Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][C@@H:25]([NH:28]C(=O)OC(C)(C)C)[C:24]4=[O:36])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH2:28][C@@H:25]1[CH2:26][CH2:27][N:23]([C:20]2[CH:21]=[CH:22][C:17]([N:13]3[CH2:12][C@H:11]([CH2:10][NH:9][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:8])[O:15][C:14]3=[O:16])=[CH:18][CH:19]=2)[C:24]1=[O:36]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](CNC(=O)c4ccc(Cl)s4)OC3=O)cc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCN(c2ccc(N3C[C@H](CNC(=O)c4ccc(Cl)s4)OC3=O)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
97 mg (0.181 mmol) of tert-butyl(3R)-1-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-2-oxo-3-pyrrolidinylcarbamate are suspended in 4 ml of methylene chloride, 1.5 ml of trifluoroacetic acid are added and the mixture is stirred at room temperature for 1 hour, The mixture is then concentrated under reduced pressure and the residue is purified on an RP-HPLC (acetonitrile/water/0.1% TFA gradient). Evaporation of the appropriate fraction gives 29 mg (37% of theory) of the target compound of melting point 241° C. (decomp.).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[C:21](Br)(Br)([Br:23])[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:22][C:21]([Br:23])=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1ccc(-c2ccc(C=O)cc2OC)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(C=C(Br)Br)cc2OC)cc1
Reaction time: 1 h

Procedure:
A solution of Example 122I (1.35 g, 5.0 mmol) in dichloromethane (30 mL) at room temperature was treated with carbon tetrabromide (1.82 g, 5.5 mmol) and triphenylphosphine (2.88 g, 11 mmol), stirred for 1 hour, treated with hexanes (50 mL), and filtered through silica gel (50 g). The solution was rinsed with 1:1 water/dichloromethane, separated, and the organic phase was concentrated. The concentrate was purified by flash column chromatography on silica gel with 2-10% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [F:1][C:2]([F:15])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCCC.C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>[C:16]1([NH:22][C:23](=[O:24])[O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:15])[F:1])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccccc1
Reactant: OCCCCCCCCCCC=C(F)F
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCCCCCC
Product: O=C(Nc1ccccc1)OCCCCCCCCCCC=C(F)F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of 2.0 grams (0.0091 mole) of 12,12-difluoro-11-dodecen-1-ol (prepared in Example 5) in 15 ml of heptane was added two drops of dibutyltin diacetate, and then 1.2 grams (0.0100 mole) of phenyl isocyanate was added dropwise. Upon completion of addition, the reaction mixture was warmed to 80° C. where it stirred for 30 minutes. The reaction mixture was allowed to cool to ambient temperature where it stirred for 18 hours. After this time the reaction mixture was cooled in a freezer, and a precipitate was collected by filtration. The filter cake was washed with cold pentane and dried yielding 2.47 grams of 12,12-difluoro-11-dodecenyl N-phenylcarbamate; m.p. 54°-56° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]([C:8]1[C:9]([C:14]#[N:15])=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OO)(=[O:18])C.C(O)(C)C>C(O)(=O)C>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[N+:10]([O-:18])[C:9]=1[C:14]#[N:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncccc1Oc1ccccc1
Reactant: CC(=O)OO
Solvent: CC(C)O
Solvent: CC(=O)O
Product: N#Cc1c(Oc2ccccc2)ccc[n+]1[O-]
Temperature: 95 °C

Procedure:
A solution of 9.6 g of 3-phenoxy-2-pyridinecarbonitrile, [J. Med. Chem. 18, 1 (1975)] in 25 ml of glacial acetic acid is treated with 25 g of 40% peracetic acid in acetic acid. The mixture is heated at 95° C. for 16 hours. One hundred ml of isopropanol is added and the mixture is concentrated at reduced pressure. The residue is dissolved in 250 ml of dichloromethane and the organic layer is washed with excess dilute sodium hydroxide solution and is dried over anhydrous MgSO4.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].[CH:11](OCC)(OCC)OCC.C(OC(=O)C)(=O)C.Cl.[NH:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:33][CH:32]=1)[NH2:30].CCN(C(C)C)C(C)C>CO>[NH2:2][C:1]1[N:29]([C:31]2[CH:32]=[CH:33][C:34]([CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:36]=2)[N:30]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: COC(=O)Cc1ccc(NN)cc1
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1ccc(-n2ncc(C(=O)OC(C)(C)C)c2N)cc1
Temperature: 125 °C

