Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[CH:22]1([CH2:25][O:26][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][C:28]=2[O:35][CH3:36])[CH2:24][CH2:23]1.[O-]CC.[Na+]>C(O)C>[CH:22]1([CH2:25][O:26][C:27]2[CH:34]=[CH:33][C:30](/[CH:31]=[CH:1]/[C:2]3[N:3]=[C:4]4[S:21][CH:20]=[CH:19][N:5]4[C:6](=[O:18])[C:7]=3[C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=3)=[CH:29][C:28]=2[O:35][CH3:36])[CH2:23][CH2:24]1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Reactant: COc1cc(C=O)ccc1OCC1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C(F)(F)F)cc2)ccc1OCC1CC1
Yield: 46.2 %

Procedure:
The title compound was synthesized by condensation of Intermediate 5 (400 mg, 1.289 mmol) with 4-cyclopropylmethoxy-3-methoxybenzaldehyde (345 mg, 1.602 mmol) in presence of sodium ethoxide (163 mg, 2.418 mmol) in ethanol (20 ml) according to the procedure described in Example 24 to give 297 mg of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.35 (d, J=4.2 Hz, 2H), 0.64 (d, J=7.8 Hz, 2H), 1.30-1.38 (m, 1H), 3.83 (s, 3H), 3.84 (d, J=8.7 Hz, 2H), 6.70 (d, J=15.6 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 6.85-6.92 (m, 1H), 6.94-7.00 (m, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.71 (d, J=7.8 Hz, 2H), 7.84 (d, J=15.0 Hz, 1H), 7.95 (d, J=5.1 Hz, 1H); ESI-MS (m/z) 499.32 (M+H)+.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][OH:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:14][CH2:13][CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1cccc2ccccc12

Procedure:
To a solution of 18.8 g of 2-(1-naphthyloxy)ethanol and 15.1 g of triethylamine in 425 ml of dichloromethane is added 12.6 g of methanesulfonyl chloride as described in Example 1 to give the product.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[N:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)=[CH:17][N:16]=3)[CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]([C:32]2[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=2)[CH:4]=[CH:3]1.FC(F)(F)C(O)=O>ClCCl>[NH2:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:17]=[N:16][C:15]([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[CH2:8][N:7]2[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:32]3[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=3)=[N:6]2)=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCCc1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCc1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
49.3 70 mg (0.127 mmol) of tert-butyl [3-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)propyl]carbamate are dissolved in 3 ml of dichloromethane, and 195 μl (2.54 mmol) of trifluoroacetic acid are added. The reaction mixture is stirred at room temperature for 15 h and evaporated. The residue is digested with diethyl ether and dried in vacuo; yield: 74 mg of “A285”; HPLC: Rt=2.63 min (method C); LC-MS: 452 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH:15]1[C:11]2=[N:12][CH:13]=[CH:14][C:9]([CH2:8][NH2:7])=[C:10]2[CH:17]=[CH:16]1
Reactant: CC(C)(C)OC(=O)NCc1ccnc2[nH]ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccnc2[nH]ccc12
Reaction time: 14 h

Procedure:
To a solution of (1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (200 mg, 0.809 mmol) in CH2Cl2 (6 mL) was added trifluoroacetic acid (1.58 mL, 20.6 mmol). After 14 hours, the reaction was concentrated in vacuo to afford the title compound which was used in the without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH:11]([N:14](C(C)C)[CH2:15]C)(C)C.CNC.O>O1CCCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:14]([CH3:15])[CH3:11])[CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: CNC
Solvent: O
Solvent: C1CCOC1
Product: CSc1nc(Cl)cc(N(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
4,6-dichloro-2-methylmercaptopyrimidine (10.0 g, 51 mmol) and diisopropyl ethylamine (17.5 ml, 102 mmol) was dissolved in tetrahydrofuran (400 ml), and a 50% aqueous dimethylamine solution (7.6 ml, 84 mmol) was dripped over the course of 1 hour into this solution under ice cooling. After this mixture liquid was agitated overnight at room temperature, water was added and extraction was carried out 2 times with ethyl acetate. After washing the organic layer with saturated saline, drying was done with MgSO4, the solvent was distilled away under reduced pressure, and 6-chloro-4-dimethylamino-2-methylmercaptopyrimidine was obtained. This was used for the next reaction without separation or refinement. Morpholine (100 ml) was added to this, and it was agitated overnight at 100 degrees Celsius. After allowing to cool, water was added and extraction was carried out 2 times with dichloromethane. After washing the organic layer with saturated saline, drying was done with MgSO4, the solvent was distilled away under reduced pressure. The residue was washed with ether and 11.3 g of coarse crystals of 4-dimethylamino-2-methylsulfanyl-6-morpholinopyrimidine was obtained (2 step yield: 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>O1CCCC1>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]3[N:3]=[C:2]([NH:1][C:20]([CH:17]3[CH2:19][CH2:18]3)=[O:21])[CH:7]=2)[CH2:11][CH2:10]1
Reactant: Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=Cc1cnn2c(NC3CC3)cc(NC(=O)C3CC3)nc12
Temperature: 60 °C

