Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29]([OH:31])=O)=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][N:33]([CH3:42])[C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29]([N:39]2[CH2:38][CH2:37][N:36]([C:34](=[O:35])[N:33]([CH3:32])[CH3:42])[CH2:41][CH2:40]2)=[O:31])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21
Reactant: CN(C)C(=O)N1CCNCC1
Product: CC(C)n1c(C(=O)N2CCN(C(=O)N(C)C)CC2)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21

Procedure:
The title compound was synthesized in analogy to example 47a), from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid and piperazine carboxylic acid dimethylamide. Off-white solid. MS (m/z): 569.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].C(Cl)(=O)C(Cl)=O.[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24][CH2:23][C:22]=12.CCN(C(C)C)C(C)C>O1CCCC1.ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[CH2:27][N:21]3[CH:20]=[CH:19][CH:18]=[C:22]3[CH2:23]2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 1050.4 %

Procedure:
A solution of 4-bromo-3-methyl benzoic acid (4.3 g, 2 mmol) in dry tetrahydrofuran (100 mL) was cooled to 0° C. under nitrogen. To this was added N,N-dimethylformamide (50 μL) followed by oxalyl chloride (2.2 mL, 25 mmol) dropwise to control the gas evolution. When the gas evolution ceased, the mixture was warmed to reflux for 5 minutes then cooled to room temperature and concentrated in vacuo. The sample was treated with tetrahydrofuran and evaporated to dryness (twice) to yield the crude acid chloride as an orange oil. A solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (3.60 g, 20 mmol) and Hünig's base (4.35 mL, 25 mmol) in dichloromethane was cooled to 0° C., and a solution of the crude acid chloride in dichloromethane (25 mL) was added dropwise. The mixture was stirred overnight at room temperature, washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The solution was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield a solid (8.01 g) which was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane to provide the title compound (6.03 g) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:27][C:28](=[O:34])[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=O)(C)(C)C.[C:35](=O)(O)[O-].[Na+].CI.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>CN(C)C=O.ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[Cl:26][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH:9]([CH2:27][C:28](=[O:34])[N:29]([CH3:35])[S:30]([CH3:33])(=[O:32])=[O:31])[CH2:10]1)(=[O:15])=[O:16])=[CH:25]2
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1CC(=O)NS(C)(=O)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)CC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (10 ml) was dissolved 1-tert-butoxycarbonyl-4-[(5-chloroindol-2-yl)sulfonyl]-2-[(N-methylsulfonylcarbamoyl)methyl]piperazine (347 mg), followed by the addition of sodium bicarbonate (55 mg) and methyl iodide (0.05 ml). The resulting mixture was stirred overnight at room temperature. The reaction mixture was then concentrated under reduced pressure. Dichloromethane was added to the residue and the resulting mixture was washed successively with water and saturated aqueous NaCl solution, each once. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (Φ1.7×12.0 cm, dichloromethane:methanol=200:1), whereby the title compound was obtained as colorless foam. The resulting foam was dissolved in dichloromethane (1 ml), followed by the addition of trifluoroacetic acid (2 ml). After the resulting mixture was stirred at room temperature for 1 minute, the reaction mixture was concentrated under reduced pressure. Diethyl ether was added to the residue and the precipitate so formed was collected by filtration, whereby the title compound (189 mg, 43%) was obtained as colorless foam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:36])=[C:19]([NH:24][S:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:38]>>[NH2:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:36])=[C:19]([NH:24][S:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide (75 mg, 0.135 mmol) and ammonium hydroxide (3 mL), the title compound was obtained as an off-white solid (50 mg, 69% yield). MS (ESI): 538 [M+H]+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].[OH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]#N)[CH2:11][CH2:10]1>C(OCC)(=O)C.[Cl-].[Cl-].[Zn+2]>[CH:4]([C:3]1[N:7]=[C:15]([N:12]2[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10][CH2:11]2)[O:1][N:2]=1)([CH3:6])[CH3:5]
Reactant: CC(C)C(=N)NO
Reactant: N#CN1CCC(O)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)c1noc(N2CCC(O)CC2)n1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
In a variation of the method described by Yarovenko et al, (Bull. Acad. Sci. USSR, Div. Chem. Sci. 1991, 40, 1924) ZnCl2 (1 N in ether, 120 mL, 120 mmol) was added in a dropwise fashion over 15 min to a magnetically stirred solution of N-hydroxy-isobutyramidine (12.2 g, 120 mmol) and 4-hydroxy-piperidine-1-carbonitrile (12.6 g, 100 mmol) in ethyl acetate (500 mL). Precipitate formed immediately upon addition, and at a point the stirring bar became immobilized in the matrix, requiring the reaction to be manually shaken for the remainder of addition. After standing for 15 min, the supernatant was decanted and filtered, and the residue was rinsed twice with ether, furnishing a hard white precipitate which was collected by filtration. This material was taken up in conc. HCl (50 mL), diluted to 4 N with EtOH (100 mL), and refluxed for 1 h. Upon cooling, a white precipitate was removed by filtration, then the filtrate was reduced to 50 mL and diluted with 100 mL water. Solid Na2CO3 was added until the mixture was basic, CH2Cl2 was added, and the resulting mixture was filtered, rinsing with CH2Cl2. The organic extract was separated, dried over MgSO4, and the solvent was removed to afford a viscous, amber oil as 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (15.0 g, 71% yield): 1H NMR (CDCl3) δ 3.95 (m, 3 H), 3.37 (m, 2 H), 2.88 (m, 1 H), 2.34 (br s, 1 H), 1.93 (m, 2 H), 1.63 (m, 2 H), 1.28 (d, 6 H, J=7.1 Hz), MS m/z 212.3 (M+).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10](Cl)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:18]>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10]([NH2:18])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Reactant: N
Product: COc1ccc(C(N)=O)cc1OC1CCCC1
Reaction time: 2 h

