Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2N(O)N=N[C:5]=2[CH:6]=1.CCN(C(C)C)C(C)C.[CH:20]1([CH:25]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[C:41](=[O:42])[CH2:40][O:39][C:38](C4C=CC=CC=4)=[N:37]3)=[CH:31][CH:30]=2)[C:26]([OH:28])=O)[CH2:24][CH2:23][CH2:22][CH2:21]1.[NH2:49][CH:50]([CH3:62])[CH2:51][CH2:52][CH2:53][CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH:20]1([CH:25]([C:29]2[CH:30]=[CH:31][C:32]([CH2:35][N:36]3[C:41](=[O:42])[CH2:40][O:39][C:38]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][CH:6]=4)=[N:37]3)=[CH:33][CH:34]=2)[C:26]([NH:49][CH:50]([CH3:62])[CH2:51][CH2:52][CH2:53][CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Reactant: On1nnc2ccccc21
Reactant: CC(N)CCCCC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(CCCCC(=O)OC(C)(C)C)NC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At RT, 41.3 mg (0.306 mmol) of HOBt and 126 μl (0.764 mmol) of DIEA were added to a solution of 100 mg (0.255 mmol) of (+)-cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetic acid and 76.9 mg (0.382 mmol) of tert-butyl(+/−)-6-aminoheptanoate in 0.3 ml of DMF. The resulting mixture was cooled to 0° C., after which 116.3 mg (0.306 mmol) of HATU were added. The reaction mixture was slowly warmed to RT, stirred at RT for 1 h and then diluted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (acetonitrile/water gradient). This gave 118 mg (about 83% pure, about 67% of theory) of the target compound as a diastereomer mixture.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1.[S:10](Cl)(Cl)=O>C1C=CC=CC=1>[SH:10][CH2:2][C:3]1[CH:4]=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: [O-][n+]1cccc(CO)c1
Solvent: c1ccccc1
Product: [O-][n+]1cccc(CS)c1

Procedure:
A solution of 30 g. of 3-hydroxymethylpyridine-N-oxide in 200 ml. of benzene and 18.4 g. of thionyl chloride was refluxed 2 hours, cooled and filtered to give 3-mercaptomethylpyridine-N-oxide.
Reaction SMILES: [C:1]([O:4][CH:5]1[NH:8][C:7](=[O:9])[CH:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:47](Cl)(=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49]>C1COCC1>[C:1]([O:4][CH:5]1[N:8]([C:47]([C:48]([CH3:51])([CH3:50])[CH3:49])=[O:52])[C:7](=[O:9])[CH:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1NC(=O)C1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OC1C(CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 43.1 %

Procedure:
To a -78° C. THF (6 mL) solution of compound 13 (trans:cis ratio, 2:1; 600 mg; 1.2 mmol) was added 1N THF solution of sodium bis(trimethylsilyl)amide (1.2 mL, 1.2 mmol), and the resultant solution was stirred for 15 min. Pivaloyl chloride (150 mg, 1.24 mmol) was added, and the solution was stirred for 30 min at -78° C. and for 1.5 h at room temperature. The reaction mixture was partitioned between pH 4.0 aqueous buffer and ether. The organic phase was dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (1:1/Et2O:hexane) to afford 300 mg (43%) of the title product as a mixture of trans and cis (3:2) isomers.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][C:4]1([CH3:17])[C:13]2[CH:8]([CH2:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[C:7]([CH3:16])([CH3:15])[CH2:6][CH2:5]1.[O-:18][Mn](=O)(=O)=O.[K+].Cl>O.N1C=CC=CC=1>[CH3:3][C:4]1([CH3:17])[CH2:5][CH2:6][C:7]([CH3:16])([CH3:15])[C:8]2[CH:9]=[C:10]([C:14]([OH:18])=[O:1])[CH:11]=[CH:12][C:13]1=2
Reactant: [OH-]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC1=CC=C2C(C1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21
Temperature: 95 °C
Yield: 57.1 %