Procedure:
To 5-amino-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (step b) (58 mg, 0.266 mmol) in 1.0 mL tetrahydrofuran was added cyclopropane carbonyl chloride (38 ul, 0.419 mmol) and DIPEA (39.0 ul). The reaction mixture was heated at 60° C. for one hour. The reaction was partitioned between ethyl acetate and water, the organic layer was dried under sodium sulfate concentrated on high vac to yield N-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)cyclopropanecarboxamide. The crude product was taken to next step without further purification. LCMS (M+1=286)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15](OC(=O)C)(=O)C>CS(C)=O.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[CH2:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CS(C)=O
Product: C=C(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a stirred solution of methyl 2-(4-nitrophenyl)acetate (8.0 g, 40.994 mmol, 1.0 eq) in DMSO (40 mL) was added tetramethyldiaminomethane (8.38 mL, 61.491 mmol, 1.5 eq) followed by acetic anhydride (12.78 mL, 135.17 mmol, 3.3 eq) at RT and the mixture was stirred for 2 h. The reaction mixture was diluted with water (40 mL), extracted with ether (80 mL×2) and the solvent evaporated. The crude product was purified by CC using EtOAc/PE (1:9) as eluent) to get methyl 2-(4-nitrophenyl)acrylate (4.0 g, 47%, solid; TLC system: EtOAc/PE (3:7), Rf: 0.60).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([CH3:12])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([CH3:12])[C:5]2[O:9][C:8]([N:18]3[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]3)=[N:7][C:6]=2[CH:11]=1
Reactant: CN1CCNCC1
Reactant: Cc1c(Cl)cc2nc(S)oc2c1C
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)cc2nc(N3CCN(C)CC3)oc2c1C

Procedure:
5-Chloro-6,7-dimethyl-2-mercaptobenzoxazole (200 mg) was dissolved in chloroform (20 ml), N-methylpiperazine (1.54 ml) was added dropwise to the solution and then the mixture was stirred with heating for 29 hours. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=20:1) to obtain the title compound 5-chloro-6,7-dimethyl-2-(4-methyl-1-piperazinyl)benzoxazole (260 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1.[Li]CCCC.[Br:15][C:16]1[C:25]2[CH2:24][CH2:23][CH2:22][C:21](=[O:26])[C:20]=2[CH:19]=[N:18][CH:17]=1.[NH4+].[Cl-]>C1COCC1>[Br:15][C:16]1[C:25]2[CH2:24][CH2:23][CH2:22][C:21]([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=3)([OH:26])[C:20]=2[CH:19]=[N:18][CH:17]=1
Reactant: Cc1ccc(Br)cc1C
Reactant: O=C1CCCc2c(Br)cncc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CCCc3c(Br)cncc32)cc1C
Temperature: 0 °C
Yield: 63.8 %

