Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[OH:8][C:9]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[C:21]([CH3:24])([CH3:23])[CH3:22]>C(O)C>[OH:8][C:9]1[C:16]([C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:15][C:12]([CH:13]=[N:2][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:11][C:10]=1[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: Nn1ccnc1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(C=Nn2ccnc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.48 g of 1-aminoimidazole hydrochloride are suspended in 30 ml of ethanol, whereupon 0.93 g of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde is added. The suspension is stirred at room temperature for 3 hours, whereby there results a clear solution which is evaporated in a vacuum. The residue is taken up in 15 ml of water, neutralized (pH=7) with ice-cold saturated sodium bicarbonate solution and extracted rapidly three times with 30 ml of methylene chloride each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated in a vacuum. By sublimation of the residue (160°/12 Torr), there is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)imidazole of m.p. 171°-174°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=O.[N:12]#[C:13][NH2:14]>C(O)(=O)C.Cl>[NH2:14][C:13]1[N:12]=[N+:9]([O-:11])[C:3]2[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: N#CN
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: Nc1nc2ccc(O)cc2[n+]([O-])n1
Temperature: 100 °C
Reaction time: 0.12 h
Yield: 51.6 %

Procedure:
7.7 g (0.05 mol) of 4-amino-3-nitrophenol was dissolved in 20 mL of glacial acetic acid and the resulting bright-red solution was heated to approximately 100° C. in 500 mL round-bottom flask equipped with a long condenser. To this solution was added a solution of 16.81 g (8.0 equivalent, 0.4 mol) of cyanamide in 20 mL of concentrated hydrochloric acid. In approximately 5-10 min the reaction mixture started to boil vigorously, so the heating was removed and it was stirred without heating until boiling subsided. Then the heating was reapplied and the reaction mixture was refluxed for 48 hrs. Then 150 mL of 30% NaOH was added and the resulting dark-reddish solution was refluxed for additional 3 hrs. Then it was cooled down to room temperature and dark-red slurry was formed. The red precipitate was filtered, re-dissolved in 200 mL of water and 1N HCl was added in portions with-stirring until pH reached 5-4. The solution changed color from dark-red into light-yellow and a light-yellow fine precipitate was formed. The precipitate was filtered, washed twice with 50 mL of water, twice with 50 mL of acetonitrile and finally twice with 50 mL of diethyl ether and dried in vacuum to give 4.6 g of a bright-yellow solid. Yield: 51.7%.
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4](OCC)=[O:5].[CH3:13][C:14]1([CH3:31])[CH2:18][C:17]2[C:19]([CH3:30])=[C:20]([CH3:29])[C:21]([CH:24]=[CH:25][C:26](=[O:28])[CH3:27])=[C:22]([CH3:23])[C:16]=2[O:15]1.[OH-].[Na+]>CO>[CH3:13][C:14]1([CH3:31])[CH2:18][C:17]2[C:19]([CH3:30])=[C:20]([CH3:29])[C:21]([CH:24]3[CH2:3][C:4](=[O:5])[CH:27]=[C:26]([OH:28])[CH2:25]3)=[C:22]([CH3:23])[C:16]=2[O:15]1
Reactant: CC(=O)C=Cc1c(C)c(C)c2c(c1C)OC(C)(C)C2
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C)c(C2CC(=O)C=C(O)C2)c(C)c2c1CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3.8 g of sodium 140 ml of absolute methanol was added 25 ml of diethyl malonate. After stirring for 20 minutes, the mixture was added 42.4 g of the 4-(2,3-dihydro-2,2,4,5,7-pentamethylbenzofuran-6-yl)-3-butene-2-one in 140 ml of absolute methanol, refluxed for 4 hours and 200 ml of 10% aqueous solution of sodium hydroxide. The reaction mixture was cooled to room temperature and washed with diethyl ether. 2N aqueous solution of hydrochloric acid was added dropwise into the aqueous layer until the bubble ceased. And then, solid was dissolved in ethyl acetate and washed with water. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford 38.8 g of 5-(2,3-dihydro-2,2,4,5,7-pentamethylbenzofuran-6-yl)-3-hydroxycyclohex-2-en-1-one.
Reaction SMILES: [Cl:1][C:2]1C=[C:4](C#CC(O)=O)[CH:5]=[CH:6][C:7]=1C1CCCCC1.N1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:20]=1[C:21]#[C:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)C#Cc1ccc(C2CCCCC2)c(Cl)c1
Reactant: c1ccc2ncccc2c1
Solvent: O
Product: Clc1ccccc1C#CC1CCCCC1

