Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.Cl[CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].[ClH:20]>C1C=CC=CC=1>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1[C:17]([CH:16]([Cl:20])[CH2:15][CH3:14])=[O:18]
Reactant: COc1cc(OC)cc(OC)c1
Reactant: O=C(Cl)CCCCl
Reactant: Cl
Solvent: c1ccccc1
Product: CCC(Cl)C(=O)c1c(OC)cc(OC)cc1OC

Procedure:
Over 1 hour 30 min. a solution of 60.5 g (0.232 mole) of stannic chloride in 75 ml of benzene is poured into a solution maintained at about 5° C. of 33.6 g (0.200 mole) of 1,3,5-trimethoxybenzene and of 30.5 g (0.216 mole) of 4-chlorobutyryl chloride in 150 ml of benzene, with agitation for 3 hours at ambient temperature. The reactional medium is poured on to 250 ml of iced 4N hydrochloric acid and the organic phase is decanted.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[C:5]([CH:9]=[N:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:4]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[C:5]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C=NCCc2ccccc2)c1OCCCN1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(CNCCc2ccccc2)c1OCCCN1CCOCC1
Yield: 80.5 %

Procedure:
N-[[3-Methoxy-2-[3-(4-morpholinyl)propoxy]-phenyl]methylene]benzeneethanamine (49.7 g) is reduced with 14.8 g of sodium borohydride in 225 ml of methanol following the procedure described in Example 1C, yielding 40.2 g of the title compound, boiling point 0.2-0.3 mm of Hg.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:16])[CH:9]=[CH:10][C:11]1[CH:15]=[CH:14][S:13][CH:12]=1.[OH-:22].[Na+].OO.Cl>C(O)C>[NH2:1][C:2]1[C:3]2[N:4]([C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:16])[CH:9]1[O:22][CH:10]1[C:11]1[CH:15]=[CH:14][S:13][CH:12]=1
Reactant: Cc1nc2c(N)c(C(=O)C=Cc3ccsc3)ccn2c1C
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2c(N)c(C(=O)C3OC3c3ccsc3)ccn2c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of 2.6 9 of 8-amino-2,3-dimethyl-7-[3-(3-thienyl)-1-oxo-2-propenyl]imidazo[1,2-a]pyridine in 80 ml of ethanol is treated successively with 5.2 ml of 6 N aqueous sodium hydroxide solution and 5 ml of 30% strength aqueous hydrogen peroxide solution, stirred at room temperature for 48 hours, poured onto 200 ml of ice water and adjusted to pH 7–8 with semisatd. aqueous hydrochloric acid. The mixture is then extracted three times with 100 ml of dichloromethane each time, the combined organic phases are washed once with saturated sodium thiosulfate solution and once with 100 ml of distilled water, the solvent is stripped off in vacuo and the residue is purified on silica gel (eluent:methylene chloride/methanol=100/3). 1.2 g of the title compound of m.p. 186–89° C. (diethyl ether) are obtained.
Reaction SMILES: [CH2:1]([CH2:3][C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]=[N+]=[N-])=[CH:10][CH:9]=1)([CH3:6])[CH3:5])[CH3:2]>CO.[Pd]>[CH2:1]([CH2:3][C:4]([O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][NH2:16])=[CH:12][CH:13]=1)([CH3:5])[CH3:6])[CH3:2]
Reactant: CCCC(C)(C)Oc1ccc(CCN=[N+]=[N-])cc1
Agent: [Pd]
Solvent: CO
Product: CCCC(C)(C)Oc1ccc(CCN)cc1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
Pd/C at 10% (16 mg) is added to a solution of ethyl 2-[4-(2-azidoethyl)phenoxy]-2-methylpropane (784 mg, 2.89 mM) in methanol (42 ml) and the suspension is maintained in agitation for the whole night at a pressure of 5 atmospheres of H2 at room temperature until the substrate disappears [TLC (silica gel; mobile phase: ethyl acetate/petroleum ether=2:8)]. The mixture is filtered to remove the catalyst and the solvent is removed at reduced pressure. 539 mg of ethyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropane is obtained as a colorless oil (74% of yield). FT-IR (neat): 3366, 2985, 2922, 2851, 1732, 1610, 1579, 1508, 1467, 1382, 1362, 1283, 1235, 1177, 1140, 1023, 971, 908, 836, 768 cm−1; 1H NMRs (400 MHz CD Cl3, δ): 7.06-7.04 (d, 2H, J=8.6 Hz, aromatic protons); 6.78-6.76 (d, 2H, J=8.6 Hz, aromatic protons); 5.70-5.55 (m, 2H, NH2); 4.25-4.19 (q, 2H, J=7.1 Hz, CH2CH3); 2.96-2.92 (t, 2H, J=7.0 Hz, CH2C6H4); 2.76-2.69 (m, 2H, CH2NH2); 1.56 (s, 6H, C(CH3)2); 1.26-1.22 (t, 3H, J=7.1 Hz, CH3CH2). 13C NMRs (100 MHz CDCl3, δ): 174.33, 153.84, 132.84, 129.42, 119.34, 79.04, 61.37, 43.07, 38.13, 25.32, 14.06. MS-ESI m/z (%): 252 [M+H]+(100). MS-MS (252): 235 (100), 121 (13).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6]NC.CN(C(ON1N=[N:24][C:19]2[CH:20]=[CH:21][CH:22]=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>C1COCC1.O>[CH3:1][N:2]([CH3:3])[CH2:4][C@H:19]([NH2:24])[CH2:20][CH:21]([CH3:6])[CH3:22]
Reactant: CNC
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CN(C)C=O
