Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[C:16]3[S:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:37][C:38]1[C:39]([O:53][CH3:54])=[C:40]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:41]=[C:42]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:43]=1>CN(C=O)C>[C:44]([C:42]1[CH:41]=[C:40]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[C:39]([O:53][CH3:54])=[C:38]([NH:37][C:20]([C:18]2[S:17][C:16]3[C:11]([NH:10][C:8](=[O:9])[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=4)=[CH:12][CH:13]=[CH:14][C:15]=3[CH:19]=2)=[O:22])[CH:43]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(Nc1cccc2cc(C(=O)O)sc12)c1ccc(Cl)nc1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1c(NC(=O)c2cc3cccc(NC(=O)c4ccc(Cl)nc4)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
To a solution of the above carboxylic acid (50 mg) in DMF (1.5 mL) was added EDC (1.5 eq) and HOBT (1.5 eq). The reaction was stirred at room temperature for 15 min, then N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (1.2 eq) was added. The reaction was stirred 12 h, then the DMF was removed in vacuo, the residue was taken up in EtOAc and washed with water, followed by brine. The organics were dried over MgSO4, filtered, and concentrated and the residue was purified by flash chromatography on silica gel (20%-60% EtOAc/hexane) to give the title compound as a white solid (36 mg, 41% yield for two steps).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:14]CC)(=[O:13])[CH3:12].[O:17]=[C:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1>>[C:25]([O:24][C:22]([N:20]1[CH2:21][C:18]([CH2:12][C:11]([OH:14])=[O:13])([OH:17])[CH2:19]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CC(O)(CC(=O)O)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15.9 %

Procedure:
LHMDS (6.43 mL of 1N solution in THF) was cooled to −78° C. Ethyl acetate (0.63 mL, 6.43 mmol) was added and the reaction mixture was stirred for 10 minutes. tert-Butyl 3-oxoazetidine-1-carboxylate (1 g, 5.84 mmol) was added to the mixture and the reaction was stirred for 15 minutes. The reaction mixture was warmed to 0° C. and was then quenched with water (25 mL). The reaction mixture was extracted with ether. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The remaining oil was dissolved in MeOH (25 mL) and 1N NaOH (15 mL) was added and the mixture was stirred at room temperature overnight. This was concentrated in vacuo to remove MeOH and then to the remaining aqueous solution was added 1N HCl (100 mL). This mixture was extracted with CH2Cl2 (100 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to afford the title intermediate (215 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[CH3:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[C:23]1[CH:28]=[C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[N:26]=[C:25]([NH2:36])[N:24]=1)[CH2:19][NH:18][CH2:17][CH2:16]2.C(N(CC)CC)C>C(#N)C>[NH2:36][C:25]1[N:24]=[C:23]([C:22]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][N:18]([C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:10])[CH2:19]3)=[CH:14][C:13]=2[CH3:12])[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[N:26]=1
Reactant: Cc1cc2c(cc1-c1cc(N3CCN(C)CC3)nc(N)n1)CNCC2
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc2c(cc1-c1cc(N3CCN(C)CC3)nc(N)n1)CN(C(=O)Nc1ccc(Cl)cc1)CC2
Reaction time: 0.5 h

Procedure:
1-Chloro-4-isocyanatobenzene (4.1 mg, 0.026 mmol) was added to a mixture of 4-(6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine HCl salt (10 mg, 0.02 mmol) and triethylamine (15 uL, 0.11 mmol) in acetonitrile (0.3 mL). After 30 min., the mixture was purified by RP-LCMS (pH=10) to afford the desired products. Analytic LCMS (M+H)+: m/z=492.2/494.1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N:12]=[C:13]=[O:14])[CH:8]=[CH:7][CH:6]=2.[C:15]([C:19]1[CH:28]=[C:27]2[C:22]([CH:23]([NH2:29])[CH2:24][CH2:25][O:26]2)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:19]1[CH:28]=[C:27]2[C:22]([CH:23]([NH:29][C:13]([NH:12][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[CH:11]=[C:2]([CH3:1])[N:3]=[CH:4]4)=[O:14])[CH2:24][CH2:25][O:26]2)=[CH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Reactant: CC(C)(C)c1ccc2c(c1)OCCC2N
Product: Cc1cc2c(NC(=O)NC3CCOc4cc(C(C)(C)C)ccc43)cccc2cn1
Reaction time: 8 h
Yield: 64 %

