Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[C:4]=2[CH:5]=[N:6][CH:7]=1.[F:17][C:18]1[CH:27]=[C:26]2[C:21]([CH2:22][CH2:23][C:24](=[O:29])[N:25]2[CH3:28])=[CH:20][C:19]=1B1OC(C)(C)C(C)(C)O1>>[F:17][C:18]1[CH:27]=[C:26]2[C:21]([CH2:22][CH2:23][C:24](=[O:29])[N:25]2[CH3:28])=[CH:20][C:19]=1[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc21
Reactant: CCS(=O)(=O)NC1CCc2c(Br)cncc21
Product: CCS(=O)(=O)NC1CCc2c(-c3cc4c(cc3F)N(C)C(=O)CC4)cncc21
Yield: 70 %

Procedure:
In analogy to the procedure described for the preparation of intermediate A-2 [E], (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)ethanesulfonamide (intermediate A-6) was reacted with 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-9). The Suzuki coupling had to be repeated three times to give the to give the title compound as off-white solid in 70% yield. MS: 404.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][C:10](OCC)=O)[CH:3]=1.Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([NH2:25])[CH:19]=1.N>Cl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]2[N:24]=[C:10]([CH2:9][S:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=3)[NH:25][C:20]=2[CH:19]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: CCOC(=O)CSc1cc(C)ccn1
Agent: Cl
Agent: N
Product: COc1ccc2nc(CSc3cc(C)ccn3)[nH]c2c1

Procedure:
10.6 g of ethyl 2-(4-methyl-2-pyridylthio)acetate (0.05 mole) and 8.8 g of 4-methoxy-1,2-phenylenediamine hydrochloride (0.05 mole) in 400 ml of 6N hydrochloric acid are heated under reflux for 2 days. The mixture is allowed to cool and is neutralized with ammonia solution. It is extracted with ethyl acetate (3×100 ml), and the extract is dried (Na2SO4), filtered and concentrated to a volume of 75 ml. From this solution, 8.4 g (59%) of 5-methoxy-2-(4-methyl-2-pyridylthiomethyl)benzimidazole, melting point 138°-140° C., crystallize. The data for the identification of the product appear in Tables 1 and 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[N:11]1.[CH:18](Br)([CH3:20])[CH3:19].[OH-].[Na+].CN(C)C=O>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:18]([CH3:20])[CH3:19])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[N:11]1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2Cl)c(C)c1C
Reactant: CC(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2Cl)c(C)c1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
A mixture of 1-(2,4-dichloro-5-hydroxyphenyl)-3,4,5-trimethylpyrazole (27.1 g), isopropyl bromide (12.3 g), aqueous sodium hydroxide (4.2 g) and dimethylformamide (150 ml) was stirred at 70° C. for 2 hours. To the reaction mixture, after cooling, were added water and toluene, to form two layers. The toluene layer as separated was washed with water and then dried over anhydrous sodium sulfate. Removal of the toluene by distillation in vacuo gave the titled compound (27.9 g) as a pale yellow oil, which was then purified through silica gel column chromatography to afford a white crystalline solid. m.p. 56°-58° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].CCN(C(C)C)C(C)C.[Br:20][C:21]1[N:26]=[C:25]([CH:27]=O)[CH:24]=[CH:23][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1(C)C=CC=CC=1.CC(O)=O>[Br:20][C:21]1[N:26]=[C:25]([CH2:27][NH:6][CH:5]([CH:7]([CH3:9])[CH3:8])[C:4]([O:3][CH3:2])=[O:10])[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)C(NCc1cccc(Br)n1)C(C)C
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a stirred solution of L-valine methyl ester hydrochloride (0.54 g, 3.24 mmol) in dry toluene (15 mL) at 80° C. was added DIEA (2.0 mL 11 mmol) followed by (6-bromo-2-pyridyl)formaldehyde (0.50 g, 2.70 mmol). The resulting mixture was heated at 80° C. for 3 h. The reaction was brought to RT and a solution of NaBH(OAc)3 (1.4 g, 6.75 mmol) in glacial AcOH (4 mL) was added. The resulting mixture was stirred for 15 h and concentrated by rotary evaporation. The resulting yellow oil was dissolved in CH2Cl2 (100 mL), washed with a saturated solution of NaHCO3 (aq) (50 mL), brine (50 mL), dried over Na2SO4, filtered, concentrated by rotary evaporation and purified by flash chromatography (2:1 hexanes/EtOAc) to afford the title compound as a pale-yellow oil. EI-MS m/z 301 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][NH:18][O:19][CH3:20].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:13]([CH:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (4.00 g, 18.6 mmol), N,O-dimethylhydroxylamine hydrochloride (1.69 g, 17.4 mmol), and DIEA (7.5 mL, 41.8 mmol) in CH2Cl2 (80 mL) was added solid EDC.HCl (4.00 g, 20.9 mmol). The mixture was stirred at rt for 18 h and concentrated under reduced pressure. The residue was taken up in ether (175 mL), washed with 5% aq HCl (2×50 mL) and satd aq NaHCO3 (50 mL), and dried over MgSO4. Removal of the solvent left tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (3.16 g, 65%) as an oil.
Reaction SMILES: C(C=C)=O.[N+](C(C)C)([O-])=O.[CH3:11][C:12]([N+:18]([O-:20])=[O:19])([CH3:17])[CH2:13][CH2:14][CH:15]=[O:16].[Br:21]Br>C(O)(=O)C.O>[CH3:11][C:12]([N+:18]([O-:20])=[O:19])([CH3:17])[CH2:13][CH2:14][CH:15]=[O:16].[Br:21][CH:14]([CH2:13][C:12]([CH3:17])([N+:18]([O-:20])=[O:19])[CH3:11])[CH:15]=[O:16]
Reactant: BrBr
Agent: C=CC=O
Agent: CC(C)(CCC=O)[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CC(C)[N+](=O)[O-]
Solvent: O
Product: CC(C)(CC(Br)C=O)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 163.1 %