Procedure:
3-chloro-4-cyclohexylphenylpropiolic acid (7.3 g.) is heated at 120°-124° for 5 hours in quinoline. The reaction product is diluted with water and washed thoroughly with dilute hydrochloric acid. This is followed by washing with sodium bicarbonate (10%). The material is passed through a short aluminum (H+) column, eluted with N-hexane to give a fraction free of carbonyl absorption (I.R.). Removal of solvent gives 3-chloro-4-cyclohexylethynylbenzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[N:12]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:19][CH2:18][CH2:17][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: NCCN1CCCC1
Solvent: C1CCOC1
Product: O=S(=O)(NCCN1CCCC1)c1cccc(Br)c1
Reaction time: 1 h
Yield: 48.5 %

Procedure:
A solution of 3-bromobenzene-1-sulfonyl chloride (1.29 g, 5.05 mmol) in 25 mL THF was charged with 2-(pyrrolidin-1-yl)ethanamine (0.6 mL, 5.05 mmol), and TEA (2.2 mL, 15.7 mmol) and allowed to stir for 1 hr. The reaction was quenched with 25 mL NaHCO3 (sat., aq.) and extracted with DCM (2×100 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by gradient flash chromatography (0 to 20% MeOH in DCM) to afford the title compound as a white solid (816 mg, 48%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([O:30][CH2:31][CH2:32]Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(=O)CC>[CH2:23]([O:30][CH2:31][CH2:32][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCCOCc1ccccc1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(Cc1ccccc1)c1ccc(OCCOCc2ccccc2)cc1

Procedure:
1-(4-Hydroxyphenyl)-2-phenyl ethanone (17 g, 0.08 mol) is dissolved in 2-butanone (200 ml) and potassium carbonate (33.1 g, 0.24 mol) and 2-benzyloxyethyl bromide (25.8 g, 0.12 mol) is added to the solution. Mixture is stirred and refluxed for three hours. Then the solution is filtered and the filtrate is evaporated to dryness. The residue is dissolved in toluene, washed with 2 N aqueous sodium hydroxide solution and with water, dried and evaporated to dryness. The product is crystallized from ethanol. Yield 23.2 g, 84%.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][C:27]#[N:28]>C(#N)C>[C:27]([CH2:26][N:5]1[C:6]2[C:11](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH:12]=[C:4]1[CH2:1][CH2:2][CH3:3])#[N:28]
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC#N
Yield: 95.4 %

Procedure:
To a solution of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 153A) (1.00 g, 3.96 mmol) in anhydrous acetonitrile (55 mL) was added Cs2CO3 (6.5 g, 20.0 mmol) and bromoacetonitrile (0.713 g, 5.95 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (1.1 g, 92% yield): MS (ES) m/z 292 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:32][CH3:33])=[C:18]([C:20]2([CH2:23][C:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH:25]=O)[CH2:22][CH2:21]2)[CH:19]=1.C(O)(=O)C.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:32][CH3:33])=[C:18]([C:20]2([CH2:23][C:24]([C:27]([F:29])([F:30])[F:28])([OH:31])[CH:25]=[N:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]4)[CH2:21][CH2:22]2)[CH:19]=1
Reactant: COc1ccc(F)cc1C1(CC(O)(C=O)C(F)(F)F)CC1
Reactant: Cc1ccc2c(N)cccc2n1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(F)cc1C1(CC(O)(C=Nc2cccc3nc(C)ccc23)C(F)(F)F)CC1

