Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C(Cl)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]=[C:23]=[S:24])=[O:21])=[CH:16][CH:15]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[C:42]([CH3:47])[C:41]=1[CH3:48].C1(C)C=CC=CC=1>C(O)C>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:22]=[C:23]=[S:24])=[O:21])=[CH:18][CH:19]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:23]([NH:22][C:20](=[O:21])[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[S:24])=[C:42]([CH3:47])[C:41]=1[CH3:48]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: COc1ccc(C(=O)Cl)cc1
Agent: COc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C)c2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
4-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-Methoxy-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (55 mg, yield 69%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])[O:5][N:4]=1)[CH3:2].[ClH:39]>C(Cl)Cl.O1CCOCC1>[ClH:39].[CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
A solution of tert-butyl 4-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (12.46 g; compound B7) in DCM (100 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (15 ml, 4.0 M) according to the procedure described in example B28 to afford the title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)#[N:2].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:4]1[C:3]([C:1]#[N:2])=[CH:8][N:7]=[C:6]([S:9][CH3:10])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc(C#N)c(=O)[nH]1
Product: CSc1ncc(C#N)c(Cl)n1
Yield: 40 %

Procedure:
Phosphorus oxychloride (150 mL) was added to 5-cyano-3,4-dihydro-2-methylthiopyrimidin-4-one (30.0 g, 0.159 mmol) obtained in Step 1, and the mixture was heated under reflux for 7 hours. The reaction mixture was left to stand to cool, and then phosphorus oxychloride was evaporated under reduced pressure. The residue was poured into ice water (about 1,000 mL), and the precipitated light yellow solid was collected by filtration and washed with water. The resulting solid was dried under reduced pressure to give 4-chloro-5-cyano-2-methylthiopyrimidine (11.9 g, yield 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](Cl)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:14]([NH2:16])=[O:15].CS(C)=O.[Cl:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:32][CH:33]1[CH2:35][CH2:34]1)=[O:31].CC(C)([O-])C.[K+]>O.O.CC(C)=O>[Cl:21][C:22]1[CH:27]=[C:26]([CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:32][CH:33]1[CH2:34][CH2:35]1)=[O:31])[O:28][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([C:14]([NH2:16])=[O:15])[CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: COc1cc2nccc(Cl)c2cc1C(N)=O
Reactant: O=C(Nc1ccc(O)cc1Cl)NC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(N)=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
In a reaction vessel were placed 7-methoxy-4-chloro-quinoline-6-carboxamide (5.00 kg, 21.13 mol), dimethylsulfoxide (55.05 kg), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (5.75 kg, 25.35 mol) and potassium t-butoxide (2.85 kg, 25.35 mol) in that order, under a nitrogen atmosphere. After stirring at 20° C. for 30 minutes, the temperature was raised to 65° C. over a period of 2.5 hours. After stirring at the same temperature for 19 hours, 33% (v/v) acetone water (5.0 L) and water (10.0 L) were added dropwise over a period of 3.5 hours. Upon completion of the dropwise addition, the mixture was stirred at 60° C. for 2 hours, and 33% (v/v) acetone water (20.0 L) and water (40.0 L) were added dropwise at 55° C. or higher over a period of 1 hour. After then stirring at 40° C. for 16 hours, the precipitated crystals were collected by filtration using a nitrogen pressure filter, and the crystals were washed with 33% (v/v) acetone water (33.3 L), water (66.7 L) and acetone (50.0 L) in that order. The obtained crystals were dried at 60° C. for 22 hours using a conical vacuum drier to give 7.78 kg of the title compound (96.3% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:13])=[O:12])=[C:7](I)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=NO)C1C(=CC=CC=1)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.[Cu-]=O.C(#N)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:13])=[O:12])=[C:7]([O:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1I
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1Oc1ccccc1
Temperature: 85 °C
Yield: 41.4 %

