Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7].[O:21]1[C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=[N:22]1.C(N(CC)CC)C>ClCCl>[CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:26]([C:25]3[O:21][N:22]=[CH:23][CH:24]=3)=[O:27])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccno1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccno3)CC2)nn1

Procedure:
To a stirred solution of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide (277 mg, 1 mmol) in dichloromethane (15 mL) was added isoxazole-5-carbonyl chloride (1.0 mmol) as a dichloromethane solution in the presence of triethylamine (0.4 mL) at ambient temperature. After 1 hour the mixture was evaporated and the residue was subjected to column chromatography. Final product was isolated as a solid (0.107 g, yield 29%). 1H NMR (300 MHz, CDCl3) δ 8.34, 8.05, 7.83, 7.00, 6.86, 3.90-3.84, 3.51-3.45, 1.75-1.62, 1.53-1.46, 0.92. MS (ES+) m/z 373.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[C:8]([I:17])=[N:7]1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[S:42][CH2:43][C:44](=[O:46])[N:45]=2)[CH2:37][CH:36]1[CH2:47][OH:48])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[S:42][C:43](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:3]=3[C:2]([F:26])([F:1])[F:27])[N:7]=[C:8]4[I:17])[C:44](=[O:46])[N:45]=2)[CH2:37][CH:36]1[CH2:47][OH:48])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)CS2)CC1CO
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(c3)c(I)nn4Cc3ccc(C(F)(F)F)cc3C(F)(F)F)S2)CC1CO

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehyde and 2-Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester following General Procedure D.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[S:8][C:9]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[O:13])=[CH:10][N:11]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31].CCN(CC)CC>CO>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([NH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[S:8][C:9]([C:12](=[O:13])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][N:11]=1)=[O:31]
Reactant: Cc1ccccc1C(=O)c1cnc(NCCCN)s1
Reactant: COc1ccccc1N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccccc1NC(=O)NCCCNc1ncc(C(=O)c2ccccc2C)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.5 %

Procedure:
A mixture of 12.5 mg (0.04 mmol) [2-(3-Amino-propylamino)-thiazol-5-yl]-o-tolyl-methanone hydrochloride, 7.6 mg (0.05 mmol) 2-Methoxyphenyl isocyanate and 39 ul NEt3 in 1 ml methanol was stirred for 16 h at room temperature. After evaporation to dryness the residue was taken up in 1.5 ml MeOH/formic acid 1/1 and subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of product fractions yielded 7.9 mg (47%) of the title compound.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].[CH2:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][C:17]#[N:18])=[CH:13][CH:14]=2)[CH2:9][CH2:8]1>CO>[OH:6][N:5]=[C:17]([NH2:18])[CH2:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[CH2:7][CH2:8][CH2:9]2
Reactant: N#CCc1ccc2c(c1)CCC2
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(Cc1ccc2c(c1)CCC2)=NO
Reaction time: 18 h
Yield: 54.2 %

Procedure:
A stirred mixture of NaOMe (25 wt % in MeOH, 16.0 mL, 0.070 mol), hydroxylamine hydrochloride (4.9 g, 0.070 mol), and MeOH (60 mL) was heated under reflux for 30 minutes. 5-Indanylacetonitrile (10.0 g, 0.063 mol) was added and heating was continued for 18 hours. The mixture was cooled, concentrated, and partitioned between H2O and ether. The organic phase was dried (MgSO4) and concentrated to give a yellow oil: 11.4 g. The crude product was purified by flash chromatography (eluant 20% EtOAc/hexane; 60% EtOAc/hexane) and recrystallized from ether/hexane to give 6.5 g (54%) of a pale yellow solid, m.p. 60° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=1.[Cl:17][C:18]([Cl:24])([Cl:23])[C:19](=N)OC.O>C(O)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:19]([C:18]([Cl:24])([Cl:23])[Cl:17])[N:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:3]=2[CH:4]=1
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Temperature: 45 °C
Reaction time: 7 h