Procedure:
4-Methyl-4-nitropentanal is prepared by condensation of acrolein and 2-nitropropane according to a known procedure (Synthesis 1986, 237). To a solution of 4-methyl-4-nitropentanal (8.5 g, 58.56 mmol) in acetic acid (125 ml) is added bromine (9.12 g, 57.07 mmol) dropwise while the temperature is kept below 15° C. After stirring for 15 minutes at room temperature the reaction is poured into a mixture of water and ice (250 ml) and extracted two times with dichloromethane. The combined organic extracts are washed with water and with brine, successively, dried over magnesium sulfate, and the solvent is removed under reduced pressure to leave 10.7 g of 2-bromo-4-methyl-4-nitropentanal which is used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.B(O)(O)[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=1>>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=1)[CH3:16]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3ccc(C(=O)O)cc3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 4-carboxylphenylboronic acid in step 1.F.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]1[C:19](=[O:20])[CH2:18][NH:17][C:16](=O)[CH:15]=[C:10]12)(=[O:4])[CH2:2][CH3:3].O=P(Cl)(Cl)Cl.[CH:27]1([C:31]2[N:32]=[CH:33][NH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1.N1C=CC=CC=1>ClCCCl.C(Cl)Cl>[CH:27]1([C:31]2[N:32]=[CH:33][N:34]([C:16]3[CH:15]=[C:10]4[C:11]5[C:6]([CH2:7][CH2:8][N:9]4[C:19](=[O:20])[CH2:18][N:17]=3)=[C:5]([C:1](=[O:4])[CH2:2][CH3:3])[CH:14]=[CH:13][CH:12]=5)[CH:35]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: CCC(=O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Reactant: c1nc(C2CCC2)c[nH]1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(=O)c1cccc2c1CCN1C(=O)CN=C(n3cnc(C4CCC4)c3)C=C21
Temperature: 110 °C
Reaction time: 0.02 h
Yield: 12 %