Procedure:
A mixture of 102 (800 mg; 1.66 mmol), phenol (103 mg; 1.09 mmol), salicylaldoxime (45.5 mg; 0.33 mmol), copper(I) oxide (11.8 mg; 0.083 mmol), cesium carbonate (811.3 mg; 2.49 mmol), powdered molecular sieves (300 mg; 3A°) and anhydrous acetonitrile (15 mL) was heated at 85° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and then was diluted with ethyl acetate (20 mL), filtered through a pad of celite and concentrated under reduced pressure. The resulting green residue was purified by automated silica gel chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 15% v/v over 600 mL gradient elution) to yield the title compound as a white solid (201 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:16][C:17]3[CH:36]=[CH:35][C:20]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[CH:25][CH:24]=4)=[CH:19][CH:18]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.O1CCCC1.[OH-].[Na+].C(OCC)(=O)C>[C:1]1([C:7]2[N:8]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:21][O:22][C:23]4[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:28]=4)=[CH:35][CH:36]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(Cn3c(-c4ccccc4)cc4ccccc43)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(OCc2ccc(Cn3c(-c4ccccc4)cc4ccccc43)cc2)cc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
Methyl 3-[4-({4-[(2-phenyl-1H-indol-1-yl)methyl]benzyl}oxy)phenyl]propanoate (0.17 g, 0.36 mmol) was dissolved in a mixed solution of methanol (4 mL) and tetrahydrofuran (8 mL), and 1 N aqueous sodium hydroxide solution (0.71 mL) was added with stirring at room temperature. The mixture was stirred at the same temperature for 2 hr. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the mixture washed successively with 5% aqueous potassium hydrogensulfate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane/ethyl acetate=4/1 to give the title compound (0.15 g, yield 88%) as colorless crystals. MS (APCI−): 460 (M−H), 1H NMR (CDCl3) δ: 2.63 (2H, t, J=7.8 Hz), 2.89 (2H, t, J=7.8 Hz), 4.97 (2H, s), 5.36 (2H, s), 6.65 (1H, s), 6.87 (2H, d, J=8.7 Hz), 7.03 (2H, d, J=8.1 Hz), 7.07-7.19 (5H, m), 7.28-7.47 (7H, m), 7.67 (1H, m).
Reaction SMILES: [C:1]([Cl:5])(Cl)(Cl)Cl.ClCl.[C:8]([S:11][C:12]([S:34][C:35](=[O:37])[CH3:36])=[C:13]([N:27]1C(SC)[CH2:29][C:28]1=[O:33])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([S:11][C:12]([S:34][C:35](=[O:37])[CH3:36])=[C:13]([N:27]1[CH:1]([Cl:5])[CH2:29][C:28]1=[O:33])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])(=[O:10])[CH3:9]
Reactant: CSC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=C(SC(C)=O)SC(C)=O
Reactant: ClC(Cl)(Cl)Cl
Agent: ClCl
Solvent: ClCCl
Product: CC(=O)SC(SC(C)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl

Procedure:
Following the procedure of Example 1(b), a carbon tetrachloride solution containing an equimolar amount of chlorine was added to a solution of p-nitrobenzyl 2-[bis(acetylthio)methylidene]-2-(4-methylthio-2-azetidinon-1-yl)acetate (144 mg, 0.306 mmole) in methylene chloride (2 ml) to give p-nitrobenzyl 2-[bis(acetylthio)methylidene]-2-(4chloro-2-azetidinon-1-yl)acetate. This crude 4-chloroazetidinone derivative was dissolved in methylene chloride (3 ml) and triethylamine (43 μl), and then 135 μl of a 30% methanol solution of methylamine were added thereto, after which the mixture was stirred for 15 minutes. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent:ethyl acetate) to afford 60 mg of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3=[CH:17][C:18]4[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]=4[CH:24]=[C:15]3[N:14]([CH3:29])[C:13]3[CH:30]=[CH:31][C:32]([B:34]4[O:38]C(C)(C)C(C)(C)[O:35]4)=[CH:33][C:12]=3[N:11]=2)=[CH:6][CH:5]=1.C1(B(O)O)C=CC=CC=1.Cl>>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:16]3=[CH:17][C:18]4[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:25])([CH3:26])[C:23]=4[CH:24]=[C:15]3[N:14]([CH3:29])[C:13]3[CH:30]=[CH:31][C:32]([B:34]([OH:35])[OH:38])=[CH:33][C:12]=3[N:11]=2)=[CH:8][CH:9]=1)=[O:43]
Reactant: COC(=O)c1ccc(C2=Nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3N(C)c3cc4c(cc32)C(C)(C)CCC4(C)C)cc1
Agent: Cl
Agent: OB(O)c1ccccc1
Product: COC(=O)c1ccc(C2=Nc3cc(B(O)O)ccc3N(C)c3cc4c(cc32)C(C)(C)CCC4(C)C)cc1
Reaction time: 5 h

Procedure:
A solution of 4-[5,7,7,10,10-pentamethyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-7,8,9,10-tetrahydro-5H-5,13diazabenzo[4,5]cyclohepta[1,2-b]naphthalen-12-yl]benzoic acid methyl ester (17) (R5=CH3, Z=H, 0.89 mmol) and phenyl boronic acid (1.8 mmol) in THF(=tetrahydrofuran)/MeOH (4:3, 14 mL) is treated with 2 N HCl (14 mL). After stirring for 5 h, the mixture is extracted with EtOAc. The extract is washed with brine, dried over MgSO4 and evaporated in vacuo. The resulting residue is purified by flash column chromatography (SiO2; hexane: EtOAc 4:1 to 1:1) to give 12-(4-methoxycarbonylphenyl)-5,7,7,10,10-pentamethyl-7,8,9,10-tetrahydro-5H-5,13-diazabenzo[4,5]cyclohepta[1,2-b]naphthalene-2-boronic acid (18) (R4=CH3, Z=H) contaminated with phenyl boronic acid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>O.C(Cl)Cl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:25]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:26]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1C(F)(F)F)C1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59 %