Procedure:
t-Butyl cyanoacetate (3.525 g, 25 mmol) was dissolved in triethyl orthoformate (6.2 mL, 37.5 mmol). Acetic anhydride (2.41 mL, 25 mmol) was added and the mixture heated to 125° C. for 3 h. Volatiles were then removed by evaporation under reduced pressure to leave an orange oil. The crude oil was dissolved in methanol and methyl 2-(4-hydrazinylphenyl)acetate hydrochloride (Intermediate#39) (1.62 g, 7.5 mmol) and DIPEA (1.3 mL, 7.5 mmol) were added. The mixture was heated to reflux for 2 h and then evaporated to dryness. The residue was dissolved in ethyl acetate (100 mL), washed with water (2×50 mL) and brine (50 mL), dried (MgSO4) and evaporated to leave a crude product which was purified by flash chromatography on silica gel (elution gradient 0-50% EtOAc in isohexane) to give the title compound as a yellow solid. (974 mg, 39%)
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[CH3:9][O:10][C:11](=[O:21])[C@H:12]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:13].C(N(CC)CC)C>ClCCl>[CH3:9][O:10][C:11](=[O:21])[CH:12]([NH:13][C:5](=[O:6])[CH2:4][CH2:3][S:2][CH3:1])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CSCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)NC(=O)CCSC
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
1.556 g (11 mmol) of 3-methylsulfanyl-propionyl chloride was added slowly to a mixture of 2.20 g (10 mmol) of phenylalanine methyl ester hydrochloride, 4.18 mL (30 mmol) of triethyl amine and 50 mL of dichloromethane and stirred at room temperature for 2 h. The reaction mixture was partitioned between DCM (50 mL) and saturated NaHCO3 solution (100 mL). The aqueous layer was separated and extracted again with dichloromethane (100 mL). The combined organic extracts were dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel gave 2.574 g (92%) of 2-(3-methylsulfanyl-propionylamino)-3-phenyl-propionic acid methyl ester. LCMS: 282 (M+1)+.
Reaction SMILES: [C:1](=[O:19])(SCC)[O:2][CH2:3][O:4][C:5](=[O:15])[CH2:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].S(Cl)([Cl:23])(=O)=O>>[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:7][CH2:6][C:5]([O:4][CH2:3][O:2][C:1]([Cl:23])=[O:19])=[O:15]
Reactant: CCSC(=O)OCOC(=O)CCC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)Cl
Product: CC(C)(C)OC(=O)CCC(=O)OCOC(=O)Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of carbonothioate 2 (1.06 g, 3.63 mmol) in ice-cold CH2Cl2 (18 mL) was added sulfuryl chloride (441 μL, 5.44 mmol) and the mixture was stirred at 0° C. for 2 h 10 min, after which an additional amount of sulfuryl chloride (147 μL, 1.82 mmol) was added. The mixture was concentrated to dryness, providing chloroformate 3 as a colorless oil (1.13 g, >quant.) which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 2.57-2.60 (m, 2H), 2.66-2.70 (m, 2H), 5.84 (s, 2H).
Reaction SMILES: [CH3:1][NH2:2].[C:3]1(=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5](=[O:13])[O:4]1>C1COCC1>[CH3:1][NH:2][C:5](=[O:13])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[C:3]([OH:4])=[O:14]
Reactant: CN
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: C1CCOC1
Product: CNC(=O)Cc1ccccc1C(=O)O
Temperature: 25 °C