Procedure:
A three neck round bottom flask (250 ml) equipped with a magnetic stirrer was charged with pyridine (37.5 mL), H2O (12.5 ml) and NaOH (0.39 g, 9.8 mmol). 1,1,4,4,6-Pentamethyltetrahydronaphtalene 1 (1.00 g, 4.9 mmol) and KMnO4 (3.12 g, 19.8 mmol) were added successively. The reaction mixture was stirred and heated at 95° C. for 16 h and cooled to 1° C. using an ice-water bath. HCl (6 N, 100 mL) was added to acidify to pH=1 and the product was extracted with EtOAc (5×100 mL), dried over Na2SO4, filtered to give after evaporation 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid 2 (0.65 g, 57% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:20])[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)[OH:12].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:20])[C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)=[O:12]
Reactant: COc1ccc(Cl)c(C(C)C(O)c2ccnc(Cl)c2)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COc1ccc(Cl)c(C(C)C(=O)c2ccnc(Cl)c2)c1
Reaction time: 2 h
Yield: 81.2 %

Procedure:
2-(2-Chloro-5-methoxy-phenyl)-1-(2-chloro-pyridin-4-yl)-propan-1-ol (140 mg) was dissolved in CH2Cl2 (20 mL). To this solution was added 3 Å molecular sieves (140 mg) and then tetrapropylammonium perruthenate (15.8 mg) and 4-methyl-morpholine-4-oxide (121 mg). The mixture was allowed to stir for 2 hours. The reaction mixture was applied directly to a silica gel column and the column was eluted with ethyl acetate:heptane=3:7. The appropriate fractions were combined and evaporated to give the title compound as a colorless gum (113 mg, 81%). MS (neg. ion, m/e)=308.4 [(M−H)−].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH2:21]([NH:17][C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:20][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: On1nnc2ccccc21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Yield: 81.2 %

Procedure:
Tertiarybutyloxycarbonyl-L-valine (25 g) in dichloromethane (200 ml) was treated with 1-hydroxybenzotriazole (15.5 g) hexylamine (11.6 g) and DCC (26 g) at room temperature for 2 days. The solution was filtered and the organic phase washed with aqueous sodium hydrogen carbonate, aqueous citric acid (1M) and water, dried over sodium sulphate and concentrated in vacuo to afford tertiary butyloxycarbonyl-L-valine N-hexylamide (28 g) which crystallised from methanol-water as needles; m.p. 74°-76° C.; (Found: C,63.8; H,10.6; N,9.4. C16H32N2O3 requires C,64.0; H,10.7; N,9.32%); νmax (Nujol): 3280 and 1630 cm-1 ; δ(CDCl3) 0.8-1 (9H,m, 3×CH3); 1.3 (8H,m,(CH2)4); 1.45 (9H,s, (CH3)3C); 2.1 (1H,m,CH(CH3)2); 3.3 (2H,m, NHCH2 ); 3.9 (1H,dd, J=8 Hz and 5 Hz., α-CH); 5.2 (1H,d, J=8Hz, CONH) and 6.26 (1H,m,NH).
Reaction SMILES: [CH:1](C1C2C(=CC=CC=2)C=C1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:27][NH2:28].C([Li])(C)(C)C.[CH:38]1([CH:41]=[O:42])[CH2:40][CH2:39]1>C1COCC1.CCOCC>[C:1](=[N:28][CH:27]([C:26]1[CH:29]=[CH:30][C:31]([F:32])=[C:24]([F:23])[CH:25]=1)[CH:41]([CH:38]1[CH2:40][CH2:39]1)[OH:42])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=CC1CC1
Reactant: C1=CC(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: NCc1ccc(F)c(F)c1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(C1CC1)C(N=C(c1ccccc1)c1ccccc1)c1ccc(F)c(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzhydrylindene-(3,4-difluoro-benzyl)-amine (2.5 g, 8.1 mmol) in 50 mL of dry THF was added tert-butyllithium (1.7M, 6.2 mL) dropwise and the resulting solution was stirred at -78° C. for 0.5 h. To the solution was added cyclopropanecarboxaldehyde (0.90 ml, 12.0 mmol) in 10 ml of THF and the solution was stirred at -78° C. for 2 h and 25° C. for 1 h. The reaction was quenched by adding 1.0 mL of dilute acetic acid. Reaction mixture was diluted with 100 ml of Et2O and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo, yielding 2-(benzhydryliden-amino)-1-cyclopropyl-2-(3,4-difluoro-phenyl)-ethanol as a yellow oil, which was subjected to the following reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.Cl>O1CCCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)c1ccc(Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C(=O)O)c1ccc(Br)cc1
Reaction time: 3 h

