Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)=[C:9]2[C:26]([O:28]CC)=[O:27])=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:9]2[C:26]([OH:28])=[O:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
Ethyl (RS-1-(Fluorophenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1-(4-fluorophenyl)-1-hydroxy-3-(3,4methylenedioxyphenyl)indene-2-carboxylate (45 mg, 0.11 mmol) in CH2Cl2 (3 ml) at 0° C. was added triethylsilane (38 μl, 0.24 mmol), followed by boron trifluoride etherate (121 μl, 0.98 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 15 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (40 mg, 90%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[NH:28][CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([S:52]([CH3:51])(=[O:54])=[O:53])[CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(Oc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2S(C)(=O)=O)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution containing 35 (228 mg, 0.4 mmol), DIPEA (104 mg, 0.8 mmol) and DMAP (cat) in DCM (5 mL) was cooled to 0° C. Methanesulfonyl chloride (55 mg, 0.48 mmol) was added. After 1 h, the reaction mixture was warmed to ambient temperature, diluted with DCM, washed successively with saturated aqueous NaHCO3, 1N HCl, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by RP-HPLC (2″ Dynamax® C18; 10-100% ACN/water containing 0.1% HOAc over 30 min; Flow: 40 mL/min) to afford compound 36 (190 mg) as a white solid. Mass spectrum, m/z [651.1] (M+H)+.
Reaction SMILES: C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[OH:25][C@@H:26]([C@H:28]1[C:49](=[O:50])[N:30]2[CH:31]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])[C:32](=O)[C@H:33]([CH3:34])[C@@H:29]12)[CH3:27].FC(F)(F)S(O)(=O)=O.FC(F)(F)S(O)(=O)=O.[SH:67][C@@H:68]1[CH2:72][N:71]([CH3:73])[C@H:70]([C:74]([N:76]2[CH2:81][CH2:80][N:79]([CH2:82][CH2:83][OH:84])[CH2:78][CH2:77]2)=[O:75])[CH2:69]1>C(#N)C>[OH:84][CH2:83][CH2:82][N:79]1[CH2:80][CH2:81][N:76]([C:74]([C@@H:70]2[CH2:69][C@H:68]([S:67][C:32]3[C@H:33]([CH3:34])[C@@H:29]4[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:49](=[O:50])[N:30]4[C:31]=3[C:36]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=3)=[O:37])[CH2:72][N:71]2[CH3:73])=[O:75])[CH2:77][CH2:78]1
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CCN(CCO)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(CCO)CC4)N(C)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 41.6 %

Procedure:
600 μl of diphenylphosphoryl chloride and 510 μl of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 1000 mg of 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 10 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. 1800 μl of diisopropylethyl-amine and a solution of 1680 mg of (2S,4S)-4-mercapto-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-1-methyl-pyrrolidine bis(trifluoromethanesulfonate) (prepared as described in Preparation 52) in 5 ml of dry acetonitrile were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 2 hours, after which it was allowed to stand overnight in a refrigerator. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was subjected to column chromatography through a Lobar column (Merck, LiChroprep RP-8, size B). The column was eluted first with 55% v/v aqueous methanol and then with 60% v/v aqueous methanol. Those fractions containing the title compound were collected, concentrated by evaporation under reduced pressure and lyophilized, to give 710 mg of the title compound, as a powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]1.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[C:23]2[CH:29]=O>>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[C:23]2[C:29]1[NH:17][C:5]2[CH:6]=[C:7]([N:8]3[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]3)[C:2]([F:1])=[CH:3][C:4]=2[N:18]=1
Reactant: O=Cc1n[nH]c2ccc(F)cc12
Reactant: CC(C)N1CCN(c2cc(N)c(N)cc2F)CC1
Product: CC(C)N1CCN(c2cc3[nH]c(-c4n[nH]c5ccc(F)cc45)nc3cc2F)CC1

