Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][N:10]([CH3:19])[N:9]=2)=[CH:4][CH:3]=1.[Br:20]Br>C(O)(=O)C.CN(C=O)C>[Br:20][C:11]1[N:10]([CH3:19])[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:12]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: BrBr
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(F)cc2)n1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1Br
Temperature: 80 °C
Yield: 35 %

Procedure:
To a solution of 4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine (2.7 g, 10.67 mmol) (prepared in accordance with Example A-212) in acetic acid (30 mL) and DMF (13 mL) was added bromine (19.5 g, 122.0 mmol). The solution was heated at 80° C. overnight. TLC indicated that the reaction was complete. The mixture was quenched slowly with K2CO3 (25 g). When pH was about 5, a precipitate was formed. The precipitate was washed with water (50 mL×5) to give 4-[5-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine (1.24 g, 35%): mp 174.38° C.; Mass spectrum m/z=332, 334; 1H NMR was consistent with the proposed structure. Anal. Calc'd for C15H11N3FBr.0.2 H2O: C, 53.66; H, 3.42; N, 12.51. Found: C, 53.58; H, 3.12; N, 12.43.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4](Cl)[C:3]=1C(OCC)=O.[BrH:25]>C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([Br:25])[CH:3]=1
Reactant: CCOC(=O)c1c(Cl)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: Br
Solvent: CC(=O)O
Product: Nc1cc(Br)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A mixture of 5-amino-4-carboethoxy-3-chloro-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (3.3 g), hydrobromic acid (45%; 30 ml) and acetic acid (50 ml) was boiled under reflux for 18 h. The mixture was evaporated to low bulk and basified with sodium hydroxide solution (2 M), and the product was filtered off, dried (2.9 g) and recrystallized from a mixture of ethanol and water to give 5-amino-3-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (2.5 g), m.p. 132.5°-134° C. in the form of a colorless solid.
Reaction SMILES: [H-].[Na+].COC1C=CC(CO)=CC=1.[H][H].[C:15]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([Br:37])[C:33](Br)([F:35])[F:34])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.C(OCC)C>[C:15]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([Br:37])=[C:33]([F:35])[F:34])(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(OCCCCCCCCC(Br)C(F)(F)Br)c1ccccc1
Reactant: [H][H]
Agent: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(OCCCCCCCCC(Br)=C(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.5 %

Procedure:
Under a nitrogen atmosphere a stirred mixture of 0.09 gram (0.0036 mole) of sodium hydride in 10 ml of tetrahydrofuran was cooled in an ice bath, and 0.5 gram (0.0036 mole) of 4-methoxyphenylmethanol was added dropwise. When the evolution of hydrogen ceased, a solution of 1.5 grams (0.0033 mole) of 9,10-dibromo-10,10-difluorodecyl benzoate in 5 ml of tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 18 hours. After this time the reaction mixture was taken up in 150 ml of diethyl ether and was washed with 50 ml of water and then with 50 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure yielding 0.44 gram of 9-bromo-10,10-difluoro-9-decenyl benzoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.C([Li])CCC.[F:15][C:16]([F:24])([F:23])[C:17]([C:19]([F:22])([F:21])[F:20])=[O:18].Cl>CCCCCC.C(OCC)C>[F:15][C:16]([F:24])([F:23])[C:17]([C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1)([OH:18])[C:19]([F:22])([F:21])[F:20]
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(c1cc(Br)cc(Br)c1)(C(F)(F)F)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
Under nitrogen atmosphere, a 500 mL glass flask was charged with 30.0 g (95.0 mmol) of 1,3,5-tribromobenzene and 400 mL of diethyl ether, followed by cooling to −78° C. At −78° C., 60 mL of a 1.6M solution containing 96.0 mmol of n-butyllithium in hexane was added dropwise by spending 1 hr, followed by aging at −78° C. for 1 hr. After confirming lithiation by gas chromatography, 16.6 g (100.0 mmol) of hexafluoroacetone was bubbled at −78° C., followed by stirring for 1 hr. After stirring, the reaction liquid was added to 400 mL of 2N hydrochloric acid to separate it into an organic layer and an aqueous layer. The aqueous layer was extracted with 100 mL of isopropyl ether. The combined organic layer was dried with anhydrous magnesium sulfate, followed by concentration with an evaporator and then solid distillation, thereby obtaining 23.0 g of 1-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-3,5-dibromobenzene (yield: 60%) represented by the following formula.
Reaction SMILES: [C:1]([N:8]([CH3:12])[CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[O-].C([O-])(O)=O.[Na+]>C(O)(CC)(C)C.CCO>[C:1]([N:8]([CH3:12])[CH2:9][CH2:10][NH:11][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: [O-][n+]1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCC(C)(C)O
Product: CN(CCNc1ccccn1)C(=O)OC(C)(C)C
Reaction time: 41.5 h

