Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]1[N:14]([CH3:26])[C:13]([CH:15]([CH3:17])[CH3:16])=[C:12]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[N:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1Sc1cccc(Cl)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)c1c(Sc2cccc(Cl)c2)nc(COCc2ccccc2)n1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 2.7 %

Procedure:
In 218 g of dry dimethylformamide was dissolved 21.8 g (58.5 mmol)of 2-benzyloxymethyl-5-(3-chlorophenylthio)-4-isopropyl-iH-imidazole (16e), followed by addition of 12.2 g (88.3 mmol)of anhydrous potassium carbonate and 11.6 g (81.7 mmol)of methyl iodide, the mixture was stirred at room temperature for 7 hours. To the reaction mixture was added ice-water, and the mixture was extracted with diethyl ether. The extract was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate:methylene chloride=1:8). From the first eluted fraction, 620 mg (yield 3%)of 2-benzyloxymethyl-4-(3-chlorophenylthio)-5-isopropyl-1-methyl-1H-imidazole (17ab') was obtained as oil. From the latter eluted fraction, 17.6 g (yield 78%)of 2-benzyloxymethyl-5-(3-chlorophenylthio)-4-isopropyl-1-methyl-1H-imidazole (17ab)was obtained as oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:34])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[C:16]=2[O:32][CH3:33])[CH2:10][CH2:9]1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>FC(F)(F)C(O)=O>[CH3:33][O:32][C:16]1[C:17]([O:21][Si:22]([CH:23]([CH3:25])[CH3:24])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:34]
Reactant: COc1c(O[Si](C(C)C)(C(C)C)C(C)C)cccc1C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1c(O[Si](C(C)C)(C(C)C)C(C)C)cccc1C(=O)C1CCNCC1
Reaction time: 2 h

Procedure:
Stir and cool in an ice bath under nitrogen, 4-(2-methoxy-3-triisopropylsilanyloxy-benzoyl) -piperidine-1-carboxylic acid tert-butyl ester, Example 2B (5.71 g, 11.6 mmol) and add trifluoroacetic acid (30 mL). Remove the cold bath after 10 minutes. After 2 h, concentrate the reaction under vacuum at 40-45° C. and then pour into saturated aqueous NaHCO3. Extract the basic layer with CH2Cl2 (2×200 mL), dry (Na2SO4), and concentrate under vacuum to an oil, which eventually solidifies to afford 4-(2-methoxy-3-triisopropylsilanyloxy-benzoyl) -piperidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:28].CC(O)=O.[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([CH2:39][C:38]3[CH:41]=[CH:42][C:35]([F:34])=[CH:36][CH:37]=3)[CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccc(F)cc3)C1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
(±)-(E)-3-[4-Oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester hydrochloride (Intermediate 2, 600 mg, 1.78 mmol) was suspended in DCM (30 ml). TEA (0.248 ml, 1.78 mmol) was added and the pH was adjusted to 5 with AcOH. 4-Fluorobenzaldehyde (265 mg, 2.14 mmol) and NaBH(OAc)3 (566 mg, 2.67 mmol) were added and the resulting mixture was stirred overnight at RT, then washed with 5% NaHCO3, brine and dried over Na2SO4. The crude mixture was purified by column chromatography (eluent: DCM/MeOH 99:1) to give (±)-(E)-3-[1′-(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (660 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([O:13][CH2:14][C:15]#[N:16])=[CH:11][C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:19][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:13][CH2:14][C:15]#[N:16]
Reactant: N#CCOc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCOc1ccc(OCc2ccccc2)c(N)c1
Yield: 97.2 %

Procedure:
A solution of 6.9 g (4-benzyloxy-3-nitro-phenoxy)-acetonitrile, 200 ml of ethyl acetate, and 27.4 g of tin (II) chloride dihydrate was stirred at room temperature for 17 hours, poured into ethyl acetate, added saturated sodium bicarbonate solution, extracted twice with ethyl acetate, dried (MgSO4), evaporated, and obtained 6.0 g of (3-amino-4-benzyloxy-phenoxy)-acetonitrile as a light brown oil.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[N+:17]([O-])=O)=[O:6])([CH3:3])[CH3:2]>CO.O1CCCC1.[Pd]>[NH2:17][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:7]=1[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(C(=O)NC(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)NC(C)C)c(N)c1
Reaction time: 24 h
Yield: 99.9 %

