Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[F:11][C:12]([F:39])([F:38])[C:13]1[CH:14]=[C:15]([NH:19][C:20]2[N:37]=[CH:36][CH:35]=[CH:34][C:21]=2[C:22](OC2C=CC([N+]([O-])=O)=CC=2)=[O:23])[CH:16]=[CH:17][CH:18]=1>C1(C)C=CC=CC=1>[C:3]([CH:5]([C:22](=[O:23])[C:21]1[C:20]([NH:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:39])([F:11])[F:38])[CH:14]=2)=[N:37][CH:36]=[CH:35][CH:34]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cccnc1Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)C(=O)c1cccnc1Nc1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a stirred mixture of NaH (524 mg, 21.8 mmol) in toluene (20 mL) was added dropwise ethyl cyanoacetate (3.7 g, 32.7 mmol, 3.5 mL). The slurry was stirred for 1 h and then 4-nitrophenyl 2-{[3-(trifluoromethyl)phenyl]amino}nicotinate (4.4 g, 10.9 mmol) was added. The reaction mixture was stirred for 1 h and then quenched with water (20 mL). CH2Cl2 (30 mL) was added and the layers were partitioned. The organic layer was washed with brine (2×) and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel flash chromatography (5:1 to 2:1 Hex:EtOAc) to afford 3 Ethyl 2-cyano-3-oxo-3-(2-{[3-(trifluoromethyl)phenyl]amino}-3-pyridinyl)propanoate. (6 g, 87%): LCMS RT: 2.83 min, MH+: 378.0.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br-].[CH2:23]([Zn+])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Cc5ccccc5)nc34)cc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
Argon was bubbled through a slurry of bis(4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine)palladium dichloride (Aldrich; 10.23 mg, 0.014 mmol), 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1, 0.043 g, 0.144 mmol), and benzylzinc bromide (0.5 M solution in THF; Aldrich; 1.155 ml, 0.578 mmol) in 1.5 mL THF for 2 min. The reaction mixture was sealed and heated to 70° C. After 1 h, the reaction was cooled to RT. The mixture was concentrated, dissolved in DMSO+1-2 drops TFA, filtered, and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 15-100% ACN/H2O with 0.1% TFA); product-containing fractions were concentrated in vacuo and the residue was treated with saturated aq. NaHCO3 and DCM. The aq. layer was extracted 3×DCM and combined organics dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(2-benzylquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.026 g, 0.074 mmol, 50.9% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 12.17 (1H, br. s), 8.35 (1H, d, J=8.6 Hz), 8.14 (1H, dd, J=7.4, 1.4 Hz), 7.76 (1H, dd, J=8.0, 1.4 Hz), 7.50-7.60 (2H, m), 7.33-7.43 (4H, m), 7.24-7.30 (1H, m), 7.11 (1H, d, J=2.3 Hz), 6.94-7.00 (1H, m), 4.45 (2H, s), 3.38-3.46 (2H, m), 2.80 (2H, t, J=6.9 Hz). m/z (ESI, +ve) 353.9 (M+H)+.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.[NH2:11][C:12]1[N:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:15]=[CH:14][C:13]=1[C:24]([O:26]C1C=CC=CN=1)=S>O1CCCC1>[NH2:11][C:12]1[N:16]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[N:15]=[CH:14][C:13]=1[C:24](=[O:26])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1
Reactant: Nc1c(C(=S)Oc2ccccn2)cnn1-c1ccc(F)cc1
Reactant: COc1cccc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into an oven dried flask containing magnesium turnings (0.408 g, 17 mmol) and tetrahydrofuran (10 ml) was added 3-bromoanisole (3.1 g, 17 mmol )and the reaction mixture was heated at reflux. After 2 h, the reaction mixture was cooled to room temperature and 5-amino-1-(4-fluorophenyl)-4-(2-pyridylthiocarboxy)pyrazole (1.5 g, 4.8 mmol) was added and the stirring was continued for 1 h. The reaction mixture was quenched with water and the product was extracted into ethyl acetate. The organic layer was washed with aqueous ammonium chloride and brine and dried over sodium sulfate. The organics were removed in vacuo and the residue was filtered and washed with hexane to give 5-amino-1-(4-fluoro-phenyl)-4-(3-methoxybenzoyl)pyrazole (1.20 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:19])[NH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O.Cl>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][N:14]1[C:15]([CH3:18])=[CH:16][CH:17]=[C:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C:13]1=[O:19])[CH3:28]
Reactant: CCOC(=O)CI
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)ccc(NC(=O)OCc2ccccc2)c1=O
Reaction time: 0.75 h
Yield: 55.5 %