Procedure:
To a solution of methyl 2-(4-bromophenyl)propanoate (2 g, 8.2 mmol) in tetrahydrofuran (30 mL) and water (20 mL) was added (1.2 g, 41 mmol) at room temperature, the mixture solution was stirred for 3 hours, then diluting with ethyl acetate (100 mL), and acidified with hydrochoric acid (6 M) to ph=3. The organic layer was dried over sodium sulfate, and concentrated to dry. The result residue 2-(4-bromophenyl)propanoic acid (2 g) was used directly for the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].[OH2:12].[C:13]1(C)C=[CH:17][C:16](S(O)(=O)=O)=[CH:15][CH:14]=1>O1CCOCC1.O1C=CCCC1.C(OCC)C>[OH:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[C:4]([O:8][CH:17]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1c(O)cccc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Agent: C1=COCCC1
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(=O)c1c(O)cccc1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 2162.3 %

Procedure:
2′,6′-Dihydroxyacetophenone (5.0 g) was dissolved in dioxane (20 mL) and 3,4-dihydro-2H-pyran (16 mL). To the solution was added p-toluenesulfonic acid monohydrate (0.21 g), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with diethyl ether, and the mixture was washed with 5% aqueous potassium carbonate solution. The organic layer was extracted with 2 mol/L aqueous sodium hydroxide solution, and the aqueous layer was neutralized until pH was about 8. The resulting mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate to give the title compound (5.64 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[CH:17]=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:29]2([C:32](O)=[O:33])[CH2:31][CH2:30]2)=[O:28])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]([C:29]2([C:32]([NH:18][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[C:10]5[CH:17]=[CH:16][NH:15][C:11]=5[N:12]=[CH:13][N:14]=4)=[C:2]([F:1])[CH:3]=3)=[O:33])[CH2:31][CH2:30]2)=[O:28])=[CH:24][CH:25]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1ccc(Oc2ncnc3[nH]ccc23)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(Oc3ncnc4[nH]ccc34)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-phenylamine (0.07 g, 0.29 mmol, 1.0 eq.), 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (0.105 g, 0.32 mmol), HATU (0.304 g, 0.58 mmol), triethylamine (0.13 ml, 0.87 mmol), and anhydrous DMF (3 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O (50 ml) and extracted with CHCl3 (3×). The combined CHCl3 extractions were washed with H2O (1×), sat'd NaHCO3 (2×), 10% LiCl (3×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The resulting crude residue was purified by HPLC to yield N-(4-fluorophenyl)-N′-[3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]-cyclopropane-1,1-dicarboxamide as a white solid (0.011 g, 9.0% yield). 1H NMR (400 MHz, DMSO): 9.59 (bs, 1H), 8.47 (s, 1H), 7.85 (m, 2H), 7.65 (m, 3H), 7.48 (d, 1H), 7.36 (t, 1H), 7.19 (d, 1H), 7.15 (t, 3H), 1.44 (s, 5H); MS (ESI) for C23H17F2N5O3: 450 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9](Cl)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]1.C(=O)(O)[O-].[Na+]>O.C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]2)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCN1CCC(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCN1CCC(NS(=O)(=O)c2ccc(NC(C)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.0 Grams of N-acetylsulphanilyl chloride were added in portions to a stirred, ice cooled, mixture of 4.7 grams of 4-amino-1-n-butyl piperidine and 6.3 grams of sodium bicarbonate in 75 milliliters of water and 35 milliliters of chloroform. After stirring overnight at room temperature the mixture was filtered, washed with water, and dried to give 4.2 grams of the title compound. Melting Point 174°-175°C.
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=O)C3C(=CC=CC=3)C=2C=CC=1.C=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:16][NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C=O
Agent: CC[SiH](CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](CC(C)C)C(=O)O
Reaction time: 22 h
Yield: 117.1 %