Procedure:
To a solution of methyl 4-[(isopropylamino)carbonyl]-3-nitrobenzoate (0.48 g, 1.78 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) was added 10% palladium on carbon (0.19 g, 0.18 mmol). The mixture was purged with H2 gas (3×) and stirred under an atmosphere of H2 for 1 d. The reaction mixture was then filtered through Celite, washed with MeOH and concentrated to afford methyl 3-amino-4-[(isopropylamino)carbonyl]benzoate (0.42 g, quant.). LC-MS: (FA) ES+ 237.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[C:7]([O:19][CH:20]2[CH2:23][CH2:22][CH2:21]2)=[C:8]2[C:13](=[C:14]([F:17])[C:15]=1[F:16])[NH:12][C@@H:11]([CH3:18])[CH2:10][CH2:9]2>ClCCl.N1C=CC=CC=1>[Br:5][C:6]1[C:7]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23]2)=[C:8]2[C:13](=[C:14]([F:17])[C:15]=1[F:16])[N:12]([C:1](=[O:3])[CH3:2])[C@@H:11]([CH3:18])[CH2:10][CH2:9]2
Reactant: C[C@H]1CCc2c(c(F)c(F)c(Br)c2OC2CCC2)N1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2c(F)c(F)c(Br)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Yield: 105.3 %

Procedure:
Acetyl chloride (0.21 mL, 3.02 mmol) was added dropwise to a 0° C. solution of (S)-6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline (1.0 g, 3.02 mmol) in dichloromethane (20 mL) and pyridine (0.6 mL), and the resulting solution was allowed to stir and warm to room temperature overnight. The reaction mixture was diluted with dichloromethane (40 mL), washed with 1 N hydrochloric acid (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-1-(6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (1.19 g, 99%) as yellow oil. MS (ESI, pos. ion) m/z 374, 376 [M+H]+.
Reaction SMILES: [N+](C1C=CC(COC([N:12]=[CH:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([C@@H:22]3[CH2:26][C@H:25]([S:27][C:28]4[C@H:29]([CH3:52])[C@@H:30]5[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]5[C:32]=4[C:33]([O:35]CC4C=CC([N+]([O-])=O)=CC=4)=[O:34])[CH2:24][N:23]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:21])[CH2:16][C@@H:15]2[CH3:66])=O)=CC=1)([O-])=O>O1CCCC1.O>[CH:13]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C@@H:22]2[CH2:26][C@H:25]([S:27][C:28]3[C@H:29]([CH3:52])[C@@H:30]4[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]4[C:32]=3[C:33]([OH:35])=[O:34])[CH2:24][NH:23]2)=[O:21])[CH2:16][C@@H:15]1[CH3:66])=[NH:12]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C=NC(=O)OCc5ccc([N+](=O)[O-])cc5)[C@@H](C)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCN(C=N)[C@@H](C)C4)C3)[C@H](C)[C@H]12
Yield: 37.9 %

Procedure:
87 mg of 4-nitrobenzyl (1R,5S,6S)-2-{(2S,4S)-2-[(3S)-4-(N-4-nitrobenzyloxycarbonylformimidoyl)-3-methylpiperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 4.5 ml of a 2:1 by volume mixture of tetrahydrofuran and water, and were hydrogenated by bubbling hydrogen through the solution at room temperature for 2 hours in the presence of 220 mg of 10% w/w palladium-on-charcoal. The reaction mixture was then worked up and purified by the same procedure as that described in Example 1(b), to give 16 mg of the title compound, as a powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][CH:22]([CH3:25])[CH2:23][OH:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:21][CH:22]([CH3:25])[CH2:23][OH:24])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Reactant: CC(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(CO)NC(=O)c1cccc(-c2ccc3ncnc(N)c3n2)c1