Procedure:
Analogously to Example 1, 352 mg (2.23 mmol) of 5-amino-2-methylquinoline is reacted with 650 mg (2.12 mmol) of 3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-hydroxy-2-(trifluoromethyl)propanal and 2.80 ml of concentrated acetic acid in 19 ml of toluene. After chromatography on silica gel with hexane-ethyl acetate (0-100%), 870 mg (92% of theory) of the product is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[C:16]([O:18][CH2:19][CH3:20])=O>N1C=CC=CC=1>[CH2:19]([O:18][C:16]1[O:13][C:12](=[O:14])[C:3]2[CH:4]=[C:5]3[C:10]([CH:9]=[CH:8][CH:7]=[CH:6]3)=[CH:11][C:2]=2[N:1]=1)[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: Nc1cc2ccccc2cc1C(=O)O
Solvent: c1ccncc1
Product: CCOc1nc2cc3ccccc3cc2c(=O)o1
Reaction time: 20 h

Procedure:
To a solution of 3-amino-2-naphthoic acid (3.74 g, 20.0 mmol, 1 equiv.) in pyridine (40 ml) at −10° C. under nitrogen was added ethyl chloroformate (7.6 ml, 8.63 g, 79.5 mmol, 4.0 equiv) dropwise over an hour. The reaction was stirred from −10° C. to room temperature over 20 hours. The solvent was evaporated under reduced pressure, water (100 ml) was added to the solid residue, and the mixture was stirred at room temperature for 1 hour. The precipitate was filtered, washed with water and dried to yield 2-ethoxy-4H-naphtho[2,3-d][1,3]oxazin-4-one (1-2) as a tan solid. LRMS m/z (M+H) 242.2 found, 242.1 required.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C:6]([CH2:5][CH2:4][OH:3])=[CH:7][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)CC1=CCN(C(=O)OC(C)(C)C)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(CCO)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 300 mg of (1-tert-butoxycarbonylpiperidin-4-ylidene)acetic acid ethyl ester (which had been prepared by Horner-Wittig reaction of commercially available 1-tert-butoxycarbonyl-4-piperidone and triethyl phosphonoacetate by the method known per se) in 30 ml of tetrahydrofuran was cooled to −78° C., to which 1.3 ml of a tetrahydrofuran solution (1.5 M) of lithium diisopropylamide was added and stirred for 15 minutes. Thereafter 150 μl of acetic acid was added, and the system was warmed up to room temperature, over an hour. The reaction liquid, to which saturated aqueous sodium hydrogencarbonate solution was added, was extracted with chloroform. The chloroform layer was dried over sodium sulfate and the solvent was distilled off therefrom to provide 329 mg of (1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridin-4-yl)acetic acid ethyl ester. This ester was dissolved in 10 ml of tetrahydrofuran, cooled to 0° C., and to which 80 mg of lithium aluminium hydride was added. The reaction liquid was stirred for 15 minutes and to which an excessive amount of sodium sulfate decahydrate was added, followed by 2 hours' stirring at room temperature. The insoluble matter was filtered off, and the filtrate was concentrated to provide 228 mg of 2-(1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridin-4-yl)ethanol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[SH:12].[Br:13][CH2:14][CH2:15]Br>>[Br:13][CH2:14][CH2:15][S:12][C:8]1[S:7][CH:11]=[CH:10][CH:9]=1
Reactant: Sc1cccs1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: BrCCSc1cccs1
Temperature: 78 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
Potassium carbonate (2.50 g, 18.07 mmol, 2.1 eq) is added at room temperature to a stirred solution of thiophene-2-thiol (813 μL, 8.61 mmol, 1.0 eq) in 1,2-dibromoethane (10 mL) and the resulting mixture is stirred at 78° C. for 3 hours. Then potassium carbonate is removed by filtration and the mother liquid is concentrated to give a crude that is purified by column chromatography (silica gel, eluent: cyclohexane 100%) to afford 2-(2-bromo-ethylsulfanyl)-thiophene as a light yellow oil (1.86 g, 95% yield).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]2[C:8]=1[C@@:9]1([CH3:30])[C@H:18]([CH2:19][S:20]2)[C@:17]2([CH3:27])[C@H:12]([C:13]([CH3:29])([CH3:28])[CH2:14][CH2:15][CH2:16]2)[CH2:11][CH2:10]1)(=O)=O.[CH3:33][N:34](C=O)C>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[C-]#N.[Zn+2]>[CH3:26][O:25][C:23]1[CH:22]=[C:21]2[C:8]([C@@:9]3([CH3:30])[C@H:18]([CH2:19][S:20]2)[C@:17]2([CH3:27])[C@H:12]([C:13]([CH3:29])([CH3:28])[CH2:14][CH2:15][CH2:16]2)[CH2:11][CH2:10]3)=[C:7]([C:33]#[N:34])[CH:24]=1
Reactant: CN(C)C=O
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(C#N)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 150 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A mixture of (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl trifluoromethanesulfonate (32) (0.20 g, 0.40 mmol), Pd(dba)2 (0.037 g, 0.11 mmol), dppf (0.09 g, 0.2 mmol), Zn(CN)2 (0.057 g, 0.48 mmol) in anhydrous DMF (5.0 mL) was placed in a microwave tube. The vessel was heated at 150° C. and 10 psi for 1 h. The reaction was cooled to room temperature, diluted with EtOAc and washed with water. The organic layer was concentrated to dryness. The crude product was purified by flash chromatography on silica gel (Hexanes/EtOAc, 10:1) to yield (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carbonitrile (77) (0.10 g, 67%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]1[N:15]([CH3:33])[C:16](=[O:32])[C:17]([OH:31])=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:21])[N:19]=1)=O)(C)(C)C.ClCCl.C(O)(C(F)(F)F)=O>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:20]([C:18]2[N:19]=[C:14]([CH:9]3[CH2:10][O:11][CH2:12][CH2:13][NH:8]3)[N:15]([CH3:33])[C:16](=[O:32])[C:17]=2[OH:31])=[O:21])=[CH:25][CH:26]=1
Reactant: Cn1c(C2COCCN2C(=O)OC(C)(C)C)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(C2COCCN2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O