Procedure:
The title compound was synthesized as described in Example 4 from 4-fluoro-5-(4-isopropyl-piperazin-1-yl)-benzene-1,2-diamine and 5-fluoro-1H-indazole-3-carbaldehyde. LC/MS (m/z) 397.5 (MH+), Rt 2.78 minutes.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1.[CH:17]([C:19]1[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([CH:27]=1)[C:24]([OH:26])=[O:25])=[O:18]>CN(C)C=O>[F:16][C:11]1[CH:10]=[C:9]([CH2:8][O:28][C:22]2[CH:21]=[CH:20][C:19]([CH:17]=[O:18])=[CH:27][C:23]=2[C:24]([O:26][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=2)=[O:25])[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: Fc1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)OCc2ccc(F)c(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (17.65 g, 54.2 mmol) and 4-(bromomethyl)-1,2-difluorobenzene (5.78 ml, 45.1 mmol) were added to a solution of 5-formyl-2-hydroxybenzoic acid (3 g, 18.06 mmol) in dimethylformamide (100 ml) was added) at room temperature. The mixture was stirred at room temperature overnight. The mixture was then filtered, the dimethylformamide was evaporated and the residue was diluted with ethyl acetate (100 ml) and washed with water (3×50 ml). The organic layer was dried (MgSO4) and evaporated under reduced pressure to give an oil which solidified on standing solidified. The solid was triturated with an 8:1 mixture of hexane/ethyl acetate. The solid was filtered and dried in air under vacuum to yield the title compound as a white solid. 7 g.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>O1CCCC1.B.O1CCCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][OH:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: OCCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3-phenoxyphenyl)acetic acid (1.157 g) in tetrahydrofuran (23 ml), 6.5 ml of borane-tetrahydrofuran complex (1.17M tetrahydrofuran solution) was added, and the reaction solution was stirred at room temperature for 2 hours. To the reaction solution was added water, and the mixture was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (10:90-80/20)) to afford the title compound as a colorless oil.
Reaction SMILES: [C:1]([Cu])#N.[Li]C.CCOCC.FC(F)(F)S(O[C:17]1[C:24]2([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[N:20]([CH2:21][CH2:22][CH2:23]2)[C:19](=[O:34])[C:18]=1[C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=1)(=O)=O.[NH4+].[OH-]>C1COCC1>[Cl:42][C:37]1[CH:36]=[C:35]([C:18]2[C:19](=[O:34])[N:20]3[C:24]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=4)([C:17]=2[CH3:1])[CH2:23][CH2:22][CH2:21]3)[CH:40]=[C:39]([Cl:41])[CH:38]=1
Reactant: N#C[Cu]
Reactant: N#Cc1ccc(CC23CCCN2C(=O)C(c2cc(Cl)cc(Cl)c2)=C3OS(=O)(=O)C(F)(F)F)cc1
Agent: [Li]C
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1=C(c2cc(Cl)cc(Cl)c2)C(=O)N2CCCC12Cc1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 14 %

Procedure:
To a suspension of CuCN (22.5 mg, 0.25 mmol) in dry THF (2 ML) at −78° C., under nitrogen atmosphere, was added a solution of MeLi in Et2O (1.4 M, 0.37 mL, 0.5 mmol). The mixture was stirred for 30 min and treated drop wise with a solution of 7a-(4-cyanobenzyl)-6-(3,5-dichlorophenyl)-5-oxo-2,3,5,7a-tetrahydro-1H-pyrrolizin-7-yl trifluoromethanesulfonate 26 (50 mg, 0.09 mmol) in THF (1 mL). The reaction was stirred for 2 h at −78° C. and 20 min. at −20° C. The reaction was treated with 10% aqueous NH4OH (10 ml), stirred at rt. for 10 min. and extracted with Et2O (4×10 mL). The extracts were combined sat. NaCl solution (10 ml), dried (MgSO4) and solvent removed. The resulting oil was purified using preparative HPLC to give 4-{[6-(3,5-Dichlorophenyl)-7-methyl-5-oxo-2,3-dihydro-1H-pyrrolizin-7a(5H)-yl]methyl}benzonitrile IX (5 mg, 14%), LCMS (m/z) 397/399 (M++H), HPLC Retention Time/Condition 1: 1.86 min.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=1.C([O-])([O-])=O.[Na+].[Na+]>O.Cl[Pd]Cl>[NH2:6][C:7]1[N:8]=[CH:9][C:10](/[CH:3]=[CH:2]/[C:1]([OH:5])=[O:4])=[CH:11][CH:12]=1
Reactant: C=CC(=O)O
Reactant: Nc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(/C=C/C(=O)O)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.5 %