Procedure:
To 20 ml of 2.0 M methylamine in THF is added 1.62 g (10 mmol) of isochroman-1,3-dione at 0° C. The mixture is stirred at 25° C. for 45 m and concentrated to dryness. The residue is stirred in 40 ml of 0.3 N HCl. The white solid is filtered off, washed with water, and dried to give 1.74 g (90%); 1H NMR (DMSO-d6) δ 7.80 (s, 1H), 7.81 (s, 1H), 7.40 (m, 3H), 3.83 (s, 2H), 2.57 (s, 3H); MS (ES−) m/z 192.1 (M−H)−1: Analysis for C10H11NO3: Calcd: C, 62.17; H, 5.74; N, 7.25. Found: C, 62.16; H, 5.81; N, 7.24
Reaction SMILES: [CH2:1]([P:7](=[O:24])([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH2:21][CH:22]=O)[CH:14]=1)[O:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([NH:32][NH2:33])=[S:31])=[CH:28][CH:27]=1>CO.C(Cl)Cl>[CH2:1]([P:7](=[O:24])([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH2:21][CH:22]=[N:33][NH:32][C:30](=[S:31])[C:29]2[CH:34]=[CH:35][C:26]([CH3:25])=[CH:27][CH:28]=2)[CH:14]=1)[O:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCP(=O)(OCCC)Oc1cccc(CCCC=O)c1
Reactant: Cc1ccc(C(=S)NN)cc1
Solvent: ClCCl
Solvent: CO
Product: CCCCCCP(=O)(OCCC)Oc1cccc(CCCC=NNC(=S)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of O-propyl O-[3-(3-formylpropyl)phenyl] hexylphosphonate (0.02 mole) in methanol (50 ml) and 4-methylthiobenzoylhydrazine (0.02 mole) are charged into a glass reaction vessel and the mixture is stirred at room temperature for a period of about 12 hours. After this time the reaction mixture is stripped of methanol under vacuum and the residue is dissolved in methylene chloride (100 ml) and the resulting solution is washed with water (75 ml), with aqueous sodium hydroxide (75 ml; 0.1 N) and again with water (75 ml). The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product O-propyl O-{3-[4(4-methylthiobenzoylhydrazono)butyl]phenyl} hexylphosphonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[O:23][CH3:24].C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[F:44][C:45]1[CH:50]=[CH:49][C:48]([CH:51]([NH2:53])[CH3:52])=[CH:47][CH:46]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:53][CH:51]([C:48]2[CH:49]=[CH:50][C:45]([F:44])=[CH:46][CH:47]=2)[CH3:52])=[O:42])=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3OC)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(N)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4ccc(F)cc4)cc3OC)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methoxyaniline (82 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, is a solution of 1-(4-fluorophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (60 mg, yield 49%).
Reaction SMILES: [C:1](=[S:3])=[S:2].C(N(CC)CC)C.[O:11]1[CH2:15][CH2:14][NH:13][C:12]21[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2.C([O-])(=O)C.[Zn+2:25].C([O-])(=O)C>CS(C)=O.C(O)(C)C>[O:11]1[CH2:15][CH2:14][NH:13][C:12]21[CH2:20][CH2:19][CH2:18][CH:17]([C:1]([S-:3])=[S:2])[CH2:16]2.[O:11]1[CH2:15][CH2:14][NH:13][C:12]21[CH2:20][CH2:19][CH2:18][CH:17]([C:1]([S-:3])=[S:2])[CH2:16]2.[Zn+2:25]
Reactant: C1CCC2(CC1)NCCO2
Reactant: S=C=S
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CC(C)O
Product: S=C([S-])C1CCCC2(C1)NCCO2
Reaction time: 8 h

Procedure:
Thirty-eight grams (0.50 mole) of carbon disulfide was added with stirring at 10° - 20° C to a mixture of 500 g. isopropanol and 50.5 g. (0.50 mole) triethylamine. To this solution was added 70.5 g. (0.50 mole) of spiro(cyclohexane-1,2'-oxazolidine) [preparation described by A. Cope and E. Hancock, J. Am. Chem. Soc. 64, 1503 (1942)] followed by 46.0 g. (0.25 mole) of anhydrous zinc acetate. The reaction mixture was stirred 4 hours at room temperature. After overnight standing, the precipitate was filtered to give 97.4 g. of the desired carbodithioate melting at 198° - 200° C (decomp.). A sample, dissolved in hot dimethylsulfoxide and precipitated by addition of methanol, melted at 212° - 213° C and had the following analysis: Found: C, 42.80; H, 5.41; N, 5.75; Zn, 12.90%. Calcd for C18H28N2O2S4Zn. C, 43.43; H, 5.63; N, 5.63; Zn, 13.15%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:24])[C:5]([C:7]1([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]=[C:8]1[O:17][CH3:18])=[O:6].C[O:26][C:27]1[C@](C(N2CCC[C@@H]2CO)=O)(CCC(C)C)C2C(C[CH:36]=1)=CC=CC=2>>[C:27]([O:1][CH2:2][CH2:3][N:4]([C:5]([C:7]1([CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]=[C:8]1[O:17][CH3:18])=[O:6])[CH3:24])(=[O:26])[CH3:36]
Reactant: COC1=CCc2ccccc2[C@]1(CCC(C)C)C(=O)N1CCC[C@@H]1CO
Reactant: COC1=CCc2ccccc2C1(CCC(C)C)C(=O)N(C)CCO
Product: COC1=CCc2ccccc2C1(CCC(C)C)C(=O)N(C)CCOC(C)=O

