Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[C:20]([OH:27])(=[O:26])[C:21]#[C:22][CH2:23][CH2:24][CH3:25]>N1CCCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[CH2:6][O:5][C:4]1[CH:3]=[C:2]([C:25]#[C:24][CH2:23][CH2:22][CH2:21][C:20]([OH:27])=[O:26])[CH:19]=[CH:18][CH:17]=1
Reactant: CCCC#CC(=O)O
Reactant: Ic1cccc(OCc2ccc3ccccc3c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Product: O=C(O)CCCC#Cc1cccc(OCc2ccc3ccccc3c2)c1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A solution of 2-(3-iodophenoxymethyl)-naphthalene (0.5 g, 1.4 mmol) and hexynoic acid (0.19 g, 1.7 mmol) in piperidine (5 mL) is purged with Argon for 20 minutes. Then bis(triphenylphosphine)palladium dichloride (0.01 g, 0.014 mmol) and cuprous iodide (0.005 g, 0.028 mmol) are added and this mixture heated in an oil bath at 75° C. for 1.5 hours and then allowed to come to room temperature overnight. The solvent was removed in vacuo and the residue purified by flash chromatography (silica, 4% methanol in dichloromethane) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.83-7.88 (m, 4H), 7.48-7.54 (m, 3H), 7.19 (t, 1H), 6.98-7.05 (m, 3H), 5.21 (s, 2H), 2.47 (t, 2H), 1.80-1.91 (m, 4H); MS (EI) 344 (M)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CC)=[N+:2]=[N-:3].[CH2:22](C1C=CC(C(Cl)=O)=CC=1)[CH2:23]CCCCC.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:23][CH:22]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: CCCCCCCc1ccc(C(=O)Cl)cc1
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 75 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 4-heptylbenzoyl chloride (0.289 g, 1.21 mmol) was reacted with 2-azidoethanamine (0.104 g, 1.21 mmol) and triethylamine (0.245 g, 2.42 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-heptylbenzamide (0.260 g, 75%). 1H NMR (300 MHz, CDCl3) δ 7.73 (d, 2H), δ 7.19 (d, 3H), δ 3.57 (q, 2H), δ 3.47 (t, 2H), δ 2.61 (t, 2H), δ 1.61 (m, 2H), δ 1.26 (m, 8H), δ 0.87 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.3, 147.3, 131.7, 128.8, 127.4, 50.9, 39.7, 36.1, 32.0, 31.4, 29.4, 29.3, 22.9, 14.3 ppm; HRMS (ESI) calcd for C16H24N4O (M+) 288.1950. found 288.1943.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].I[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CCCCCCI
Agent: [Na+]
Product: CCCCCCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12

Procedure:
In the same manner as in Example 81, 162 mg of the title compound was prepared from 218 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 0.095 ml of 1-iodohexane.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]2([CH2:9][CH2:8][NH:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH:28]([CH3:30])[CH3:29])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:7]2[CH2:8][CH2:9][C:5]3([N:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2][CH2:3][CH2:4]3)[CH2:6]2)=[CH:19][C:20]=1[O:27][CH:28]([CH3:30])[CH3:29])([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCCC12CCNC2
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(N2CCC3(CCCN3C(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
A mixture of 3.0 g of tert-butyl 1,7-diazaspiro[4.4]nonane-1-carboxylate and 2.64 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene (obtained according to method 6), and 2.75 g of potassium carbonate in DMSO is stirred at ambient temperature overnight. The mixture is taken up with ethyl acetate and washed twice with 10 volumes of water. The organic phase is dried over magnesium sulfate and concentrated under vacuum. The crude product is purified on 120 g of silica, elution being carried out with dichloromethane, so as to obtain 3.40 g of 2-methylpropan-2-yl 7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane-1-carboxylate in the form of a dark yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([N+:15]([O-])=O)[N:12]=[C:11]1[CH3:18])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([NH2:15])[N:12]=[C:11]1[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc([N+](=O)[O-])cn1CCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: Cc1nc(N)cn1CCNC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 78 %

Procedure:
10% wt Pd/C (0.17 g 0.16 mmol) was added to a solution of compound 40.1 (0.44 g, 1.6 mmol) in MeOH (10 mL). The resulting reaction mixture was stirred under a hydrogen atmosphere (1 atm via a balloon). After 2 hours, the reaction mixture was filtered thru a plug of Celite and the resulting filtrate concentrated to provide [2-(4-amino-2-methyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (compound 40.2; 0.3 g, 77%). ES (+) MS m/e=241(M+1).
Reaction SMILES: [CH2:1]([O:8][N:9]1C(=O)C2C(=CC=CC=2)C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>>[CH2:1]([O:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccccc1
Agent: NN
Solvent: O
Product: NOCc1ccccc1
Yield: 64 %