Procedure:
A mixture of N-Boc-N-(methyl)ethylenediamine (Synth. Commun. 1993, 23, 2443-2449)(849.2 mg, 4.87 mmol), 2-chloropyridine N-oxide hydrochloride (970 mg, 5.84 mmol), and NaHCO3 (2.05 g, 24.4 mmol) in tert-amyl alcohol (12 mL) was heated at reflux under argon. After 41.5 h, the reaction was cooled, diluted with EtOH, filtered, and concentrated. The residue was reconcentrated from toluene and chromatographed (silica gel, 5% CH3OH/CHCl3) to give the title compound as a viscous, yellow oil which was used without further purification (863.1 mg, 66%), MS (ES) m/e 268 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[N:7]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:6](=[O:19])[C:5]2([CH3:21])[CH3:20].[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl.CO>[CH3:20][C:5]1([CH3:21])[C:4]2[C:8](=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH:3]=2)[N:7]([CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:6]1=[O:19]
Reactant: CC(C)CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])N(CCC(C)C)C(=O)C3(C)C)cc1
Yield: 27.3 %

Procedure:
N-[3,3-Dimethyl-1-(3-methyl-butyl)-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl]-4-methoxy-benzamide is prepared from A9 (419 mg) and 4-methoxy-benzoyl chloride (491 mg; 2.88 mmol) as described in Example 1a. N-[3,3-dimethyl-1-(3-methyl-butyl)-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl]-4-methoxy-benzamide (167 mg) is obtained by flash chromatography on silica gel eluting with CH2Cl2/MeOH (50:1)
Reaction SMILES: [N+:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([NH:15][NH2:16])=[O:14])[CH:11]=2)[NH:6][CH:5]=1)([O-:3])=[O:2].[CH:17]([N:20]=[C:21]=[S:22])([CH3:19])[CH3:18]>CN(C=O)C>[CH:17]([NH:20][C:21]([NH:16][NH:15][C:13]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[N+:1]([O-:3])=[O:2])=[O:14])=[S:22])([CH3:19])[CH3:18]
Reactant: CC(C)N=C=S
Reactant: NNC(=O)c1ccc2[nH]cc([N+](=O)[O-])c2c1
Solvent: CN(C)C=O
Product: CC(C)NC(=S)NNC(=O)c1ccc2[nH]cc([N+](=O)[O-])c2c1
Yield: 85.6 %

Procedure:
To a suspension of 3-nitro-1H-indole-5-carbohydrazide (1.2 g, 5.454 mmol) in DMF (5 mL) was added isopropyl isothiocyanate (661 mg, 6.545 mmol) in one lot and the reaction was heated to reflux for 4 h. The mixture was quenched with water (20 mL) to get a pale yellow precipitate. The precipitate was filtered, washed with water (2×10 mL) and dried. The crude product was treated with 20% EtOAc in petroleum ether (2×20 mL) to afford N-isopropyl-2-(3-nitro-1H-indole-5-carbonyl)hydrazinecarbothioamide (1.5 g, 88%) as pale yellow solid. MS (ESI, pos. ion) m/z: 322.1 (M+1); 1H-NMR (300 MHz, DMSO-d6): δ 12.90 (brs, 1H), 10.43 (brs, 1H), 9.19 (s, 1H), 8.75 (s, 1H), 8.71 (s, 1H), 7.87-7.93 (m, 1H), 7.76 (d, 1H, J=8.4 Hz), 7.62 (d, 1H, J=8.4 Hz), 4.40-4.53 (m, 1H), 1.11 (d, 6H, J=6.6 Hz).
Reaction SMILES: [CH2:1]([NH:7][NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:9][S:10]([C:12]1[S:16][C:15]([N:17]=[C:18]=[O:19])=[N:14][N:13]=1)=[O:11].NN>C(Cl)Cl>[CH2:1]([N:7]([C:18]([NH:17][C:15]1[S:16][C:12]([S:10]([CH3:9])=[O:11])=[N:13][N:14]=1)=[O:19])[NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CS(=O)c1nnc(N=C=O)s1
Reactant: CCCCCCNN
Agent: NN
Solvent: ClCCl
Product: CCCCCCN(N)C(=O)Nc1nnc(S(C)=O)s1
Temperature: 25 °C