Procedure:
The compound of Example 13 (1.80 g, 7.0 mmole) was added to a stirred suspension of sodium hydride (0.33 g, 8.4 mmole) in dry dimethylformamide (50 mL). After 45 minutes, ethyl iodoacetate (1.43 g, 6.7 mmole) was added, and the mixture was stirred overnight, diluted with 10% hydrochloric acid (300 mL) and extracted with ethyl acetate (3×150 mL). The organic layer was washed with brine (twice), dried and evaporated. The resulting yellow, wary solid was chromatographed, eluting with 3% ethyl acetate in dichloromethane, to give the title compound (1.28 g, 53% yield). Rf =0.52 (silica gel, 5:95 methanol:dichloromethane). Fast atom bombardment mass spectrometry confirmed the theoretical molecular weight of 344.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=1)#[CH:14].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1>[F:23][C:17]1[CH:16]=[C:15]([C:13]#[C:14][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: C#Cc1ccc(OC)c(F)c1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C#Cc1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
To the mixture of diisopropylamine (0.262 mL, 1.87 mmol) in tetrahydrofuran (5 mL) at −78° C. under nitrogen was added slowly the solution of n-butyllithium (1.17 mL, 1.87 mmol, 1.6M in hexanes). After stifling for 30 minutes, the solution of 4-ethynyl-2-fluoro-1-methoxybenzene (622) (0.180 g, 0.94 mmol) in tetrahydrofuran (1 mL) was added slowly into the reaction mixture. The mixture was allowed to reach 0° C. over 1 hour and ethyl chloroformate (0.134 mL, 1.4 mmol) was added. The resulting mixture was stirred to room temperature for 12 hours, quenched with saturated ammonium chloride and extracted with ethyl ether. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5-10% EtOAc in hexanes) to provide ethyl 3-(3-fluoro-4-methoxyphenyl)propiolate (623) (0.070 g, 6.3%) as a colorless oil.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>N1C=CC=CC=1>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:22]([NH:21][CH2:19][CH3:20])=[O:23])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCN=C=O
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Product: CCNC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 50 °C
Yield: 77.5 %

Procedure:
To a stirred solution of 1-(2-tert-butylphenyl)piperazine dihydrochloride (0.12 g, 0.41 mmol) in pyridine (4.0 mL) was added ethyl isocyanate (0.036 g, 0.51 mmol) at room temperature and the reaction mixture was heated at 50° C. for 16 h. After this time, the reaction mixture was cooled to room temperature and concentration under reduced pressure. The residue was partitioned between ethyl acetate and 0.5 N hydrochloric acid (2×10 mL), separated and the organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 1:9 to 1:1 ethyl acetate/heptanes) to provide 4-(2-tert-butylphenyl)-N-ethylpiperazine-1-carboxamide (0.092 g, 77%) as a white solid, mp 196-198° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(OCC)=O)[N:8]=[CH:9][N:4]2[CH:3]=1.O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: CCOC(=O)c1ncn2cc(Br)sc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1cn2cncc2s1
Temperature: 105 °C
Reaction time: 30 h
Yield: 68.8 %

Procedure:
Ethyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate (2.00 g, 7.3 mmol) was suspended in a mixed solvent composed of water (16 ml) and acetic acid (24 ml), concentrated sulfuric acid (7.84 g, 80.0 mmol) was added to the suspension at room temperature, and the mixture was stirred at 105° C. for about 30 hr. After the completion of the reaction, sodium carbonate (9.32 g, 88.0 mmol) was added to the reaction solution, and acetic acid was removed by distillation under the reduced pressure. Further, water (10 ml) was again added to the concentrate, and the solvent was removed by distillation under the reduced pressure. Water (10 ml) and ethyl acetate (20 ml) were added to the residue, and the mixture was adjusted to pH 7 by the addition of a 25 wt % aqueous solution of sodium hydroxide with stirring. The insolubles were removed by filtration, followed by separation. The aqueous layer was then extracted twice with ethyl acetate (20 ml, 20 ml). The organic layer was washed with 15 wt % brine (20 ml). After washing, while concentrating the organic layer, the solvent was replaced with n-hexane to crystallize 2-bromoimidazo[5,1-b]thiazole. Subsequently, the suspension was cooled to 5° C. or below and was stirred overnight. The crystals were collected by filtration, were washed with n-hexane (20 ml) and were dried under the reduced pressure to give 2-bromoimidazo[5,1-b]thiazole (1.02 g, yield 68.5%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:15]([C:16]#[N:17])=[CH:14][C:13]([C:18]([F:21])([F:20])[F:19])=[N:12][CH:11]=1.[Cl:22][S:23](O)(=[O:25])=[O:24]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([C:10]2[CH:11]=[N:12][C:13]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:15]=2[C:16]#[N:17])=[CH:4][C:5]([S:23]([Cl:22])(=[O:25])=[O:24])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1ccc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 5-(2-chloro-4-methoxy-phenyl)-2-trifluoromethylisonicotinonitrile (0.7 g, 2.24 mmol) in chloroform (6 mL), was added to ClSO3H (0.62 mL). The solution was stirred at rt for 16 hrs. The solvent was removed and MeCN (3 mL) was added, followed by addition of POCl3 (3 mL). The mixture was heated at 60° C. for 16 hrs, then concentrated. The remainder was poured into ice water with stirring. The resulting solid was filtered, dried in vacuo over 2 days to yield 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzenesulfonyl chloride (0.79 g) as a pale yellow solid. tR=2.92 min (method 1).
Reaction SMILES: [NH3:1].CO.[CH2:4]([O:11][N:12]1[C:18](=[O:19])[N:17]2[CH2:20][C@H:13]1[CH2:14][CH2:15][C@H:16]2[C:21]1[O:25][N:24]=[C:23]([C:26]([O:28]CC)=O)[N:22]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)(C)C>[CH2:4]([O:11][N:12]1[C:18](=[O:19])[N:17]2[CH2:20][C@H:13]1[CH2:14][CH2:15][C@H:16]2[C:21]1[O:25][N:24]=[C:23]([C:26]([NH2:1])=[O:28])[N:22]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Reactant: N
Solvent: CO
Solvent: CC(C)O
Product: NC(=O)c1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Temperature: 40 °C
Yield: 40 %