Procedure:
Example 124. A solution of 9-propionyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (225 mg, 0.77 mmol) in DCE (20 mL) was treated with POCl3 (0.22 mL, 2.30 mmol) and the mixture was heated to 110° C. for 1 h. The mixture was then allowed to cool to RT, diluted with DCM and washed with H2O. The org. phase was then dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was taken up in DCE (20 mL) and 4-cyclobutyl-1H-imidazole (188 mg, 1.54 mmol) and pyridine (0.12 mL, 1.54 mmol) were then added. The mixture was heated to 110° C. for 1 h, and then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. layer was then dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 85:15) and SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60 A, Princeton; eluent: 7% MeOH/CO2 for 1 min, then from 7% MeOH/CO2 to 12% MeOH/CO2 in 6 min; then from 12% MeOH/CO2 to 50% MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) afforded the title compound (36 mg). UPLC-MS: MS 389.2 (M+H+); UPLC rt 0.95 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.06 (t, J=7.23 Hz, 3 H); 1.55-1.90 (m, 2 H); 1.99-2.27 (m, 4 H); 2.91-3.05 (m, 4 H); 3.36 (m, 1 H); 3.70 (t, J=6.06 Hz, 2 H); 4.22 (s, 2 H); 7.10 (s, 1 H); 7.41 (s, 1 H); 7.49 (t, J=8.02 Hz, 1 H); 7.88 (d, J=7.43 Hz, 1 H); 8.05-8.20 (m, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>ClCCl>[C:10]([Si:14]([CH3:16])([CH3:15])[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.4 %

Procedure:
3-Hydroxybenzaldehyde (5.14 g, 42.1 mmol) was added to a suspension of tert-butyl-dimethyl-silyl chloride (6.7 g, 44.4 mmol) and imidazole (3.03 g, 44.5 mmol) in dichloromethane (100 ml) under an atmosphere of nitrogen at room temperature. The reaction mixture was stirred at room temperature for 18 hours, and the mixture washed sequentially with 1 M hydrochloric acid (2-fold 50 ml) followed by a saturated aqueous solution of sodium hydrogen carbonate (50 ml). The organic phase was separated, dried over anhydrous magnesium sulphate and the solvent removed in vacuo. The residual yellow oil was passed through a plug of silica gel eluting with 1:1, by volume, dichloromethane:pentane giving 3-(tert-butyl-dimethyl-silanyloxy)-benzaldehyde (9.2 g) as a golden yellow oil.
Reaction SMILES: O[CH2:2][CH:3]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].S(Cl)([Cl:19])=O>C(Cl)Cl>[Cl:19][CH2:2][CH:3]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)C(=O)C(CO)Oc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)C(CCl)Oc1ccccc1
Yield: 77.3 %

Procedure:
1-Hydroxy-2-phenoxy-4,4-dimethyl-pentan-3-one (111.1 g, 0.5 mol) is dissolved in 500 ml of methylene chloride. Thionyl chloride (62 g, 0.52 mol) is added dropwise to the solution at room temperature. The start of the reaction can be accelerated by gentle warming. After a reaction time of two hours at room temperature, the solvent is distilled off in vacuo and the oily residue is degassed in a high vaccum to afford 93.0 g (77% of theory) of 1-chloro-4,4-dimethyl-2-phenoxy-pentan-3-one as an oil having a refractive index of nD20 = 1.5081 and a boiling point of (0.4 mm Hg)/110°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5]([NH2:8])[C:6]#[N:7])[CH3:2].N1C=CC=CC=1.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:1]([O:3][C:4](=[O:9])[CH:5]([NH:8][C:24]([O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25])[C:6]#[N:7])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C(N)C#N
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C(C#N)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 60 %