Procedure:
6 mL of the 3-methyl-5-isocyanato-isoquinoline solution was added to the product of Example 1C (123 mg, 0.6 mmol). The reaction mixture was stirred overnight, and the precipitate formed was collected by filtration and washed with diethyl ether to give 0.15 g of the title compound (64% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 9.17 (s, 1H), 8.46 (s, 1H), 8.34 (d, J=6.8 Hz, 1H), 7.66-7.73 (m, 2H), 7.51 (t, J=8.0 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.12 (d, J=7.1 Hz, 1H), 6.98 (dd, J=8.0, 1.9 Hz, 1H), 6.80 (d, J=2.0 Hz, 1H), 4.82-4.89 (m, 1H), 4.24-4.31 (m, 1H), 4.10-4.18 (m, 1H), 2.63 (s, 3H), 1.99-2.14 (m, 2H), 1.25 (s, 9H). MS (ESI+) m/e 390 (M+H)+. Calc'd. For C24H27N3O2.0.5H2O: C, 72.34; H, 7.08; N, 10.54. Found C, 72.52; H, 7.23; N, 10.53.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][O:9][C:10](=[C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17](F)[CH:18]=4)[NH:13][C:12]3=[O:21])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:22]([O-])=O.[NH4+]>C(O)C.[Pd]>[C:10]1(=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH3:22])[CH:18]=3)[NH:13][C:12]2=[O:21])[C:6]2[CH:5]=[CH:4][N:3]=[CH:2][C:7]=2[CH2:8][O:9]1
Reactant: O=C[O-]
Reactant: O=C1Nc2ccc(F)cc2C1=C1OCc2c1ccnc2Cl
Agent: [Pd]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccc2c(c1)C(=C1OCc3cnccc31)C(=O)N2
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
A solution of 3-(4-chloro-3H-furo[3,4-c]pyridin-1-ylidene)-5-fluoro-1,3-dihydro-indol-2-one (50 mg, 0.17 mmol) is dissolved in ethanol (10 mL) and treated with 5% Pd/C (50 mg), ammonium formate (500 mg, 7.93 mmol) The reaction mixture is stirred at room temperature for 24 h. The reaction mixture is evaporated and the residue is loaded onto silica gel and purified by chromatography (silica gel). The product containing fractions are concentrated to give the title compound as a yellow solid (20 mg, 45%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[O:20]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21]1>[OH-].[K+].CCO>[O:20]1[CH:24]=[CH:23][C:22]([CH:25]=[C:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:10]=3)[C:15]2=[O:19])=[CH:21]1
Reactant: O=Cc1ccoc1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccoc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 69.8 %

Procedure:
According to the method of Example 8, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.20 g, 0.78 mmol) was reacted with 3-furaldehyde (0.083 g, 0.86 mmol) in 2 mL of 4% KOH in EtOH for 48 hours at room temperature to afford 0.182 g (70%) of the title compound, mp 116-117° C.: APCI-MS m/e 335.3 M++1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-]S([O-])(=O)=O.[Mg+2].CCN(CC)CC>>[CH2:12]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.1 %