Procedure:
A solution of 4-bromo-1,2-dimethylbenzene (78.6 mg, 425 μmol) in THF (1.3 mL) was cooled (−78° C.) and treated with n-BuLi (1.6 M in n-hexane, 265 μL, 425 μmol). After 15 min a solution of 4-bromo-6,7-dihydroisoquinolin-8(5H)-one (intermediate A-1[C]) (80 mg, 354 μmol) in THF (1.3 mL) was added and after 1 h the brown suspension was warmed up 0° C. The mixture was poured on aq. sat. NH4Cl-solution and extracted with EtOAc (3×). The organic layers were washed with aq. sat. NaHCO3 and aq. sat. NaCl solution, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH (1 to 2%)) gave the title compound (75 mg, 64%) as off-white foam. MS: 332.1 (M+H+, 1 Br).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[N+:13]([C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11])([O-:15])=[O:14]
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc(F)cc(F)c1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,5-difluorophenylacetic acid (20 g, Fluorochem) in c.H2SO4 (150 ml) was stirred at -15° C. and c.HNO3 (75 ml) added dropwise over 1 hour at a temperature of from -5° to -10° C. The mixture was stirred for a further 1/2 hour at -10° C. and then poured into ice-water (1.0 1). The latter was extracted with ether (×3) and the combined extracts washed with water (×2), dried over MgSO4, and evaporated under reduced pressure to give a solid which was crystallised and then recrystallised from ether/hexane (1:4 v/v) to give 20.8 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[Br:17]Br.O>C(O)(=O)C>[Br:17][C:4]1[C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=[C:2]([CH3:1])[C:3]=1[OH:16]
Reactant: BrBr
Reactant: Cc1cc2c(cc1O)C(C)(C)CCC2(C)C
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(c(Br)c1O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.2 %

Procedure:
In 500 mL roundbottom flask, 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenol (10.2 g, 46.72 mmol) was dissolved in 100 mL Acetic Acid. To this solution Bromine (8.2 g, 51.39 mmol) was added. The reaction was stirred at room temperature for 20 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography eluted with hexane to yield 1-Bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenol (12.8 g, 92% yield).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH2:5])=[NH:4].C(=O)([O-])[O-].[K+].[K+].C([O:16][C:17](=O)[CH:18]([Cl:22])[C:19]([CH3:21])=O)C>O>[Cl:22][C:18]1[C:17]([OH:16])=[N:4][C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])=[N:5][C:19]=1[CH3:21]
Reactant: N=C(N)C(Cl)(Cl)Cl
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Reaction time: 18 h
Yield: 31 %