Procedure:
To a stirred mixture of 2-amino-2-cyanoacetic acid ethyl ester (19.7 g) and pyridine (12.2 g) in water (123 ml) was added portionwise benzyloxycarbonyl chloride (27.9 g) under ice cooling. The resulting mixture was stirred under ice cooling for 1 hour. Precipitated crystals were collected, washed thoroughly with water, and recrystallized from ethanol to give the title compound (24.2 g, 60.2%) as colorless crystals, mp 111°-112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[I-].[K+].[CH3:27][CH:28]=[CH:29][CH2:30][NH2:31]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:31][CH2:30][CH2:29][CH:28]=[CH2:27])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: CC=CCN
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 39, 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide, and methylallylamine in tetrahydrofuran are reacted to give 8-chloro-1-[(allylmethylamino)methyl]-6-(o-chlorophenyl)-4-H-s-triazolo [4,3-a][1,4]benzodiazepine. Preparation 41 8-Nitro-1-[(allylmethylamino)methyl]-6-(o-chlorophenyl)-4-H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:11][N:10]([CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:21]S(N=C=O)(=O)=O.CN(C)C=O>C(COC)OC.O>[Cl:21][C:9]1[N:10]([CH3:20])[CH:11]=[C:12]([S:13]([C:16]([F:17])([F:19])[F:18])(=[O:14])=[O:15])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cn1cc(-c2ccc(Cl)cc2)c(S(=O)(=O)C(F)(F)F)c1
Solvent: COCCOC
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(S(=O)(=O)C(F)(F)F)c(-c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.2 %

Procedure:
A solution of 3-(p-chlorophenyl)-1-methyl-4-[(trifluoromethyl)sulfonyl]pyrrole (0.5 g, 0.0015 mol) in dimethoxyethane is treated with chlorosulfonyl isocyanate (0.3 mL, 0.0034 mol), stirred for 24 hours at room temperature, treated with additional chlorosulfonyl isocyanate (0.6 mL, 0.0068 mol), stirred for 24 hours, treated with dimethylformamide (2 mL), stirred for one hour, diluted with water and extracted with ether. The combined organic extractes are washed with water, dried and concentrated in vacuo to obtain a semi-solid. Flash chromatography of the semi-solid using silica gel and a 1:4 ethyl acetate/hexanes solution gives the title product as a white solid (0.2 g, mp 117°-119° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].[CH3:19][Mg]Br>C1COCC1>[CH2:2]([O:3][C:4](=[O:5])[C@@H:6]([NH:7][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][C:8](=[O:11])[CH3:19])[CH3:1]
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CCC(C)=O)NC(=O)OC(C)(C)C
Temperature: -43 °C
Reaction time: 2 h
Yield: 1390.3 %

Procedure:
A solution of (S)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (20 g, 10 mmol) in dry THF (150 mL) was cooled to −50° C., and then methylmagnesium bromide (31 mL, 93.28 mmol) was added dropwise at a temperature between −50 and −44° C. in 30 min. The reaction mixture was stirred at −43° C. for 2 h and placed in a freezer (ca. −20° C.) overnight. The mixture was quenched with sat. NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (8:1-3:1 petroleum ether:EtOAc) to give the title intermediate (38 g) as light yellow oil. 1H NMR (400 MHz, CDCl3): δ(ppm) 5.11-5.09 (m, 1H), 4.25-4.24 (m, 1H), 4.19 (q, J=7.2 Hz, 2H), 2.63-2.52 (m, 2H), 2.15 (s, 3H), 2.12-2.08 (m, 1H), 1.92-1.82 (m, 1H), 1.44 (s, 9H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[CH2:17][CH2:18][C:19]([OH:21])=O)=[O:8])=[CH:3][CH:2]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([CH2:17][CH2:18][C:19]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:21])[N:9]([C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:2][CH:3]=2)=[O:8])[CH2:13]1
Reactant: C1COCCN1
Reactant: CON=C1C[C@@H](CCC(=O)O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](CCC(=O)N2CCOCC2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 97 %

Procedure:
The same method as employed in the preparation of Example 7, but starting from 3-[(2R,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]propanoic acid (Intermediate 8) and morpholine, gave the title compound. Yield: 97%. HPLC purity: 96%
Reaction SMILES: [O:1]=[CH:2][CH2:3][C:4]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5]1.[CH3:10][Mg]Cl>C1COCC1>[OH:1][CH:2]([CH3:10])[CH2:3][C:4]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5]1
Reactant: N#CCC1(CC=O)CC1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)CC1(CC#N)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a -5° C. solution of the aldehyde from Step 2 (3.00 g, 24.4 mmol) in 65 mL of THF was added methyl magnesium chloride (3.0M solution in THF, 9.5 mL, 29 mmol) and the reaction was stirred 2 h at 0° C. The reaction was quenched with 1M HCl and extracted with ethyl acetate. The organic extracts were washed with saturated NaHCO3 and brine and dried over MgSO4. Purification by flash chromatography (30% ethyl acetate/hexanes) provided 2.46 g of the title product.
Reaction SMILES: I[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[C:15]=1[F:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=2)=[C:16]([F:23])[C:15]=1[F:24]
Reactant: COC(=O)c1c(I)ccnc1C
Reactant: OB(O)c1ccc(Br)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1c(-c2ccc(Br)c(F)c2F)ccnc1C
Temperature: 110 °C
Yield: 43.8 %