Procedure:
To a solution of tert-butyl 2-aminoethylcarbamate (3.7 g, 22.3 mmol), benzaldehyde (2.36 g, 22.3 mmol) and MgSO4 (1.33 g) in 1,2-dicholoroethane (300 mL) and Et3N (3.1 mL, 22.3 mmol) at RT was added NaHB(AcO)3. The mixture was stirred (RT, 16 h) and filtered. The solution was washed with saturated NaHCO3 (200 ml), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with MeOH-DCM (0-10%) to afford tert-butyl 2-(benzylamino)ethylcarbamate (1.4 g, 23%). Mass calculated for C14H22N2O2=250.34. found: [M+H]+=251.3.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:26][C:27](=[O:29])[CH3:28])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:5][CH:4]=1.O[N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(=O)([O-])O.[Na+]>O1CCCC1>[O:41]=[C:32]1[C:33]2[C:34](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](=[O:36])[N:31]1[O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:26][C:27](=[O:29])[CH3:28])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(=O)Nc1nc(CCc2ccc(CO)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(CON3C(=O)c4ccccc4C3=O)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
N-{4-{2-[4-(Hydroxymethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide (100 mg), N-hydroxyphthalimide (39.8 mg), triphenylphosphine (64 mg) and tetrahydrofuran (2 ml) were combined under nitrogen atmosphere, then, diethyl azodicarboxylate (40 wt % solution in toluene) (0.111 ml) was added to the solution at 0° C., and the mixture was stirred at 20° C. for 5 hrs. The reaction mixture was poured into saturated sodium hydrogen carbonate aqueous solution, and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude material was purified by preparative thin-layer chromatography over silica gel with chloroform/methanol (30:1) as an eluent to give N-{4-[2-(4-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}phenyl)ethyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[C:4]([I:16])[CH:3]=1.C([O-])(O)=O.[Na+]>Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([I:16])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1cnc(Cl)cc1I
Temperature: 25 °C
Yield: 92.6 %

Procedure:
The solution of tert-butyl 6-chloro-4-iodopyridin-3-ylcarbamate (10.0 g, 28 mmol) in 3M HCl (600 mL) was heated at 60° C. for 12 h. The mixture was allowed to cool to room temperature and treated with sat. NaHCO3 to pH=8. The aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated and purified by chromatography on silica gel (10% ethyl acetate in petroleum ether as eluant) to afford 6-chloro-4-iodopyridin-3-amine (6.6 g, 93%). 1H-NMR (CDCl3, 400 MHz) δ 7.81 (s, 1H), 7.60 (s, 1H), 4.13 (br s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[C:10]=1[CH3:11].C([O-])(O)=O.[Na+].CCOC(C)=O.[CH3:23][N:24](C=O)C>>[CH3:11][C:10]1[C:6]2[NH:7][CH:8]=[N:9][C:5]=2[CH:4]=[CH:3][C:2]=1[C:23]#[N:24]
Reactant: Cc1c(Br)ccc2nc[nH]c12
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1c(C#N)ccc2nc[nH]c12
Temperature: 150 °C
Reaction time: 5 h

Procedure:
In a 100 ml reaction vessel, to a solution of 6-bromo-7-methyl-1H-benzimidazole (500 mg) in DMF were added Zu(CN)2 (834 mg) and Pd (PPh)4 (547 mg) at room temperature, followed by stirring at 150° C. for 5 hours. The reaction solution was poured into a 1:1 mixed solvent of a saturated NaHCO3 solution and EtOAc, followed by stirring for 1 hour. The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. It was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH=98:2 to 90:10) to obtain 7-methyl-1H-benzimidazole-6-carbonitrile (161.8 mg) as a brown solid.
Reaction SMILES: [Cl:1][C:2]([Cl:21])([Cl:20])[CH:3]1[O:8][CH:7]([C:9](Cl)([Cl:11])[Cl:10])[C:6]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:5]=2[O:4]1.[Cl-].[NH4+].[N-]=[N+]=[N-].[Na+]>CS(C)=O>[Cl:11][C:9]([Cl:10])=[C:7]1[C:6]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:5]=2[O:4][CH:3]([C:2]([Cl:1])([Cl:21])[Cl:20])[O:8]1
Reactant: O=C(O)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Agent: [Cl-]
Agent: [N-]=[N+]=[N-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: O=C(O)c1ccc2c(c1)C(=C(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reaction time: 16 h