Procedure:
A mixture of 30.0 g (0.18 mole) trichloroacetamidine, 25.2 g (0.18 mole) potassium carbonate, 30.3 g (0.18 mole) ethyl-2-chloroacetoacetate, and 300 ml water was stirred 18 hours. The aqueous solution was decanted from heavier tars and acidified with hydrochloric acid. The precipitate that was formed, was filtered, washed, and dried to give 14.7 g (31% yield; mp 130°-145° C.) of crude product. An analytical sample recrystallized from cyclohexane had mp 156°-157° C. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[OH:6][NH:7][CH2:8][CH2:9][CH2:10][P:11](=[O:14])([OH:13])[OH:12].C(=O)(O)[O-].[Na+].[OH-].[Na+]>O.CC(C)=O>[Cl:1][CH2:2][C:3]([N:7]([CH2:8][CH2:9][CH2:10][P:11](=[O:12])([OH:14])[OH:13])[OH:6])=[O:4]
Reactant: O=P(O)(O)CCCNO
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCl)N(O)CCCP(=O)(O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
Chloroacetyl chloride (4.52 g.) was added dropwise to a solution of 3-(N-hydroxyamino)propylphosphonic acid (2.46 g.) in a mixture of water (15 ml.) and acetone (15 ml.) over a 20 minutes-interval with stirring under ice-cooling and maintaining the pH at around 7-8 by adding 5% aqueous sodium bicarbonate solution. After stirring for further hour, the reaction mixture was adjusted to pH 9 with 1 N aqueous sodium hydroxide solution and stirred at ambient temperature for 35 minutes. After acetone was distilled off under reduced pressure, the aqueous solution was acidified to pH 1.8 with 10% hydrochloric acid and evaporated to dryness under reduced pressure. The residue was dissolved in ethanol (40 ml.) and heated for 10 minutes at 60° C. The insoluble substance was separated out and the ethanolic layer was allowed to stand overnight at ambient temperature to give crystalline 3-(N-chloroacetyl-N-hydroxyamino)propylphosphonic acid (1.85 g.), mp: 163°-165° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10]Br.[NH:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1
Reactant: C1CSCCN1
Reactant: N#Cc1ccc(Br)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)c(CN2CCSCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-(bromomethyl)benzonitrile (0.95 g, 3.46 mmol) in DMF (13.40 ml) was added thiomorpholine (0.417 ml, 4.15 mmol) and potassium carbonate (0.573 g, 4.15 mmol). The reaction mixture was allowed to stir at RT overnight. The reaction mixture was poured onto water and extracted with EtOAc (×2). The organic extractions were combined, washed with brine (×3), dried (MgSO4) and evaporated to give a yellow oil. This was purified by flash silica chromatography (Biotage column) (eluent=25% ether/isohexane) to give the sub-title compound as a colourless oil. Yield: 0.951 g
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:31](O)(=[O:42])[CH2:32][NH:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:34]([NH:33][CH2:32][C:31]([N:14]([CH2:13][CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:30][CH:29]=2)[CH2:8][CH2:9]1)[CH2:15][CH:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:42])(=[O:35])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Clc1ccc(CN2CCC(CNCC(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCC(=O)N(CC1CCN(Cc2ccc(Cl)cc2)CC1)CC(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A solution of 1-(4-chlorobenzyl)-4-{N-(2,2-diphenylethyl)aminomethyl}piperidine (0.084 mmol) in CH2Cl2 was treated with hippuric acid (1.1 equiv.), HBTU (1.1 equiv.), HOBt (1.1 equiv.). The reaction mixture was stirred at 40° C. for 24 h. General workup and preparative TLC (SiO2) afforded 4-{N-(N-benzoylglycyl)-N-(2,2-diphenylethyl)aminomethyl}-1-(4-chlorobenzyl)piperidine (Compound No. 524) (8.5 mg, 17%): The purity was determined by RPLC/MS (98%); ESI/MS m/e 580 (M++H, C36H38ClN3O2).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:31]CC3C=CC=CC=3)=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[O:26][C:27]([CH3:30])=[CH:28][CH:29]=4)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=2)[CH2:3]1.[OH-]>C(O)C.CN(C)C=O>[CH3:8][C@H:6]1[NH:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:10]=[CH:11][C:12]([OH:31])=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[O:26][C:27]([CH3:30])=[CH:28][CH:29]=4)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=2)[CH2:5]1
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Nc3cc(N4C[C@@H](C)N[C@@H](C)C4)ccc3OCc3ccccc3)cc2)o1
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3cc(N4C[C@@H](C)N[C@@H](C)C4)ccc3O)cc2)o1
Reaction time: 3.75 h

Procedure:
A solution of N-{5-(cis-3,5-dimethyl-1-piperazinyl)-2-[(phenylmethyl)oxy]phenyl}-4-(5-methyl-2-furanyl)benzenesulfonamide (D43) (100 mg, 0.19 mmol) in ethanol (4 ml) and N,N-dimethylformamide (2.5 ml) was treated with palladiwn hydroxide on carbon (25 mg) and the mixture stirred under an atmosphere of hydrogen for 3.75 h. The mixture was then filtered through celite, washing with ethanol and the filtrate reduced in vacuo and the residue purified by mass directed autoprep HPLC to afford the title compound. MS (ES+) m/e 442 [M+H]+.
Reaction SMILES: CCO[C:4]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O)=[O:5].Cl.[C:16]([NH2:24])(=[NH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl>[C:17]1([C:16]2[N:24]=[C:4]([OH:5])[CH:6]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:23]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Oc1cc(-c2ccccc2)nc(-c2ccccc2)n1

