Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:8])[NH:7][CH2:6][CH2:5][S:4]1.C(N(CC)CC)C.[C:16](=[S:18])=[S:17].C([O-])(=O)C.[Zn+2:23].C([O-])(=O)C>C(O)(C)C>[CH3:2][C:3]1([CH3:8])[N:7]([C:16]([S-:18])=[S:17])[CH2:6][CH2:5][S:4]1.[CH3:2][C:3]1([CH3:8])[N:7]([C:16]([S-:18])=[S:17])[CH2:6][CH2:5][S:4]1.[Zn+2:23]
Reactant: S=C=S
Reactant: CC1(C)NCCS1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Zn+2]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC1(C)SCCN1C(=S)[S-]
Temperature: 10 °C
Reaction time: 8 h

Procedure:
While cooling and stirring at 10°C, 76.8 g. (0.50 mole) 2,2-dimethylthiazolidine hydrochloride [preparation described by B. Sweetman et al, J. Med. Chem. 12, 888 (1969)] was added to a mixture of 30 ml isopropanol and 101 g. (1.00 mole) triethylamine. Likewise, 38.0 g. (0.50 mole) of carbon disulfide was gradually added, followed by 45.8 g. (0.25 mole) of anhydrous zinc acetate. After standing overnight at room temperature, the precipitate was filtered, twice water-washed with 1 liter portions of water and air-dried to give 80.5 g. of the yellow product melting at 148° - 153°C (decomp.) and having the following analysis: Found: C, 31.51; H, 4.70%. Calcd for C12H20N2S6Zn: C, 32.04; H, 4.45%.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])[CH2:16]C.[C:25]1(=O)[CH2:30][CH2:29][CH2:28][CH:27]=[CH:26]1.F[C:33](F)(F)S(O)(=O)=O>C(Cl)Cl.CCN(CC)CC>[CH3:33][C:23]1[CH:22]2[CH2:21][CH2:20][CH:19]([C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15](=[O:18])[CH2:16]2
Reactant: CCC(=O)c1ccccc1
Reactant: O=C1C=CCCC1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(c2ccccc2)C2CCC1CC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 0.5 g of phosphorous pentoxide in 30 mL anh. DCM were added 1.3 mL of propiophenone followed by 2.9 mL of 2-cyclohexen-1-one at rt. The suspension was cooled to 0° C. with an ice bath before 2.6 mL of trifluoromethanesulfonic acid was carefully added. The reaction mixture was warmed to rt and then heated at 40° C. overnight. 5.4 mL of NEt3 were dropwise added at 0° C., the mixture was stirred at rt for 10 min and then evaporated to dryness. Purification by CC with EtOAc-Hept (2:8) yielded 1.2 g of rac-(1R*,4R*)-5-methyl-6-phenyl-bicyclo[2.2.2]oct-5-en-2-one as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]1[CH2:37][C:36]([F:39])([F:38])[CH2:35]1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:37][C:36]([F:39])([F:38])[CH2:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: O=S(=O)(OCC1CC(F)(F)C1)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(CC2CC(F)(F)C2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
600 mg (1.60 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in the presence of 1.92 ml (1.92 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 1162 mg (purity 70%, 3.20 mmol, 2.0 eq.) of (3,3-difluorocyclobutyl)methyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 417 mg (52% of theory)
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:32])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)(C)(C)C.[NH:34]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35]1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:33])=[C:10]2[C:15]=1[N:14]=[C:13]([O:20][CH:21]([F:22])[F:23])[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:37]3[CH:38]=[N:34][NH:35][CH:36]=3)=[CH:27][CH:26]=1)=[C:11]2[CH3:32]
Reactant: Cc1c(Cc2ccc(Br)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Reactant: OB(O)c1cn[nH]c1
Product: Cc1c(Cc2ccc(-c3cn[nH]c3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)O)c12