Procedure:
Acrylic acid (23 mL, 0.33 mole) was added carefully to a solution of 2-amino-5-bromopyridine (25.92 g, 0.15 mole) and Na2CO3 (55.64 g, 0.53 mole) in H2O (600 mL). PdCl2 (0.53 g, 0.003 mole) was then added, and the mixture was heated at reflux. After 24 hr, the reaction was cooled to RT and filtered, and the filtrate was adjusted to pH 6 with aqueous HCl. Additional H2O (0.5 L) was added to improve mixing, and the mixture was stirred for 1 hr. The pH was readjusted to 6, then the solid was collected by suction filtration. The filter pad was washed sequentially with H2O (2×0.5 L), cold absolute EtOH (100 mL), and Et2O (2×250 mL). Drying in high vacuum at elevated temperature gave the title compound (15.38 g, 62%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=2.0 Hz, 1H), 7.75 (dd, J=8.7, 2.0 Hz, 1H), 7.43 (d, J=15.8 Hz, 1H), 6.53 (s, 2H), 6.45 (d, J=8.7 Hz, 1H), 6.22 (d, J=15.8 Hz, 1H); MS (ES) m/e 165 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.COCN[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[CH3:26][C:23]([O:22][C:21](=[O:27])[NH:20][CH2:19][CH2:18][CH2:17][C:16]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)=[O:28])([CH3:24])[CH3:25]
Reactant: COCNC(=O)CCCNC(=O)OC(C)(C)C
Reactant: Cn1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ccnc1C(=O)CCCNC(=O)OC(C)(C)C
Temperature: -70 °C
Yield: 61 %

Procedure:
N-methylimidazole (0.83 g, 10.1 mmol) was dissolved in anhydrous tetrahydrofuran (30 ml) and the solution cooled to −70° C. n-Butyllithium (2.29M, 3.48 ml, 10.1 mmol) was added dropwise and the solution stirred for 0.5hat −70° C. 1,1-Dimethylethyl [4-(methoxymethylamino)-4-oxobutyl]-carbamate (1.24 g, 5.03 mmol) as a solution in tetrahydrofuran (50 ml) was added dropwise and the resultant solution stirred at −70° C. for 1 h. The cooling bath was removed and the reaction mixture allowed to warm to 0° C. The reaction was quenched with saturated aqueous ammonium chloride solution (30 ml) and extracted with ethyl acetate (3×70 ml). The combined extracts were washed with water (2×20 ml), dried (magnesium sulphate) and evaporated. The residue was eluted down a flash chromatography column eluting with hexane:ethyl acetate (3:1) to afford the sub-title compound as a pale straw-coloured oil (0.82 g, 61%);
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2([OH:17])[CH2:15][CH2:14][O:13][CH:12]2[CH3:16])=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:20]([N:23]([CH3:25])[CH3:24])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2([OH:17])[CH2:15][CH2:14][O:13][CH:12]2[CH3:16])=[CH:8][C:9]=1[N:10]=[CH:20][N:23]([CH3:25])[CH3:24])=[O:4]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1sc(C2(O)CCOC2C)cc1N
Product: COC(=O)c1sc(C2(O)CCOC2C)cc1N=CN(C)C

Procedure:
3-Amino-5-(3-hydroxy-2-methyltetrahydrofuran-3-yl)thiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 312.39 (C14H20N2O4S) was obtained in this way; MS (ESI): 313 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:37](O)=[O:38])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:74][CH2:75][C:76]1[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:77]=1[C:78]([O:80][CH2:81][CH3:82])=[O:79]>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:37]([NH:74][CH2:75][C:76]2[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:77]=2[C:78]([O:80][CH2:81][CH3:82])=[O:79])=[O:38])=[N:11][C:12]([N:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:23][CH2:24]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCCN1CCN(c2nc(C(=O)O)c(OCc3ccccc3)c3ncccc23)CC1
Reactant: CCOC(=O)c1cc(F)ccc1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCN(CCCCNC(=O)OC(C)(C)C)CC2)c2cccnc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.9 %