Procedure:
Vigorously stirred aqueous ammonia solution (70 mL; 32% w/w) is treated dropwise with warm molten 3-cyclopentyloxy-4-methoxybenzoyl chloride (25.7 g) during a period of 20 minutes, keeping the temperature below 20° C. Stirring is continued at 20° C. for 2 hours, and then the suspension is filtered. The resulting solid is washed with water until free of ammonia, and is then dried under vacuum at 40-45° C., to give 3-cyclopentyloxy-4-methoxybenzamide (21.78 g), in the form of a buff solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:6]=[C:7]=[S:8])[CH2:4][CH3:5].Cl[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12].C(OCC)C.CCCCCC>CN(C=O)C>[C:14]1([N:13]2[C:11](=[O:12])[CH2:10][S:8]/[C:7]/2=[N:6]\[CH2:3][CH2:4][CH3:5])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CCl)Nc1ccccc1
Reactant: CCCN=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC/N=C1\SCC(=O)N1c1ccccc1
Reaction time: 2 h

Procedure:
At rt, NaH (154 mg of 55% dispersion in mineral oil, 3.54 mmol) is added in portions to a solution of n-propylisothiocyanate (596 mg, 5.90 mmol) and the above 2-chloro-N-phenyl-acetamide (1000 mg, 5.90 mmol) in DMF (30 mL). Stirring is continued for 2 h after completion of the addition. The mixture is poured onto EA (150 mL) and is extracted twice with 1 N aq. HCl (200 mL). The aq. layer is neutralised by adding 3 N NaOH followed by sat. aq. NaHCO3, and extracted twice with EA (200 mL). The organic extracts are washed with water (200 mL) and evaporated to give a pale yellow, crystalline solid. This material is suspended in a small amount of diethyl ether/hexane 1:1, filtered, washed with additional diethyl ether/hexane and dried under high vacuum to give 3-phenyl-2-[(Z)-propylimino]-thiazolidin-4-one.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[NH2:15])[CH2:5][C@H:6]1[CH2:10][O:9][C:8](=[O:11])[NH:7]1.C([Si](CC)(CC)[CH:19]([OH:30])[CH2:20][C:21]#[C:22][Si](CC)(CC)CC)C.C(NC[C@@H]1CCN(CCC2C3C(=CC=C(CS(N)(=O)=O)C=3)NC=2)C1)C1C=CC=CC=1>CS(C)=O>[O:11]=[C:8]1[NH:7][C@@H:6]([CH2:5][C:4]2[CH:3]=[C:2]3[C:14](=[CH:13][CH:12]=2)[NH:15][CH:22]=[C:21]3[CH2:20][CH2:19][OH:30])[CH2:10][O:9]1
Reactant: Nc1ccc(C[C@H]2COC(=O)N2)cc1I
Reactant: CC[Si](C#CCC(O)[Si](CC)(CC)CC)(CC)CC
Agent: NS(=O)(=O)Cc1ccc2[nH]cc(CCN3CC[C@@H](CNCc4ccccc4)C3)c2c1
Solvent: CS(C)=O
Product: O=C1N[C@@H](Cc2ccc3[nH]cc(CCO)c3c2)CO1