Procedure:
A solution of n-hexylhydrazine (0.3 mole) in methylene chloride (150 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 5-Methylsulfinyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.1 mole) is then added, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of solvent and excess hydrazine to yield the desired product 2-n-hexyl-4-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)semicarbazide as the residue.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:36]1([CH2:42]/[CH:43]=[CH:44]/B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH:44]=[CH:43][CH2:42][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Reactant: OB(O)/C=C/Cc1ccccc1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(C=CCc4ccccc4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using trans-3-phenyl-1-propen-1-ylboronic acid (49 mg, 0.3 mmol) to give 5-(3-{4-(2,4-dichloro-phenyl)-2-[4-(3-phenyl-propenyl)-benzyl]-imidazol-1-yl}-phenyl)-1, 2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [Li][CH2:2]CCC.[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1.CN(CCN(C)C)C.CI>C1COCC1>[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]([CH3:2])[C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: [Li]CCCC
Agent: CN(C)CCN(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CC1C(=O)Nc2cc(Cl)ccc21
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
BuLi (2.2 M in cyclohexane, 22 mL, 48 mmol) was added dropwise at −78° C. to a solution of 6-chloro-1,3-dihydro-indol-2-one (4 g, 24 mmol) and TMEDA (11.2 mL, 79 mmol) in THF (100 mL) under N2. The solution was stirred for 30 minutes at the same temperature and then MeI (2.2 mL, 36 mmol) was added. The reaction mixture was warmed to −20° C. and stirred at this temperature for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. Chromatography gave the title compound (2.7 g) as a pale pink solid. MS: [M+H]+=182.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]([C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])[CH3:2].[CH3:16][N:17]([CH3:20])[CH:18]=O>OC1CCOC1>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:6]([C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])=[CH:16][N:17]([CH3:20])[CH3:18])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1ncccc1F
Reactant: CN(C)C=O
Agent: OC1CCOC1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ncccc1F
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 3-(3-fluoro-pyridin-2-yl)-3-oxo-propionic acid ethyl ester (3) (15 mg, 0.07 mmol) in 3-hydroxytetrahydrofuran (2 mL) was added slowly dimethylformamide diethylacetale (0.085 mL, 0.5 mmol) at room temperature. The mixture was stirred at 50° C. for 6 h. After completion of the reaction, solvent was evaporated under vacuum to get the crude 3-dimethylamino-2-(3-fluoro-pyridine-2-carbonyl)-acrylic acid ethyl ester (4) (18 mg, crude) as a brown sticky liquid LC-MS: 267.4 (M+H). The crude compound was used in the next step without purification.
Reaction SMILES: C[O-].[Na+].[CH2:4]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[O:16])[CH:5]=[CH2:6].[CH3:17]N(C)C=O.CI>C(OCC)C>[CH3:17][CH:10]1[CH2:9][C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH2:4][CH:5]=[CH2:6])[C:11]1=[O:16]
Reactant: C=CCc1cccc2c1CCC2=O
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Product: C=CCc1cccc2c1CC(C)C2=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.88 g of sodium methylate in 15 ml of ethyl ether is cooled to 0° C., a solution composed of 2.8 ml of ethyl formiate and 3 g of 4-(2-propenyl)-indanone in 6 ml of ether is introduced over 15 minutes, 5 ml of ether is added, with agitation for 15 minutes, and the suspension is allowed to rise to 20° C. 70 ml of dimethylformamide is added, with agitation for 2 hours, 2.15 ml of methyl iodide and 2 ml of ether are introduced, followed by agitation for 2 hours. The resulting mixture is then poured over 100 ml of ice water and extracted with ethyl ether, the extracts are dried and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica, eluting with a hexane-ethyl acetate mixture (95-5) and 1.62 g of expected product is obtained.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[C:14]([OH:25])[CH:13]=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]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>O1CCCCC1.C1C=CC=CC=1>[CH:1]1([NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[C:17]([C:18]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:16][CH:15]=[C:14]([O:25][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:13]=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCN1CCOCC1
Reactant: O=C(NC1CCCCC1)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOCC1
Product: O=C(NC1CCCCC1)C1=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
6-Hydroxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid cyclohexylamide (141 mg, 0.41 mmol) obtained in Step 3 was dissolved in tetrahydropyran/benzene (3 mL/2 mL), and 4-(2-hydroxyethyl)morpholine (99 μl, 0.82 mmol) and triphenylphosphine (215 mg, 0.82 mmol) were added thereto. Then, diisopropyl azodicarboxilate (149 μl, 0.82 mmol) was added slowly thereto at 0° C., and stirred for 2 hrs at RT. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 165 mg of the titled compound (yield: 88.3%).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C@@H:9]([CH:16]([CH3:18])[CH3:17])[N:10]=[C:11]([O:14][CH3:15])[CH2:12][N:13]=1.Cl[CH2:20][C:21]1[C:22]([CH3:27])=[N:23][O:24][C:25]=1[CH3:26]>CCCCCC.C1COCC1>[CH3:6][O:7][C:8]1[C@@H:9]([CH:16]([CH3:18])[CH3:17])[N:10]=[C:11]([O:14][CH3:15])[C@H:12]([CH2:20][C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])[N:13]=1
Reactant: Cc1noc(C)c1CCl
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1c(C)noc1C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 1.55M solution of butyllithium (10 ml, 15.5 mmol) in hexane was added by syringe to a stirred solution of (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (2.85 g, 15.5 mmol) in THF (50 ml) at -78° C. and the solution stirred for 1 hour at -78° C. A solution of 4- chloromethyl-3,5-dimethylisoxazole (2.34 g, 16 mmol) in THF (10 ml) was added gradually and the stirring continued overnight. The solvent was removed under reduced pressure, the residue dissolved in ethyl acetate (50 ml) and extracted with phosphate buffer (pH 7). The water phase was extracted twice with ethyl acetate (2×20 ml). The organic layer was dried (MgSO4), solvent evaporated under reduced pressure and the residue purified by flash chromatography (diethyl ether/hexane 4/1, silica gel).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](=[NH:30])OCC>C(O)C>[ClH:17].[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:26](=[NH:30])[CH2:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH3:18])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=N)Cc1ccccc1C
Reactant: Nc1ncccc1OCc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1CC(=N)Nc1ncccc1OCc1ccc(F)cc1
Yield: 15.5 %

