Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[O:5][CH:6]=[C:7]([CH2:9]P(=O)(OCC)OCC)[N:8]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:20][O:21][CH2:22][O:23][C:24]1[C:28]([CH:29]=O)=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1.O>O1CCCC1>[CH:1]([C:4]1[O:5][CH:6]=[C:7](/[CH:9]=[CH:29]\[C:28]2[C:24]([O:23][CH2:22][O:21][CH3:20])=[N:25][N:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)[N:8]=1)([CH3:2])[CH3:3]
Reactant: CCOP(=O)(Cc1coc(C(C)C)n1)OCC
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1nn(-c2ccccc2)cc1/C=C\c1coc(C(C)C)n1
Reaction time: 0.5 h
Yield: 1.3 %

Procedure:
To a solution of diethyl [(2-isopropyl-1,3-oxazol-4-yl)methyl]phosphonate (1.16 g) in tetrahydrofuran (15 mL) was added sodium hydride (60% in oil, 0.24 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (1.57 g) was added to the reaction mixture and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-1:2, v/v) to give 2-isopropyl-4-{(Z)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-oxazole as a pale-yellow oil (0.02 g, yield 1.2%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([CH:20]=[O:21])[C:15]=2[O:16][CH2:17][O:18][CH3:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)C.[CH:27]([Mg]Br)([CH3:29])[CH3:28].[Cl-].[NH4+]>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([CH:20]([OH:21])[CH:27]([CH3:29])[CH3:28])[C:15]=2[O:16][CH2:17][O:18][CH3:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOc1c(C=O)csc1-c1ccc(C(C)(C)C)cc1
Reactant: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCOc1c(C(O)C(C)C)csc1-c1ccc(C(C)(C)C)cc1
Reaction time: 2.5 h
Yield: 34 %

Procedure:
To a solution of 2-(4-t-butylphenyl)-3-methoxymethyloxy-4-formylthiophene (3.0 g, 10 mmol) in THF (2.5 mL), 2.0 M ethyl ether solution (6.0 mL, 12 mmol) of isopropylmagnesium bromide was added dropwise under cooling with ice, followed by stirring for 2.5 hours under cooling with ice. A saturated ammonium chloride aqueous solution was added to the reaction solution, and then extraction was carried out with ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The obtained organic layer was concentrated, and then purification was carried out with a silica gel column chromatography (n-hexane/ethyl acetate=3/1) to obtain the desired product as a pale yellow oil (1.18 g, yield 34%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[CH:13]1(B(O)O)[CH2:15][CH2:14]1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH:13]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]3)[CH2:15][CH2:14]1
Reactant: OB(O)C1CC1
Reactant: O=C1NCCc2cc(Br)ccc21
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NCCc2cc(C3CC3)ccc21
Temperature: 100 °C
Yield: 97.2 %

Procedure:
To a round bottomed flask charged with 6-Bromo-3,4-dihydro-2H-isoquinolin-1-one (16.9 g, 74.7 mmol), cyclopropylboronic acid (9.45 g, 1.5 equiv), tricyclohexylphosphine (1.04 mg, 0.025 equiv), and K3PO4 hexahydrate (50 g, 2 equiv) in toluene (210 mL) and H2O (15 mL) was added Pd(OAc)2 (100 mg, 0.05 equiv). The combined mixture was heated for 4 h at 100° C. The reaction mixture was cooled, filtered and washed with toluene. The organic phase was partitioned and washed with water and brine, dried over Na2SO4, filtered and concentrated to an oil. Addition of hexanes produced 6-Cyclopropyl-3,4-dihydro-2H-isoquinolin-1-one as a tan solid (13.6 g). MS (ESI) 187.1 (M+H)+.
Reaction SMILES: O[C:2]1C2NC(=O)COC=2C=CC=1.C([O-])([O-])=O.[K+].[K+].BrCC(OCC)=O.[O:26]=[C:27]1[CH2:32][O:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:29]=2[NH:28]1.CI>CN(C=O)C>[CH3:2][N:28]1[C:27](=[O:26])[CH2:32][O:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:29]1=2
Reactant: O=C1COc2cccc(O)c2N1
Reactant: CCOC(=O)COc1cccc2c1NC(=O)CO2
Agent: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1N(C)C(=O)CO2
Reaction time: 16 h
Yield: 56 %

