stirred for 1 hour under N2. A solution of (CH3S)2 (2.7 ml, 30.0 mmol) in THF (20 ml) was added and the resulting solution was successively stirred at −40° C. for 1 h, allowed to attain room temperature and stirred for another 16 h. A saturated aqueous NH4Cl solution (250 ml) was added and the resulting solution was extracted twice with ethyl acetate (EtOAc). The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated to give tert-butyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfanyl-1H-imidazole-4-carboxylate in 90% yield as an oil which slowly solidified; 1H-NMR (200 MHz, CDCl3) δ 1.66 (s, 9H), 2.28 (s, 3H), 7.05 (br d, J˜8 Hz, 2H), 7.25 (dd, J=8 and 2 Hz, 1H), 7.28 (d, J=2 Hz, 1H), 7.32–7.41 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[N:25][C:24]([Na])=[N:23]1.O>C(O)CC>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:11]([CH3:13])([CH3:12])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:9])[CH2:10][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[CH:16][CH:17]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Reactant: [Na]c1nc[nH]n1
Solvent: CCCO
Solvent: O
Product: CC(C)(Oc1ccc(Cl)cc1)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Reaction time: 48 h
Yield: 18.4 %

Procedure:
A solution of 30 g (0.093 mol) of 2-(4-chlorophenyl)-2-[2-(p-chlorophenoxy)-prop-2-yl]-oxirane in 40 ml of n-propanol is added dropwise to a solution of 7.6 g (0.107 mol) of 1,2,4-triazolyl-sodium in 60 ml of n-propanol, at room temperature. The reaction mixture is stirred at the reflux temperature for a further 48 hours and is cooled, water is added and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated in vacuo. The oily residue is purified by column chromatography. 6.7 g (18.4% of theory) of 3-(4-chlorophenoxy)-2-(4-chlorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-butan-2-ol are obtained. This is stirred with 20 ml of saturated hydrogen chloride/ether solution, at room temperature. The precipitate which separates out is filtered off under suction, rinsed with a small amount of ether and dried in vacuo at 40° C. 6.5 g (89% of theory, relative to base employed) of 3-(4-chlorophenoxy)-2-(4-chlorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-butan-2-ol hydrochloride of melting point 135° C. are obtained.