Procedure:
The title compound was prepared by the method of Preparation 22b using [3-(4-bromobenzyl)-8-chloro-2-difluoromethoxy-4-methylquinolin-5-yloxy]acetic acid tert-butyl ester and pyrazole-4-boronic acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.[H-].[Na+].I[CH3:20].O>CN(C=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1
Reactant: CCOC(=O)Cc1ccc(OCOC)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc(OCOC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(4-(methoxymethoxy)phenyl)acetate (1.75 g, 7.80 mmol) in DMF (50 mL) was slowly added sodium hydride (330 mg, 8.25 mmol) and iodomethane (1.13 g, 7.96 mmol) at 0° C. The reaction mixture was stirred for 1 hour at 0° C. The mixture was added water (50 mL) and extracted with EtOAc. The organic layer was dried with MgSO4. The organic layer was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with n-Hexane/EtOAc=15/1.
Reaction SMILES: [H-].[Na+].C([N:10]1[C@H:13](CCO)[C@@H:12]([C@H:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])[C:11]1=[O:27])C1C=CC=CC=1.C(Br)C1C=CC=CC=1>O.C1COCC1.CN(C)C=O>[Si:20]([O:19][C@@H:17]([C@@H:12]1[CH2:13][NH:10][C:11]1=[O:27])[CH3:18])([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:22])[CH3:21]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(Cc2ccccc2)[C@@H]1CCO
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CNC1=O
Temperature: 25 °C
Yield: 58 %

Procedure:
There were added 1 ml of THF and 0.6 ml of dimethylformamide to 13 mg (0.26 mmol) of sodium hydride (oiliness: 50%), to which 2 ml of a THF solution of 64 mg (0.18 mmol) of 1-benzyl-3(S)-[1(R)-t-butyldimethylsilyloxyethyl]-4(R)-(2-hydroxyethyl)-2-azetidinone on the ice bath and the mixture was stirred for 10 minutes. Thereto 0.03 ml (0.25 mmol) of benzyl bromide was added and the mixture was stirred at room temperature for a night. The reaction mixture was added with water, extracted three times with diethyl ether, and the obtained extract was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated. The obtained residue was purified by 10 g of silica gel-column chromatography (eluent; hexane:diethyl ether=1:1) to give 46 mg of 1-benzyl-4(R)-2-benzyloxyethyl)-3(S)-[1(R)-t-butyldimethylsilyloxyethyl]-2-azetidinone (yield: 58%).
Reaction SMILES: C[P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CO[C:15](=[O:23])[C:16]([CH3:22])([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20].Cl.[O:25]1[CH2:29]CCC1>CCOCC>[P:2]([O:25][CH2:29][C:15](=[O:23])[C:16]([CH3:21])([CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])([O:5][CH3:6])([O:3][CH3:4])=[O:7]
Reactant: C1CCOC1
Reactant: COP(C)(=O)OC
Reactant: CCCCC(C)(C)C(=O)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCC(C)(C)C(=O)COP(=O)(OC)OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Dimethyl methylphosphonate (14.88 g) is dissolved in dry tetrahydrofuran (THF, 34 ml) under a nitrogen atmosphere. The solution is cooled to -78° C. Butyllithium (7.68 g, 52 ml of 2.3 molar solution, 3 equiv.) is added very slowly during 1 hour. The mixture is stirred at -78° C for 15 minutes. A solution of 2,2-dimethylhexanoic acid methyl ester (6.32 g) in dry THF (16 ml) is added to the cold solution over a period of 1 hour. The mixture is stirred for 30 minutes and then allowed to warm up to room temperature. The reaction mixture is diluted with ether. Dilute (10%) hydrochloric acid (30 ml) is added and the reaction mixture shaken well. The organic phase is separated and washed several times with water, dried (MgSO4) and the solvent removed. The residue is distilled under reduced pressure to give the title compound, b.p. 110° - 120° C/0.1mm, γmaxfilm 1700, 1250, 1020 cm-1.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:11][CH:10]=1.CCN(CC)CC.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:18]=[C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=1
Reactant: Nc1ccc(CCC(=O)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CCC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (2.45 mL, 26 mmol) was added to a solution of 3-(4-amino-phenyl)-1-phenyl-propan-1-one from Example X (4.5 g, 20 mmol), NEt3 (3.1 mL, 22.2 mmol), and a crystal of DMAP in CH2Cl2 (50 mL). The reaction mixture was stirred overnight at room temperature, then poured onto 1N HCl. The product was partitioned between CH2Cl2 and H2O, and the organic phase was dried (MgSO4) and concentrated to give the title compound. 1H NMR (CDCl3) δ 2.16 (s, 3 H), 3.03 (t, 2 H), 3.28 (t, 2 H), 7.20 (d, 2 H), 7.37-7.60 (m, 6 H), 7.94 (d, 2 H).
Reaction SMILES: C([Al]([CH2:6][CH3:7])CC)C.[C:8]([O:11][CH:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:13]12[CH3:14])[C@:26]1([CH3:27])[C@H:21]([CH2:22][C:23](=[O:31])[CH:24]=[CH:25]1)[CH2:20][CH2:19]3)(=[O:10])[CH3:9].[Cu](C#N)C#N.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:8]([O:11][CH:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:13]12[CH3:14])[C@:26]1([CH3:27])[C@H:21]([CH2:22][C:23](=[O:31])[CH2:24][C@@H:25]1[CH2:6][CH3:7])[CH2:20][CH2:19]3)(=[O:10])[CH3:9]
Reactant: CC[Al](CC)CC
Reactant: CC(=O)OC1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: N#C[Cu]C#N
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC[C@H]1CC(=O)C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)C(OC(C)=O)CC[C@@H]34)[C@@]12C
Temperature: 25 °C
Reaction time: 12 h
Yield: 39 %