Procedure:
Following the same reaction and purification procedure, the acid 14 (80 mg, 0.30 mmol) was reacted with 2-aminopropan-1-ol (CAS 78-91-1) (0.05 mL, 0.6 mmol), HATU (141 mg, 0.36 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(1-hydroxypropan-2-yl)benzamide 17. LC/MS (ESI+): m/z 323 (M+H). 1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 8.61 (t, J=13.5 Hz, 1H), 8.57-8.48 (m, 1H), 8.43 (s, 1H), 8.29 (d, J=7.9 Hz, 1H), 8.19 (dd, J=8.8, 3.1 Hz, 1H), 8.05 (d, J=30.8 Hz, 2H), 7.97 (d, J=7.7 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 4.76 (s, 1H), 4.18-4.00 (m, 1H), 3.52 (dd, J=10.5, 5.7 Hz, 1H), 3.46-3.35 (m, 1H), 1.19 (d, J=6.7 Hz, 3H).
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[S:29][C:30]([C:33]([OH:35])=[O:34])=[CH:31][N:32]=2)[CH2:24][CH:23]1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:43].C(OCC)(=O)C>C1COCC1>[ClH:43].[F:42][C:38]1[CH:37]=[C:36]([CH:23]2[CH:22]([CH2:21][NH:8][C@@H:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:33]([OH:35])=[O:34])=[CH:31][N:32]=3)[CH2:24]2)[CH:41]=[CH:40][CH:39]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2ncc(C(=O)O)s2)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](NCC1CCN(c2ncc(C(=O)O)s2)CC1c1cccc(F)c1)c1cccc2ccccc12
Reaction time: 1 h

Procedure:
To a solution of 172 mg of the crude 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1,3-thiazole-5-carboxylic acid in 2.0 mL of THF was added 1.00 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 1 hour. The solvent was removed by distillation under reduced pressure. The residue was purified by reverse phase silica gel column chromatography (acetonitrile-0.001 M hydrochloric acid) to obtain 19 mg of 2-[3-(3-fluorophenyl)-4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]-1,3-thiazole-5-carboxylic acid hydrochloride as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13](O)=[O:14])[CH2:9][CH2:8]1)=[O:5])[CH3:2]>C1COCC1>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][OH:14])[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)C[C@H]1CC[C@H](C(=O)O)CC1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H]1CC[C@H](CO)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of trans-4-ethoxycarbonylmethyl-cyclohexanecarboxylic acid (1 mmol; 214 mg) in THF (3 mL) is added 1.0 M THF solution of borane THF complex (2 mmol; 2 mL) at 0° C. under nitrogen. The solution is stirred for 1.5 hours at room temperature, quenched by dropwise addition of 1 mL of MeOH. The mixture after concentration is diluted with dichloromethane and saturated aqueous ammonium chloride solution. The product is extracted with 100 ml of dichloromethane. The organic layer after dried is separated, concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (n-hexane/EtOAc) to give trans-(4-hydroxymethylcyclohexyl)-acetic acid ethyl ester (166 mg, 83%); ESI-MS m/z: 201 [M++1], Retention time 1.67 min (condition A).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14].CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:66]([SH:73])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:66]([S:73][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: COc1cc2c(Cl)ccnc2cc1Br
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Cl)ccnc2cc1SCc1ccccc1
Temperature: 110 °C
Yield: 115.8 %