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](N)CN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (R)-Boc-D-Leu-OH (1 g, 4.1 mmol), DMF (5 mL), and dimethylamine (4.3 mL of a 2M solution in THF, 8.6 mmol) was treated with HBTU (2 g, 5.2 mmol) and stirred at ambient temperature overnight. The reaction mixture was added to saturated NaHCO3 (25 mL) and water (25 mL). The layers were separated and the aqueous layer was extracted with Et2O (3×40 mL). The combined organic extracts along with the white insoluble material, were stripped of solvent and treated with TFA (10 mL) during 3 h, at which point the TFA was evaporated in vacuo. The residue was coevaporated with toluene, dissolved in THF (50 mL), treated with LiAIH4 (1.6 g, 42 mmol), and the suspension held at reflux overnight. The reaction mixture was cooled in an ice bath and treated successively with IPA (10 mL) and 6M NaOH (5 mL); after stirring for 2 h, the suspension was filtered, concentrated in vacuo. The residue was suspended in brine (50 mL) and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (MgSO4), filtered and concentration in vacuo to afford an oil of (2R)-1-dimethylamino-2-amino-4-methyl-pentane which was used without further purification.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[F:18][C:19]1[C:24](O)=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:20]=1[F:29].C1CCC(N=C=NC2CCCCC2)CC1.O>CN(C=O)C>[F:18][C:19]1[C:24]([O:16][C:15](=[O:17])[C@H:12]([CH2:13][OH:14])[NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:20]=1[F:29]
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@@H](CO)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1ccccc1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
A mixture of N-Cbz-L-serine (Novabiochem) (100 g, 0.42 mol) and pentafluorophenol (Aldrich) (84.7 g, 0.46 mol) in anhydrous DMF (250 ml) are cooled with stirring under N2 to -10° C. To this solution, a solution of DCC (95.0 g, 0.46 mol) in anhydrous DMF (125 ml) is added over 30 min while keeping the reaction temperature at -10° C. The reaction mixture is stirred at -10° to -5° C. for an additional 30 min and then at room temperature for 3 hours. The reaction mixture is poured into water (3.76 1). After stirring for 15 min, the solid that precipitated out is filtered, washed over the filter with water (3×500 ml) and air dried at room temperature. The solid is then taken up in EtOAc (1 l) and the residual solid (mainly dicyclohexylurea) is filtered off and washed with more EtOAc (3×150 ml). The combined EtOAc solutions are evaporated to dryness under reduced pressure. The residual solid is dissolved in hot CH2Cl2 (3.2 l). The hot solution is gravity filtered and the solvent is boiled off until solid began to crystallize. The solid which crystallized is filtered and air dried to ambient temperature to give N-Cbz-L-serine pentafluorophenyl ester as a white solid.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]([OH:10])=[O:9].O=O.[C:30]([OH:33])(=[O:32])C>C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:30]([C:7]([C:2]1[CH:1]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]([OH:10])=[O:9])([OH:33])=[O:32]
Reactant: CCCCCCCCCCCCCCCCC(C(=O)O)c1ccccc1C
Reactant: CC(=O)O
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=O
Product: CCCCCCCCCCCCCCCCC(C(=O)O)(C(=O)O)c1ccccc1
Temperature: 105 °C

Procedure:
One-hundred and eight grams of the distilled tolylstearic acid was charged to a one-liter stirred Parr autoclave with 400 mls acetic acid and 50 gms cobalt (II) acetate. The reactor was sealed, heated to 105° C. and pressured with oxygen to 350 psig.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:28]=1[CH2:29][NH2:30]>C(#N)C>[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:28]=1[CH2:29][NH:30][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:7]=1
Reactant: NCc1c(F)cccc1F
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cccc(F)c1CNCCCOc1cccc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 2,6-difluorobenzylamine, and acetonitrile essentially as described above in example 56. Purity by LC/MS (APCI)=97%, [M+H]+=401.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)C=C(c2ccccn2)c2ccccc2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(c2ccccn2)c2ccccc2O1
Yield: 72.3 %

Procedure:
6.95 g of 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 100 ml of ethanol and shaken at room temperature with 10% palladium-on-charcoal under a hydrogen atmosphere. After the required volume of hydrogen had been taken up the catalyst was filtered off, the filtrate was evaporated and the residue was recrystallized from n-hexane to give 5.07 g of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran of melting point 99°-101° C.