Procedure:
A solution of 2-trifluoromethylaniline (3 mL), triethylamine (3.5 mL) and CH2Cl2 (30 mL) was stirred at room temperature under N2 and added dropwise with cyclohexanecarbonyl chloride (3.34 mL). After 2.5 h stirring at room temperature, the mixture was poured into H2O and alkalinized with 1 N NaOH. The organic phase was dried on anhydrous Na2SO4 and the crude was crystallized from EtOH to give 3.82 g (59%) of the title compound. M. p. 153-154° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N+:11]([O-])(O)=O>C(O)(=O)C.C(O)C.[Pd]>[NH2:11][C:7]1[C:8]([OH:10])=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1ccc(O)cc1F
Reactant: O=[N+]([O-])O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: N#Cc1cc(N)c(O)cc1F

Procedure:
This was prepared by from 2-fluoro-4-hydroxy-benzonitrile by nitration (concentrated nitric acid in acetic acid at 40° C.) followed by hydrogenation in ethanol over 10% palladium/carbon.
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][C:3]1[C:4]([NH2:5])=[CH:6][CH:7]=[CH:8][C:2]=1[C:15]1[CH:16]=[CH:17][C:12]([C:11]([F:22])([F:21])[F:10])=[CH:13][CH:14]=1
Reactant: Cc1c(N)cccc1Br
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(N)cccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 79 %

Procedure:
To a solution of 3-bromo-2-methylaniline (1.19 g, 6.4 mmol) in DME (30 mL) and water (15 mL) was added para-trifluoromethylphenyl boronic acid (1.82 g, 9.6 mmol) and sodium carbonate (1.76 g, 16.6 mmol). The apparatus was flushed with nitrogen prior to the addition of tetrakis (triphenylphosphine) palladium (0) (0.22 g, 0.19 mmol). The resultant mixture was heated to reflux and stirred under nitrogen for 17 h, then allowed to cool to room temperature and the solvents removed in vacuo. The residue was partitioned between EtOAc (2×60 mL) and water (60 mL). The organic solution was dried (MgSO4) and the solvent was removed in vacuo. Purification by Biotage™ chromatography (90 g Silica column) eluted with 1:4 EtOAc:cyclohexane afforded the title compound as a cream coloured solid (1.27 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:20])=[C:4]([CH2:8][N:9]([CH2:17][CH2:18]O)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[C:3]2[O:20][CH2:18][CH2:17][N:9]([C:10]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:16])[CH2:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1cccc(Br)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A mixture of 1,1-dimethylethyl [(3-bromo-2-hydroxyphenyl)methyl](2-hydroxyethyl)carbamate (Preparation 100) (2.35 g, 6.79 mmol) and triphenylphosphine (1.96 g, 7.47 mmol) in tetrahydrofuran (40 ml) under nitrogen was cooled to 0° C. Diisopropyl azodicarboxylate (DIAD) (1.47 ml, 7.47 mmol) was added dropwise and the resulting mixture stirred for 1 h then concentrated in vacuo. The solvent was removed and the material washed twice with brine, dried (magnesium sulphate) then concentrated in vacuo. Purification of the residue by flash chromatography on silica gel, eluting with 5-25% ethyl acetate in cyclohexane gave the title compound (1.35 g). MS (ES) C14H1879BrNO2 requires 327 found 228 [M+H—COOC(CH3)3]+.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1.Cl[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Cl>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2([C:15]#[N:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:11]=[CH:12][CH:13]=1
Reactant: N#CCc1cccc(Cl)c1
Reactant: ClCCOCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(Cl)c2)CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 156.3 %