Procedure:
To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (3.0 g, 10.71 mmol) in acetic acid (10 mL) was added methyl 2,2,2-trichloroethanimidoate (1.4 mL, 11.25 mmol). The reaction was stirred at 45° C. for 7 hr. Water (15 mL) was then added. The precipitate was collected by filtration and dried under vacuum to give the title product (3.94 g as the acetic acid salt); 1H NMR (500 MHz, DMSO) delta 1.90 (3H, s), 7.01 (1H, d, J=5.0 Hz), 7.21 (2H, s), 7.75-7.46 (2H, m), 8.09-7.75 (1H, m), 8.58 (1H, d, J=5.0 Hz); LC-MS: m/z=+406/408/410/412 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:23][CH3:24])[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:5][CH2:4]1)[CH3:2].[O:25]1[CH2:30][CH2:29][CH:28]([CH:31]=O)[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:23]([C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH2:18][CH2:19][N:20]([CH2:31][CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[CH2:21][CH2:22]2)=[CH:5][CH2:4]1)[CH3:24]
Reactant: O=CC1CCOCC1
Reactant: CCC1(CC)CC=C(c2ccc(OC)cc2N2CCNCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC1(CC)CC=C(c2ccc(OC)cc2N2CCN(CC3CCOCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To a solution of 1-[2-(4,4-diethylcyclohex-1-enyl)-5-methoxyphenyl]piperazine (90 mg, 0.27 mmol) prepared in Example (6f) in tetrahydrofuran (10 mL) were added tetrahydropyran-4-carbaldehyde (37 mg, 0.32 mmol), sodium triacetoxyborohydride (87 mg, 0.41 mmol) and acetic acid (32 mg, 0.57 mmol) in that order, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 50 mg of 1-[2-(4,4-diethylcyclohex-1-enyl)-5-methoxyphenyl]-4-(tetrahydropyran-4-ylmethyl)piperazine as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]([O:28]CC)=[O:27])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[ClH:31]>>[ClH:31].[ClH:31].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]([OH:28])=[O:27])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: Cl
Product: O=C(O)CN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Yield: 52 %

Procedure:
A mixture of 6 parts of ethyl 4-[[1-[(4-fluorophenyl)methyl]1H-benzimidazol-2-yl]methyl]-1-piperidineacetate and 120 parts of a hydrochloric acid solution 6N was stirred and refluxed overnight. The reaction mixture was cooled and filtered. The filtrate was evaporated and the semi-solid residue was taken up in about 120 parts of 2-propanol. The solution was filtered and about 70 parts of 2,2'-oxybispropane were added to the filtrate. After stirring for 2 hours at room temperature, the precipitated product was filtered off, dried overnight in vacuo at 80° C. and pulverized in a mortar, yielding 3 parts (52%) of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidineacetic acid dihydrochloride. monohydrate; mp. 207.4° C. (457).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.C([Li])CCC.[CH:17]12[O:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22]2>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[OH:23])=[CH:10][CH:9]=[N:8]1
Reactant: C1CCC2OC2C1
Reactant: c1cnn(C2CCCCO2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O[C@H]1CCCC[C@@H]1c1ccnn1C1CCCCO1
Yield: 3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 8a by using 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (5.50 g, 36.1 mmol), n-butyl lithium (1.63 M solution in hexane; 24 mL, 39.1 mmol), cyclohexene oxide (3.80 g, 38.7 mmol) and THF (100 mL), to yield the title compound (270 mg, 3.0%) in the form of a diastereomeric mixture as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2[C:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:15]=[C:16]([Cl:17])[C:4]=2[N:3]=1.[Cl:23][C:24]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:25]=1[NH2:26].C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:17][C:16]1[C:4]2[N:3]=[C:2]([NH:26][C:25]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:24]=3[Cl:23])[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]=2[C:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:15]=1
Reactant: CCOC(=O)Cn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: Nc1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cn1c(Nc2ccc(Cl)cc2Cl)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 100 °C
Reaction time: 84 h
Yield: 11.9 %

Procedure:
A mixture of ethyl [2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate (708 mg, 2.06 mmol), 2,4-dichloroaniline (1.00 g, 6.19 mmol) and N-methyl-2-pyrrolidinone (0.5 mL) was stirred at 100° C. for 3.5 days. After cooling, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by basic silica gel column chromatography eluting with a 3-15% ethyl acetate/n-hexane gradient mixture. The resulting solid was washed with n-hexane to give the title compound (115 mg, 0.245 mmol, 12%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH3:19][O:20][CH2:21][C@H:22]([NH2:25])[CH2:23][CH3:24]>CCO>[Cl:11][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:25][C@@H:22]([CH2:21][O:20][CH3:19])[CH2:23][CH3:24])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC[C@@H](N)COC
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC[C@H](COC)Nc1nccc(Cl)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 155.4 %