Procedure:
8-(Benzyloxy)-5-(4-(4-(tert-butoxycarbonylamino)butyl)piperazin-1-yl)-1,6-naphthyridine-7-carboxylic acid (Example 4.2; 1.4 mmol) was dissolved in dichloro methane (14 ml). DIPEA (5.4 mmol) and HBTU (1.6 mmol) were added. The reaction mixture was stirred at room temperature during 5 min. Ethyl 2-(aminomethyl)-5-fluorobenzoate hydrochloride (Example 4; 1.6 mmol) was added portionwise at room temperature. The mixture was stirred overnight at room temperature. The mixture was diluted with CH2Cl2 and washed with a saturated aqueous Na2CO3 solution (2×) and H2O. The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was purified by flash column chromatography over silica gel (eluent: hexane/EtOAc 10:1 up to 1:1) to afford 0.97 gr of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[Cl:19][C:20]1[N:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[Cl:19][C:20]1[N:25]=[CH:24][C:23]([S:26]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:11])[CH3:1])[CH2:6][CH2:7]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CN(C)CCN1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
To a solution of N,N-dimethyl-N-(2-piperazin-1-ylethyl)amine (0.80 g, 5.0 mmol) and triethylamine (1.0 g, 10 mmol) in dichloromethane (7 mL) was added 6-chloropyridine-3-sulfonyl chloride (1.0 g, 5.0 mmol; described in: Naegeli et al. Helv. Chim. Acta, 1938, 21, 1746, 1750) in dichloromethane (3 mL) at room temperature. After stirring over night at room temperature the solvent was removed in vacuo, the residue was partitioned between aqueous sodium hydroxide (2 M), diethyl ether (3×15 mL), and dichloromethane (3×15 mL). The combined extracts were dried (MgSO4), and the solvents were removed in vacuo to afford 1.3 g of the crude product. The residue was purified on a silica gel column using acetonitrile/triethylamine, (90:10), as the eluent to afford 1.0 g (60% yield) of title compound: 1H NMR (CDCl3, 400 MHz) δ 8.73 (d, J=2 Hz, 1H), 7.95 (dd, J=8, 2 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 3.08 (t, J=5 Hz, 4H), 2.56 (t, J=5 Hz, 4H), 2.47 (t, J=7 Hz, 2H), 2.35 (t, J=7 Hz, 2H), 2.19 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 155.8, 148.8, 137.8, 131.3, 124.6, 56.7, 56.0, 52.4, 45.8, 45.8.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][NH2:15])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 23 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A suspension of 1-benzyl-4-phenylpiperidine-4-carbonitrile (2.0 g, 6.39 mmol) in THF (25 mL) was slowly added to a suspension of lithium aluminum hydride (0.340 g, 8.95 mmol) in THF (10 mL) and the reaction was stirred at 23° C. for 3 hours. The reaction was then quenched with sodium sulfate decahydrate and stirred for 30 minutes. Ethyl acetate was added and the reaction was stirred for 10 more minutes, and then filtered on celite. The filtrate was concentrated to give an oil (1.45 g, 81%) which was used as such for the next reaction. 1H NMR (400 MHz, CDCl3) δ ppm: 1.81-1.91 (2H, m), 2.23-2.28 (4H, m), 2.65-2.67 (2H, m), 2.78 (2H, s), 3.45 (2H, s), 7.23-7.34 (8H, m), 7.36-7.41 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([C:10]([O-:12])=O)[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH2:18][CH2:17]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([C:10]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([F:13])=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)=[O:12])[CH:3]=1
Reactant: Fc1ccc2c(c1)CCN2
Reactant: COc1cc(Cl)cc(C(=O)[O-])n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C(=O)N2CCc3cc(F)ccc32)n1