Procedure:
Prepared from (S)-4-(3-iodo-4-aminobenzyl)-1,3-oxazolidin-2-one and 1,4-bis-triethylsilyl-3-butyn-1-ol as described for Intermediate 2, δ (360 MHz, D6 -DMSO) 2.74-2.91 (4H, m, 2 of CH2), 3.64 (2H, t, J=7.3Hz, CH2), 4.00-4.08 (2H, m, CH2), 4.20-4.26 (1H, m, CH), 6.92 (1H, dd, J=1.4 and 8.2Hz. Ar--H), 7.10 (1H, s, Ar--H), 7.25 (1H, d, J=8.2Hz, Ar--H), 7.36(1H, s, Ar--H), 7.75 (1H, s, NH), 10.69 (1H, s. NH).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[CH3:17].[CH3:18][C:19](=[O:23])[O:20][CH2:21]C>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:21][O:20][C:19](=[O:23])[CH:18]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[CH3:17])[C:19]([O:20][CH3:21])=[O:23]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(Br)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)c1ccc(C)cc1C
Temperature: 25 °C

Procedure:
(In analogy to a procedure given in J. Am. Chem. Soc. 122 (2000), 1360–1370.) To a suspension of Pd(OAc)2 (758 mg), 2-(di-tert.-butlylphosphino)-biphenyl (2.02 g) and K3PO4 (65.95 g) in THF (350 ml) dimethylmalonate (21.42 g) and 1-bromo-2,4-dimethyl-benzene (25 g) was added under argon. The mixture was refluxed for 96 h, cooled to rt and diluted with EA (300 ml) and filtered. The filtrate was evaporated and the resulting brown oil was purified on silica gel eluting with heptane:EA 4:1 to 1:1 followed by distillation (bp 95–100° C. at 0.064 mbar) to give 2-(2,4-dimethyl-phenyl)-malonic acid dimethyl ester (5.66 g) as a colourless oil. 1H-NMR(300 MHz, CDCl3): 2.30(s, 6H), 3.75(s, 6H), 4.87(s, 1H), 6.98–7.05(m, 2H), 7.25–7.28(m, 1H).
Reaction SMILES: N[C@@H](CC(C)C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O.C(O)(=O)C.[BH4-].[Na+].[Cl:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[C:35](/[N:42]2[CH:46]=[N:45][CH:44]=[N:43]2)\[C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][CH:29]=1>C(Cl)Cl.CN(C)C=O.C(Cl)(Cl)Cl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[C:35](/[N:42]2[CH:46]=[N:45][CH:44]=[N:43]2)\[CH:36]([OH:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][CH:29]=1
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Agent: CC(C)C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Temperature: -60 °C
Reaction time: 17 h