Procedure:
5.78 ml (11 mmol) of a 1.9 molar solution of triethyl aluminum in toluene is added at room temperature to 3.3 g (10 mmol) of 17-acetoxy-5α-androst-1-en-3-one in 15 ml of ethyl acetate and 44.78 mg (0.5 mmol) of copper cyanide (CuCN). It is stirred 12 hours more at 25° C. The reaction solution is hydrolyzed with 1 ml of water and stirred again for 15 minutes. The inorganic solid is filtered off. The solid is washed again with ethyl acetate. After evaporation of the solvent and chromatography of the substance on silica gel with hexane/ethyl acetate as eluent, 1.44 g (39% of theory) of 17-acetoxy-1α-ethyl-5α-androstan-3-one is obtained.
Reaction SMILES: C[C:2]1([CH3:14])S[C@@H]2[C@H](N)C(=O)N2[C@H:3]1[C:11]([OH:13])=O.CC(O[CH2:19][C:20]1CS[C@@H]2[C@H](N)C(=O)N2[C:21]=1C(O)=O)=O.[CH3:33]C1CS[C@@H]2[C@H](N)C(=O)N2C=1C(O)=O>>[C:11]([C:3]1[CH:2]=[CH:14][CH:21]=[CH:20][CH:19]=1)(=[O:13])[CH3:33]
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: CC(=O)c1ccccc1

Procedure:
The 6-substituted penicillins and the 7-substituted cephalosporins represented by the Formula I are prepared by reacting an ester of 6-aminopenicillanic acid, 7-aminocephalosporanic acid or 7-aminodeacetoxycephalosporanic acid with an aromatic aldehyde or an acetophenone to provide a 6-iminopenicillanic acid ester or a 7-iminocephalosporin ester.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[CH:18]=[C:19]([Cl:34])[C:20]([C:32]#[N:33])=[C:21]4[C:27]=3[O:26][CH2:25][CH2:24][N:23]([CH:28]3[CH2:31][NH:30][CH2:29]3)[CH2:22]4)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12.C(N(CC)C(C)C)(C)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>CN(C)C=O>[C:44]([N:30]1[CH2:31][CH:28]([N:23]2[CH2:22][C:21]3=[C:20]([C:32]#[N:33])[C:19]([Cl:34])=[CH:18][C:17]([CH:15]([N:11]4[C:7]5=[N:8][CH:9]=[N:10][C:5]([NH2:4])=[C:6]5[C:13]([CH3:14])=[N:12]4)[CH3:16])=[C:27]3[O:26][CH2:25][CH2:24]2)[CH2:29]1)(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(C2CNC2)C3)c2ncnc(N)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CC(N2CCOc3c(C(C)n4nc(C)c5c(N)ncnc54)cc(Cl)c(C#N)c3C2)C1
Reaction time: 1 h
Yield: 29.9 %

Procedure:
The crude 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile trishydrochloride (0.015 g, 0.0278 mmol) was dissolved in N,N-dimethylformamide (2 mL) and cooled in an ice bath, and then N,N-diisopropylethylamine (0.0142 g, 0.112 mmol) and acetic anhydride (0.0032 mL, 0.033 mmol) were added. After stirring for 1 h, the product was purified without work up, by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give 4-(1-acetylazetidin-3-yl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile as a white amorphous solid (0.004 g, 33%). LCMS calculated for C23H26ClN8O2 (M+H)+: m/z=481.2; found: 481.2.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([C:16]([NH:18][NH2:19])=[O:17])=[CH:5][N:4]=1.[C:20](=O)([O-])[OH:21].[Na+].ClC([CH2:28][C:29]([O:31][CH3:32])=[O:30])=O>C(Cl)(Cl)Cl>[C:29]([O:31][CH2:32][C:20]([NH:19][NH:18][C:16]([C:6]1[C:7]([O:9][CH2:10][CH2:11][Si:12]([CH3:14])([CH3:15])[CH3:13])=[N:8][C:3]([S:2][CH3:1])=[N:4][CH:5]=1)=[O:17])=[O:21])(=[O:30])[CH3:28]
Reactant: COC(=O)CC(=O)Cl
Reactant: CSc1ncc(C(=O)NN)c(OCC[Si](C)(C)C)n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CSc1ncc(C(=O)NNC(=O)COC(C)=O)c(OCC[Si](C)(C)C)n1