Reaction SMILES: C1(OC([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C(C)C)[CH:17]=3)[CH2:12][CH2:11]2)=O)C=CC=CC=1.C(O)(=O)C.O>Br>[NH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1
Reactant: CC(C)Oc1cccc(C2CCN(C(=O)Oc3ccccc3)CC2)c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Oc1cccc(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
4-(3-(1-Methylethoxy)phenyl)-1-piperidine-carboxylic acid phenyl ester (Preparation 46, 1.7 g, 5.01 mmol) was heated under reflux in 47% aqueous hydrobromic acid:glacial acetic acid (1:1, 20 ml) for 16 h. The solution was allowed to cool to room temperature and water (10 ml) was added. The solution was extracted with methyl tert-butyl ether (3×10 ml) to remove phenol as a by-product. The pH was adjusted to 10.3-10.5 with 15% w:v aqueous sodium hydroxide solution and the reaction mixture was left at room temperature for 2 h to precipitate the product. After cooling to 0° C. the precipitate was filtered and washed with cold water (5 ml) to give the title compound as a solid (380 mg, 43%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH:5]=[CH:4][C:3]1=2.[OH-:21].[K+]>C(O)(C)(C)C>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([NH2:18])=[O:21])=[CH:19][CH:20]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: [OH-]
Reactant: N#Cc1ccc(Oc2ccc3c(c2)CCCC3=O)cc1
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3=O)cc1
Reaction time: 72 h
Yield: 91.1 %

Procedure:
Combine 4-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-benzonitrile (5.34, 20.3 mmol), t-butyl alcohol (100 ml), and KOH (5.7 g, 101.5 mmol). After the reaction stirs for 72 hours at room temperature, concentrate under reduced pressure and then add ethyl acetate. Wash the organic phase with water, a brine solution, and then dry the organic layer over Na2SO4. Flash chromatograph using 2/1 CH2Cl2/ethyl acetate eluent to afford 5.20 g, 18.5 mmol (91% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 2.1-2.2 (2H, m), 2.6-2.7 (2H, m), 2.9-3.0 (2H, m), 5.6-6.2 (2H, br m); 6.85 (1H, s), 6.9-7.0 (1H, m), 7.05-7.15 (2H, m), 7.8-7.9 (2H, m) 8.05-8.10 (1H, m); MS m/z 284 (M+3).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.Cl[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH2:6][CH2:7]1
Reactant: OCC1CCN(c2nccnc2C2CCNCC2)CC1
Reactant: Clc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: OCC1CCN(c2nccnc2C2CCN(c3ccc4ccccc4n3)CC2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of [1-(3-piperidin-4-yl-pyrazin-2-yl)-piperidin-4-yl]-methanol hydrochloride (156 mg, 0.5 mmol) and 2-chloro-quinoline (81.5 mg 0.5 mmol) in DMF (5 mL) was added Cs2CO3 (325 mg, 1 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give {1-[3-(1-quinolin-2-yl-piperidin-4-yl)-pyrazin-2-yl]-piperidin-4-yl}-methanol (142 mg, 0.35 mmol, yield 70.47%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][C:24]1[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:25]=1[O:31][CH2:32][CH2:33]Br>CC#N>[Br-:23].[Br:23][C:24]1[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:25]=1[O:31][CH2:32][CH2:33][N+:1]12[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH2:3][CH2:2]1)[CH2:7][CH2:8]2
