Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][NH:9][C:10]([C:12]1[CH:36]=[CH:35][C:15]([O:16][C:17]([C:19]2([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=3)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:14][CH:13]=1)=[O:11])C1C=CC=CC=1>[Pd].CO.C(OCC)C>[OH:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]([C:19]2([C:25]3[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=3)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[O:18])=[CH:35][CH:36]=1)=[O:11]
Reactant: COC(=O)c1ccc(C2(C(=O)Oc3ccc(C(=O)NOCc4ccccc4)cc3)CCCCC2)cc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1ccc(C2(C(=O)Oc3ccc(C(=O)NO)cc3)CCCCC2)cc1
Reaction time: 0.83 h
Yield: 64.4 %

Procedure:
A mixture of methyl 4-{1-[(4-{[(benzyloxy)amino]carbonyl}phenoxy)carbonyl] cyclohexyl)-benzoate (E23) (0.063 g, 0.129 mmol) and 5% palladium on activated carbon (0.026 g) in methanol (1 ml) was hydrogenated at room temperature for 50 minutes. The black suspension was filtered, the catalyst was washed with methanol (3×1 ml), and the filtrate was evaporated to give a viscous oil. The oil was converted to white crystals by stirring in diethyl ether (3 ml) overnight. The solid was filtered, washed with diethyl ether (0.5 ml), and dried in vacuum to give the title compound (0.033 g, 64%) as white crystals, m.p. 129-131° C. 1H NMR (DMSO-d6, HMDSO) δ: 1.13-1.99 (8H, m); 2.35-2.58 (2H, m, overlapped with a signal of DMSO); 3.86 (3H, s); 7.05 (2H, d, J=8.6 Hz); 7.65 (2H, d, J=8.4 Hz); 7.77 (2H, d, J=8.6 Hz); 8.01 (2H, d, J=8.4 Hz); 9.07 (1H, s); 11.25 (1H, s). HPLC analysis on Symmetry C8 column: impurities 2.5% (column size 3.9×150 mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 60:40; detector UV 254 nm; sample concentration 0.5 mg/ml; flow rate 1.0 ml/min). Anal. Calcd for C22H23NO6*0.35H2O, %: C, 65.45; H, 5.92; N, 3.47. Found, %: C, 65.17; H, 5.76; N, 3.49.
Reaction SMILES: C([NH:4][C:5]1[C:13]2[CH:12]3[CH2:14][CH2:15][CH2:16][CH2:17][CH:11]3[O:10][C:9]=2[C:8]([C:18]([O:20]C)=[O:19])=[CH:7][C:6]=1[Cl:22])(=O)C.C([NH:26][C:27]1[C:35]2[C:34]3[CH2:36][CH2:37][CH2:38][CH2:39][C:33]=3[O:32][C:31]=2[C:30]([C:40]([O:42]C)=[O:41])=[CH:29][C:28]=1[Cl:44])(=O)C.C(NC1C2C3C=CC=CC=3OC=2C(C(OC)=O)=CC=1Cl)(=O)C>>[NH2:4][C:5]1[C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][C:9]=2[C:8]([C:18]([OH:20])=[O:19])=[CH:7][C:6]=1[Cl:22].[NH2:26][C:27]1[C:35]2[C:34]3[CH2:36][CH2:37][CH2:38][CH2:39][C:33]=3[O:32][C:31]=2[C:30]([C:40]([OH:42])=[O:41])=[CH:29][C:28]=1[Cl:44]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c2c3c(oc12)CCCC3
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OC1CCCCC21
Agent: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1oc1ccccc12
Product: Nc1c(Cl)cc(C(=O)O)c2oc3c(c12)CCCC3
Product: Nc1c(Cl)cc(C(=O)O)c2oc3ccccc3c12