Procedure:
The title compound was prepared from 2-(benzyloxy)isoindoline-1,3-dione and hydrazine monohydrate in 64% yield using the same procedure as described in the synthesis of intermediate G. 1H-NMR (400 MHz, CDCl3) δ ppm 7.37 (m, 5H), 6.70 (s, 2H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH2:16][C:17](=[O:29])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH:9]=1)[C:4](O)=[O:5])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.CC(C)([O-])C.[K+].[CH2:50]([C@H:57]1[CH2:61][O:60][C:59](=[O:62])[NH:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>O1CCCC1>[CH2:1]([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH2:16][C:17](=[O:29])[NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=2)[CH:9]=1)[C:4]([N:58]1[C@@H:57]([CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:61][O:60][C:59]1=[O:62])=[O:5])[CH3:2]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCC(Cc1ccc(OC)c(CC(=O)Nc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(Cc1ccc(OC)c(CC(=O)Nc2ccc(C(F)(F)F)cc2)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Yield: 13.4 %

Procedure:
(±)-2-Ethyl-3-[4-methoxy-3-[[N-[4-(trifluoromethyl)phenyl]carbamoyl]methyl]phenyl]propanoic acid (compound in Example 88: 14.2 g, 34.7 mmol) and dehydrated tetrahydrofuran (100 mL) were mixed under an argon atmosphere, and triethylamine (4.86 ml, 35.0 mmol) and pivaloyl chloride (4.27 mL, 34.7 mmol) were added dropwise under stirring and cooling with ice. Thereafter, the mixture was stirred for 1 hour at room temperature to synthesize mixed acid anhydride. On the other hand, potassium tert-butoxide (4.67 g, 41.6 mmol) and dehydrated tetrahydrofuran (45 mL) were mixed under cooling with ice and argon atmosphere in another vassel, and (S)-4-benzyl-oxazolidine-2-one (7.38 g, 41.6 mmol) dissolved into dehydrated tetrahydrofuran (60 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred for 30 minutes. Next, a suspension of the mixed acid anhydride synthesized previously was added dropwise while filtering under an atmosphere of argon. After completion of the drop-wise addition, the reaction mixture was concentrated and then poured in water, which was extracted with ethyl acetate. The extracte was washed with 5% hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate and brine, then dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by means of silica gel column chromatography (eluent: isopropyl ether) to afford 2.65 g (13%) of (4S)-3-[2-ethyl-3-[4-methoxy-3-[[N-[4-(trifluoromethyl)phenyl]carbamoyl]methyl]phenyl]-propanoyl]-4-benzyloxazolidine-2-one with high polarity as a oily product. Also, 3.84 g (20%) of (4S)-3-[2-ethyl-3-[4-methoxy-3-[[N-[4-(trifluoromethyl)phenyl]carbamoyl]-methyl]phenyl]propanoyl]-4-benzyloxazolidine-2-one with low polarity were obtained by purifying by silica gel column chromatography, followed by further recrystallization from a mixed solvent of n-hexane with isopropyl ether, as colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[N+:6]([O-:26])[CH:7]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(F)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(F)c[n+]1[O-]
Reaction time: 4.5 h
Yield: 88.6 %

Procedure:
To a solution of tert-butyl [(1R)-1-(5-fluoropyridin-2-yl)ethyl]carbamate (5.77 g, 24.0 mmol) in dichloromethane (96 mL) was added 3-chloroperbenzoic acid (6.51 g, 26.4 mmol). After 4.5 h, excess 3-chloroperbenzoic acid (0.59 g, 2.6 mmol) was added. After 72 h, saturated aqueous sodium sulfite was added. After 1 h, saturated aqueous sodium bicarbonate was added. The organic layer was isolated and the aqueous layer was extracted with dichloromethane (2×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol with 1% ammonium hydroxide) gave the title compound (5.45 g). MS 257.1 (M+1).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].C(N[C:18]1[CH:27]=[C:26]([NH:28][C:29](=[O:33])[CH2:30][CH2:31][CH3:32])[C:25]([O:34]C(=O)CCC)=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH3:40])=[N:23]2)(=O)CCC.[OH2:41]>C(O)(=O)C>[C:29]([NH:28][C:26]1[C:25](=[O:34])[C:24]2[N:23]=[C:22]([CH3:40])[CH:21]=[CH:20][C:19]=2[C:18](=[O:41])[CH:27]=1)(=[O:33])[CH2:30][CH2:31][CH3:32]
Reactant: CCCC(=O)Nc1cc(NC(=O)CCC)c2ccc(C)nc2c1OC(=O)CCC
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCCC(=O)NC1=CC(=O)c2ccc(C)nc2C1=O
Yield: 77 %