Procedure:
2-Methylthio-4-(2-trimethylsilylethoxy)pyrimidine-5-carbohydrazide [Compound (E) in which R1 represents 2-trimethylsilylethoxy] (1.00 g, 3.33 mmol) obtained in Step 3 of Reference Example 3 was dissolved in chloroform (10 mL), and a saturated aqueous sodium hydrogencarbonate solution (10 mL) was added thereto. While stirring the mixture under ice-cooling, a chloroform (10 mL) solution of methyl chlorocarbonylacetate (0.477 g, 3.50 mmol) was added to the mixture, and was stirred at the same temperature for 1 hour. After completion of the reaction was confirmed by thin-layer chromatography, the reaction mixture was separated into organic layer and aqueous layer. The aqueous layer was extracted with chloroform and the extract was combined with the organic layer. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to give crude N′-acetoxymethylcarbonyl-2-methylthio-4-(2-trimethylsilylethoxy)pyrimidine-5-carbohydrazide [Compound (G) in which R1 is 2-trimethylsilylethoxy, and R3B represents acetoxymethyl].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:35]([CH3:37])[CH3:36])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:34])[CH2:23][C@@H:24]([OH:33])[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:35]([CH3:37])[CH3:36])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:34])[CH2:23][C@@H:24]([OH:33])[CH2:25][C:26]([OH:28])=[O:27])[C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O
Yield: 77.3 %

Procedure:
A solution of 1,1-dimethyleth-1-yl (3R,5S,E)-7-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-3,5-dihydroxy-6-heptenoate (726 mg) in redistilled THF (40 ml) was treated with 0.1M aqueous sodium hydroxide solution (14.5 ml). After 1/2 h the mixture was concentrated to ca. 10 ml and then diluted with water (50 ml). The mixture was acidified to pH2 with 2N-hydrochloric acid, brought back to pH4 with aqueous sodium hydrogen carbonate solution, ammonium sulphate added and then the mixture was extracted with ethyl acetate (3×50 ml). The combined extracts were dried and concentrated to ca. 4 ml when a solid crystallised. The crystals were collected and dried to give the title compound (500 mg), m.p. 172°-3° C., [α]D +15.7° (c 1.02, DMSO), (RS:SR=99.5:0.5).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][C:7]=1[CH2:14][N:15]([CH:17]1[CH2:19][CH2:18]1)[CH3:16])([CH3:3])[CH3:2].[CH3:21][O:22][C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:28]2[CH:29]=[CH:30][C:25]([CH2:24][C:23]([O:22][CH3:21])=[O:32])=[CH:26][CH:27]=2)=[CH:8][C:7]=1[CH2:14][N:15]([CH:17]1[CH2:19][CH2:18]1)[CH3:16])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc(C(=O)OC(C)C)c(CN(C)C2CC2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(C(=O)OC(C)C)c(CN(C)C3CC3)c2)cc1

Procedure:
Following General Procedure B and using 2-[(cyclopropyl-methyl-amino)-methyl]-4-ethynyl-benzoic acid isopropyl ester (Intermediate 122, 0.09 g, 0.33 mmol), 4-iodophenyl acetic acid methyl ester (0.09 g, 0.33 mmol), triethyl amine (2 mL), copper(I)iodide (0.04 g, 0.21 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.1 g, 0.14 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10-15% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil. (0.1 g, 72%).
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([C:29]3[CH:60]=[CH:59][C:32]([CH2:33][O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH2:41][CH2:42][NH:43][CH:44]4[CH2:53][CH2:52][CH2:51][C:50]5[N:49]=[C:48]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH:47]=[CH:46][C:45]4=5)=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH:61]=1>C(#N)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([C:29]3[CH:60]=[CH:59][C:32]([CH2:33][O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH2:41][CH2:42][N:43]([CH2:2][CH2:3][C:4]4[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=4)[CH:44]4[CH2:53][CH2:52][CH2:51][C:50]5[N:49]=[C:48]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH:47]=[CH:46][C:45]4=5)=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH:61]=1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1ccccc1OCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Reactant: COC(=O)c1ccc(CCI)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1ccccc1OCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1