Procedure:
Potassium tert-butoxide (8.90 g, 79.3 mmol, 2.20 eq) was added to a stirred solution of 2-(3-chlorophenyl)acetonitrile (4.26 mL, 36.1 mmol) in DMF (50 mL) at 0° C. under a nitrogen atmosphere. The mixture was stirred for 10 minutes at 0° C. before 1-chloro-2-(2-chloroethoxy)ethane (4.65 mL, 39.7 mmol) was added dropwise via syringe. The reaction mixture was allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was then cooled to 0° C. and quenched with 10% HCl. The aqueous mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo to give the product as an orange oil (12.51 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]#[N:11])=[N:6][CH:7]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]#[N:11])=[N:6][C:7]=1[Br:19]
Reactant: N#CCCc1cnc(N)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: N#CCCc1cnc(N)c(Br)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(5-aminopyrazin-2-yl)propanenitrile (45 mg, 0.304 mmol) in DCM (1519 μL) was added NBS (48.7 mg, 0.273 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min. After quenched with NaHCO3, the reaction mixture was extracted with EtOAc 3 times. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate. Filtered and concentrated in vacuo. The crude product was used in next step reaction without purification. LCMS (m/z): 227/229.1 (MH+), 0.45 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:16][C:17]([F:41])([F:40])[CH2:18][NH:19][C:20]([C:22]1([CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21]>>[F:16][C:17]([F:40])([F:41])[CH2:18][NH:19][C:20]([C:22]1([CH2:35][CH2:36][CH2:37][CH2:38][N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(4-nitro-phenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:22])[S:12][C:13]=2[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:5][CH:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28]([NH:22][C:11]1[S:12][C:13]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)=[O:29]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: COc1ccc(-c2nc(N)sc2CCc2ccccc2)cc1
Product: COc1ccc(-c2nc(NC(=O)c3ccc(OC)c(OC)c3)sc2CCc2ccccc2)cc1
Yield: 76.4 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-methoxy-phenyl)-5-phenylethyl-thiazol-2-ylamine prepared in Example 57 and 3,4-dimethoxy-benzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to give a crude product, which was recrystallized with petroleum ether and ethyl acetate at a ratio of 2:1 (V:V) to obtain a product as a white solid in a yield of 76.4%, mp: 74-75 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.02 (2H, t, J=7.60 Hz, CH2), 3.19 (2H, t, J=7.60 Hz, CH2), 3.83 (3H, s, OCH3), 3.94 (3H, s, OCH3), 3.96 (3H, s, OCH3), 9.85˜7.95 (3H, m, ArH), 7.15˜7.37 (7H, m, ArH), 7.51 (2H, s, ArH), 10.48 (1H, br, CONH); EI-MS m/e (%): 474.1 (M+, 21), 383.0 (58), 165.0 (100); HREI-MS Calcd. for C27H26N2O4S: 474.1613. found: 474.1613.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([SH:30])[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[F:48][C:49]1[CH:59]=[CH:58][C:52]([O:53][CH2:54][C:55](Cl)=[O:56])=[CH:51][CH:50]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.[Ag]>[CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([S:30][C:55](=[O:56])[CH2:54][O:53][C:52]2[CH:58]=[CH:59][C:49]([F:48])=[CH:50][CH:51]=2)[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1S
Reactant: O=C(Cl)COc1ccc(F)cc1
Agent: [Ag]
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(=O)COc1ccc(F)cc1

Procedure:
1.74 g of the silver salt of 2-[(3S,4R)-3-[(1R)-1allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester are reacted in 30 ml of methylene chloride with 0.41 ml of pyridine, 20 mg of 4-dimethylaminopyridine and 0.7 g of 4-fluorophenoxyacetyl chloride. After working up analogously to Example 1, 2-[(3S,4R)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-(4-fluorophenoxyacetylthio)-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester is obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:25][CH2:26][CH:27]([NH:35][C:36]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[N+:45]([O-:47])=[O:46])=[O:37])[C:28]([O:30]C(C)(C)C)=[O:29])=[N:5][CH:6]=[N:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:16]=2)[CH2:11][CH2:10]1)[CH3:2].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].ClCCl.CO.O.C(O)(=O)C.C1(C)C=CC=CC=1>ClCCl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[CH2:1]([C:3]1[C:4]([NH:25][CH2:26][CH:27]([NH:35][C:36]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[N+:45]([O-:47])=[O:46])=[O:37])[C:28]([OH:30])=[O:29])=[N:5][CH:6]=[N:7][C:8]=1[N:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:16]=2)[CH2:13][CH2:14]1)[CH3:2]
Reactant: CCc1c(NCC(NC(=O)Nc2ccccc2[N+](=O)[O-])C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCc1c(NCC(NC(=O)Nc2ccccc2[N+](=O)[O-])C(=O)O)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1

Procedure:
30 mg (0.046 mmole) of tert-butyl 3-[5-ethyl-6-[4-(5,6,7,8-tetrahydro-(1,8)naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino]-2-[3-(2-nitrophenyl)-ureido]-propionate in 3 ml of dichloromethane with 0.5 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silica gel, eluent: CH2Cl2-MeOH—H2O—AcOH 90-10-1-1). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane then poured into diisopropyl ether. The precipitate is filtered. 35 mg of expected product is obtained in the form of a yellow solid.