Procedure:
When the procedure of Example 15 is followed however methyl 1-acetylamino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate is replaced by methyl 1-acetylamino-2-chloro-6,7,8,9-tetrahydro-dibenzofuran-4-carboxylate or methyl 1-acetylamino-2-chlorodibenzofuran-4-carboxylate then the captioned products are prepared.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.[CH3:9][CH:10]([CH3:29])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:28])[C:19]([O:21][CH2:22][CH2:23][CH2:24][C:25]([O-:27])=[O:26])=[O:20])=[CH:14][CH:13]=1.IC1C=CC=CC=1>>[CH3:9][CH:10]([CH3:29])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH3:28])[C:19]([O:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:4]2([N:7]=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:26])=[O:20])=[CH:16][CH:17]=1
Reactant: CC(C)Cc1ccc(C(C)C(=O)OCCCC(=O)[O-])cc1
Reactant: ON=C1CCOCC1
Solvent: Ic1ccccc1
Product: CC(C)Cc1ccc(C(C)C(=O)OCCCC(=O)OC2(N=O)CCOCC2)cc1

Procedure:
4-Nitrosotetrahydro-2H-pyran-4-yl 4-({2-[4-(2-methylpropyl)phenyl]propanoyl}oxy)butanoate was prepared from tetrahydropyran-4-one oxime and bis 4-({2-[4-(2methylpropyl)phenyl]propanoyl}oxy)butanoate) iodobenzene (synthesized from 4-({2-[4-(2-methylpropyl)phenyl]propanoyl}oxy)butanoic acid and iodobenzene diacetate) and using conditions of General Method 4. 1H NMR (250 MHz, CHLOROFORM-d) δ 7.16-7.25 (2H, m), 7.03-7.14 (2H, m), 4.15 (2H, dt, 12.3, 6.2 Hz), 3.98-4.09 (2H, m), 3.59-3.79 (3H, m), 2.40-2.53 (4H, m), 2.27-2.37 (1H, m), 2.11-2.28 (1H, m), 1.74-2.07 (5H, m), 1.50 (3H, dd, 7.2, 4.3 Hz), 0.90 (6H, d, 6.2 Hz).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH:18]=1>>[N:12]1[CH:11]=[CH:10][C:9]([NH:8][C:7]2[C:6](=[O:15])[C:5](=[O:16])[C:4]=2[NH:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][O:23][C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Reactant: NCCCCCCOc1cccnc1
Product: O=c1c(NCCCCCCOc2cccnc2)c(Nc2ccncc2)c1=O

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 6-(pyridin-3-yloxy)-hexylamine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][N:5]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1.C(Cl)Cl>[ClH:1].[ClH:1].[C:14]1([CH2:13][N:20]2[CH2:21][CH2:22][N:23]([CH2:2][CH2:3][C:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[O:6][N:5]=3)[CH2:24][CH2:25]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: ClCCc1noc2ccccc12
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: Cl
Product: c1ccc(CN2CCN(CCc3noc4ccccc34)CC2)cc1
Temperature: 150 °C