Procedure:
2,4-Dichloro-3-nitropyridine (1.0 g, 5,18 mmol) was dissolved in EtOH (20 mL), followed by the addition of Et3N (1.05 g, 10.4 mmol) and (R)-1-methoxymethyl-propylamine (0.72 g, 5.18 mmol) and the reaction was heated at 60° C. for 3 h. The reaction was concentrated in vacuo to yield 2.09 g of (R)-(4-chloro-3-nitro-pyridin-2-yl)-(1-methoxymethyl-propyl)-amine as a crude viscous oil: MS (AP) m/z 259.69 [(M+H)+, 97].
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[S:22]1[C:26](B(O)O)=[CH:25][C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]1=2.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:22]1[C:26]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:25][C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]1=2
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Reactant: OB(O)c1cc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3cc4ccccc4s3)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), benzo[b]thien-2-ylboronic acid (103 mg, 0.578 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL)-water (2 mL) was purged with nitrogen followed by addition of Pd(PPh3)4 (16 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 5-(2-(benzo[b]thiophen-2-yl)cyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.2 (d, 1H), 7.5 (d, 1H), 7.38 (s, 1H), 7.2-7.3 (m, 3H), 7.1 (d, 1H), 7.04 (d, 1H), 4.4 (m, 2H), 3.6 (m, 2H), 3.2 (m, 2H), 3.1 (s, 3H), 2.9 (m, 2H), 2.7 (m, 2H), 2.41 (s, 3H), 2.3 m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:31][C:32]([CH3:37])([CH3:36])[CH2:33][C:34]#[N:35]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:31][C:32]([CH3:37])([CH3:36])[CH2:33][C:34]#[N:35])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:17][C:18](=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:20]1(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CI)CC#N
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: CC(C)(CC#N)Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1

Procedure:
The title compound is prepared 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and 4-iodo-3,3-dimethylbutyronitrile analogous to Example 292, step A.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:22]/[N:23]=[C:24](/[C:55]2[N:56]=[C:57]([NH:60][C:61]([C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[S:58][CH:59]=2)\[C:25]([NH:27][CH:28]2[C:53](=[O:54])[N:30]3[C:31]([C:37]([O:39][CH:40]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])=[C:32]([CH2:35][Cl:36])[CH2:33][S:34][C@H:29]23)=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:88])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([O:14][C:15]([C:17]1([O:22]/[N:23]=[C:24](/[C:55]2[N:56]=[C:57]([NH:60][C:61]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)([C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)[S:58][CH:59]=2)\[C:25]([NH:27][CH:28]2[C:53](=[O:54])[N:30]3[C:31]([C:37]([O:39][CH:40]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)=[O:38])=[C:32]([CH2:35][Cl:36])[CH2:33][S:34](=[O:88])[C@H:29]23)=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1)=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS[C@@H]2C(NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CCCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS(=O)[C@@H]2C(NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CCCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Reaction time: 0.33 h

Procedure:
The residue obtained in (A) was dissolved in 50 ml of methylene chloride, and 710 mg (3.3 mmol) of m-chloroperbenzoic acid (purity: 80%) was added under cooling with ice. The mixture was stirred for 20 minutes. Then, 30 ml of methylene chloride and 40 ml of a 5% sodium bicarbonate aqueous solution were added to the reaction solution. The organic layer was separated and washed with water and with a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and then concentrated to obtain the residue of the above identified compound, which was used for the subsequent reaction without purification.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[N:21]1[CH2:26][CH2:25]O[CH2:23][CH2:22]1.ClC(OCC(C)C)=O.N1CCCC1>C1COCC1>[O:19]=[C:17]([N:21]1[CH2:26][CH2:25][CH2:23][CH2:22]1)[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccncc1)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccncc1)C(=O)N1CCCC1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 27.5 %