Procedure:
A stirred mixture of 5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.604 mmol) and K2CO3 (167 mg, 1.21 mmol) in anhydrous DMF (5 mL) was treated with ethyl 2-bromoacetate (121 mg, 0.727 mmol) and stirring continued at room temperature for 16 h. To this solution of crude ethyl 2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yloxy)acetate was added K2CO3 (39.6 mg, 0.287 mmol) followed by MeI (40.7 mg, 0.287 mmol). After being stirred at room temperature for 16 h, the reaction mixture was partitioned between water (50 mL) and DCM (100 mL). The organic layer was washed by water followed by and brine, dried over anhydrous Na2SO4, filtered and concentrated and the resulting residue was purified by preparative TLC to give desired product (43 mg, 56% yield). 1H NMR (400 MHz, CDCl3): 6.99 (t, J=8.3 Hz, 1H), 6.74 (d, J=7.5 Hz, 1H), 6.55 (d, J=8.3 Hz, 1H), 4.69 (s, 2H), 4.51 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 3.56 (s, 3H), 1.34-1.33 (m, 1H), 1.33 (t, J=7.2 Hz, 3H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:31])[C@@H:19]([N:21]([CH3:30])[C:22](=[O:29])/[CH:23]=[CH:24]/[CH2:25][N:26]([CH3:28])[CH3:27])[CH3:20])=[CH:4][N:3]=1.[Cl:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36].[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(NCC)C>O1CCCC1>[Cl:32][C:33]1[CH:34]=[C:35]([NH:36][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:31])[C@@H:19]([N:21]([CH3:30])[C:22](=[O:29])/[CH:23]=[CH:24]/[CH2:25][N:26]([CH3:28])[CH3:27])[CH3:20])=[CH:4][N:3]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: CCCNc1nc(Cl)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)/C=C/CN(C)C
Reactant: Nc1cccc(Cl)c1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCCNc1nc(Nc2cccc(Cl)c2)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)/C=C/CN(C)C
Temperature: 70 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
To a solution of (S,E)-N-(1-((5-(2-chloro-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)-4-(dimethylamino)-N-methyl-2-butenamide (L4, 20 mg) and 3-chloroaniline (28 mg) in tetrahydrofuran (3 mL), (1S)-(+)-10-camphorsulfonic acid (52 mg) was added at room temperature, and the mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature, and then diethylamine was added until the mixture became basic. The solvent was evaporated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography to obtain (S,E)-N-(1-((5-(2-((3-chlorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)-4-(dimethylamino)-N-methyl-2-butenamide (12-2, 4 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.[CH:13]([NH:16][NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:15])[CH3:14].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:16]([CH:13]([CH3:15])[CH3:14])[NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:12]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)CCc1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Yield: 59.2 %

Procedure:
A solution of (3-(2-bromophenyl)propionic acid (257 mg, 1.12 mmoles) and benzoic acid N′-isopropyl-hydrazide (200 mg, 1.12 mmoles) in DMF (6 mL) was treated with triethylamine (0.47 mL, 3.36 mmol), HOBT (182 mg, 1.34 mmoles) and EDCI (2.58 g, 1.34 mmol) at room temperature for 72 h. The reaction mixture was partitioned between water and dichloromethane. The organic layer was successively washed with water and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a solid (258 mg, 59%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([OH:3])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=[N:47][C:42]2[CH:43]=[CH:44][CH:45]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.C1(CN)CC1>CN(C)C=O>[CH:43]1([CH2:42][NH:47][C:1]([C:4]2[CH:5]=[CH:6][C:7]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]3)=[CH:8][CH:9]=2)=[O:3])[CH2:45][CH2:44]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)NCC3CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.8 %

