Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH:12]=O)[C:8]=1[C:9]([OH:11])=[O:10].[S:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[S:16].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:9]([C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=1[CH:12]=[C:20]1[S:14][C:15](=[S:16])[NH:17][C:18]1=[O:19])([OH:11])=[O:10]
Reactant: O=C1CSC(=S)N1
Reactant: COc1cccc(C=O)c1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(C=C2SC(=S)NC2=O)c1C(=O)O
Temperature: 0 °C

Procedure:
To a stirred hot solution of 2.10 g. (11.65 mM) of 6-methoxyphthalaldehydic acid and 1.57 g. (11.75 mM) of rhodanine in 8 ml. of acetic acid is added 3.12 g. (38.1 mM) of sodium acetate. The resulting solution is refluxed 0.5 hour and then poured into ice water to give a tan precipitate. The solid is collected and partially air-dried to give 5-(2-carboxy-3-methoxybenzylidene)rhodanine as a tan solid.
Reaction SMILES: BrCC([C:5]1[CH:6]=[C:7]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C:8](=[O:22])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:10]=1[CH3:11])=O.[C:37]([NH2:40])(=[O:39])[CH3:38].[C:41]1(C)C(C)=CC=C[CH:46]=1.OS(O)(=O)=O>O.CC#N>[CH3:11][C:10]1[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[C:8](=[O:22])[C:7]([C:23]([NH:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=2)=[O:24])=[CH:6][C:5]=1[C:41]1[N:40]=[C:37]([CH3:38])[O:39][CH:46]=1
Reactant: CC(N)=O
Reactant: Cc1c(C(=O)CBr)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: Cc1ccccc1C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: Cc1nc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)co1
Reaction time: 3 h
Yield: 45 %

Procedure:
A mixture of 5-(bromoacetyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (90 mg, 0.15 mmol) and acetamide (44 mg, 0.75 mmol), xylene (300 μl) and cone. H2SO4 (10 μl) was heated with stirring for 3 h. The reaction was diluted with water and CH3CN and purified on preparative HPLC affording the title compound (37 mg, 45%).
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[I:41])[CH:36]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH2:25]([O:32][C:33]1[CH:34]=[C:35](/[CH:36]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:38]=[CH:39][C:40]=1[I:41])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(I)c(OCc2ccccc2)c1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(I)c(OCc2ccccc2)c1
Yield: 86.6 %

Procedure:
170 g (506 mmol) of methyl (triphenylphosphoranylidene)acetate are added to a solution of 114 g (337 mmol) of 3-benzyloxy-4-iodobenzaldehyde in 570 ml of toluene. The reaction mixture is refluxed for 2 hours. The solvent is evaporated off and the oil obtained is purified by chromatography on a column of silica eluted with a 50/50 heptane/dichloromethane mixture. 115 g (87%) of methyl(E)-3-(3-benzyloxy-4-iodophenyl)acrylate are obtained in the form of pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([CH2:10][O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:13]=[N+:14]=[N-:15].[Na+].Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:12][O:11][CH2:10][C:8]1[N:9]=[C:2]([NH2:1])[C:3]([C:4]2[N:13]=[N:14][NH:15][N:5]=2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COCc1ccc(C#N)c(N)n1
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COCc1ccc(-c2nn[nH]n2)c(N)n1
Temperature: 160 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
2-Amino-6-methoxymethyl-nicotinonitrile (0.20 g) described in Manufacturing Example 6-2, sodium azide (0.40 g), triethylamine hydrochloride (1.7 g), and NMP (25 mL) were stirred for 2 hours at 160° C. The reaction solution was directly purified by silica gel chromatography (ethyl acetate, then ethyl acetate:methanol:concentrated aqueous ammonia=6:2:1). The organic layer thus obtained was concentrated and purified by silica gel chromatography (ethyl acetate:methanol=4:1) to obtain the titled compound (170 mg).
Reaction SMILES: ClC1C=C(C(OO)=[O:9])C=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=[CH2:21])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]2[CH2:21][O:9]2)=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Fc1ccc(CC2CO2)cc1
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a stirred mixture of 86 parts of 3-chlorobenzeneperoxoic acid and 650 parts of dichloromethane are added dropwise (slowly) 53 parts of 1-fluoro-4-(2-propenyl)benzene. Upon completion, stirring is continued overnight at room temperature. Then there are added dropwise 92 parts of a potassium carbonate solution and the layers are separated. The organic phase is washed with a sodium bisulfite solution, dried, filtered and evaporated, yielding 58.4 parts (98.5%) of 2-(4-fluorophenylmethyl)oxirane as an oily residue.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].O.CS[C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=1)[C:13]([OH:15])=[O:14].[C:23](O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.CCOC(C)=O>[CH3:23][S:3]([C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[N:18]=1)[C:13]([OH:15])=[O:14])(=[O:5])=[O:2]
Reactant: CSc1cc(C(=O)O)cc(C(F)(F)F)n1
Reactant: O=S([O-])OO
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice-cold suspension of Oxone® (525 mg, 854 μmol, CAS RN 10058-23-8) in methanol (0.6 mL) and water (0.6 mL) was added dropwise a solution of 2-methylsulfanyl-6-trifluoromethyl-isonicotinic acid (0.09 g, 341 μmol) in methanol (1.2 mL) and the reaction mixture was stirred in an ice-bath for 2 hours. After stirring at room temperature for another 4.5 hours the reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc and the organic layers were washed with water, 10% aqueous Na2S2O3 solution and brine, dried over MgSO4, filtered, and evaporated. Colorless solid (0.106 g; 98%). MS (ESI): m/z=267.99 [M−H]−. This material was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].Br[C:17]1C=C(C)C(F)=C([CH:24]=1)C#N.C([O-])([O-])=O.[K+].[K+].N1C=NC=N1>CN(C=O)C.O>[CH3:15][C:4]1[C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=[C:2]([CH:17]=[CH2:24])[CH:3]=1)[C:7]#[N:8]
Reactant: Cc1cc(Br)cc(C#N)c1-n1cncn1
Reactant: Cc1cc(Br)cc(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1nc[nH]n1
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cc(C)c(-n2cncn2)c(C#N)c1
Temperature: 140 °C
Yield: 49 %