Procedure:
The compound from Step 9 was treated with a mixture of dichloromethane/TFA (2/1) for 1 hour at room temperature. Organics were removed in vacuo to give the title compound as a solid.
Reaction SMILES: CN(C=O)C.[C:6]([C:8]1[CH:9]=[C:10](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1)#[N:7].Cl.[C:26]1([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[CH2:35][NH2:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1>C(Cl)CCl>[C:32]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:39]=[CH:38][CH:37]=[C:34]([CH2:35][NH:36][C:22](=[O:24])/[CH:21]=[CH:20]/[C:10]2[CH:11]=[CH:12][C:13]([N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]3)=[C:8]([C:6]#[N:7])[CH:9]=2)[CH:33]=1
Reactant: Cc1cn(-c2ccc(/C=C/C(=O)O)cc2C#N)cn1
Reactant: NCc1cccc(-c2ccccc2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cn(-c2ccc(/C=C/C(=O)NCc3cccc(-c4ccccc4)c3)cc2C#N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a DMF (0.2 mL) solution of (E)-3-[3-cyano-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (15 mg) and 3-phenylbenzylamine monohydrochloride (16 mg), TEA (0.007 mL), HOBT (10 mg) and EDC (14 mg) were added one by one, and the reaction mixture was agitated at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (Carrier: Chromatorex®NH, elution solvent:hexane-ethyl acetate system), and 5 mg of the title compound was obtained.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl.CCCCCC.C(OCC)C>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:27][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(CO)cc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.4 %

Procedure:
4.15 g (27.5 mmol) of t-butyldimethylsilyl chloride, 3.85 ml (27.6 mmol) of triethylamine and 815 mg (0.503 mmol) of 4-N,N-dimethylaminopyridine were added, with ice-cooling, to a solution of 5.24 g (25.0 mmol) of 2-t-butyl-5-hydroxymethyl-1-nitrobenzene (prepared as described in Preparation 10) in 50 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 40 minutes. The reaction mixture was then diluted with a 1:1 by volume mixture of hexane and diethyl ether, and the 10 diluted solution was washed with water, with dilute aqueous hydrochloric acid, with water, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 100 g of silica gel, using a 1:1 by volume mixture of methylene chloride and hexane as the eluent, to give 8.04 g (yield 99%) of the title compound as an oily substance.
Reaction SMILES: C(=O)(O)O.[NH:5]([C:7](=[NH:9])[NH2:8])[NH2:6].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15].[OH-].[Na+]>N1C=CC=CC=1.O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:6][NH:5][C:7](=[NH:8])[NH2:9])=[O:15]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: N=C(N)NN
Agent: O=C(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: N=C(N)NNC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 42.8 %