Procedure:
112 mg (0.39 mmol) of methyl 4-(2-iodoethyl)benzoate and 41 mg (0.39 mmol) of anhydrous sodium carbonate were added to a solution of 149 mg (0.26 mmol) of ethyl 5-{[2-(2-{[4-(5-chloro-1,3-benzoxazol-2-yl)benzyl]oxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 1, Example 61A) in 10 ml of dry acetonitrile, and the mixture was heated under reflux overnight. A further 112 mg of methyl 4-(2-iodoethyl)benzoate were then added, and the mixture was once more heated under reflux overnight. The reaction was then evaporated to dryness, the residue was taken up in water and ethyl acetate and the phases were separated. The organic phase was evaporated to dryness and the residue obtained was purified by preparative HPLC. This gave 72 mg (0.10 mmol, 38% of theory) of the title compound.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:3])[CH3:2].[ClH:19].[CH:20]1([C:23]2[C:24]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:25][CH:26]=[C:27]([CH:29]3[CH2:31][CH2:30]3)[CH:28]=2)[CH2:22][CH2:21]1>>[ClH:19].[CH:20]1([C:23]2[C:24]([N:32]3[CH2:33][CH2:34][N:35]([C:14]([C:13]4[CH:12]=[CH:11][C:10]([N:5]5[C@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][O:7][C:6]5=[O:9])=[CH:18][CH:17]=4)=[O:16])[CH2:36][CH2:37]3)=[N:25][CH:26]=[C:27]([CH:29]3[CH2:31][CH2:30]3)[CH:28]=2)[CH2:21][CH2:22]1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: CC(C)[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Agent: Cl
Product: CC(C)[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1
Yield: 45.9 %

Procedure:
By reaction and treatment in the same manner as in Example 87 and using (R)-4-(4-isopropyl-2-oxooxazolidin-3-yl)benzoic acid (499 mg) described in Preparation Example 18 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine hydrochloride (560 mg) described in Preparation Example 50, the title compound (469 mg) was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.O=S(Cl)Cl.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:16]([N:18]([CH2:19][CH3:20])[C:1](=[O:3])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH3:17]
Reactant: CCNCC
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc(C=O)cc1
Reaction time: 1 h

Procedure:
To a suspension of 4-carboxybenzaldehyde (30 g, 0.2 mole) in 100 ml of toluene was added SOCl2 (97 ml, 1.3 moles) at 60° C. The reaction was heated until gas evolution ceased followed by evaporation to dryness with toluene (3×50 mL) This yielded a residue, which was dissolved in CH2Cl2 (200 mL). To this solution, cooled in an ice bath while stirring, was added diethylamine (50 mL). Stirring was continued for one hour and then the mixture heated at reflux for a further hour. After cooling, the mixture was washed successively with H2O, 2 N HCl, H2O then 2 N NaOH and finally with H2O. The solution was dried over MgSO4, filtered and concentrated to dryness yielding 41 g of oil. Distillation at 140-150° C./1.5 torr gave 36.9 g, 90% of INTERMEDIATE 1.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:9])=[O:8].C(=O)(O)[O-].[Na+].[NH:18]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:19]([C:23](ON1C(=O)CCC1=O)=[O:24])[CH:20]([CH3:22])[CH3:21].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(COC)OC.O1CCCC1>[NH:18]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[C@H:19]([C:23]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:9])=[O:8])=[O:24])[CH:20]([CH3:21])[CH3:22]
Reactant: NC(=O)NCCC[C@H](N)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: COCCOC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Citrulline (2.54 g, 14.50 mmole) and Sodium Bicarbonate (1.28 g) in water (40 mL) was added Boc-Val-OSu (4.34 g, 13.81 mmole) dissolved in dimethoxyethane (DME). To aid the solubility of the mixture tetrahydrofuran (10 mL) was added. The mixture thus obtained was let stir overnight at room temperature. Aqueous citric acid (15%, 75 mL) was added and the mixture was extracted with 10% 2-propanol/ethyl acetate (2×100 mL). The organic layer was washed with brine (2×150 mL) and the solvents were removed on the rotovap. The resulting white solid was dried in vacuo for 5 hours and then treated with ether (100 mL). After brief sonication and trituration, the white solid product was collected by filtration (1.39 g, 27%). 1H NMR (CD3OD)δ 0.91 (dd, 3H), 0.98 (dd, 3H), 1.44 (s, 9H), 1.70 (m, 2H), 1.87 (m, 2H), 2.02 (m, 2H), 3.11 (t, 2H), 3.89 (t, 1H), 4.39 (q, 1H), 8.22 (d, 1H) ppm; LC-MS (ESI) 375 (M+H+).