Procedure:
To a solution of N-Boc-(2S)-3-(pyridin-4-yl)alanine (500 mg, 1.9 mmol) in THF (12 mL) was added N-methylmorpholine (200 μL, 1.9 mmol) and the solution was stirred for 5 min, cooled at −15° C. and treated dropwise with isobutyl chloroformate (249 μL, 1.9 mmol). The mixture was stirred for 10 min and pyrrolidine (1.08 g, 15.2 mmol) was added and allowed to warm to 25° C. with stirring for 3 h. The solvent were removed under reduced pressure and the residue was partitioned between EtOAc and NaH2PO4 pH=7.2. The aqueous layer was discarded and the organic layer was washed with aqueous saturated NaHCO3, dried over Na2SO4, filtered and evaporated. The resulting solid was purified by column chromatography (SiO2) with a gradient of 0% to 10% [v/v] MeOH in EtOAc to give tert-butyl(S)-1-oxo-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-2-ylcarbamate EBE 06190 (167 mg, 28% yield) as a white solid.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:8]([C@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=O)C)C=O)(=[O:3])[CH3:2].[CH2:28]([S:30][Si](C)(C)C)[CH3:29].FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(Cl)Cl>[C:25]([O:24][C@@H:23]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:9][C@H:10]1[S:30][CH2:28][CH3:29])(=[O:27])[CH3:26]
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C=O)OC(C)=O
Reactant: CCS[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCS[C@@H]1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A mixture of galactose pentaacetate (38.00 g, 97.43 mmol), (ethylthio)trimethylsilane (19.60 g, 146.15 mmol) and trimethylsilyl trifluoromethanesulfonate (23.60 g, 106.20 mmol) in CH2Cl2 (150 ml) was stirred overnight at room temperature. The reaction mixture was diluted with CH2Cl2 (150 ml) and washed with 1M Na2CO3 solution (300 ml), water (300 ml), dried over MgSO4 and concentrated. The residue was crystallised from hexane/di-isopropyl ether 1:1 (v/v) to give ethyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranoside (34.00 g, 89%).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1.[CH3:27][C:28](O)([CH3:30])[CH3:29].CCN=C=NCCCN(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH:8]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:9][C:10]([O:12][C:28]([CH3:30])([CH3:29])[CH3:27])=[O:11])=[CH:5][CH:6]=1
Reactant: CC(C)(C)O
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 62 h
Yield: 38 %

Procedure:
A solution of 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoic acid (250 mg, 0.703 mmol), tBuOH (0.135 ml, 1.407 mmol), EDCI (270 mg, 1.407 mmol) and 4-dimethylaminopyridine (86.0 mg, 0.704 mmol) in DCM (7 ml) is allowed to stir at room temperature under nitrogen for 62 hours. The reaction is quenched with water, and the organic layer is separated and concentrated. The residue is purified by flash column chromatography on silica gel to give tert-butyl 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (110 mg); HPLC retention time=1.77 minutes (condition B); MS (ES+)=412.1 (m+1) 300.0 (m-tBux2+3; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 (s, 9 H) 1.47 (s, 9 H) 2.36 (A of ABX, Jab=15.5 Hz, Jax=6.2 Hz, 1 H) 2.44 (B of ABX, Jab=15.5 Hz, Jbx=5.6 Hz) 2.82-2.94 (m, 2 H) 4.11-4.17 (m, 1 H) 5.08-5.10 (m, 1 H) 7.25-7.34 (m, 3H) 7.41-7.44 (m, 2 H) 7.51-7.58 (m, 4 H).
Reaction SMILES: C[Si](C)(C(C)(C)C(C)C)[O:3][C:4]1[C:9]2[CH2:10][O:11][CH2:12][C@H:13]([C:21]3[O:25][N:24]=[C:23]([CH3:26])[N:22]=3)[NH:14][C:15](=[O:20])[CH2:16][S:17][C:18](=[O:19])[C:8]=2[C:7]([CH3:27])=[C:6]([O:28][CH3:29])[CH:5]=1.[F-].[NH4+]>CO.C(OCC)(=O)C>[OH:3][C:4]1[C:9]2[CH2:10][O:11][CH2:12][C@H:13]([C:21]3[O:25][N:24]=[C:23]([CH3:26])[N:22]=3)[NH:14][C:15](=[O:20])[CH2:16][S:17][C:18](=[O:19])[C:8]=2[C:7]([CH3:27])=[C:6]([O:28][CH3:29])[CH:5]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)SCC(=O)N[C@@H](c1nc(C)no1)COC2
Agent: [F-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(O)c2c(c1C)C(=O)SCC(=O)N[C@@H](c1nc(C)no1)COC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of 268 mg of (4R)-13-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-11-methoxy-10-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-3,4,5,6,7,9-hexahydro-1H-8,2,5-benzoxathiaazacycloundecine-6,9-dione in 10 ml of methanol were added 100 mg of ammonium fluoride, and the mixture was stirred for 30 min at room temperature. The mixture was diluted with 50 ml of ethyl acetate and washed with 30 ml of water and with 30 ml of brine. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate, then hexane was added, and the white solid was isolated by filtration to give 178 mg of (4R)-13-hydroxy-11-methoxy-10-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-3,4,5,6,7,9-hexahydro-1H-8,2,5-benzoxathiaazacycloundecine-6,9-dione as a white powder, m.p. 194°-196° C.