Procedure:
500 mg tert-butyl 4-(4-carboxyphenyl)-piperidine-1-carboxylate are placed in 28 ml dimethylformamide, then 1.14 ml diisopropylethylamine and 747 mg HATU are added. The reaction mixture is stirred for 15 min at ambient temperature, then 194 mg cyclopropylmethylamin hydrochloride are added. The reaction mixture is stirred overnight at ambient temperature. Then the product is purified by preparative HPLC (method A). 480 mg product are obtained as an oil. Analytical HPLC-MS (method B): RT=1.64 min.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])=[CH:6][CH:5]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>O1CCCC1>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([Br:3])=[CH:17][CH:16]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(CO)CCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCC(CO)CCOc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
To a suspension of NaH (0.11 g, 4.58 mmol) in anhydrous tetrahydrofuran (10 mL) was added a solution of 2-(2-(4-bromophenoxy)ethyl)propane-1,3-diol (0.63 g, 2.29 mmol) in anhydrous tetrahydrofuran (10 mL) dropwise. The reaction mixture was stirred at room temperature for 30 minutes. Then, tosyl chloride (0.44 g, 2.3 mmol) was added in portions. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was carefully quenched with water and extracted with ethyl acetate (4×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (0-35% ethyl acetate/petroleum ether) to afford the title compound (0.45 g, 46%) as white solid. 1H NMR (400 MHz, CDCl3) ppm 7.80 (d, 2H), 7.40-7.30 (m, 4H), 6.71 (d, 2H), 4.21-4.09 (m, 2H), 4.00-3.90 (m, 2H), 3.74-3.62 (m, 2H), 2.45 (s, 3H), 2.14 (m, 1H), 1.89-1.74 (m, 3H).
Reaction SMILES: Cl[NH:2][C:3](=[NH:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[S-:12][C:13]#[N:14].[K+]>CO.C(OCC)(=O)C>[CH2:4]([C:3]1[N:11]=[C:13]([NH2:14])[S:12][N:2]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N=C(Cc1ccccc1)NCl
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1nc(Cc2ccccc2)ns1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
N-Chloro-2-phenyl-acetamidine (154 mg, 0.92 mmol) was dissolved in methanol (4.6 mL) and cooled to 0° C. then potassium thiocyanate (89 mg, 0.92 mmol) was added and it was stirred for 1 h. The mixture was diluted with ethyl acetate (50 mL), stirred for 5 min and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford 3-benzyl-[1,2,4]thiadiazol-5-ylamine (93 mg, 53%) as an off-white solid: H1-NMR (400 MHz, CDCl3) δ=4.02 (2H, s), 5.94 (2H, br), 7.28 (5H, m).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]([CH3:19])([CH2:17][CH3:18])[CH2:13][CH2:14][C:15]#N.[OH2:20].Cl>C(OCC)C.O1CCOCC1>[CH3:11][C:12]([CH3:19])([CH2:17][CH3:18])[CH2:13][CH2:14][CH:15]=[O:20]
Reactant: O
Reactant: CCC(C)(C)CCC#N
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCC(C)(C)CCC=O

Procedure:
Diisobutylaluminium hydride (1M solution in toluene, 18.5 ml.) was added to a solution of 4,4-dimethylhexanenitrile (2.0 g.) in dry diethyl ether (100 ml.) stirred under nitrogen. The mixture was refluxed for 3 hours and cooled. A solution of water (2 ml.) and dioxane (10 ml.) was added dropwise followed by dilute hydrochloric acid (80 ml.) and the solution stirred for 1 hour. Diethyl ether was added and the ethereal extracts separated. The ethereal extracts were dried (anhydrous magnesium sulphate) and evaporated to give 4,4-dimethylhexanal (1.3 g.). Nuclear Magnetic Resonance Spectrum (NMR) was as follows: 0.9,6H,s; 1.4,7H,m; 2.4,2H,m; 9.7,1H,t.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][CH2:15][CH2:16][OH:17])=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1>C(O)(=O)C>[Br:1][C:9]1[CH:10]=[N:11][C:12]2[C:7]([C:8]=1[NH:14][CH2:15][CH2:16][OH:17])=[CH:6][CH:5]=[C:4]([Cl:3])[CH:13]=2
Reactant: OCCNc1ccnc2cc(Cl)ccc12
Reactant: BrBr
Solvent: CC(=O)O
Product: OCCNc1c(Br)cnc2cc(Cl)ccc12
Reaction time: 8 h

Procedure:
Bromine (4.3 g) was added dropwise to a solution of 7-chloro-N-(2-hydroxyethyl)-4-quinolinamine (6 g) in 60 ml of acetic acid. The mixture was stirred overnight and the solid separated by filtration. This solid was dispensed in 100 ml of water and the mixture made alkaline (pH=8) with a sodium bicarbonate solution. After two hours of stirring, the product was filtered and recrystallized twice from isopropanol and from ethanol. The yield was 3.5 g, mp 169°-170° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[C:10]([C:30]([F:33])([F:32])[F:31])=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19](O)=[O:20])=[C:14]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:13]=[CH:12]2.Cl.[CH3:35][O:36][C:37](=[O:41])[CH2:38][NH:39][CH3:40].C(N(CC)CC)C.OP(O)(O)=O>C(Cl)Cl>[CH3:35][O:36][C:37](=[O:41])[CH2:38][N:39]([C:19]([C:15]1[C:16]2[C:11](=[C:10]([C:30]([F:33])([F:31])[F:32])[C:9]([O:8][CH3:7])=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH3:40]
Reactant: CNCC(=O)OC
Reactant: COc1ccc2c(C(=O)O)c(OCc3ccccc3)ccc2c1C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)C(=O)c1c(OCc2ccccc2)ccc2c(C(F)(F)F)c(OC)ccc12
Reaction time: 1.5 h
Yield: 61.7 %