Procedure:
To a vial charged with 7-bromo-4-chloro-6-methoxyquinoline (0.240 g, 0.881 mmol) was added Dioxane (3.52 ml), DIEA (0.308 ml, 1.761 mmol), Xantphos (0.102 g, 0.176 mmol), Pd2(dba)3 (0.081 g, 0.088 mmol) and benzyl mercaptan (0.104 ml, 0.881 mmol). The vessel was sealed and heated to 110° C. for 90 mins affording complete conversion according to LC-MS. The mixture was filtered through Celite and dried under reduced pressure and purified with a 25 g Interchim column ramping EtOAc in heptane (0-50%, 10% DCM throughout) affording 7-(benzylthio)-4-chloro-6-methoxyquinoline (322 mg, 1.020 mmol, quant. yield) as a yellow solid with minor impurity. m/z (ESI) 316.3 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)([OH:3])=O.[NH2:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[CH:30][C:29]=1[Cl:35]>>[Cl:25][C:24]1[CH:23]=[N:22][CH:21]=[C:20]([Cl:26])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([NH:27][C:28]3[C:33]([Cl:34])=[CH:32][N:31]=[CH:30][C:29]=3[Cl:35])=[O:3])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Reactant: Nc1c(Cl)cncc1Cl
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)Nc1c(Cl)cncc1Cl
Yield: 17 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.30 g) obtained in Example 9 and 4-amino-3,5-dichloropyridine to give Compound 32 (0.06 g, 17%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][NH:8][CH2:9][CH2:10][S:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[N:15]#[N:16].Cl.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[CH:26]=[C:25]([S:32]([NH:35][C@H:36]([C:44](Cl)=[O:45])[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[NH:43])[NH2:42])(=[O:34])=[O:33])[CH:24]=[CH:23]2>C(Cl)(Cl)Cl>[N:15]#[N:16].[C:1]([O:5][C:6](=[O:14])[CH2:7][N:8]([C:44](=[O:45])[C@H:36]([CH2:37][CH2:38][CH2:39][NH:40][C:41](=[NH:42])[NH2:43])[NH:35][S:32]([C:25]1[CH:24]=[CH:23][C:22]2[C:27](=[CH:28][C:29]([O:30][CH3:31])=[C:20]([O:19][CH3:18])[CH:21]=2)[CH:26]=1)(=[O:34])=[O:33])[CH2:9][CH2:10][S:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2cc1OC
Reactant: CCSCCNCC(=O)OC(C)(C)C
Agent: Cl
Agent: N#N
Solvent: ClC(Cl)Cl
Product: CCSCCN(CC(=O)OC(C)(C)C)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Reaction time: 8 h

Procedure:
To a stirred solution of 4.80 g of N-(2-ethylthioethyl)-glycine tert-butyl ester in 40 ml of chloroform was carefully added N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl chloride hydrochloride obtained above. The reaction mixture was allowed to stand at room temperature overnight. The reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness. The residue was triturated with a small amount of water to give a powder. This was collected by filtration and reprecipitated with ethanol-diethyl ether to give 5.00 g of N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-ethylthioethyl)glycine tert-butyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[CH:19]([C:20](O)=[O:21])[NH:18][CH:17]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]32[C:35]2[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=2)[NH:29][C:28]3=[O:37])[CH:12]=[CH:13][CH:14]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][C:65]=1[O:72][CH3:73]>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:20]([CH:19]2[NH:18][CH:17]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[C:16]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH:15]2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Br:8])[C:10]=2[F:38])=[O:21])=[C:65]([O:72][CH3:73])[CH:66]=1)#[N:69]
Reactant: COc1cc(C#N)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Br)c1F
Yield: 40.2 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 97 (0.4 g, 0.66 mmol), was reacted with diisopropylethylamine (0.43 g, 3.3 mmol), diphenylphosphinic chloride (0.31 g, 1.3 mmol), then reacted with 4-amino-3-methoxy-benzonitrile prepared in Example 57 (0.29 g, 2.0 mmol) to give rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a white foam (Yield 0.17 g, 40%).
Reaction SMILES: [CH2:1]([OH:10])[C:2]([CH2:4][O:5]P(O)(O)=O)=[O:3].[N:11]([CH2:14][C@@H:15]([OH:18])[CH:16]=[O:17])=[N+:12]=[N-:13].[OH-].[Na+].CO>C(O)C(N)(CO)CO>[N:11]([CH2:14][C@@H:15]([OH:18])[C@H:16]([OH:17])[C@@H:1]([OH:10])[C:2](=[O:3])[CH2:4][OH:5])=[N+:12]=[N-:13]
Reactant: O=C(CO)COP(=O)(O)O
Reactant: [N-]=[N+]=NC[C@@H](O)C=O
Agent: NC(CO)(CO)CO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [N-]=[N+]=NC[C@@H](O)[C@H](O)[C@@H](O)C(=O)CO
Reaction time: 48 h
Yield: 30 %