Reactant: BrCCOc1ccc(Br)cc1Br
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCOc3ccc(Br)cc3Br)(CC1)CC2
Product: [Br-]
Yield: 52.6 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0557 g, 0.190 mmol) and 2-bromoethyl 2,4-dibromophenyl ether (0.110 g, 0.306 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0525 g, 43.8%). EI-MS m/z 572 (M+) Rt (2.26 min).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]1[S:7][C:8](Br)=[CH:9][N:10]=1.[C:12]([C:15]1[CH:16]=[C:17]([SH:21])[CH:18]=[CH:19][CH:20]=1)([OH:14])=[O:13].Cl.O1CCO[CH2:25][CH2:24]1>CO>[CH2:24]([O:13][C:12](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([S:21][C:8]2[S:7][C:6]([NH2:5])=[N:10][CH:9]=2)[CH:16]=1)[CH3:25]
Reactant: O=C(O)c1cccc(S)c1
Reactant: Nc1ncc(Br)s1
Reactant: C1COCCO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cccc(Sc2cnc(N)s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
A 4.37 M solution of sodium methoxide in methanol (10 mL, 43.7 mmol) was added dropwise to a stirred suspension of 2-amino-5-bromothiazole hydrochloride (2.16 g, 10 mmol) and 3-carboxythiophenol (1.85 g, 12 mmol) in methanol (75 mL) at 0-5° C. The solution was allowed to warm to rt. for 2 h and a 4 M solution of hydrogen chloride in dioxane (15 mL, 60 mmol) was added. The suspension was stirred at rt. overnight and concentrated. The crude residue was diluted with satd. aqueous sodium bicarbonate solution (50 mL). The precipitated solid was filtered and washed with water (20 mL, 5×) and ether (20 mL, 5×). The solid was filtered and dried in vacuo at 60° C. to obtain the titled compound (1.97 g, 75%).
Reaction SMILES: [O-]CC.[Na+].[CH3:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH2:18])=[NH:17])[CH2:8][CH2:7]1.Cl.[C:20]([C:23](=[CH:26]OCC)[C:24]#[N:25])(=O)[CH3:21]>C(O)C>[CH3:21][C:20]1[C:23]([C:24]#[N:25])=[CH:26][N:18]=[C:16]([NH:15][CH2:14][CH2:13][CH2:12][CH:9]2[CH2:8][CH2:7][N:6]([CH3:5])[CH2:11][CH2:10]2)[N:17]=1
Reactant: CN1CCC(CCCNC(=N)N)CC1
Reactant: CCOC=C(C#N)C(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1C#N
Temperature: 25 °C

Procedure:
A flask containing sodium ethoxide (0.64 mL of a 21 wt % solution in ethanol, 1.7 mmol) and N-[3-(1-methyl-piperidin-4-yl)-propyl]guanidine.HCl (200 mg, 0.85 mmol) in ethanol (2.45 mL) was aged for 15 minutes at room temperature. To the resultant mixture was then added 2-acetyl-3-ethoxy-acrylonitrile (148 mg, 1.06 mmol). The resultant mixture was warmed to 80° C. for 5 h, then cooled to room temperature and concentrated. The resultant residue was partitioned between 1 N NaOH and dichloromethane. After separation of the layers, the aqueous layer was extracted with additional dichloromethane (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated to yield the title compound as a solid.