Procedure:
This compound was prepared by the oxidation of the corresponding acylamido with potassium dichromate in glacial acetic acid. In a 500 ml. round-bottomed flask equipped with a magnetic bar, 5,7-dibutyramido-8-butyroxy-2-methylquinoline (34) (prepared as described in Examples 31-34) (3.29 g., 8.25 mmol) was suspended in 122 ml of glacial acetic acid. A solution of potassium dichromate (8.8 g., 0.03 mol) in 115 ml. of water was added and stirred. The stirred suspension began to dissolve but, after two hours, more solid continued to precipitate. Dichloromethane (70 ml.) was added to promote solution. The resulting two-phase solution mixture was stirred at room temperature overnight. The two-phase solution mixture was extracted with dichloromethane (12×50 ml.). The organic extracts were washed with a 3% sodium bicarbonate solution (200 ml.), dried with magnesium sulfate, and rotoevaporated to yield an orange-yellow solid. After vacuum drying, the solid weighed 1.65 g. (a yield of 77%). The product was recrystallized from ethyl acetate: mp. 188-189EC; 1H NMR (CDCl3) 1.00 (3H, t, J=7.4 Hz, C-7NHCOCH2CH2CH3), 1.69-1.82 (2H, m, C-7NHCOCH2CH2CH3), 2.48 (2H, t, J=7.4 Hz, C-7NHCOCH2CH2CH3), 2.74 (3H, s, C-2CH3), 7.53 (1H, d, J=8.0 Hz, C-3H), 7.90 (1H, s, C-6H), 8.28 (1H, d, J=8.0 Hz, C-4H), 8.36 (1H, br. s, C-7NH); IR (KBr) vmax 3338, 3275, 2964, 2935, 2875, 1711, 1682, 1654, 1644, 1615, 1588, 1502, 1323, 1310, 1133 cm−1; EIMS, m/e (relative intensity) 258 (81), 215 (7), 188 (base), 161 (66); HRMS, m/e for C14H14N2O3 calculated 258.100442, found 258.100227; analysis for C14H14N2O3 calculated C, 65.11; H, 5.46; N, 10.85; found C, 65.22; H. 5.51; N 10.01.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.C(N(C(C)C)CC)(C)C.[N:24]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[OH:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][N:27]2[CH2:26][CH2:25][N:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:29][CH2:28]2)=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: Oc1ccc(CCl)c2cccnc12
Reactant: CCOC(=O)N1CCNCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(Cc2ccc(O)c3ncccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
To a mixture of 5-chloromethyl-8-hydroxyquinoline hydrochloride (A2) (2.36 g, 10.2 mmol) and diisopropylethylamine (3.6 ml, 20.4 mmol, 2 eq) in 50 ml CHCl3 at 0° C., ethyl 1-piperazinecarboxylate (1.5 ml, 10.2 mmol, 1 eq) was added. The mixture was stirred for 24 h at room temperature, and then 100 ml of CHCl3 was added and the solution was washed with 5% NaHCO3 (3×50 ml), brine (2×50 ml), and then dried over Na2SO4. The solution was filtered and evaporated to dryness. The residue was crystallized from a mixture of benzene-hexane (1:1) to yield the title compound HLA16 as white solid. (1.38 g, 42% yield, m.p.=92-93° C.). H1 NMR (250 MHz, CDCl3), 1.25 (dd, J=7.1, 7.1 Hz 3H), 2.42 (s, 4H), 3.43 (s, 4H), 3.81 (s, 2H), 4.14 (dd, J=14.21, 7.12 Hz, 2H), 7.08 (d, J=7.72 Hz, 1H), 7.31 (m, 1H), 7.47 (dd, J=8.52, 4.20 Hz, 1H), 8.66 (dd, J=8.56, 1.58 Hz, 1H), 8.79 (dd, J=4.18. 1.54 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[C:13]([OH:19])[C:14]([OH:18])=[CH:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O:22][C:23](=[O:27])[CH:24](Cl)Cl)C.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CO.COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]3[O:18][CH:24]([C:23]([OH:27])=[O:22])[O:19][C:13]=3[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(O)c(O)cc1S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: Cc1cc2c(cc1S(=O)(=O)c1ccc(Cl)cc1)OC(C(=O)O)O2