Procedure:
A solution of oxalyl chloride (0.51 mL, 5.8 mmol) in CH2Cl2 (6 mL) was added dropwise to a suspension of 6-methoxy-2-(phenylmethoxy)-5-(trifluoromethyl)-1-naphthalenecarboxylic acid (2.00 g, 5.3 mmol, described in Example 8) in 50 mL of CH2Cl2 under a nitrogen atmosphere. The suspension became homogeneous upon stirring for 1.5 hours. The mixture was then placed under mild vacuum for about 5 minutes to remove the dissolved gases and then was transfered via syringe to a flask containing a suspension of N-methylglycine methyl ester hydrochloride (1.11 g, 8.0 mmol) and triethylamine (3.7 mL, 27 mmol) in 50 mL of CH2Cl2. The suspension was stirred for 20 hours then was poured into additional CH2Cl2 and 1M H3PO4. The organic phase was separated and washed successively with 1M H3PO4, water, saturated NaCl and then dried over Na 2 SO4. After filtration, concentration and silica gel chromatography with 20:1 CH2Cl2 :ethyl acetate as eluent, the residue was recrystallized from ethanol to give 1.51 g (62% yield) of the title compound as a white powder, m.p. 95°-98° C.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][Se:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34]>CC(OC)(C)C.[Cu]I.CN(C=O)C>[Br:7][C:6]1[C:2]([C:37]#[C:36][Si:33]([CH3:35])([CH3:34])[CH3:32])=[CH:3][Se:4][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1c[se]cc1Br
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Solvent: COC(C)(C)C
Product: C[Si](C)(C)C#Cc1c[se]cc1Br
Temperature: 90 °C
Yield: 79.5 %

Procedure:
To a pressure vessel purged with N2 was added 3,4-dibromo-selenophene (3.69 g, 12.77 mmol), DMF (10.0 mL), triphenylphosphine (0.669 g, 2.55 mmol), copper(I) iodide (0.161 g, 0.843 mmol), diethylamine (dried over KOH, 20.0 mL, 191.55 mmol), (trimethylsilyl)acetylene (0.910 mL, 6.39 mmol), and palladium dichloride-bis-triphenylphosphine (0.592 g, 0.843 mmol). The reaction vessel was sealed and the mixture heated to 90° C. for 1 h. Upon cooling to room temperature, the reaction mixture was diluted with MTBE (100.0 mL) and was washed with 0.1 M HCl (3×50.0 mL). The combined aqueous layers were extracted with MTBE (50.0 mL). The combined MTBE extracts were quenched with saturated sodium bicarbonate (50.0 mL), dried over magnesium sulfate, and concentrated to an oil. The crude oil was purified by column chromatography (silica gel, cyclohexane) to provide (4-bromo-selenophen-3-ylethynyl)-trimethyl-silane (1.55 g, 5.08 mmol, 79.5 mol %): 500 MHz 1H NMR (CDCl3) δ 8.15 (d, J=2.9 Hz, 1H), 7.58 (d, J=2.9 Hz, 1H), 0.26 (S, 9h); 125 MHz 13C NMR (CDCl3) δ 135.4, 127.0, 126.4, 114.1, 99.8, 96.8, 0.2.
Reaction SMILES: [N+](C1C=C(C=CC=1)C=O)([O-])=O.[Cl:12]C1C(F)=C(F)C=C2C=1N(C1CC1)C=C(C(O)=O)C2=O.[Cl:32][C:33]1[C:34]([N:51]2[CH2:55][CH2:54][C@H:53]([N:56]=CC3C=CC=C([N+]([O-])=O)C=3)[CH2:52]2)=[C:35]([F:50])[CH:36]=[C:37]2[C:42]=1[N:41]([CH:43]1[CH2:45][CH2:44]1)[CH:40]=[C:39]([C:46]([OH:48])=[O:47])[C:38]2=[O:49]>>[ClH:12].[NH2:56][C@H:53]1[CH2:54][CH2:55][N:51]([C:34]2[C:33]([Cl:32])=[C:42]3[C:37]([C:38](=[O:49])[C:39]([C:46]([OH:48])=[O:47])=[CH:40][N:41]3[CH:43]3[CH2:44][CH2:45]3)=[CH:36][C:35]=2[F:50])[CH2:52]1
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3CC[C@H](N=Cc4cccc([N+](=O)[O-])c4)C3)c(F)cc2c1=O
Agent: O=Cc1cccc([N+](=O)[O-])c1
Product: Cl
Product: N[C@H]1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)C1