Procedure:
To 3 ml of a chloroform solution containing 0.117 g (0.43 mmole) of (S)-2-amino-1,1-diphenyl-4-methylpentan-1-ol was added 0.052 g (0.87 mmole) of acetic acid, and the mixture was cooled to -60° C. Thereafter, 0.5 ml of a dimethylformamide solution containing 0.033 g (0.87 mmole) of sodium borohydride was added, and the temperature of the mixture was raised to room temperature over 2 hours. To this suspension was added 3 ml of a methylene chloride solution containing 0.084 g (0.29 mmole) of (E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one, and stirring was carried out at room temperature for 17 hours. The same treatment as in Example 1 was applied to obtain (+)-(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol. The conversion was 53.7%, and the composition of the product was: E-form alcohol, 85.4% and Z-form alcohol, 14.5%. The enantiomer ratio of the E-form alcohol was: (+)-isomer, 86.0% and (-)-isomer, 14.0%.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21][CH2:20][CH2:19]2)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[CH2:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:13](=[O:14])[CH2:12][N:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=3)=[O:34])=[CH:24][CH:23]=2)[CH2:19][CH2:20]1
Reactant: NCC(=O)N(CC(=O)Nc1ccc2c(c1)CCC2)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)Nc2ccc3c(c2)CCC3)c2ccccc2)c1
Yield: 19.4 %

Procedure:
The procedure is analogous to that described in Example 1, but 3.0 g of 2-(2-amino-N-phenylacetamido)-N-(5-indanyl)acetamide and 1.2 g of 3-methylphenyl isocyanate are used as the starting material. After recrystallization from acetonitrile, 0.8 g of N-(5-indanyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 210° C. is obtained.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@@H:10]([OH:22])[C@@H:9]([CH2:23][O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:8][C@H:5]1[S:6][CH3:7])=[N+:2]=[N-:3].[C:42]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:43]([C:48](Cl)=[O:49])=[CH:44][CH:45]=[CH:46][CH:47]=1>CN(C)C1C=CN=CC=1.ClCCCl>[N:1]([C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C@@H:10]([O:22][C:48]([C:43]2[C:42]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:49])[C@@H:9]([CH2:23][O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:8][C@H:5]1[S:6][CH3:7])=[N+:2]=[N-:3]
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: COc1ccc(CO[C@H]2[C@@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H]2OC(=O)c2ccccc2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 6.5 %

Procedure:
A mixture of methyl 2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-galactopyranoside (16) (213 mg, 0.36 mmol), 4-dimethylaminopyridine (67 mg, 0.55 mmol) in dry 1,2-dichloroethane (10 mL) was stirred at room temperature. Biphenylcarbonyl chloride (119 mg, 0.55 mmol) was added to the stirred reaction mixture. The resulting suspension was stirred under reflux for 3 hours. The reaction mixture was cooled to 10° C. and filtered. The crystalline solid was washed on the funnel with dry 1,2-dichloroethane (5 mL) and filtered. The filtrates were combined, diluted with CHCl3 (20 mL) and washed twice with diluted brine solution (water-brine 2:1) (15 mL). The organic layer was dried over MgSO4 and evaporated. The residue was purified by chromatography using hexane—CHCl3 1:1 as the mobile phase to give methyl 2-azido-6-O-tert-butyldiphenylsilyl-4-O-biphenylcarbonyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-galactopyranoside (17) (18mg, 65%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:22]([NH:24][CH2:25][C@@H:26]([C:56]([O:58]C(C)(C)C)=[O:57])[CH2:27][C:28]1([C:33]([NH:35][C@H:36]([C:49]([O:51]C(C)(C)C)=[O:50])[CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44]C(C)(C)C)=[CH:40][CH:39]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:23])[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.O>ClCCl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:22]([NH:24][CH2:25][C@@H:26]([C:56]([OH:58])=[O:57])[CH2:27][C:28]1([C:33]([NH:35][C@H:36]([C:49]([OH:51])=[O:50])[CH2:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:23])[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NS(C)(=O)=O)CC1(C(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)OC(C)(C)C)CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)NC[C@H](CC1(C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)CCCC1)C(=O)O
Temperature: 35 °C
Reaction time: 6 h