Procedure:
Ammonia in MeOH solution (2.3 mL, 16.11 mmol) was added to a solution of ethyl 5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazole-3-carboxylate (600 mg, 1.61 mmol) in isopropanol (8 mL) and the reaction mixture was heated at 40° C. for 1 h. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (0 to 10% MeOH/DCM) to afford 5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazole-3-carboxamide (220 mg, 40%). ESI-MS (EI+, m/z): 344.3.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[NH:8])=[CH:12][CH:11]=1
Reactant: N#Cc1ccccc1
Reactant: Nc1ccc(F)cc1
Product: N=C(Nc1ccc(F)cc1)c1ccccc1
Yield: 85.1 %

Procedure:
The title compound was prepared from benzonitrile (13.9 g, 135 mmol) and 4-fluoroaniline (15 g, 135 mmol) by following the procedure described in preparation 10 (24.6 g, yield 85.1%, purity 99.7% by HPLC). MS m/z:215.2 (M+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1>C(O)(=O)C.C1COCC1>[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH:30][C:2]3[N:3]=[C:4]([NH:18][CH3:19])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccc(Cl)cc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
2-Chloro-7-(4-chlorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (101 mg, 0.343 mmol) was added to a solution of 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (77 mg, 0.343 mmol) in acetic acid (2 mL) and THF (2 mL). The reaction mixture was heated at 80° C. overnight. Partial conversion to the desired product was observed. The reaction was further heated at 120° C. for 6 h. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, TFA salt (35.5 mg, 0.059 mmol, 17.19% yield). LC-MS (M+H)+=481.3. 1H NMR (500 MHz, CDCl3) δ ppm 11.08 (1H, s), 8.33 (1H, s), 7.48 (2H, d, J=2.1 Hz), 7.30 (2H, d, J=8.2 Hz), 7.20 (1H, d, J=1.5 Hz), 7.13 (2H, d, J=8.5 Hz), 5.83-5.93 (1H, m), 4.38-4.48 (1H, m), 3.97 (1H, s), 3.86 (3H, s), 3.22 (3H, d, J=4.9 Hz), 2.85-2.95 (1H, m), 2.77 (2H, dd, J=8.7, 5.3 Hz), 2.20-2.32 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][P:10]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])(=[O:12])[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][P:10]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])(=[O:11])[O:12][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCP(=O)(O)CNC(=O)OC(C)(C)C
Reactant: OCc1ccccc1
Product: CC(C)(C)OC(=O)NCP(=O)(CNC(=O)OC(C)(C)C)OCc1ccccc1
Yield: 55 %

Procedure:
In analogy to Example 4, the benzyl phosphinate 5 was prepared from the phosphinic acid 1 and benzyl alcohol in a yield of 55%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]=[C:27]=[S:28]>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:27](=[S:28])[NH:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[Cl:18]
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCCO
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.7 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (13.1 g, 50.6 mmol) and 2,4-dichloro-1-isothiocyanatobenzene (13.4 g, 65.8 mmol) in tetrahydrofuran (150 mL) was stirred at room temperature for 3 days. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, concentrated in vacuo, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give methyl 4-chloro-3-{[(2,4-dichlorophenyl)carbamothioyl]amino}-2-[(3-hydroxypropyl)amino]benzoate as a colorless powder (19.6 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:25][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc(C(F)(F)F)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 4-(trifluoromethyl)benzylamine in DME. ES-MS m/e (%): 360 (M+H+, 100).
Reaction SMILES: [CH:1]12[C:9](=[O:10])[NH:8][C:7](=[O:11])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[H-].[Na+].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][Br:18].O>CN(C)C=O>[Br:18][CH2:17][CH2:16][CH2:15][CH2:14][N:8]1[C:7](=[O:11])[CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]2[C:9]1=[O:10]
Reactant: BrCCCCBr
Reactant: O=C1NC(=O)C2CCCCC12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C2CCCCC2C(=O)N1CCCCBr
Reaction time: 3 h