Procedure:
In a manner analogous to that described in Example 4, using 25.0 g (83.7 mmol) of 4-(4-chlorophenylsulphonyl)-5-methyl-1,2-benzenediol, 13.2 g (83.7 mmol) of dichloroacetic acid ethyl ester, 57 g (418 mmol) of potassium carbonate and 220 ml of 1,2-dimethoxyethane, with subsequent hydrolysis with sodium hydroxide solution in methanol, the desired 5-(4-chlorophenylsulphonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is obtained in the form of white crystals having a melting point of 169°-171° (from 1,2-dichloroethane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]([CH2:18][CH2:19]Cl)[CH3:17])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH2:21]([NH2:24])[CH2:22][NH2:23].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]([CH3:17])[CH2:18][CH2:19][N:23]3[CH2:22][CH2:21][NH:24][C:7]3([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:15]=1
Reactant: CN(CCCl)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NCCN
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCN2CCNC2(c2ccccc2)c2cc(Cl)ccc21

Procedure:
A solution of 5.0 g. (16 mmole) of 5-chloro-2-(2-chloroethylmethylamino)benzophenone, 3.0 g. (50 mmole) of ethylenediamine, 50 ml. of triethylamine and 250 ml. of ethanol was stirred at reflux for 48 hours. The solvents were removed by evaporation and the residue containing starting material and the product was washed with water, chromatographed over Florisil, and recrystallized from petroleum ether to give the above-titled product as yellow prisms, m.p. 100°-102°.
Reaction SMILES: [C:1]([O:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([O-])=[O:5].C(Cl)(=O)C(Cl)=O>>[OH:5][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([O:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18])=[O:11]
Reactant: CCCCC=COC(=O)c1ccccc1C(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Product: CC/C=C\CCOC(=O)c1ccccc1CO
Reaction time: 2.5 h
Yield: 31.8 %

Procedure:
1 g (4.03 mmol) monohexenyl phthalate was heated at reflux in 6 ml oxalyl chloride (17.3 eq.) for 1.5 h. The excess oxalyl chloride was distilled under vacuum. The crude acid chloride was then diluted in 10 ml dichloromethane cooled to 0° under argon, and introduced dropwise on a solution of 2.07 g (2 eq.) nBuNBH4 in 10 ml dichloromethane. The reaction mixture was maintained under stirring at 0° for 2.5 h. The mixture was then poured over 5% KHSO4 and cold ethyl ethyl acetate, and extracted. Chromatography of the crude product over silica gel (85:15 cyclohexane/AcOEt) yielded 0.3 g (32%) (Z)-3-hexenyl 2-hydroxymethylbenzoate containing about 10% phthalide, in the form of a colourless oil.
Reaction SMILES: [CH2:1]1[O:25][C:4]2=[CH:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=4[Cl:22])=[N:11][NH:10][C:9](=[O:23])[CH2:8][C:7]=3[CH:24]=[C:3]2[O:2]1.C(O)C.CC(C)=O.O>[Pd].C(O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:6]3[CH:5]=[C:4]4[O:25][CH2:1][O:2][C:3]4=[CH:24][C:7]=3[CH2:8][C:9](=[O:23])[NH:10][N:11]=2)=[C:14]([Cl:22])[CH:15]=1
Reactant: O=C1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2Cl)=NN1)OCO3
Agent: [Pd]
Solvent: CC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21 %