Procedure:
A suspension of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-leucine (1.67 g, 5 mmol) in toluene(100 ml) was charged with paraformaldehyde (1 g, 33.3 mmol) and 4-toluenesulfonic acid (100 mg, catalytic). The mixture was refluxed for 30 minutes in a Dean Stark apparatus for azeotropic distillation. The solution was washed with a saturated solution of sodium bicarbonate (×2), dried over magnesium sulfate and evaporated. The resulting oil in a 1:1 mixture of chloroform:trifluoroacetic acid (50 ml), at room temperature, was charged with triethylsilane (2.38 ml, 15 mmol). Stirring was continued for 22 hr. The solvents were removed in vacuum and the oil was crystallized from a mixture of ether:hexane. Recrystalyzation from EtOAc:hexane afforded 0.85 g (46%) of the product as a colorless solid, mp 101°-3° C.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:1][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:3])[CH:10]=1
Reactant: BrBr
Reactant: Nc1ccccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Product: Nc1ccc(Br)cc1F
Reaction time: 0.5 h

Procedure:
Cycle 1. Methylene chloride, 125 ml, and 32.2 g (0.1 mol) tetrabutylammonium bromide were mixed in a 200-ml, 3-necked roundbottom flask, equipped with a mechanical stirrer, a thermometer, an addition funnel and a water condenser leading to a mineral oil bubbler. Bromine, 16.0 g (0.1 mol), was added to the mixture over 15 minutes at room temperature. The temperature of the mixture rose from 24° C. to 30° C. The contents of the flask were stirred for 30 minutes. 2-Fluoroaniline, 11.1 g (0.1 mol), at room temperature was added to the mixture in one portion. The temperature of the mixture rose to 40° C. The orange solution immediately turned yellowish. After stirring for 15 minutes, the solution turned milky and the temperature was 32° C. After 30 more minutes solids were observed. The solution was filtered and the solids washed with ice-cold methylene chloride until white. On air-drying 9 g of product (Solid I) was obtained. The melting point was >200° C. LC analysis showed only desired product with a trace of impurity. LC analysis of the mother liquor (I) showed that it contained some desired product and some dibrominated compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]3=[O:19])[CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[C:11]3=[O:19])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: BrCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1N(Cc2ccncc2)c2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.6 %

Procedure:
(1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (135 mg, 0.5 mmol), 4-bromomethyl-pyridine (98 mg, 0.6 mmol) and Cs2CO3 (245 mg, 0.75 mmol) were dissolved in DMF (2 mL). The mixture was stirred at room temperature for 14 hours. The mixture was poured into water, extracted with ethyl acetate, dried and concentrated under reduced pressure. The residue was dissolved in 2 mL of DMF. Purification by preparative HPLC gave the title compound as little yellow solid (140 mg, 76%). LC/MS m/e calcd. for C22H17ClN2O: 360, observed (M+H)+: 361.2 1HNMR (400 MHz, MeOD-d4) δppm 2.22-2.37 (m, 2 H) 3.32-3.40 (m, 1 H) 5.39 (s, 2 H) 6.15 (d, J=7.58 Hz, 1 H) 6.74-6.85 (m, 1 H) 6.92 (d, J=7.83 Hz, 1 H) 7.10-7.19 (m, 1 H) 7.24-7.42 (m, 4 H) 7.93 (d, J=6.32 Hz, 2 H) 8.80 (d, J=6.06 Hz, 2 H). MS calcd. for C22H17ClN2O 360, obsd. (ESI+) [(M+H)+] 361.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[Br-].[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:11])=[O:10]>>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]([OH:11])=[O:10])=[CH:2]1
Reactant: O=Cc1ccsc1
Reactant: O=C(O)CCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: O=C(O)CCCCCCCC=Cc1ccsc1