Procedure:
A mixture of 2-amino-3-(4-fluorobenzyloxy)pyridine (4.36 g, 20 mmol) and ethyl 2methylphenylacetimidate hydrochloride (4.69 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil, which was purified by flash chromatography (chloroform/methanol) to obtain the product (1.2 g), m.p. 199°-200° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[CH:6]=[CH:5]2.[C:13]([Cu])#[N:14].CN(C=O)C>C(Cl)Cl>[Cl:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:13]#[N:14])[CH:3]=2)[N:8]=1
Reactant: N#C[Cu]
Reactant: Clc1ccc2cc(Br)ccc2n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(Cl)ccc2c1
Temperature: 150 °C

Procedure:
To a flask containing a stir bar was added 6-bromo-2-chloroquinoline (0.90 g, 3.7 mmol), CuCN (0.50 g, 5.6 mmol) followed by addition of DMF (10 mL). The resulting mixture was then refluxed at 150° C. overnight. When the reaction appeared complete by LC analysis, the reaction flask was taken out of the oil bath and cooled to room temperature. To the reaction mixture was then poured DCM (20 mL) and a precipitate formed immediately, which was filtered, redissolved in DCM, absorbed onto silica gel, and purified by flash chromatography to provide the title product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([NH2:17])=[O:16].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]([N:13]1[CH2:20][CH2:19][CH2:18][CH:14]1[C:15](=[O:16])[NH2:17])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCCC1C(N)=O
Temperature: 25 °C
Yield: 96 %

Procedure:
N-tert-butyloxycarbonyl glycine 1a (5 g, 28.56 mmol) and L-prolinamide (3.25 g, 28.50 mmol) were dissolved in 75 mL of N,N-dimethylformamide, the resulting solution was cooled down to 0° C. (centigrade), and 1-hydroxybenzotriazole (11.8 g, 87.3 mmol), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide (11.3 g, 59 mmol) and triethylamine (12.1 mL, 87.3 mmol) were then added with stirring. Upon completion of the addition, the reaction mixture was allowed to increase to room temperature, and stirred overnight. After thin lay chromatography showed the starting material disappeared, N,N-dimethylformamide was evaporated below 50° C., and the reaction solution was extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by recrystallization with ethyl acetate to obtain the title compound [2-(2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1b (7.42 g, yield 95.8%) as a white powder.
Reaction SMILES: C(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[C:9](O)=[N:10][CH:11]=1>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:3][C:9]1[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)cnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
75 g of phosgene are introduced at a temperature of 85°-95° C. over 1 hour into a mixture of 87.5 g of 5-chloro-2-hydroxy-3-nitropyridine in 500 ml of toluene and 3 ml of N,N-dimethylformamide. The reaction mixture is kept for 2 hours under reflux at 85°-95° C. and then allowed to cool to room temperature over a period of 18 hours. The reaction mixture is washed 3 times with water and the organic phase is dried over sodium sulfate and thereafter concentrated by evaporation. The crude product, obtained in the form of a brown oil, is crystallised from 200 ml of n-hexane, giving 67.5 g of 2,5-dichloro-3-nitropyridine (70% of theory) with a melting point of 38°-39° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][OH:13])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(O)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a solution of 1-O-monobenzyl glycerol (1.58 g) in methylene chloride (20 ml), t-butyldimethylsilyl chloride (1.44 g) and then triethylamine (1.33 ml) and N,N-dimethylaminopyridine (0.04 g) were added, and the mixture was stirred overnight at room temperature. Methylene chloride (20 ml) was further added to the reaction liquid, and the mixture was washed with water (20 ml×3) and saturated ammonium chloride (20 ml×3), dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain pale yellow oil. The product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=7/1) to obtain the desired product (1.93 g) as pale yellow liquid.