Procedure:
To a suspension of 7,8-methylenedioxy-1-(2-chloro-4-nitrophenyl)-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (1.4 g, 3.9 mmol) in 1:1:1 ethanol/acetone/water (45 mL) was added 5% Pd/C (106 mg) and HCO2NH4 (2.5 g, 40 mmol). The mixture was stirred at room temperature for 3 h and 15 mL of ethanol was added to the mixture which was then stirred at room temperature for three days. The catalyst was filtered out. The filtrate was extracted with EtOAc (100 mL). The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (1:4 hexane/EtOAc) to afford the title compound as a light yellow solid (0.27 g, 0.82 mmol, 21%), mp: 238°-240° C. 1H NMR (CDCl3) 8.34 (s, 1H), 7.41 (d, J=8.6, 1H), 6.81 (s, 1H), 6.69-6.67 (m, 3H), 6.02 (s, 2H), 3.92 (s, 2H), 3.42 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)=[CH:14][CH:15]=3)[C:10]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[CH:9]2)=[CH:4][CH:3]=1.[C:29](#[N:32])[CH:30]=[CH2:31]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)=[CH:14][CH:15]=3)[C:10]([C:23]3[CH2:24][CH2:25][N:26]([CH2:31][CH2:30][C:29]#[N:32])[CH2:27][CH:28]=3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Cn1nnc(-c2ccc3c(c2)c(C2=CCNCC2)cn3-c2ccc(F)cc2)n1
Reactant: C=CC#N
Solvent: ClCCl
Product: Cn1nnc(-c2ccc3c(c2)c(C2=CCN(CCC#N)CC2)cn3-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-fluorophenyl)-5-(2-methyl-5-tetrazolyl)-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (21a), (10.2 g) in dichloromethane (100 mL) was added acrylonitril (7.5 g). The mixture was stirred at room temperature for 16 hours. After evaporation of the solvent, the crude title compound 15a remained as a viscous oil which was used without further purification. Yield 12 g.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([N:29]([CH3:40])[C:30](=[O:39])[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36]CO)[CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[Br:5][CH2:2][CH2:36][CH2:35][CH2:34][CH2:33][O:32][CH2:31][C:30]([N:29]([CH2:25][CH2:26][CH2:27][CH3:28])[CH3:40])=[O:39]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCN(C)C(=O)COCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCN(C)C(=O)COCCCCCBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
13 g of tetrabromo-methane and 10.3 g of triphenyl-phosphine were added at -10° C. to a solution of 7.2 g of the product of Step C in 73 ml of methylene chloride. The reaction medium was stirred for one hour at 0° C. and chromatographed on silica (eluant: ethyl acetate-cyclohexane 7-3) to obtain 7.49 g of the desired compound.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]2=[N:18][C:19](=[O:21])[N:20]=[C:16]2[CH:15]=1>C(O)C>[O:12]=[C:4]1[NH:5][C:6]2[C:11](/[C:3]/1=[CH:2]/[NH:13][C:14]1[CH:23]=[CH:22][C:17]3[NH:18][C:19](=[O:21])[NH:20][C:16]=3[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C1Nc2ccccc2C1=CO
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Solvent: CCO
Product: O=C1Nc2ccccc2/C1=C/Nc1ccc2[nH]c(=O)[nH]c2c1
Yield: 51.3 %

Procedure:
A solution of 161 mg (1.00 mMol) of 3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one, 149 mg (1.00 mMol) of 5-aminobenzimidazolone, and 5 ml of ethanol was heated at 55° C. for 1.5 hr. The resulting solid was isolated by filtration and recrystallized from DMSO/methanol to yield 150 mg (51%) of a yellow solid, 1H NMR (DMSO-d6): δ6.80 (d, J=7.7 Hz, 1H), 6.85-6.98 (m, 4H), 7.00 (s, 1H), 7.54 (d, J=7.4 Hz, 1H), 8.50 (d, J=12.7 Hz, 1H), 10.39 (s, 1H), 10.56 (s, 1H), 10.72 (d, J=12.7 Hz, 1H), 10.74 (s, 1H); APCI-MS m/z291 (M−H)−.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23]([OH:25])=O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23]([NH:31][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[O:25])=[O:18])=[CH:29][CH:30]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cccc(C(=O)O)c1
Reactant: NCCc1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cccc(C(=O)NCCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.9 %

Procedure:
To a solution of 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid (50 mg, 0.123 mmol), 4-(2-aminoethyl)pyridine (22.59 mg, 0.184 mmol) and DIPEA (23.90 mg, 0.184 mmol) in DMF 1 mL was added EDC (35.45 mg, 0.184 mmol) and HOBt (24.99 mg, 0.184 mmol) at room temperature and continued stirring for 16 h at room temperature. Reaction mixture was diluted with ethyl acetate and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by column chromatography on silica gel (n-Hexane:EtoAC=1:5) to give 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-(2-pyridine-4-yl-ethyl)benzamide as a colorless crystal (25 mg, 40% yield).