Procedure:
5-Bromo-3-methyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (DI71): To a stirred solution of 5-bromo-2-fluoro-3-methylbenzonitrile (1.0 g, 47.716 mmol), in DMF (10.0 mL) was added K2CO3 (1.95 g, 14.14 mmol) followed by 1H-1,2,4-triazole (0.811 g, 9.433 mmol) at ambient temperature. The reaction mixture was heated to 140° C. for 18 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with EtOAc (2×100 mL). The combined EtOAc layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% EtOAc/pet ether) to afford the title compound as a pink solid (0.6 g, 49%): 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.23 (s, 1H), 7.91 (d, J=2.4 Hz, 2H), 2.21 (s, 3H), ESIMS m/z 262.57 ([M+H]+); IR (thin film) 2231, 554 cm−1.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]6[CH:45]=[CH:46][CH:47]=[CH:48][C:43]6=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]6[CH:45]=[CH:46][CH:47]=[CH:48][C:43]6=[N:42][CH:41]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cnc5ccccn45)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cnc5ccccn45)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(imidazo[1,2-a]pyridin-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (0.80 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.44 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., sodium thiosulfate solution was added to the mixture at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 3:1→ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(imidazo[1,2-a]pyridin-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 167) (642 mg) as yellow amorphous.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH2:14][CH2:13][CH2:12][CH:11]=3)=[C:7]([C:15](O)=[O:16])[C:6]=2[CH:18]=1.C1C=CC2N(O)N=[N:31][C:29]=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.CN>CN(C=O)C>[Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH2:14][CH2:13][CH2:12][CH:11]=3)=[C:7]([C:15]([NH:31][CH3:29])=[O:16])[C:6]=2[CH:18]=1
Reactant: On1nnc2ccccc21
Reactant: CN(c1cc2oc(C3=CCCC3)c(C(=O)O)c2cc1Br)S(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C2=CCCC2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A solution of 5-bromo-2-(cyclopent-1-en-1-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylic acid (3.5 g, 7.70 mmol), HOBT (1.6 g, 11.55 mmol) and EDCI (2.2 g, 11.55 mmol) in dry DMF (40 mL) was stirred at 25° C. After 2 hours, Et3N (2.4 g, 23.11 mmol) and MeNH2 (1.6 g, 23.11 mmol) were added to the mixture and then stirred overnight. The solvent was removed by vacuum, the mixture was washed with H2O (50 mL) and extracted with EtOAc (50 mL*3), and dried over Na2SO4. After concentration, the residue was purified by column chromatography (DCM) to give the product of 5-bromo-2-(cyclopent-1-en-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (2 g, yield: 56%). 1H-NMR (CDCl3, 400 MHz) δ 8.00 (s, 1H), 7.59 (s, 1H), 6.70 (t, J=3.2 Hz, 1H), 5.95 (s, 1H), 3.31 (s, 3H), 3.30 (s, 3H), 3.06 (s, 3H), 2.76˜2.81 (m, 2H), 2.58˜2.62 (m, 2H), 2.07 (t, J=7.6 Hz, 2H). MS (M+H)+: 427/429.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[C:14]([O:15][CH2:16][CH:17]2[CH:21]=[CH:20][CH2:19][N:18]2C(OC(C)(C)C)=O)=[C:13]([C:29]([O:31][CH3:32])=[O:30])[C:12]([N:33](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:33][C:12]1[C:13]([C:29]([O:31][CH3:32])=[O:30])=[C:14]([O:15][CH2:16][CH:17]2[CH:21]=[CH:20][CH2:19][NH:18]2)[C:9]([Br:8])=[CH:10][CH:11]=1
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1OCC1C=CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(N)ccc(Br)c1OCC1C=CCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
TFA (5 mL) was slowly added to a suspension of tert-butyl 2-(6-bromo-3-[bis-(tert-butoxycarbonyl)amino]-2-methoxycarbonylphenoxymethyl)-2,5-dihydropyrrole-1-carboxylate (Intermediate 19, 3.55 g) in DCM (5 mL). The resultant dark solution was stirred at room temperature for 3 hours. The volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous potassium carbonate solution. The layers were separated and the aqueous layer was extracted with more ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to give methyl 6-amino-3-bromo-2-(2,5-dihydro-1H-pyrrol-2-ylmethoxy)-benzoate (1.64 g) as a dark oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24](O)=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:7]=1[C:8]#[CH:9].Cl.[CH3:28][NH:29][O:30][CH3:31].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl.Cl.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]([N:29]([O:30][CH3:31])[CH3:28])=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:7]=1[C:8]#[CH:9]
Reactant: C#Cc1c(Cl)cc(C(=O)O)c(-c2cccc(F)c2)c1/N=N/N1CCCC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C#Cc1c(Cl)cc(C(=O)N(C)OC)c(-c2cccc(F)c2)c1/N=N/N1CCCC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 101.9 %