Procedure:
550 mg (2.93 mmol) 4-chloro-6-methoxy-pyridine-2-carboxylate, 411 mg (3.00 mmol) 5-fluoroindoline, 1.06 g (3.30 mmol) TBTU and 927 μL (6.60 mmol) triethylamine in 5.00 mL DMF were stirred for 3 h at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and evaporated down using the rotary evaporator.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[C:13]1(OB(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)Oc1ccccc1
Reactant: Oc1ccc2cc(Br)ccc2c1
Product: Oc1ccc2cc(-c3ccccc3)ccc2c1
Reaction time: 20 h
Yield: 87 %

Procedure:
The compound is prepared by the reaction of 6-bromo-2-naphthol (500 mg, 2.24 mmol, 1 eq) with phenylboric acid (1 eq) according to method A within 20 h. Purification by column chromatography with hexane/ethyl acetate 7/3 as the eluent yields the desired product in a yield of 87%, 429 mg.
Reaction SMILES: [N+:1]([O-])([OH:3])=[O:2].S(=O)(=O)(O)O.[C:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH3:21])=[CH:15][CH:14]=1)([OH:12])=[O:11]>>[C:10]([C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH3:21])=[C:17]([N+:1]([O-:3])=[O:2])[CH:18]=1)([OH:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: CC(=Cc1ccc(C(=O)O)cc1)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CC(=Cc1ccc(C(=O)O)cc1[N+](=O)[O-])[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Fuming nitric acid (95-98% w/w, 3.7 ml) was added dropwise with stirring to concentrated sulphuric acid (98% w/w, 30 ml), whilst maintaining the temperature at 0°-10° C. 1-(4-Carboxyphenyl)-2-nitropropene (15.3 g) was then added in portions with vigorous stirring over 15 minutes, whilst maintaining the temperature at 0°-10° C. The mixture was stirred for 30 minutes at the same temperature. The viscous reaction mixture was poured onto an ice/water mixture (600 ml) and the resulting yellow solid was filtered off and washed with water to give 1-(4-carboxy-2-nitrophenyl)-2-nitropropene (17.17 g), m.p. 200°-202° C. (with decomposition).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[N:26]=[C:27]=[O:28]>O1CCOCC1>[C:13]([C:12]1[CH:11]=[C:10]([NH:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([N:2]([CH3:1])[C:27]([NH:26][C:20]3[C:19]([Cl:18])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:25])=[O:28])[CH:4]=2)[CH:17]=[CH:16][CH:15]=1)#[N:14]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CNc1cc(Nc2cccc(C#N)c2)ncn1
Solvent: C1COCCO1
Product: CN(C(=O)Nc1c(Cl)cccc1Cl)c1cc(Nc2cccc(C#N)c2)ncn1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-(6-methylamino-pyrimidin-4-ylamino)-benzonitrile (450.5 mg, 2 mmol), 2,6-dichlorophenyl isocyanate (413.6 mg, 2.2 mmol) in dry dioxane (5 mL) is shaken for 1.5 h at 80° C. and then evaporated in vacuo. The residue is suspended in half-concentrated aqueous K2CO3 solution, filtered off, washed with H2O and acetone and dried in vacuo to afford the title compound.
Reaction SMILES: O[C:2]1[CH:3]=[N:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[CH:3]=[N:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Oc1cnc2ccccc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Clc1cnc2ccccc2n1
Yield: 87.5 %

Procedure:
A mixture of 74 g (0.5 mole) of 2-hydroxy-benzopyrazine, 12 g of dimethylaniline and 250 ml of phosphorus oxychloride was heated under reflux for 10 minutes. At about 80° C, all the material had dissolved; the reaction solution was cooled and poured onto ice, and the product was filtered off. The residue was dried on clay and was then taken up in petroleum ether, and the solution was filtered through active charcoal. The reaction solution was evaporated and 78 g (87.5% of theory) of 2-chloro-benzopyrazine of melting point 48°-49° C, were obtained. ##STR33##