Procedure:
Tert-butyl (S,S,S)-N-(1-[3-(N6-benzyloxycarbonyl-N2-mesyllysylamino)-2-(tert-butoxycarbonyl)propyl]-1-cyclopentylcarbonyl)-O4-tert-butyltyrosinate (404 g) was dissolved in dichloromethane (810 ml). Anisole (769 g) was added in one portion and then trifluoroacetic acid (1.158 kg) added dropwise over approximately 10 minutes. On completion of the addition, the reaction was stirred at 35° C. for 6 hours and then stirred at room temperature overnight. Water (1000 ml) was added and three layers formed. The top and bottom layers were combined, dissolved in ethyl acetate (2 l) and the resulting solution washed with brine. The organic phase was mixed with brine, the pH adjusted to 3 and the layers allowed to separate. Three layers formed. The organic phases were separated, taken up in ethyl acetate and extracted with saturated aqueous sodium bicarbonate (1.6 l) solution and brine (0.5 l). The combined aqueous layers were washed with ethyl acetate, then acidified and extracted with ethyl acetate to give an ethyl acetate solution (1.54 l) of the title compound. This solution was either used directly (e.g. see Example 1) or the solvent removed to provide the title compound.
Reaction SMILES: Cl[CH2:2][N:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.CCOCC>ClCCl>[CH2:9]([N:3]([CH2:2][N:22]1[CH:23]=[C:18]([Cl:17])[CH:19]=[N:20][C:21]1=[O:24])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)N(CCl)Cc1ccccc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)N(Cc1ccccc1)Cn1cc(Cl)cnc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
N-Chloromethyl-N-ethoxycarbonylbenzylamine (see German Offenlegungsschrift No. 2,119,518) (10 mmol) in dichloromethane (20 ml) was added dropwise with stirring to a solution of 5-chloropyrimidin-2-one hydrochloride (20 mmol) in dichloromethane (80 ml). The reaction mixture was stirred at room temperature for 2 hours, extracted with water, the solution dried (MgSO4) and evaporated. The residual crude product (yield 80%, 2.57 g) was triturated with ether to leave the title compound in 53% yield (1.70 g), m.p. 143° C. 1H NMR (CDCl3): δ1.31 and 4.22 (EtO), 4.73 (CH2Ph), 5.23 (CH2N), 7.20 (Ph), 8.03 and 8.38 (H-4, H-6, J 4 Hz). IR(KBr): 1670 cm-1 (CO), 1720 (CO-carbamate).
Reaction SMILES: CN1CCOCC1.[CH:8]1([CH2:13][C@H:14]([CH2:35][N:36]([CH:45]=[O:46])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:15]([N:17]2[C@H:21]([C:22](O)=[O:23])[CH2:20][CH2:19][N:18]2[C:25](OCC2C=CC=CC=2)=O)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH3:64][O:65][C:66]1[C:67]([NH2:72])=[N:68][CH:69]=[CH:70][N:71]=1>C(#N)C.CN(C=O)C>[CH:8]1([CH2:13][C@H:14]([CH2:35][N:36]([CH:45]=[O:46])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:15]([N:17]2[C@H:21]([C:22]([NH:72][C:67]3[C:66]([O:65][CH3:64])=[N:71][CH:70]=[CH:69][N:68]=3)=[O:23])[CH2:20][CH2:19][N:18]2[CH3:25])=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: COc1nccnc1N
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1nccnc1NC(=O)[C@@H]1CCN(C)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
4-Methylmorpholine (47.4 μl, 0.431 mmol) was added into a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (150 mg, 0.359 mmol) and 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (141 mg, 0.431 mmol) in acetonitrile (5.94 ml). The resulting solution was cooled to 0° C. and stirred at 0° C. for 15 min. To the reaction mixture was added 3-(methyloxy)-2-pyrazinamine (67.4 mg, 0.539 mmol). The reaction mixture was stirred for 2 days at rt. The reaction mixture was concentrated in vacuo and the residue was dissolved in DCM, washed with saturated NaHCO3 solution, followed by brine. The solution was dried over sodium sulfate and filtered. The solvent was removed to give a residue which was redissolved in DMF (3.75 ml) and purified by RP-HPLC to afford (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-methyl-N-[3-(methyloxy)-2-pyrazinyl]-3-pyrazolidine carboxamide (96 mg, 0.183 mmol, 51% yield) as a white solid. LC-MS (ES) m/e 525.5 (M+H)+.