Procedure:
Ethyl benzoyl acetate (60 g, 312 mmol), benzamidine hydrochloride (65 g, 375 mmol) and potassium carbonate (172 g, 1250 mmol) were dissolved in 1,4-dioxane (1.2 liter) the reaction mixture was refluxed for 12 hours under nitrogen atmosphere. Reaction mixture was diluted with water, neutralized with cold 2N HCl, solid was filtered, washed with water and dried to yield the desired compound.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH:16]([N:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[C:35]#[N:36])=[CH:22][C:21]2=[O:37])[C:17]([OH:19])=O)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:38][C:39]1[CH:51]=[CH:50][C:42]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:41][CH:40]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Si:1]([O:8][CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][CH:16]([N:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[C:35]#[N:36])=[CH:22][C:21]2=[O:37])[C:17]([NH:38][C:39]2[CH:51]=[CH:50][C:42]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])=[CH:41][CH:40]=2)=[O:19])[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COc1cn(C(CC2CCC(O[Si](C)(C)C(C)(C)C)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1cn(C(CC2CCC(O[Si](C)(C)C(C)(C)C)CC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
400 mg (734 μmol) of 3-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoic acid (mixture of two racemic diastereomers), 142 mg (734 μmol) of tert-butyl 4-aminobenzoate, 104 mg (734 μmol) of Oxima and 114 μl (734 μmol) of DIC in 7.3 ml of dimethylformamide were reacted according to General Method 5B. The crude product was purified by flash chromatography (40 g cartridge, 40 ml/min, cyclohexane/ethyl acetate gradient). Yield: 341 mg (64% of theory)
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[N:10]=[C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1>>[CH3:1][N:2]([CH3:3])[C:5]1[N:10]=[C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(-c2ccnc(Cl)n2)cc1
Product: CN(C)c1nccc(-c2ccc(C(=O)O)cc2)n1

Procedure:
Using dimethylamine and 4-[2-chloro-pyrimidin-4-yl]-benzoic acid as substrates. MS (ion spray) m/z 244 (M+H)+.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[CH:5]1([S:11]N2C(=O)C3=CC=CC=C3C2=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C1C=CC=CC=1>[C:1]([S:3][S:11][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: O=C1c2ccccc2C(=O)N1SC1CCCCC1
Solvent: c1ccccc1
Product: CC(=O)SSC1CCCCC1
Yield: 98 %

Procedure:
Thioacetic acid, 0.444 moles, 3.35 grams, is reacted with N-(cyclohexylthio)phthalimide in 100 ml of benzene and the product recovered following a procedure similar to Example 11. Acetylcyclohexyl disulfide, an amber oil, is recovered in 98% yield (7.5 grams). Analysis gives 51.27%C, 7.41%H and 31.78%S compared to 50.6%C, 7.38%H and 33.7%S calculated for C8H14OS2.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][N+:17]([O-])=[CH:16][C:15]=2[CH3:21])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(Cl)(=O)=O)=CC=1.C(C[NH2:36])O>N1C=CC=CC=1.C(#N)C>[NH2:36][C:18]1[CH:19]=[C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:15]([CH3:21])=[CH:16][N:17]=1
Reactant: Cc1c[n+]([O-])ccc1-c1cccc(C(=O)OC(C)(C)C)c1
Reactant: NCCO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1cnc(N)cc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 75 °C
Reaction time: 72 h
Yield: 36.3 %

Procedure:
4-(3-(tert-Butoxycarbonyl)phenyl)-3-methylpyridine 1-oxide (0.467 g, 1.64 mmol) was dissolved in a mixture of pyridine (0.53 mL) and acetonitrile (15 mL) under an atmosphere of argon. 4-Methylbenzene-1-sulfonyl chloride (0.406 g, 2.13 mmol) was added and the reaction mixture was stirred at 75° C. for 72 hours. Ethanolamine (7 mL) was then added and the reaction mixture was allowed to stir for 5 minutes at room temperature. The crude product was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The layers were separated and the organic layer was washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate and then purified on 40 g of silica gel utilizing a gradient of 0-100% ethyl acetate in hexanes to yield the pure product (0.169 g, 0.594 mmol, 36.3%). ESI-MS m/z calc. 284.2. found 285.1 (M+1)+. Retention time of 1.28 minutes. 1H NMR (400.0 MHz, DMSO-d6) δ 7.94-7.91 (m, 1H), 7.84 (s, 1H), 7.79 (d, J=1.7 Hz, 1H), 7.62-7.56 (m, 2H), 6.33 (s, 1H), 5.78 (s, 2H), 1.99 (s, 3H), 1.55 (s, 9H).