Procedure:
DHAP (0.5 mmole) was added to an aqueous solution of (R)-3-azido-2-hydroxypropanal (1 mmole in 40 ml) and the pH value adjusted to 7.0 with 10N NaOH. To this solution was added fuculose-1-phosphate aldolase from E. coli (4 g), which had been treated with egg white lysozyme (40 mg) in Tris buffer (pH 7.5, 25 ml) for 1 hour at 35° C., to form a mixture and the mixture stirred slowly for 2 days. The stirred mixture was adjusted to a pH value of 4.7, and acid phosphatase (400 units) added. The resulting mixture was incubated at 37° C. for 48 hours, neutralized to a pH value of 7.0 and lyophilized. The residue was treated with MeOH and filtered to remove the insoluble material. The MeOH was removed under reduced pressure and the crude product purified with silica gel column chromatography (CHCl3 :MeOH=6:1) to give 6-azido-6-deoxy-D-xylo-hexulose in 30% yield.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[CH2:14][F:15].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:15][CH2:14][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: FCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCF
Temperature: 0 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
N-hydroxyphthalimide (80 g) and bromofluoromethane (63.2 g) were added to dry dimethyl sulfoxide (350 ml) which had been cooled to 0° C. Potassium carbonate (135 g) was added further, followed by stirring at room temperature for 4 hours. Thereafter, nitrogen gas was introduced for 1 hour. The reaction mixture was added to ice water (800 ml), followed by extraction three times with ethyl acetate (500 ml). After washing the extract with saturated saline, anhydrous magnesium sulfate was added to the extract to dry the same. The solvent was distilled off under reduced pressure. Deposited crystals were washed with isopropyl ether and petroleum ether to obtain the target product (55 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[S:15][CH:16]=[C:17]([CH2:19]Cl)[N:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:21]1([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH:25]=[N:24][N:23]=[N:22]1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:32][C:29]3[CH:30]=[CH:31][C:26]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[CH:27][CH:28]=3)[N:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(-n2cnnn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2nc(CCl)cs2)C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)C1

Procedure:
A mixture of 3-(4-Chloromethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (From Step 1) (300 mg, 0.946 mmol), 4-tetrazol-1-yl-phenol (155 mg, 0.946 mmol), CsCO3 (467 mg, 1.42 mmol) and KI (16 mg, 0.095 mmol) in acetonitrile (10 mL) was heated under reflux for 4 hours. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 1:1) to afford the desired product. 1H NMR (CDCl3): δ 8.91 (1H, s), 7.63 (2H, d), 7.26 (1H, s), 7.17 (2H, d), 5.24 (2H, s), 4.30 (1H, br), 4.02 (1H, m), 3.20 (1H, m), 3.10 (1H, br), 2.88 (1H, t), 2.21 (1H, m), 1.77 (2H, m), 1.61 (1H, m), 1.47 (9H, s).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:7])[CH3:6].[Cl:19][CH:20]([CH3:24])[C:21](Cl)=[O:22]>ClC(Cl)C>[C:5]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:21](=[O:22])[CH:20]([Cl:19])[CH3:24])=[CH:17][CH:18]=1)(=[O:7])[CH3:6]
Reactant: CC(Cl)C(=O)Cl
Reactant: CC(=O)NCCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)NCCCCc1ccc(C(=O)C(C)Cl)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Under ice cooling, 20.9 g of anhydrous aluminum chloride was added to 200 ml of a dichloroethane solution containing 10.0 g of [4-(acetylamino)butyl]benzene and 9.96 g of 2-chloropropionyl chloride, and the mixture was stirred at 5° C. for 1 hour. The reaction mixture was poured into ice water, and the organic layer was collected by separation. After the organic layer was washed with water and dried, the solvent was removed to obtain 13.71 g of 4-[4-(acetylamino)butyl]-1-(2-chloropropionyl)benzene.