Procedure:
A solution of 4-chloro-5-ethynyl-3′-fluoro-6-[(E)-pyrrolidin-1-yldiazenyl]biphenyl-2-carboxylic acid (830 g, 2.2 mol), N,O-dimethylhydroxylamine hydrochloride (280 g, 2.9 mol), 1-hydroxybenzotriazole hydrate (360 g, 2.4 mol), and N,N-diisopropylethylamine (1.4 L, 7.8 mol) in tetrahydrofuran (5 L) was treated with EDCI HCl (520 g, 2.7 mol) and stirred at room temperature for 36 hours. The reaction mixture was cooled to approximately 5° C. and treated with 2.0 M hydrogen chloride in water (3.4 L, 6.7 mol) in portions while maintaining the internal temperature lower than 10° C. The organic layer was separated and the aqueous layer was extracted with tetrahydrofuran (2 L). The combined organic layers (˜6 L, pH ˜5) were washed with 2.0 M hydrogen chloride in water (2 L), 0.5 M sodium carbonate in water (2 L), and brine, dried over sodium sulfate, filtered, and concentrated to give a crude oil. This material was azeotroped with toluene to give the desired product (theoretical yield 930 g) as a brown oil. This material was used in the next step without further purification. A small sample was purified for spectroscopic analysis. LCMS for C21H21ClFN4O2 (M+H)+: m/z=415.1; Found: 415.0; 1H NMR (400 MHz, DMSO-d6): δ 7.44 (s, 1H), 7.35-7.29 (m, 1H), 7.12-7.06 (m, 1H), 6.93-6.84 (m, 2H), 4.48 (s, 1H), 3.62-3.58 (m, 2H), 3.29 (s, 3H), 3.25-3.17 (m, 2H), 2.93 (s, 15 H), 2.85 (s, 1.5H), 1.89-1.77 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([S:11][CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[N:3]=1.[C:22]([O:25][CH2:26][CH:27]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[CH2:28][CH2:29]I)(=[O:24])[CH3:23]>>[C:22]([O:25][CH2:26][CH:27]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[CH2:28][CH2:29][C:7]1[NH:6][C:5]2[C:9](=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[S:11][CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[N:8]=1)(=[O:24])[CH3:23].[C:22]([O:25][CH2:26][CH:27]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[CH2:28][CH2:29][N:6]1[C:5]2[C:9](=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[S:11][CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[N:8]=[CH:7]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OCC(CCI)COC(C)=O
Reactant: Nc1nc(SCCC(=O)c2ccccc2)c2[nH]cnc2n1
Product: CC(=O)OCC(CCc1nc2nc(N)nc(SCCC(=O)c3ccccc3)c2[nH]1)COC(C)=O
Product: CC(=O)OCC(CCn1cnc2nc(N)nc(SCCC(=O)c3ccccc3)c21)COC(C)=O
Yield: 77.4 %
Yield: 7.4 %