Procedure:
A mixture of 3-(2-chloroethyl)-1,2-benzisoxazole (0.55 g, 3.03 mmol) and N-benzylpiperazine (1.06 mL, 6.06 mmol) in xylene (4 mL) was heated at 150° C. for 4.75 hours. The cooled mixture was diluted with CH2Cl2 and washed with H2O. The organic layer was dried (MgSO4), filtered and concentrated. Purification by silica gel flash chromatography (50% EtOAc-hexanes→100% EtOAc) gave the title compound, free base (0.337 g, 35%) as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:33]1([CH:43]([NH2:45])[CH3:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>CN1C(=O)CCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:10]([NH:9][C:7](=[O:8])[C:6]1[CH:22]=[CH:23][C:3]([CH2:2][NH:45][CH:43]([C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[CH3:44])=[CH:4][CH:5]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(CCl)cc1
Reactant: CC(N)c1cccc2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCCCCCCCCCCCNC(=O)c1ccc(CNC(C)c2cccc3ccccc23)cc1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
The resin-bound 4-chloromethyl-N-dodecyl-benzamide (described in step b, 0.0426 mmol) was swelled in NMP (0.25 mL) for 15 min at rt. DIEA (33 mg, 0.256 mmol), tetrabutyl-ammonium iodide (94.4 mg, 0.256 mmol) and 1-naphthalen-1-yl-ethylamine (44 mg, 0.256 mmol) dissolved in NMP (0.75 mL) were added and the reaction mixture was shaken 14 h at 80° C. The resin was washed successively with THF (1×15 min), MeOH (1×15 min), THF (1×15 min), MeOH (3×10 min), DMF (3×10 min), MeOH (1×5 min), THF (3×10 min), MeOH (1×5 min), DCM (3×10 min) and with Et2O (1×10 min). The resin was then dried under vacuum to afford the resin-bound N-dodecyl-4-({[1-(1-naphthyl)ethyl]amino}-methyl)benzamide which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]([CH2:19][CH3:20])[S:17][C:16](=[O:21])[NH:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:12])F.Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30]O[CH2:28][CH2:27]1>>[N:26]1([CH2:25][CH2:24][CH2:23][N:15]2[N:14]=[C:13]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH2:10][F:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]([CH2:19][CH3:20])[S:17][C:16]2=[O:21])[CH2:31][CH2:30][CH2:28][CH2:27]1
Reactant: CCC1SC(=O)NN=C1c1ccc(OC(F)F)c(OC)c1
Reactant: ClCCCN1CCOCC1
Product: CCC1SC(=O)N(CCCN2CCCC2)N=C1c1ccc(OCF)c(OC)c1

Procedure:
of 5-(3-methoxy-4-difluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one with 1-chloro-3-morpholinopropane:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:3].[NH2:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[NH:13][C:14](=[O:20])/[CH:15]=[C:16](\[O:18][CH3:19])/[CH3:17].O1CCCC1>C(N(CC)CC)C>[CH2:5]([O:4][C:2]([NH:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[NH:13][C:14](=[O:20])/[CH:15]=[C:16](\[O:18][CH3:19])/[CH3:17])=[O:3])[CH2:6][CH2:7][CH3:8]
Reactant: CO/C(C)=C\C(=O)Nc1cccc(N)c1
Reactant: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOC(=O)Nc1cccc(NC(=O)/C=C(/C)OC)c1
Temperature: 5 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
12 g of n-butyl chloroformate were slowly added to a mixture of 16.5 g of m-amino-3-methoxy-crotonanilide, 320 ml of tetrahydrofuran and 8.9 g of triethylamine cooled to 5° C. and the mixture was stirred for 16 hours and then vacuum filtered. The residue was chromatographed over silica gel and was eluted with an 8- 2 methylene chloride-acetone mixture to obtain 22 g of m-(n-butoxycarbonylamino)-3-methoxy-crotonanilide melting at 100° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH2:45][CH3:46])=[C:37]([F:47])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:45]([O:44][CH2:43][CH2:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][C:37]=1[F:47])[CH3:46]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCOc1ccc(OB([O-])[O-])cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 4-(2-ethoxyethoxy)-3-fluorophenyl borate (145 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 7 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give colorless crystals of 7-[4-(2-ethoxyethoxy)-3-fluorophenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 65) (244 mg).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27](O)(=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CCCCC(=O)O
Agent: Cl
Product: CCCCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (77 mg, 75%), MS (ISP) m/z=413.4 [(M+H)+], mp 186° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and pentanoic acid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[OH-].[Na+].Cl>O1CCCC1.O>[CH2:5]([O:4][C:2](=[O:3])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: NCCc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
Add dropwise via an addition funnel a solution of ethyl chloroformate (0.74 mL, 7.7 mmol) in tetrahydrofuran (7 mL) to a stirred solution of tyramine (1.0 g, 7.3 mmol), sodium hydroxide (0.7 g, 17.1 mmol), and water (7 mL). Stir at room temperature for 18 hours then pour the reaction into 1 N aqueous hydrochloric acid so the pH=1-2. Extract with ethyl acetate (3×25 mL). Dry the combined ethyl acetate extracts over sodium chloride/magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 1.3 g, 6.2 mmol of [2-(4-hydroxy-phenyl)-ethyl]-carbamic acid ethyl ester: 1H NMR (CDCl3, 300.00 MHz): 7.01 (d, 2H); 6.78 (d, 2H); 6.26 (s, 1H); 4.78 (s, 1H); 4.14-4.09 (m, 2H); 3.40-3.38 (m, 2H); 2.74-2.69 (m, 2H); 1.24-1.19 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[Br:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([Cl:16])=[O:6]
Reactant: O=C(O)c1cc(F)c(F)c(Br)c1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(F)c(F)c(Br)c1Cl