Procedure:
To a solution of hydrazinecarboximidamide carbonic acid salt (14 g, 241.12 mmol) in pyridine (100 ml) was added 3-chlorobenzoyl chloride (15 g, 85.71 mmol), and the reaction mixture was stirred for 10 h at room temperature. The resulting mixture was concentrated under vacuum to give a residue, which was dissolved in water (30 ml) and adjusted to pH 12 with sodium hydroxide (aq., sat.). The product was precipitated and collected by filtration and dried in an oven under reduced pressure to afford 2-(3-chlorobenzoyl)hydrazinecarboximidamide as a light yellow solid (7.8 g, 43%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[C:12]3[N:17]=[C:16](O)[CH:15]=[C:14]([CH3:19])[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.O=P(Cl)(Cl)[Cl:22]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[C:12]3[N:17]=[C:16]([Cl:22])[CH:15]=[C:14]([CH3:19])[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(/C=C/c2ccc3c(c2)OCO3)n1
Product: Cc1cc(Cl)nc(/C=C/c2ccc3c(c2)OCO3)n1
Yield: 89.6 %

Procedure:
In analogy to example 12c), by heating (E)-2-(2-benzo[1,3]dioxol-5-yl-vinyl)-6-methyl-pyrimidin-4-ol (0.5 g, 1.95 mmol) in POCl3 (3.5 ml, 39 mmol) at 130° C. for 4.5 h there was obtained (E)-2-(2-benzo [1,3]dioxol-5-yl-vinyl)-4-chloro-6-methyl-pyrimidine (0.48 g, 90%) as a yellow solid. ISP mass spectrum, m/e: 275.2 (M+1 calculated for C14H11Cl2N2: 275).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][P:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:19][CH3:20])[CH:13]=1)(=[O:10])[O:6][CH2:7][CH2:8][OH:9].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])[C:25]([C:39]([F:42])([F:41])[F:40])=[CH:24][N:23]=1>>[OH:9][CH2:8][CH2:7][O:6][P:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:22]2[N:27]=[C:26]([NH:28][C:29]3[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=3[C:31](=[O:32])[NH:33][CH3:34])[C:25]([C:39]([F:42])([F:40])[F:41])=[CH:24][N:23]=2)=[C:14]([O:19][CH3:20])[CH:13]=1)(=[O:10])[O:4][CH2:3][CH2:2][OH:1]
Reactant: COc1cc(CP(=O)(OCCO)OCCO)ccc1N
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(CP(=O)(OCCO)OCCO)cc2OC)ncc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedure for Example 102 using bis(2-hydroxyethyl)(4-amino-3-methoxybenzyl)phosphonate (Compound 113A, 30 mg, 0.1 mmol) and 2-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)-N-methylbenzamide (Compound 104A, 33 mg, 0.1 mmol). The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford the title compound. 1H-NMR (DMSO-d6, 400 MHz): δ=2.83 (s, 3H), 3.35 (d, J=21.6 Hz, 2H), 3.60 (dd, J=5.2, 10.4 Hz, 4H), 3.84 (s, 3H), 3.99-4.03 (m, 4H), 4.95 (t, J=5.2 Hz, 2H), 6.92 (d, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.16 (t, J=7.6 Hz, 1H), 7.45 (m, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.73 (dd, J=1.2, 8.0 Hz, 1H), 8.43 (s, 1H), 8.48 (m, 1H), 8.80 (m, 2H), 11.49 (s, 1H). MS (ES+): m/z 600.11 [MH+]; HPLC: tR=2.80 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:15]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCC(=O)Cl
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Solvent: ClCCl
Product: CCC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under N2, 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (40.7 mg, 0.10 mmol) was dissolved in absolute CH2Cl2 (5 ml) and propionyl chloride (11.4 mg, 0.12 mmol) was added dropwise. The mixture was stirred at room temperature for 2.5 hours and then evaporated in vacuo. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9:1:0.1, l=16 cm, V=3 ml). A yellow resin was obtained.