Reaction SMILES: [CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][OH:7].[CH2:9]([O:11][CH:12]=[CH2:13])[CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][O:7][CH:9]([O:11][CH2:12][CH3:13])[CH3:10]
Reactant: CSC(=S)NCCO
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(C)OCCNC(=S)SC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice cold and stirred mixture of N-(2-hydroxyethyl)dithiocarbamic acid methyl ester (1.513 g) and ethoxyethylene (1.92 ml) is added toluene-p-sulfonic acid monohydrate (9.5 mg). After stirring for 30 minutes at room temperature, the homogeneous solution is mixed with triethylamine (8 μl) and concentrated under reduced pressure to yield N-[2-(1-ethoxyethoxy)ethyl]dithiocarbamic acid methyl ester (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][CH:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:29][CH2:30][OH:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][CH:17]2[CH2:22][C:21]([CH3:23])([CH3:24])[N:20]([CH2:29][CH2:30][OH:31])[C:19]([CH3:26])([CH3:25])[CH2:18]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(Nc2ncccc2C(=O)Nc2cccc(Cl)c2)CC(C)(C)N1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CC(Nc2ncccc2C(=O)Nc2cccc(Cl)c2)CC(C)(C)N1CCO
Temperature: 25 °C
Yield: 37.1 %

Procedure:
A solution of N-(3-chlorophenyl)-2-(2,2,6,6-tetramethylpiperidin-4-ylamino)nicotinamide (330 mg, 1 mmol, 1 eq), 2-bromoethanol (1.2 mmol), and anhydrous potassium carbonate (1.2 mmol) in 5 ml of acetonitrile was stirred for 18 hrs under reflux. The reaction mixture was cooled to a room temperature and filtered. The filtrate was concentrated in a reduced pressure. Silica gel column chromatography (mobile phase: 10 (v/v) % methanol in chloroform) afforded the title compound. Yield: 37.1% 1H NMR (CDCl3) δ 8.22 (d, 1H), 7.79 (d, 1H), 7.69 (d, 1H), 7.65 (s, 1H), 7.37 (d, 1H), 7.27 (t, 1H), 7.10 (d, 1H), 6.51-6.45 (m, 1H), 4.64-4.45 (m, 1H), 3.88 (t, 2H), 3.49 (t, 2H), 2.08-1.96 (m, 3H), 1.28 (s, 6H), 1.13 (s, 6H), 1.0 (t, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:15]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][NH:23][C@H:22]([CH3:26])[CH2:21]3)[CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1)[CH3:10].C(OC([N:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[C:39](O)=[O:40])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:15]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:39]([C@H:35]4[CH2:36][CH2:37][CH2:38][NH:34]4)=[O:40])[C@H:22]([CH3:26])[CH2:21]3)[CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1)[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: C[C@@H]1CN(c2ccc3nnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2ccc3nnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a stirred solution of 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-((R)-3-methylpiperazin-1-yl)-1H-benzo[d][1,2,3]triazole (0.075 g, 0.19 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.048 g, 0.22 mmol) in DMF (1.5 mL) was added HATU (0.090 g, 0.23 mmol) and iPr2NEt (0.064 mg, 0.48 mmol). The reaction mixture was stirred at room temperature for 30 min, and diluted with diethyl ether. The mixture was washed with deionized water, and the aqueous layer was extracted with diethyl ether (2×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 5-20% methanol in dichloromethane) to afford the desired product (0.075 g, 0.13 mmol, 67%).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([CH:23]=O)=[CH:10][CH:9]=1)[CH3:2].C(O)=O.[OH-].[Na+].[CH3:32][NH:33]C=O>>[CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([CH2:23][NH:33][CH3:32])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CNC=O
Reactant: CCN(CC)CCCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CCN(CC)CCCNc1ccc(CNC)c2sc3ccccc3c(=O)c12

Procedure:
A solution of 1-[[3-(diethylamino)propyl]amino]-9-oxothioxanthen-4-carboxaldehyde (3.3 g, 8.96 mmol) and 3 g of formic acid in 50 mL of N-methylformamide was allowed to reflux for 2 h. The mixture was basified with 5 mL of a 5N sodium hydroxide solution and extracted into chloroform (3×150ml). The organic layer was dried over sodium sulfate, concentrated in vacuo, and a crude oil was dissolved in a 3N aqueous HCl solution (50 ml) and heated on a steam bath for 3 h. The above mixture was cooled, basified with 30 mL of 35% NaOH, extracted into chloroform (3×150ml), the organic layer dried over sodium sulfate and concentrated in vacuo to afford a brown oil. The brown oil was purified by flash chromatography (silica gel; 5% triethylamine/Et2O, then 5% Et3N/EtOAc, then triethylamine/methanol/EtOAc (5:5:90)) to afford 1.1 g of 1-[[3-(diethylamino)propyl]amino]-4-(methylaminomethyl)thioxanthen-9-one, as a clear orange gum. The above gum was converted into the corresponding dihydrochloride by treatment with 6N HCl in ether to afford 1.04 g of the dihydrochloride.3/2 hydrate as a yellow powder, m.p. 222°-224° C.