Procedure:
A mixture of 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxylic acid (2.08 g.), ammonium chloride (0.33 g.) and sodium azide (0.36 g.) in anhydrous dimethylsulphoxide (10 ml.) was warmed on the steam bath for 16 hours. The reaction mixture was cooled, poured onto ice and kept for 16 hours. The white product was filtered off, washed with water and dried, and crystallised from aqueous ethanol to give 4-dichloromethylene-2-trichloromethybenzo[1,3]dioxin-6-carboxylic acid, m.p. 222°-223° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH2:51])[CH2:48][CH2:49][CH3:50]>>[CH2:47]([NH:51][C:41](=[O:43])[CH2:40][CH:37]1[CH2:38][CH2:39][N:34]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][C:7]=2[O:44][CH2:45][CH3:46])=[O:33])[CH2:35][CH2:36]1)[CH2:48][CH2:49][CH3:50]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CCCCN
Product: CCCCNC(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with n-butylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H52Cl2N5O3 [(M+H)+] 720.3442, observed 720.3438.
Reaction SMILES: [C:1](Cl)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>C1COCC1>[C:1]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: NCCc1ccc(O)cc1
Reactant: CCCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC(=O)NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-tridecanoyl tyramine was prepared by adding dropwise about 2.80 ml of tridecanoyl chloride to a cooled solution comprising about 1 g of tyramine and about 1.52 ml of triethylamine in THF. The reaction mixture was stirred at room temperature for 48 hours. The mixture was then poured into about 70 ml of a 10% HCl solution and the mixture extracted with ethyl acetate (3×50 ml). The ethyl acetate layer was separated, dried (Na2SO4) and concentrated under reduced pressure to yield about 2 g of crude N-tridecanoyl tyramine. The product was purified by chromatography on a silica gel column eluted with methylene chloride/ethyl acetate (30:1). About 1 g of N-tridecanoyl tyranine was added to a stirred solution comprising about 152 mg of N-tridecanoyl tyramine, sodium hydroxide in 20 ml anhydrous DMF at 0° C. under nitrogen. The solution was stirred for 30 minutes; about 1 g of chlorosulfonamide was slowly added in one portion. The solution was then stirred at room temperature for 24 hours. After this time, the mixture was poured into a cold saturated sodium bicarbonate solution and the resulting solution was extracted with methylene chloride (3×50 ml). The organic layer was separated, dried (Na2SO4) and concentrated under reduced pressure to yield about 677 mg of product, which was then purified by chromatography on a silica gel column eluted with methylene chloride/ethyl acetate (20:1). The product produced is (p-o-sulfamoyl)-N-tridecanoyl tyramine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH:7]=[N:8]O)([O-])=O.C(=O)=O.[H][H].[OH-].[Na+]>[Ni].CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][NH2:8]
Reactant: O=[N+]([O-])c1cccc(C=NO)c1
Reactant: [H][H]
Agent: [Ni]
Agent: O=C=O
Agent: [Na+]
Solvent: CO
Product: NCc1cccc(N)c1
Reaction time: 8 h
Yield: 86.8 %

Procedure:
16.6 g (0.1 mol) of this m-nitrobenzaldoxime, 22 g (0.5 mol) of a solid CO2, 1 g of Raney nickel catalyst and 150 ml of methanol were charged into an autoclave and hydrogen was charged while maintaining the pressure at 20 to 30 Kg/cm2 ·G. Reaction was continued at temperatures of 20° to 25° C. for 8 hours under stirring. Thereafter, the resulting mixture was filtered to remove the catalyst, added with 6 g (0.15 mol) of sodium hydroxide and was subject to distillation. 10.6 g of m-aminobenzylamine of 99.1% in purity by means of gas chromatography was obtained. Yield 86.9%; B.P. 129°-130° C./5 mmHg; M.P. 39°-42° C.
Reaction SMILES: C[O:2][C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([CH:12]=[O:13])=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].Cl.C(N(C(S)C)CC)C.Cl>CN(C=O)C>[OH:2][C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([CH:12]=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)c2ccsc12
Agent: CC(C)(C)[O-]
Agent: CCN(CC)C(C)S
Agent: Cl
Solvent: CN(C)C=O
Product: O=Cc1ccc(O)c2sccc12