Procedure:
The title compound was prepared using the procedure described for Example 171C, substituting the product from Example 176B for the product from Example 171B. The title compound was purified by column chromatography on silica gel using a solvent gradient of 35-65% ethyl acetate in hexane, and was obtained as a colorless solid.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:11](=[O:23])[N:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:3][CH:2]=1.C1C(=O)N([Br:32])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>>[Br:32][C:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:11](=[O:23])[N:12]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=[CH:14][CH:15]=2)=[O:9])=[C:3]([CH3:2])[CH:24]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(NC(=O)c2cccn(-c3ccc(F)cc3)c2=O)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)ccc1NC(=O)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 80 °C

Procedure:
The mixture of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid p-tolylamide (183 mg, 0.482 mmol), NBS (108 mg, 0.603 mmol) and 2,2′-Azo-bis-isobutyronitrile (8.08 mg, 0.0482 mmol) in carbon tetrachloride (5 ml, 50 mmol) was heated at 80° C. under an atmosphere of nitrogen for 24 h. After that time, the mixture was filtered to give the title compound as a beige solid that was used for further reaction without purification. MS (ES+): m/z 400.92/402.96 [MH+]. HPLC: tR=3.66 min (polar—5 min, ZQ3).
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[NH:6][C:7]([C@@H:9]([NH:14][C:15](=[O:39])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[CH2:29][NH:30]C(OC(C)(C)C)=O)=[O:23])=[C:18]([Cl:38])[CH:17]=3)[CH2:10][CH2:11][S:12][CH3:13])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[NH:6][C:7]([C@@H:9]([NH:14][C:15](=[O:39])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[CH2:29][NH2:30])=[O:23])=[C:18]([Cl:38])[CH:17]=3)[CH2:10][CH2:11][S:12][CH3:13])=[N:8][C:4]=2[CH:3]=1
Reactant: CSCC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CSCC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 81 %

Procedure:
Prepared analogously to Example 17 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfanylpropyl]-3-chloro-4-[(2S)-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]benzamide and trifluoroacetic acid. Yield: 81%; Rf value: 0.18 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C24H27Cl2N5O2S (520.48); mass spectrum: (M+H)-=520/522/524 (chlorine isotope).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].[CH2:6](I)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C1CCN2C(=NCCC2)CC1>CC#N>[OH:3][CH2:2][C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:4]
Reactant: O=C(O)CO
Reactant: CCCCCCI
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCCCOC(=O)CO
Yield: 73.7 %