Procedure:
To a solution of cyclohexane-1,2-dicarboximide (10 g; 65.3 mmol) in anhydrous dimethylformamide (50 ml), there was added 60% sodium hydride (2.6 g; 68.5 mmol) under nitrogen at room temperature, and the resultant mixture was stirred at the same temperature for 3 hours. Tetramethylene bromide (70.5 g; 0.327 mol) was added thereto, and the mixture was stirred for 3 hours. After completion of the reaction, the resultant mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water twice and with a saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent and excessive tetramethylene bromide were removed by evaporation to give N-(4-bromobutyl)cyclohexane-1,2-dicarboximide. IR νmaxFilm (cm-1): 1770, 1700.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[C:24]([F:31])[CH:23]=1.[CH3:32][C:33]([Si:36](Cl)([CH3:38])[CH3:37])([CH3:35])[CH3:34]>N1C=CC=CC=1>[Si:36]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[C:24]([F:31])[CH:23]=3)[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:33]([CH3:35])([CH3:34])[CH3:32])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1F
Solvent: c1ccncc1
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1F
Reaction time: 16 h
Yield: 100 %

Procedure:
(2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 4f (5.7 g, 12.5 mmol) was dissolved in 50 mL pyridine, followed by addition of TBSCl (2.26 g, 15 mmol) and 4-dimethyl-amino pyridine (305 mg, 2.5 mmol) in turn. The reaction mixture was stirred for 16 hours. Thereafter, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 200 mL ethyl acetate and washed with saturated copper sulfate solution (50 mL×3). The organic extract was combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 4g (7.14 g, colourless grease), which was used directly without purification in the next step.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(OC([N:18]1[C:23](=[O:24])[CH:22]2[CH:20]([CH:21]2[C:25]([O-:27])=[O:26])[CH:19]1[C:28]([O-:30])=[O:29])=O)(C)(C)C.O>C(Cl)Cl>[C:25]([CH:21]1[CH:22]([C:23]([N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[O:24])[CH:20]1[CH:19]([C:28]([OH:30])=[O:29])[NH2:18])([OH:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Reactant: C1COCCN1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: NC(C(=O)O)C1C(C(=O)O)C1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 112.9 %

Procedure:
To a solution of AlCl3 (73 mg, 0.54 mmol) in dry CH2Cl2 (3 mL) at 0° C., morpholine (90 μl, 1.04 mmol) in dry CH2Cl2 (3 mL) was added dropwise. The mixture was stirred at room temperature for 20 min, and then ethyl (1SR, 2SR, 5RS, 6RS) 3-tert-butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (143 mg, 0.41 mmol) in dry CH2Cl2 (1 mL) was added. After stirring at room temperature for 1 h, a mixture of ice and water was added. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate 1/1) to give 126 mg of the desired compound (70% yield).
Reaction SMILES: [CH:1]1([Li:6])[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl[P:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10].C([Li])CCC.CCCCCC>CCOCC>[CH:9]([P:8]([C:1]1([Li:6])[CH:5]=[CH:4][CH:3]=[CH:2]1)[CH:12]([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)P(Cl)C(C)C
Reactant: [Li]C1C=CC=C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li]C1(P(C(C)C)C(C)C)C=CC=C1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
50 ml of ether were placed in a round-bottomed flask containing 1.68 g (0.023 moles) of cyclopentadienyllithium. After cooling of the reaction flask to −20° C., 3.6 g (0.023 moles) of chlorodiisopropylphosphine were added dropwise. When the addition was complete, the cooling bath was heated to 0° C. and the reaction mixture was stirred for 1 h. Ether was then removed under vacuum, the product was dissolved in toluene and the solution was filtered. After the frit had been rinsed with 2×10 ml of toluene, the reaction mixture was cooled to −20° C. and 9.3 ml of a 2.5 molar solution of butyllithium in hexane (0.023 moles) were added to form an orange coloured solution. A small fraction was taken for NMR studies and, after separation of the toluene under vacuum and washing of the resulting oil with hexane, a pale yellow solid (18) was obtained. 1H NMR (400 MHz, THF): δ=5.89 (m, 2H); 5.83 (bs, 2H); 1.86 (m, 2H); 1.0-0.8 (m, 12H).