Procedure:
A solution of 3-bromo-2-chloro-4,5-difluorobenzoic acid (9.0 g) in thionyl chloride (33 ml) was refluxed for 2.5 hours, and then concentrated. The resulting residue was purified by distillation to give the title compound (8.8 g), bp 109° C./22 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2.C(N(CC)CC)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C)C=O.CN(C)C1C=CN=CC=1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:6][CH2:5]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCc2cc(Br)ccc21
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of 5-bromoindan-1-ol (4.00 g, 18.8 mmol) in N,N-dimethylformamide (25.00 mL) were added triethylamine (5.23 mL, 37.5 mmol), tert-butyldimethylsilyl chloride (4.244 g, 28.16 mmol) and 4-dimethylaminopyridine (115 mg, 0.939 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with ether (100 mL) and quenched with water. The aqueous phase was extracted with ether (4×40 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. Chromatography on silica gel with 5% EtOAc/hexane afforded the desired product (6.05 g, 98%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:34](=[O:37])[CH2:35][CH3:36])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f9) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]1([C@H:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]#[N:18])[CH:11]=[CH:10][C:9]=3[CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][N:4]2[CH2:3][CH2:2][N:1]([C@H:7]3[CH2:16][CH2:15][C:14]4[CH:13]=[C:12]([C:17]#[N:18])[CH:11]=[CH:10][C:9]=4[CH2:8]3)[CH2:6][CH2:5]2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: N#Cc1ccc2c(c1)CC[C@H](N1CCNCC1)C2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)CC[C@H](N1CCN(CCc3ccc([N+](=O)[O-])cc3)CC1)C2

Procedure:
A mixture (6S)-6-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (0.31 mg, 0.13 mmol), 1-(2-bromoethyl)-4-nitrobenzene (80 mg, 0.35 mmol), and triethylamine (0.15 mL, 1.1 mmol) in DMF was heated to 60° C. for 30 hours. LC showed formation of the desired product. The reaction was diluted with EtOAc, washed with water and brine, dried over MgSO4, and purified by MPLC to deliver 13 mg of (65)-6-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}-5,6,7,8-tetrahydronaphthalene-2-carbonitrile. LC-MS (IE, m/z): 391 [M+1]+. (0.083 μM)
Reaction SMILES: [C:1]([C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[NH:8][C:9]([SH:11])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].Cl.[CH2:16]1[CH2:25][O:24][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:26]Cl)[C:18]=2[O:17]1>CO>[C:1]([C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[NH:8][C:9]([S:11][CH2:26][C:19]3[C:18]4[O:17][CH2:16][CH2:25][O:24][C:23]=4[CH:22]=[CH:21][N:20]=3)=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2nc(S)[nH]c2cc1C
Reactant: ClCc1nccc2c1OCCO2
Agent: Cl
Solvent: CO
Product: CC(=O)c1cc2nc(SCc3nccc4c3OCCO4)[nH]c2cc1C
Yield: 79.7 %