Procedure:
If, for example, the reaction mixture of 3-nitrobenzaldehyde and (S)-3-aminopyrrolidne is reacted with 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in a one-pot reaction, the course of the reaction via the intermediately formed 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[(S)-3-(3-nitrobenzylideneamino)-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylic acid to give 7-[(S)-3-amino-1-pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride can be represented by the following equation: ##STR22##
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([CH3:6])([OH:5])[CH3:4].C([Li])CCC.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>C1COCC1.CCCCCC.C(OCC)(=O)C>[C:15](=[O:16])([O:5][C:3]([CH3:6])([CH3:4])[C:2]([F:8])([F:7])[F:1])[O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 1,1,1-trifluoro-2-methylpropan-2-ol (1.0 g) in THF (30 ml) was added a 2M solution of n-butyl lithium in n-hexane (3.9 ml) and then 4-nitrophenyl chloroformate (2.4 g) at −75° C. The mixture was warmed to room temperature and diluted with ethyl acetate, washed with water, dried over sodium sulfate, and filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% EtOAc/Hexane) to give 4-nitrophenyl 1,1,1-trifluoro-2-methylpropan-2-yl carbonate as a pale yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3]CN.C([N:8]([CH2:11]C)CC)C.[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.O>C(Cl)Cl>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:8]([O:3][CH3:2])[CH3:11])=[O:19])=[CH:16][CH:15]=1
Reactant: CCN(CC)CC
Reactant: COCN
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.5 %

Procedure:
To a mixture containing methoxymethylamine hydrochloride (44 g, 0.45 mol) and triethylamine (138 mL, 0.99 mol) in CH2Cl2 (500 mL) at 0° C. was added over 30 min, 4-fluorobenzoyl chloride (50 mL, 0.41 mol). The result-ing mixture was allowed to warm to rt and stirring was continued for 30 min, at which time the mixture was poured into H2O and extracted with Et2O. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). Removal of the solvent in vacuo afforded the title compound (80 g, 100%), which was used without further purification: 1H NMR (CDCl3): d 7.72 (dd, 2H); 7.06 (apparent t, 2H); 3.52 (s, 3H); 3.43 (s, 3H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:38]([CH3:40])[CH3:39])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Br:37])[N:15]=1)=[O:13])(C(C)(C)C)(C)C.C(OCC)(=O)C>O1CCCC1.Cl.CCCCCC>[OH:8][CH2:9][CH2:10][N:11]([CH:38]([CH3:40])[CH3:39])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Br:37])[N:15]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccc(Cl)cc2Br)nc(O)c1OCc1ccccc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)N(CCO)C(=O)c1nc(Cc2ccc(Cl)cc2Br)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a stirred solution of 5-benzyloxy-2-(2-bromo-4-chlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (378) (5.7 g, 8.80 mmol) in tetrahydrofuran (50 mL), 1N HCl (15 mL) was added and the reaction mixture was stirred for 1 h at room temperature while silica thin layer chromatography was performed (70% ethyl acetate in hexane; Rf=0.2). After completion of the reaction, volatiles were removed and the residue was diluted with water (30 mL) and adjusted to pH 8 using NaHCO3. The aqueous mixture was extracted with ethyl acetate (2×150 mL) and the combined extracts were dried and concentrated. The resulting residue was purified by column over normal silica gel (100-200) to get 5-benzyloxy-2-(2-bromo-4-chlorobenzyl)-6-hydroxypyrimidine-4-carboxylicacid(2-hydroxyethyl)-isopropylamide (379) (4.02 g, 85.45%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:16]/[CH:17]=[CH:18]/[C:19]#[C:20][C:21]([CH3:24])([CH3:23])[CH3:22]>C1COCC1.CN(C=O)C>[CH3:22][C:21]([CH3:24])([CH3:23])[C:20]#[C:19]/[CH:18]=[CH:17]/[CH2:16][O:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)C#C/C=C/CBr
Reactant: OCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)C#C/C=C/COCc1cccc2ccccc12
Reaction time: 1 h

Procedure:
5 g of 1-(Hydroxymethyl)naphthalin are in THF are treated at room temperature with 900 mg of 80% NaH (dissolved in mineral oil) and stirred until the evolution of gas ceases (ca. 1 hr.). A solution of 6.36 g of (E)-1-bromo-6,6-di-methyl-2-hepten-4-ine in DMF are added dropwise and the reaction mixture stirred overnight at room temperature.