Procedure:
To 215 mg (2.82 mmol) glycolic acid in 12.8 ml CH3CN was added 719 mg (3.39 mmol) 1-hexyl iodide and 429 mg (2.82 mmol) DBU. After stirring over night and reflux for 4 h, the solvent was evaporated, ethylacetat and 1 M KHSO4 was added and the phases were separated. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give 333 mg (74%) of the product.
Reaction SMILES: C[Mg]Br.[C:4]([NH:7][C:8]1[CH:13]=[C:12]([C:14]2[O:15][C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[C:17]([C:19](N(OC)C)=[O:20])[N:18]=2)[C:11]([CH3:32])=[CH:10][N:9]=1)(=[O:6])[CH3:5].Cl.[C:34]([O-])(O)=O.[Na+]>>[C:19]([C:17]1[N:18]=[C:14]([C:12]2[C:11]([CH3:32])=[CH:10][N:9]=[C:8]([NH:7][C:4](=[O:6])[CH3:5])[CH:13]=2)[O:15][C:16]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])(=[O:20])[CH3:34]
Reactant: CON(C)C(=O)c1nc(-c2cc(NC(C)=O)ncc2C)oc1-c1ccccc1Cl
Reactant: O=C([O-])O
Agent: C[Mg]Br
Agent: Cl
Agent: [Na+]
Product: CC(=O)Nc1cc(-c2nc(C(C)=O)c(-c3ccccc3Cl)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
Methylmagnesium bromide (3.0 M in diethyl ether, 0.18 mL, 0.53 mmol) was added to 2-(2-acetamido-5-methylpyridin-4-yl)-5-(2-chlorophenyl)-N-methoxy-N-methyl-1,3-oxazole-4-carboxamide (0.19 g. 0.45 mmol) in THY (1 mL) under an atmosphere of argon at 0° C. The reaction mixture was allowed to warm to rt and stir overnight and then additional methylmagnesium bromide (3.0 M in diethyl ether, 0.30 mL, 0.90 mmol) was added. The reaction mixture was then allowed to stir for 24 hr. Aqueous HCl was added and then the mixture was basified with NaHCO3 and washed with EtOAc. The organic solutions were combined, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-{4-[4-acetyl-5-(2-chlorophenyl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (0.12 g, 54%). LCMS (FA): m/z=370.0 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O>[N+:15]([C:12]1[CH:13]=[CH:14][C:6]2[N:5]([CH2:4][CH2:3][CH2:2][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:10][CH2:9][S:8][C:7]=2[CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc2c(c1)SCCN2CCCCl
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)SCCN2CCCN1CCCC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 93.6 %

Procedure:
A solution of 4-(3-chloropropyl)-7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (0.54 g, 1.980 mmol) in dry acetonitrile (20 mL) was treated with pyrrolidine (1.637 mL, 19.80 mmol), potassium carbonate (2.74 g, 19.80 mmol), and potassium iodide (0.657 g, 3.96 mmol) at room temperature. The resulting mixture was stirred at 60° C. overnight (18 hours). The reaction was brought to room temperature and diluted with water (50 mL), and the product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layers were washed with brine (20 mL) and then dried (Na2SO4). The solvent was evaporated, and the crude material was purified by flash column chromatography (5:95 (2 M NH3 in MeOH):CH2Cl2) to obtain the title product (0.57 g, 94%) as a syrup. 1H NMR (DMSO-d6) δ 7.84-7.80 (m, 2H), 6.87 (d, 1H, J=9.6 Hz), 3.79-3.75 (m, 2H), 3.49 (t, 2H, J=6.9 Hz), 3.08-3.05 (m, 2H), 2.44-2.40 (m, 6H), 1.76-1.69 (m, 6H); ESI-MS (m/z, %): 308 (MH+, 100).
Reaction SMILES: [ClH:1].Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][CH:59]([OH:62])[CH2:58][CH2:57]2)CC1>>[ClH:1].[ClH:1].[OH:62][CH:59]1[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:57][CH2:58]1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (106, see example 55) and amine 21 analogously to the method described in example 1.
Reaction SMILES: [CH2:1]([C@H:3]1[C:7](=[O:8])[O:6][C:5](=[O:9])[NH:4]1)[CH3:2].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].CN1CCOCC1.C(OCC)(=O)C.Cl>O1CCCC1>[CH2:1]([C@H:3]1[C:7](=[O:8])[O:6][C:5](=[O:9])[N:4]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH3:2]
Reactant: CC[C@@H]1NC(=O)OC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC[C@H]1C(=O)OC(=O)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
A solution of (4S)-4-ethyl-1,3-oxazolidine-2,5-dione (69.57 g) and benzyl chloroformate (101.1 g) in tetrahydrofuran (800 mL) was cooled to 0° C., N-methylmorpholine (81.74 g) was added dropwise, and the mixture was stirred at 0° C. for 2 hr. A 4 mol/L hydrogen chloride-ethyl acetate solution (86.9 mL) was added dropwise at 0° C. to the reaction mixture, and the precipitated morpholine hydrochloride was filtered off with celite. The filtrate was concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield: 91.58 g, 52%).