Procedure:
To a solution of 5-acetyl-6-methyl-2-mercapto-1H-benzimidazole (0.14 g, 0.66 mmol) in methanol (2 ml) aqueous NaOH (0.25 ml 5M, 1.25 mmol) and 3,4-ethylendioxy-2-chloromethyl pyridine hydrochloride (0.13 g, 0.60 mmol) dissolved in methanol (2 ml) were added in the given order. The mixture was refluxed for one hour whereupon the solution was evaporated. The residue was partitioned between methylene chloride and water. After separation the organic solution was dried over Na2SO4 and evaporated giving a yellow syrup (0.17 g, 81%).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S(Cl)(Cl)=O.N1C=CC=CC=1.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]1[C:49]2[C:40](=[C:41]3[C:46](=[CH:47][CH:48]=2)[CH:45]=[CH:44][CH:43]=[N:42]3)[N:39]=[CH:38][CH:37]=1>O>[C:1]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]1[C:49]2[C:40](=[C:41]3[C:46](=[CH:47][CH:48]=2)[CH:45]=[CH:44][CH:43]=[N:42]3)[N:39]=[CH:38][CH:37]=1)(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCCCCc1ccnc2c1ccc1cccnc12
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCCc1ccnc2c1ccc1cccnc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of octadecanoic acid (170 mg, 0.6 mmol) and thionyl chloride (4 mL) was heated at 60° C. for 1 hour. The mixture was then cooled to room temperature, whereupon it was concentrated in vacuo. Residue from this mixture was then dissolved in CH2Cl2 (10 mL), whereupon pyridine (5 equivalents) and 4-(aminobutyl)-1,10-phenanthroline (1 equivalent) (Wang et al., Adv. Funct. Mater., 12, 415-419 (2002)) were added. The resulting mixture was stirred at room temperature overnight and then poured into H2O. The resulting precipitate was collected by suction filtration and dried to a constant weight to give 4-(4-(octadecanoylamino)butyl)-1,10-phenanthroline.
Reaction SMILES: C(SC1C(=CC=CC=1)C(Cl)=O)C1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:36]=[CH:35][C:23]([CH2:24][S:25][C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28]([OH:30])=O)=[CH:22][CH:21]=1.O=S(Cl)Cl.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>C1C=CC=CC=1.O>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][S:25][C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28]([N:45]2[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]2)=[O:30])=[CH:35][CH:36]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(CSc2ccccc2C(=O)O)cc1
Agent: O=C(Cl)c1ccccc1SCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(CSc2ccccc2C(=O)N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound N1-(S-(4-methoxybenzyl) thiosalicyloyl)-N4-methylpiperazine (compound 2) was prepared in a manner similar to that described above for S-(4-methoxybenzyl)-N-(2-(N′,N′-dimethylamino)ethyl) thiosalicylamide. After preparing the S-benzylthiosalicyloyl chloride from 0.02M(5.487 g) of S-(4-methoxybenzyl)thiosalicylic acid and 20 mL of SOCl2, the mixture was suspended in warm benzene (30 mL) and was slowly added to a 20 mL cold solution of 4.007 g(0.04M) 1-methylpiperazine in benzene. The mixture was stirred overnight at room temperature. The next day 40 mL of water were added, the aqueous layer was separated, and extracted twice with 15 mL CH2Cl2. The extracts were combined with the benzene layer, washed with 10% NaOH solution and dried over anhydrous MgSO4. Removal of the solvents under reduced pressure left an oily product which was dissolved in petroleum ether (10 ml). A precipitate separated out upon cooling in an ice bath. The separated solid was collected by suction filtration and washed with petroleum ether to give 3.372 g(47%) of the product in the form of white crystals and having a melting point of 77-78° C. and the following specifications:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[C:10]([C:16]([OH:18])=[O:17])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C.N1C=CC=CC=1>C(COC)OC>[C:1]1([C:7]2[N:12]=[C:11]3[C:13]([O:18][C:16](=[O:17])[C:10]3=[CH:9][CH:8]=2)=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1C(=O)O
Solvent: COCCOC
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=C1OC(=O)c2nc(-c3ccccc3)ccc21
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 5.56 g (22.9 mmol) of 6-phenylpyridine-2,3-dicarboxylic acid and 7 ml (121.8 mmol) of acetic anhydride in 25 ml of dimethoxyethane (DME) is added 3.7 ml (45.7 mmol) of pyridine. A small exotherm ensues, and the anhydride begins to precipitate. After one hour, the reaction mixture is diluted with ether and hexane to the cloud point, chilled in an ice bath, and filtered. The solid is washed with ether to give 4.73 g of the desired anhydride as a white solid, mp 187°-192° C.