Procedure:
In a microwave vessel, methyl 4-iodo-2-methylnicotinate (1.00 g, 3.61 mmol) was taken in a mixture of 1,4-dioxane (18 mL) and water (2 mL) under inert atmosphere. (4-bromo-2,3-difluorophenyl)boronic acid (1.03 g, 4.33 mmol) and Na2CO3 (765 mg, 7.22 mmol) were added to the reaction mixture and degassed for 5 minutes. Pd(Ph3P)4 (83 mg, 0.072 mmol) was added to the reaction mixture and heated in microwave at 110° C. for 90 min. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with brine (2×100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient of ethyl acetate and petroleum ether) to afford methyl 4-(4-bromo-2,3-difluorophenyl)-2-methylnicotinate (540 mg, 1.58 mmol, 44% yield) as a yellow liquid. LC/MS (ESI) m/e 344.0 [(M+2H)+, calcd for C14H12BrF2NO2 344.1]; LC/MS retention time (method C): tR=2.48 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[CH2:22]([S:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:22]([S:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH:32][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CC(C)(CN)SCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CNC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.70 g), 2-(benzylthio)-2-methylpropylamine (0.47 g), 1H-1,2,3-benzotriazol-1-ol (0.35 g) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.50 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.86 g, yield 77%) was obtained as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:9-42:3, volume ratio). melting point 170-171° C.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].[CH3:10][C:11]1([CH3:18])[CH2:16][CH:15]([NH2:17])[CH2:14][CH2:13][O:12]1>>[CH3:10][C:11]1([CH3:18])[CH2:16][CH:15]([N:17]2[CH2:8][CH2:7][CH:2]2[C:3]([O:5][CH3:6])=[O:4])[CH2:14][CH2:13][O:12]1
Reactant: COC(=O)C(Br)CCBr
Reactant: CC1(C)CC(N)CCO1
Product: COC(=O)C1CCN1C1CCOC(C)(C)C1
Yield: 33 %

Procedure:
The reaction of methyl 2,4-dibromobutanoate 17 with 2,2-dimethyltetrahydro-2H-pyran-4-amine 18H yielded methyl 1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)azetidine-2-carboxylate as a light brown solid (33%). MS ISP (m/e): 228.3 (100) [(M+H)]+.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:12][CH:13]([CH3:14])[N:9]3[C:10]=2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]3)=[CH:4][C:3]=1[F:19].[O:20]=[C:21]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22]1>CN(C)P(=O)(N(C)C)N(C)C>[O:20]=[C:21]1[NH:22][CH2:23][CH2:24][N:25]([C:2]2[C:11]3[CH2:12][CH:13]([CH3:14])[N:9]4[C:10]=3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]4)=[CH:4][C:3]=2[F:19])[CH2:26]1
Reactant: O=C1CNCCN1
Reactant: CC1Cc2c(Cl)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1Cc2c(N3CCNC(=O)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 32.6 %

Procedure:
A mixture of 6 g of 9-chloro-8-fluoro-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid, 8.6 g of 2-oxo-piperazine and 60 ml of hexamethylphosphoric triamide was reacted at 140°-150° C. on an oil bath for 6 hours. After completion of reaction, hexamethylphosphoric triamide was distilled off and to the residue was added ethyl acetate to form crystals, which then were collected by filtration. The crystals thus obtained were recrystallized twice each from dimethylformamide to give 2.4 g of 9-(3-oxo-1-piperazinyl)-8-fluoro-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid. m.p. not lower than 300° C., white rhombic crystals.