Procedure:
Reaction of 3-thiophenecarboxaldehyde with (8-carboxy-octyl)-triphenyl-phosphonium bromide, in analogy with intermediate 22, step 2, produced 10-(thiophen-3-yl)-dec-9-enoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](OC)=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[CH2:6][C:7]#[C:8][CH3:9])[CH3:2].[CH3:27]C1C=CC=CC=1CBr.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:27])=[CH:12][CH:11]=1)[CH2:6][C:7]#[C:8][CH3:9])[CH3:2]
Reactant: Cc1ccccc1CBr
Reactant: CC#CCC(C(=O)OCC)c1ccc(OCc2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC#CCC(C(=O)OCC)c1ccc(OCc2ccccc2C)cc1
Temperature: 80 °C

Procedure:
Ester 15.1 (3.19 g, 9 mmol) was taken up in glacial acetic acid (100 mL) in a 250 mL RB Flask, and the suspension was heated to reflux for 16 h. The solvent was removed under reduced pressure, and the residue was re-dissolved in ethyl acetate (200 mL). The solution was washed with 1 N HCl(aq) (200 mL) and saturated brine (200 mL), dried over MgSO4 and concentrated to a thick yellow oil, to which was added 2-methylbenyl bromide (2.57 g, 13.9 mmol), cesium carbonate (6.03 g, 18.5 mmol) and DMF (20 mL). The suspension was heated to 80° C. for overnight. After cooling, the reaction was quenched with water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with NaHCO3 (sat. 2×100 mL), and NaCl (sat. 3×100 mL), dried over MgSO4, and concentrated to a white powder (2.41 g, 79%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27]=O)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH2:34])[CH3:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>C1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH:27]=[N:34][CH2:33][CH2:32][N:31]([CH2:35][CH3:36])[CH2:29][CH3:30])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C1=C(C)NC(C=NCCN(CC)CC)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 96.3 %

Procedure:
A mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (970.9 mg), N,N-diethylethylenediamine (290.5 mg) and p-toluenesulfonic acid (catalytic amount) in dried benzene (20 ml) was refluxed under azeotropic dehydration for 4 hours. To the resultant solution was added diethyl ether and the solution was washed with water and dried. The solvent was removed to give red oil (1.1711 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-[2-(N,N-diethylamino)ethyl]iminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(Cc2ccc(Cl)c(Cl)c2)nc1O
Product: CCOC(=O)c1cnc(Cc2ccc(Cl)c(Cl)c2)nc1Cl
Yield: 62 %

Procedure:
The title compound was prepared by (a) of diethyl ethoxymethylenemalonate (6 g, 27 mmol) with 3',4'-dichlorophenylacetamidine (5.5 g, 27 mmol) to afford 37% of ethyl 4-hydroxy-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 4-hydroxy-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (2 g, 6 mmol) with POCl3 (14 g, 92 mmol) to afford 62% of ethyl 4-chloro-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of ethyl 4-chloro-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (1 g, 2.8 mmol) with hydrazine (0.27 g, 8.3 mmol) to afford 99% of ethyl 4-hydrazino-2-(3',4'-dichlorophenyl)pyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (0.9 g, 2.7 mmol) with citraconic anhydride (0.49 g, 4.4 mmol) in analogy to Example 21 to afford 47% (0.3 g) of the title compound; m.p. 119-121° C.