Procedure:
Using the previously described procedure 2-amino-6-[(phenacylmethyl)thio]purine (5.71 g) and 2-acetoxymethyl-4-iodobut-1-yl acetate (6.93 g) gave the title compound 7.3 g (77.4%) m.p. 130°-131° and 0.7 g (7.4%) of 7-(4-acetoxy-3-acetoxymethylbut-1-yl)-2- amino-6-[(phenacylmethyl)thio]purine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26][C:27]([CH3:48])([CH3:47])[CH2:28][CH2:29][N:30]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33]([CH2:43][CH2:44][CH3:45])([CH2:40][CH2:41][CH3:42])[O:32][C:31]1=[O:46]>CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:26][C:27]([CH3:47])([CH3:48])[CH2:28][CH2:29][N:30]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[C:33]([CH2:43][CH2:44][CH3:45])([CH2:40][CH2:41][CH3:42])[O:32][C:31]2=[O:46])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: CCCC1(CCC)OC(=O)N(CCC(C)(C)N)c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCC1(CCC)OC(=O)N(CCC(C)(C)NCC(O)c2ccc(OCc3ccccc3)c3c2OCC(=O)N3)c2ccccc21

Procedure:
The product is prepared analogously to Example 12a starting from 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 1-(3-amino-3-methyl-butyl)-4,4-dipropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one hydrochloride. The crude product is dissolved in EtOAc, washed with 5% aqueous NaOH solution and purified by column chromatography (silica gel, dichloromethane/MeOH 98:2→90:10).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([C@H:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH3:50])[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=[O:2].O[N:68]1[C:72](=[O:73])[CH2:71][CH2:70][C:69]1=[O:74].Cl.CN(C)CCCN=C=NCC>ClCCl>[O:74]=[C:69]1[CH2:70][CH2:71][C:72](=[O:73])[N:68]1[O:2][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([C@H:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH3:50])[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)ON1C(=O)CCC1=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
16 mg (17 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3S)-1-(benzyloxy)-1-oxo-3-phenylbutan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 70) were dissolved in 2 ml of dichloromethane and admixed with 2.6 mg (23 mmol) of 1-hydroxypyrrolidine-2,5-dione and then with 4 mg (21 μmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. After stirring at RT for 2 h, the same amounts of 1-hydroxypyrrolidine-2,5-dione and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added once again. Then stirring at RT overnight, the reaction mixture was concentrated under reduced pressure. The remaining residue was purified by means of preparative HPLC. After lyophilization, 10 mg (56% of theory) of the title compound were obtained.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[CH3:35][NH:36][CH3:37]>>[CH3:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([C:29]2[CH:30]=[CH:31][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:27][CH:28]=2)=[O:7])[C@H:9]([C:16]([N:36]([CH3:37])[CH3:35])=[O:18])[CH2:10]1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CNC
Product: CON=C1C[C@@H](C(=O)N(C)C)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and dimethylamine (5.6M in ethanol), the title compound was obtained in 94% purity by HPLC. MS(ESI+): m/z=380.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH3:7])[C:3](O)=[O:4].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.Cl.C(N=C=NCCCN(C)C)C.OC1C2NN=NC=2C=CC=1>CN(C)C=O.O>[Br:1][CH:2]([CH2:6][CH3:7])[C:3]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:4]
Reactant: C1COCCN1
Reactant: CCC(Br)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2nn[nH]c12
Solvent: O
Solvent: CN(C)C=O
Product: CCC(Br)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 48.7 %

Procedure:
To a solution of 2-bromobutanoic acid (0.3 mL, 2.81 mmol) in N,N-dimethylformamide (14 mL) are added morpholine (0.3 mL, 3.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (650 mg, 3.39 mmol) and 7-hydroxybenzotriazole (456 mg, 3.38 mmol), and the mixture is stirred at room temperature for 4.5 hours. After the reaction is completed, water is added to the mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with 1N-hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated, and the obtained residue is purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to give the title compound (323 mg, yield: 49%).
Reaction SMILES: [C:1]1([S:7][Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)P(=O)(N(C)C)N(C)C.[CH2:23](Br)[CH3:24].C(OCC)(=O)C>O>[C:1]1([S:7][CH2:23][CH3:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCBr
Reactant: C[Si](C)(C)Sc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCSc1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A mixture of 11.52 g (63 mmoles) of phenylthio(trimethyl)silane, 22 ml of hexamethylphosphoric triamide and 18.8 ml (250 mmoles) of ethyl bromide was heated in a bath at 40° C. for 2 hours after which the conversion was complete. A solid formed in the reaction mixture and heating was continued for 1 hour after which the mixture was poured into a mixture of 150 ml of ethyl acetate and 50 ml of water. The ethyl acetate layer was separated and washed sequentially twice with 50 ml of water, 50 ml of a saturated sodium bicarbonate solution and twice with 25 ml of water. The combined water layers were extracted three times with 25 ml of ethyl acetate and the combined organic phases were washed twice with 25 ml of water, dried and evaporated to dryness. The residue was vacuum distilled to obtain 7.25 g (83% yield) of ethyl phenyl sulfide with a boiling point of 81.5°-84° C./14 mm Hg and a refractive index of nD25 =1.5632.