Procedure:
7-Methoxybenzo[b]thiophene-4-carbaldehyde (Preparation 68) (844 mg, 4.39 mmol) was added to a suspension of potassium tert-butoxide (1.5 g, 14.0 mmol) and diethylaminoethanethiol hydrochloride (1.12 g, 6.58 mmol) in DMF (22 mL). The mixture was refluxed for 1 h. After cooling the mixture was acidified to pH 1 with 1N HCl and the aqueous phase extracted with EtOAc. The organic phase was washed with water, brine and dried (MgSO4). Solvent was removed in vacuo to give the title compound: RT=2.59 min; m/z (ES+)=178.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])=[C:9]([Cl:11])[Cl:10])=[CH:4][C:3]=1[N+:13]([O-])=O>[Fe].C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])=[C:9]([Cl:10])[Cl:11])=[CH:4][C:3]=1[NH2:13]
Reactant: CC(=C(Cl)Cl)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CCO
Product: CC(=C(Cl)Cl)c1ccc(N)c(N)c1

Procedure:
A mixture of 2.1 g. (8.5 mmoles) of 1-amino 2-nitro-4-(2,2-dichloro-1-methylethenyl) benzene 2.1 g. (0.038 moles) of iron powder is suspended in 80 ml. of 40% ethanol and refluxed for 30 minutes. The reaction mixture is filtered while hot, the solid material washed with ethanol and extracted with chloroform and evaporated to dryness in vacuo affording 1.66 g. of a brown glassy substance, which is used as is in the next step.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>C(Cl)Cl>[C:22]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1cccnc1
Yield: 74.9 %

Procedure:
To a solution of 10.0 g (41.5 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 27.7 ml (200 mmol) of triethylamine in methylene chloride (100 ml), 8.86 g (49.8 mmol) of nicotinoyl chloride hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain powder. The powder was washed with ether and dried to obtain the desired compound (8.50 g, yield: 75.8%, pale yellow powder).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([O:33][C:34](=[O:37])[CH2:35]Br)[CH3:32]>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[C:7]=2[O:24][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:37])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OCC1CC1
Temperature: 80 °C

Procedure:
To a stirring solution of 5-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (250 mg, 0.766 mmol) in acetonitrile (20 mL) was added potassium carbonate (312 mg, 2.3 mmol) and ethylbromoacetate (256 mg, 1.533 mmol) and the reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated under reduced pressure to afford Ethyl 2-(2-(cyclopropylmethoxy)-3-methoxy-6-(1-oxo-1,3-dihydroisobenzofuran-5-yl)phenoxy)acetate as a crude product which was used as such in further reaction (300 mg).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([CH2:24][CH:25]=O)=[CH:16]1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29][CH2:28]1.[OH-].[Na+]>ClCCl.C(O)(=O)C>[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([CH2:24][CH2:25][N:27]2[CH2:28][CH2:29][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH2:32]2)=[CH:16]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CCc1coc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(CCc2coc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
13 ml of acetic acid and 61 g of sodium triacetoxyborohydride are added in succession to a solution of 33 g of 2-(benzofuran-3-yl)acetaldehyde and 41.3 g of tert-butyl 4-piperidylcarbamate in 1.4 litres of dichloromethane. After 24 hours' stirring at room temperature, a 20% sodium hydroxide solution is added. After 10 minutes, the reaction mixture is decanted and the organic phase is washed, dried and concentrated. Chromatography over silica gel (cyclohexane/ethyl acetate 30/70) enables the expected product to be isolated.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][O:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)CO.[OH-].[Na+:14]>O>[CH2:1]([O-:8])[CH2:2][O:3][CH2:4][CH2:5][CH2:6][CH3:7].[Na+:14]
Reactant: CCCCOCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCCCOCC[O-]
Temperature: 120 °C

Procedure:
Into a 1 liter three-necked flask, equipped as described in Example 1, 590 g of 3-oxaheptan-1-ol (i.e., the butyl monoether of ethylene glycol) are introduced. 40 g of sodium hydroxide in pellet form are added and the mixture is heated to 120° C. Sodium 3-oxaheptan-1-olate and water are formed, with the latter being removed by distillation.